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Hirschey, Matthew

Overview:

The overall objective of the Hirschey Lab is to better understand metabolism and mitochondrial function, which is important for human health and several human diseases. Their research focuses on metabolism, with a particular interest in how cells use metabolites and chemical modifications to protein in order to regulate metabolism. The lab studies the regulation of this process by a family of enzymes called sirtuins, and how they maintain energy homeostasis. Their work has important implications for diabetes and obesity, cardiovascular disease, cancer, inborn errors, and the aging process itself.

Positions:

Associate Professor in Medicine

Medicine, Endocrinology, Metabolism, and Nutrition
School of Medicine

Assistant Professor in Pharmacology & Cancer Biology

Pharmacology & Cancer Biology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Member of Sarah W. Stedman Nutrition and Metabolism Center

Sarah Stedman Nutrition & Metabolism Center
School of Medicine

Education:

Ph.D. 2006

Ph.D. — University of California at Santa Barbara

News:

Grants:

The role of ATM in Metabolic Stress Responses

Administered By
Pharmacology & Cancer Biology
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
January 01, 2011
End Date
June 30, 2021

Organization and Function of Cellular Structure

Administered By
Basic Science Departments
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
July 01, 1975
End Date
June 30, 2020

Pharmacological Sciences Training Program

Administered By
Pharmacology & Cancer Biology
AwardedBy
National Institutes of Health
Role
Participating Faculty Member
Start Date
July 01, 1975
End Date
June 30, 2020

Pharmacology Industry Internships for Ph.D. Students

Administered By
Pharmacology & Cancer Biology
AwardedBy
American Society for Pharmacology and Experimental Therapeutics
Role
Participating Faculty Member
Start Date
January 01, 2017
End Date
December 31, 2019

Systemic, maternal and transgenerational effects of nutrient stress

Administered By
Biology
AwardedBy
National Institutes of Health
Role
Collaborator
Start Date
September 18, 2015
End Date
August 31, 2019

Novel SIRT5 Enzymatic Activity Regulates Cellular Mechanisms of Aging and Disease

Administered By
Sarah Stedman Nutrition & Metabolism Center
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
February 01, 2014
End Date
January 31, 2019

Role of Protein Malonylation in Regulating Mitochondrial Function

Administered By
Sarah Stedman Nutrition & Metabolism Center
AwardedBy
National Institutes of Health
Role
Co-Sponsor
Start Date
September 30, 2015
End Date
September 29, 2018

Ethanol-induced Protein Acylation Regulates Metabolism

Administered By
Sarah Stedman Nutrition & Metabolism Center
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
August 05, 2013
End Date
June 30, 2018

The Role of SIRT5 in Regulating Cardiac Function and Metabolism

Administered By
Sarah Stedman Nutrition & Metabolism Center
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
May 01, 2015
End Date
April 30, 2018

SIRT5 Regulates Mitochondrial Metabolism in Aging and Disease

Administered By
Sarah Stedman Nutrition & Metabolism Center
AwardedBy
Ellison Medical Foundation
Role
Principal Investigator
Start Date
October 01, 2013
End Date
September 30, 2017

Novel SIRT4 Enzymatic Activity Influence Cellular Mechanisms of Aging

Administered By
Sarah Stedman Nutrition & Metabolism Center
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 30, 2016
End Date
August 31, 2017

NRSA Predoctoral Fellowship

Administered By
Sarah Stedman Nutrition & Metabolism Center
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
July 01, 2014
End Date
June 30, 2017

Reversible Mitochondrial Protein Acetylation and Metabolic Regulation

Administered By
Sarah Stedman Nutrition & Metabolism Center
AwardedBy
Gladstone
Role
Co Investigator
Start Date
June 01, 2010
End Date
February 28, 2017

Metabolic Sensing and Stress Response Deficit in Ataxia Telangiectasia

Administered By
Pharmacology & Cancer Biology
AwardedBy
A-T Children's Project
Role
Collaborator
Start Date
August 01, 2014
End Date
July 31, 2016

The Role of Adipose-Specific SIRT3 in Regulating Glucose and Lipid Metabolism

Administered By
Sarah Stedman Nutrition & Metabolism Center
AwardedBy
Canadian Diabetes Association
Role
Principal Investigator
Start Date
July 01, 2015
End Date
June 30, 2016

The Role of Adipose-Specific SIRT3 in Regulating Glucose and Lipid Metabolism

Administered By
Sarah Stedman Nutrition & Metabolism Center
AwardedBy
Canadian Diabetes Association
Role
Principal Investigator
Start Date
July 01, 2013
End Date
June 30, 2016

Cancer Biology Training Grant

Administered By
Pharmacology & Cancer Biology
AwardedBy
National Cancer Institute
Role
Mentor
Start Date
July 01, 1993
End Date
March 31, 2016

Metabolic Regulators of Insulin Secretion and Insulin Resistance

Administered By
Sarah Stedman Nutrition & Metabolism Center
AwardedBy
National Institutes of Health
Role
Collaborator
Start Date
September 30, 2013
End Date
August 31, 2015
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Publications:

SIRT4 Is a Lysine Deacylase that Controls Leucine Metabolism and Insulin Secretion.

Sirtuins are NAD+-dependent protein deacylases that regulate several aspects of metabolism and aging. In contrast to the other mammalian sirtuins, the primary enzymatic activity of mitochondrial sirtuin 4 (SIRT4) and its overall role in metabolic control have remained enigmatic. Using a combination of phylogenetics, structural biology, and enzymology, we show that SIRT4 removes three acyl moieties from lysine residues: methylglutaryl (MG)-, hydroxymethylglutaryl (HMG)-, and 3-methylglutaconyl (MGc)-lysine. The metabolites leading to these post-translational modifications are intermediates in leucine oxidation, and we show a primary role for SIRT4 in controlling this pathway in mice. Furthermore, we find that dysregulated leucine metabolism in SIRT4KO mice leads to elevated basal and stimulated insulin secretion, which progressively develops into glucose intolerance and insulin resistance. These findings identify a robust enzymatic activity for SIRT4, uncover a mechanism controlling branched-chain amino acid flux, and position SIRT4 as a crucial player maintaining insulin secretion and glucose homeostasis during aging.

Authors
Anderson, KA; Huynh, FK; Fisher-Wellman, K; Stuart, JD; Peterson, BS; Douros, JD; Wagner, GR; Thompson, JW; Madsen, AS; Green, MF; Sivley, RM; Ilkayeva, OR; Stevens, RD; Backos, DS; Capra, JA; Olsen, CA; Campbell, JE; Muoio, DM; Grimsrud, PA; Hirschey, MD
MLA Citation
Anderson, KA, Huynh, FK, Fisher-Wellman, K, Stuart, JD, Peterson, BS, Douros, JD, Wagner, GR, Thompson, JW, Madsen, AS, Green, MF, Sivley, RM, Ilkayeva, OR, Stevens, RD, Backos, DS, Capra, JA, Olsen, CA, Campbell, JE, Muoio, DM, Grimsrud, PA, and Hirschey, MD. "SIRT4 Is a Lysine Deacylase that Controls Leucine Metabolism and Insulin Secretion." Cell metabolism 25.4 (April 2017): 838-855.e15.
PMID
28380376
Source
epmc
Published In
Cell Metabolism
Volume
25
Issue
4
Publish Date
2017
Start Page
838
End Page
855.e15
DOI
10.1016/j.cmet.2017.03.003

A Prob(e)able Route to Lysine Acylation

© 2017 Elsevier LtdNon-enzymatic modification of proteins by acyl-CoA species involved in intermediary metabolism is a possible explanation for widespread protein acylation. In this issue, Kulkarni et al. (2017) develop a set of chemoproteomic probes to interrogate the role of malonyl-CoA in mediating protein malonylation and find malonylation influences glycolysis in cancer cells.

Authors
Wagner, GR; Hirschey, MD
MLA Citation
Wagner, GR, and Hirschey, MD. "A Prob(e)able Route to Lysine Acylation." Cell Chemical Biology 24.2 (February 16, 2017): 126-128.
Source
scopus
Published In
Cell chemical biology
Volume
24
Issue
2
Publish Date
2017
Start Page
126
End Page
128
DOI
10.1016/j.chembiol.2017.01.011

Role of NAD+ and mitochondrial sirtuins in cardiac and renal diseases

Authors
Hershberger, KA; Martin, AS; Hirschey, MD
MLA Citation
Hershberger, KA, Martin, AS, and Hirschey, MD. "Role of NAD+ and mitochondrial sirtuins in cardiac and renal diseases." Nature Reviews Nephrology 13.4 (February 6, 2017): 213-225.
Source
crossref
Published In
Nature Reviews Nephrology
Volume
13
Issue
4
Publish Date
2017
Start Page
213
End Page
225
DOI
10.1038/nrneph.2017.5

Arsenite Uncouples Mitochondrial Respiration and Induces a Warburg-Like Effect in Caenorhabditis elegans.

Authors
Luz, AT; Godebo, TR; Bhatt, DP; Ilkayeva, OR; Maurer, LL; Hirschey, MD; Meyer, JN
MLA Citation
Luz, AT, Godebo, TR, Bhatt, DP, Ilkayeva, OR, Maurer, LL, Hirschey, MD, and Meyer, JN. "Arsenite Uncouples Mitochondrial Respiration and Induces a Warburg-Like Effect in Caenorhabditis elegans." Toxicological sciences : an official journal of the Society of Toxicology 154.1 (November 2016): 195-.
PMID
27794142
Source
epmc
Published In
Toxicological Sciences (Elsevier)
Volume
154
Issue
1
Publish Date
2016
Start Page
195

Lipids Reprogram Metabolism to Become a Major Carbon Source for Histone Acetylation.

Cells integrate nutrient sensing and metabolism to coordinate proper cellular responses to a particular nutrient source. For example, glucose drives a gene expression program characterized by activating genes involved in its metabolism, in part by increasing glucose-derived histone acetylation. Here, we find that lipid-derived acetyl-CoA is a major source of carbon for histone acetylation. Using (13)C-carbon tracing combined with acetyl-proteomics, we show that up to 90% of acetylation on certain histone lysines can be derived from fatty acid carbon, even in the presence of excess glucose. By repressing both glucose and glutamine metabolism, fatty acid oxidation reprograms cellular metabolism, leading to increased lipid-derived acetyl-CoA. Gene expression profiling of octanoate-treated hepatocytes shows a pattern of upregulated lipid metabolic genes, demonstrating a specific transcriptional response to lipid. These studies expand the landscape of nutrient sensing and uncover how lipids and metabolism are integrated by epigenetic events that control gene expression.

Authors
McDonnell, E; Crown, SB; Fox, DB; Kitir, B; Ilkayeva, OR; Olsen, CA; Grimsrud, PA; Hirschey, MD
MLA Citation
McDonnell, E, Crown, SB, Fox, DB, Kitir, B, Ilkayeva, OR, Olsen, CA, Grimsrud, PA, and Hirschey, MD. "Lipids Reprogram Metabolism to Become a Major Carbon Source for Histone Acetylation." Cell reports 17.6 (November 2016): 1463-1472.
PMID
27806287
Source
epmc
Published In
Cell Reports
Volume
17
Issue
6
Publish Date
2016
Start Page
1463
End Page
1472
DOI
10.1016/j.celrep.2016.10.012

From the Cover: Arsenite Uncouples Mitochondrial Respiration and Induces a Warburg-like Effect in Caenorhabditis elegans.

Millions of people worldwide are chronically exposed to arsenic through contaminated drinking water. Despite decades of research studying the carcinogenic potential of arsenic, the mechanisms by which arsenic causes cancer and other diseases remain poorly understood. Mitochondria appear to be an important target of arsenic toxicity. The trivalent arsenical, arsenite, can induce mitochondrial reactive oxygen species production, inhibit enzymes involved in energy metabolism, and induce aerobic glycolysis in vitro, suggesting that metabolic dysfunction may be important in arsenic-induced disease. Here, using the model organism Caenorhabditis elegans and a novel metabolic inhibition assay, we report an in vivo induction of aerobic glycolysis following arsenite exposure. Furthermore, arsenite exposure induced severe mitochondrial dysfunction, including altered pyruvate metabolism; reduced steady-state ATP levels, ATP-linked respiration and spare respiratory capacity; and increased proton leak. We also found evidence that induction of autophagy is an important protective response to arsenite exposure. Because these results demonstrate that mitochondria are an important in vivo target of arsenite toxicity, we hypothesized that deficiencies in mitochondrial electron transport chain genes, which cause mitochondrial disease in humans, would sensitize nematodes to arsenite. In agreement with this, nematodes deficient in electron transport chain complexes I, II, and III, but not ATP synthase, were sensitive to arsenite exposure, thus identifying a novel class of gene-environment interactions that warrant further investigation in the human populace.

Authors
Luz, AL; Godebo, TR; Bhatt, DP; Ilkayeva, OR; Maurer, LL; Hirschey, MD; Meyer, JN
MLA Citation
Luz, AL, Godebo, TR, Bhatt, DP, Ilkayeva, OR, Maurer, LL, Hirschey, MD, and Meyer, JN. "From the Cover: Arsenite Uncouples Mitochondrial Respiration and Induces a Warburg-like Effect in Caenorhabditis elegans." Toxicological sciences : an official journal of the Society of Toxicology 152.2 (August 2016): 349-362.
Website
http://hdl.handle.net/10161/12419
PMID
27208080
Source
epmc
Published In
Toxicological Sciences (Elsevier)
Volume
152
Issue
2
Publish Date
2016
Start Page
349
End Page
362
DOI
10.1093/toxsci/kfw093

In Vivo Determination of Mitochondrial Function Using Luciferase-Expressing Caenorhabditis elegans: Contribution of Oxidative Phosphorylation, Glycolysis, and Fatty Acid Oxidation to Toxicant-Induced Dysfunction.

Mitochondria are a target of many drugs and environmental toxicants; however, how toxicant-induced mitochondrial dysfunction contributes to the progression of human disease remains poorly understood. To address this issue, in vivo assays capable of rapidly assessing mitochondrial function need to be developed. Here, using the model organism Caenorhabditis elegans, we describe how to rapidly assess the in vivo role of the electron transport chain, glycolysis, or fatty acid oxidation in energy metabolism following toxicant exposure, using a luciferase-expressing ATP reporter strain. Alterations in mitochondrial function subsequent to toxicant exposure are detected by depleting steady-state ATP levels with inhibitors of the mitochondrial electron transport chain, glycolysis, or fatty acid oxidation. Differential changes in ATP following short-term inhibitor exposure indicate toxicant-induced alterations at the site of inhibition. Because a microplate reader is the only major piece of equipment required, this is a highly accessible method for studying toxicant-induced mitochondrial dysfunction in vivo. © 2016 by John Wiley & Sons, Inc.

Authors
Luz, AL; Lagido, C; Hirschey, MD; Meyer, JN
MLA Citation
Luz, AL, Lagido, C, Hirschey, MD, and Meyer, JN. "In Vivo Determination of Mitochondrial Function Using Luciferase-Expressing Caenorhabditis elegans: Contribution of Oxidative Phosphorylation, Glycolysis, and Fatty Acid Oxidation to Toxicant-Induced Dysfunction." Current protocols in toxicology 69 (August 2016): 25.8.1-25.8.22.
PMID
27479364
Source
epmc
Published In
Current Protocols in Toxicology
Volume
69
Publish Date
2016
Start Page
25.8.1
End Page
25.8.22
DOI
10.1002/cptx.10

Proteomic Profiling Reveals Adaptive Responses to Surgical Myocardial Ischemia-Reperfusion in Hibernating Arctic Ground Squirrels Compared to Rats.

Hibernation is an adaptation to extreme environments known to provide organ protection against ischemia-reperfusion (I/R) injury. An unbiased systems approach was utilized to investigate hibernation-induced changes that are characteristic of the hibernator cardioprotective phenotype, by comparing the myocardial proteome of winter hibernating arctic ground squirrels (AGS), summer active AGS, and rats subjected to I/R, and further correlating with targeted metabolic changes.In a well-defined rodent model of I/R by deep hypothermic circulatory arrest followed by 3 or 24 h of reperfusion or sham, myocardial protein abundance in AGS (hibernating summer active) and rats (n = 4 to 5/group) was quantified by label-free proteomics (n = 4 to 5/group) and correlated with metabolic changes.Compared to rats, hibernating AGS displayed markedly reduced plasma levels of troponin I, myocardial apoptosis, and left ventricular contractile dysfunction. Of the 1,320 rat and 1,478 AGS proteins identified, 545 were differentially expressed between hibernating AGS and rat hearts (47% up-regulated and 53% down-regulated). Gene ontology analysis revealed down-regulation in hibernating AGS hearts of most proteins involved in mitochondrial energy transduction, including electron transport chain complexes, acetyl CoA biosynthesis, Krebs cycle, glycolysis, and ketogenesis. Conversely, fatty acid oxidation enzymes and sirtuin-3 were up-regulated in hibernating AGS, with preserved peroxisome proliferator-activated receptor-α activity and reduced tissue levels of acylcarnitines and ceramides after I/R.Natural cardioprotective adaptations in hibernators involve extensive metabolic remodeling, featuring increased expression of fatty acid metabolic proteins and reduced levels of toxic lipid metabolites. Robust up-regulation of sirtuin-3 suggests that posttranslational modifications may underlie organ protection in hibernating mammals.

Authors
Quinones, QJ; Zhang, Z; Ma, Q; Smith, MP; Soderblom, E; Moseley, MA; Bain, J; Newgard, CB; Muehlbauer, MJ; Hirschey, M; Drew, KL; Barnes, BM; Podgoreanu, MV
MLA Citation
Quinones, QJ, Zhang, Z, Ma, Q, Smith, MP, Soderblom, E, Moseley, MA, Bain, J, Newgard, CB, Muehlbauer, MJ, Hirschey, M, Drew, KL, Barnes, BM, and Podgoreanu, MV. "Proteomic Profiling Reveals Adaptive Responses to Surgical Myocardial Ischemia-Reperfusion in Hibernating Arctic Ground Squirrels Compared to Rats." Anesthesiology 124.6 (June 2016): 1296-1310.
PMID
27187119
Source
epmc
Published In
Anesthesiology
Volume
124
Issue
6
Publish Date
2016
Start Page
1296
End Page
1310
DOI
10.1097/aln.0000000000001113

Investigating the Sensitivity of NAD+-dependent Sirtuin Deacylation Activities to NADH.

Protein lysine posttranslational modification by an increasing number of different acyl groups is becoming appreciated as a regulatory mechanism in cellular biology. Sirtuins are class III histone deacylases that use NAD(+)as a co-substrate during amide bond hydrolysis. Several studies have described the sirtuins as sensors of the NAD(+)/NADH ratio, but it has not been formally tested for all the mammalian sirtuinsin vitro To address this problem, we first synthesized a wide variety of peptide-based probes, which were used to identify the range of hydrolytic activities of human sirtuins. These probes included aliphatic ϵ-N-acyllysine modifications with hydrocarbon lengths ranging from formyl (C1) to palmitoyl (C16) as well as negatively charged dicarboxyl-derived modifications. In addition to the well established activities of the sirtuins, "long chain" acyllysine modifications were also shown to be prone to hydrolytic cleavage by SIRT1-3 and SIRT6, supporting recent findings. We then tested the ability of NADH, ADP-ribose, and nicotinamide to inhibit these NAD(+)-dependent deacylase activities of the sirtuins. In the commonly used 7-amino-4-methylcoumarin-coupled fluorescence-based assay, the fluorophore has significant spectral overlap with NADH and therefore cannot be used to measure inhibition by NADH. Therefore, we turned to an HPLC-MS-based assay to directly monitor the conversion of acylated peptides to their deacylated forms. All tested sirtuin deacylase activities showed sensitivity to NADH in this assay. However, the inhibitory concentrations of NADH in these assays are far greater than the predicted concentrations of NADH in cells; therefore, our data indicate that NADH is unlikely to inhibit sirtuinsin vivo These data suggest a re-evaluation of the sirtuins as direct sensors of the NAD(+)/NADH ratio.

Authors
Madsen, AS; Andersen, C; Daoud, M; Anderson, KA; Laursen, JS; Chakladar, S; Huynh, FK; Colaço, AR; Backos, DS; Fristrup, P; Hirschey, MD; Olsen, CA
MLA Citation
Madsen, AS, Andersen, C, Daoud, M, Anderson, KA, Laursen, JS, Chakladar, S, Huynh, FK, Colaço, AR, Backos, DS, Fristrup, P, Hirschey, MD, and Olsen, CA. "Investigating the Sensitivity of NAD+-dependent Sirtuin Deacylation Activities to NADH." The Journal of biological chemistry 291.13 (March 2016): 7128-7141.
PMID
26861872
Source
epmc
Published In
The Journal of biological chemistry
Volume
291
Issue
13
Publish Date
2016
Start Page
7128
End Page
7141
DOI
10.1074/jbc.m115.668699

Dysregulated metabolism contributes to oncogenesis.

Cancer is a disease characterized by unrestrained cellular proliferation. In order to sustain growth, cancer cells undergo a complex metabolic rearrangement characterized by changes in metabolic pathways involved in energy production and biosynthetic processes. The relevance of the metabolic transformation of cancer cells has been recently included in the updated version of the review "Hallmarks of Cancer", where dysregulation of cellular metabolism was included as an emerging hallmark. While several lines of evidence suggest that metabolic rewiring is orchestrated by the concerted action of oncogenes and tumor suppressor genes, in some circumstances altered metabolism can play a primary role in oncogenesis. Recently, mutations of cytosolic and mitochondrial enzymes involved in key metabolic pathways have been associated with hereditary and sporadic forms of cancer. Together, these results demonstrate that aberrant metabolism, once seen just as an epiphenomenon of oncogenic reprogramming, plays a key role in oncogenesis with the power to control both genetic and epigenetic events in cells. In this review, we discuss the relationship between metabolism and cancer, as part of a larger effort to identify a broad-spectrum of therapeutic approaches. We focus on major alterations in nutrient metabolism and the emerging link between metabolism and epigenetics. Finally, we discuss potential strategies to manipulate metabolism in cancer and tradeoffs that should be considered. More research on the suite of metabolic alterations in cancer holds the potential to discover novel approaches to treat it.

Authors
Hirschey, MD; DeBerardinis, RJ; Diehl, AME; Drew, JE; Frezza, C; Green, MF; Jones, LW; Ko, YH; Le, A; Lea, MA; Locasale, JW; Longo, VD; Lyssiotis, CA; McDonnell, E; Mehrmohamadi, M; Michelotti, G; Muralidhar, V; Murphy, MP; Pedersen, PL; Poore, B; Raffaghello, L; Rathmell, JC; Sivanand, S; Vander Heiden, MG; Wellen, KE
MLA Citation
Hirschey, MD, DeBerardinis, RJ, Diehl, AME, Drew, JE, Frezza, C, Green, MF, Jones, LW, Ko, YH, Le, A, Lea, MA, Locasale, JW, Longo, VD, Lyssiotis, CA, McDonnell, E, Mehrmohamadi, M, Michelotti, G, Muralidhar, V, Murphy, MP, Pedersen, PL, Poore, B, Raffaghello, L, Rathmell, JC, Sivanand, S, Vander Heiden, MG, and Wellen, KE. "Dysregulated metabolism contributes to oncogenesis." Seminars in cancer biology 35 Suppl (December 2015): S129-S150. (Review)
PMID
26454069
Source
epmc
Published In
Seminars in Cancer Biology
Volume
35 Suppl
Publish Date
2015
Start Page
S129
End Page
S150
DOI
10.1016/j.semcancer.2015.10.002

Designing a broad-spectrum integrative approach for cancer prevention and treatment.

Targeted therapies and the consequent adoption of "personalized" oncology have achieved notable successes in some cancers; however, significant problems remain with this approach. Many targeted therapies are highly toxic, costs are extremely high, and most patients experience relapse after a few disease-free months. Relapses arise from genetic heterogeneity in tumors, which harbor therapy-resistant immortalized cells that have adopted alternate and compensatory pathways (i.e., pathways that are not reliant upon the same mechanisms as those which have been targeted). To address these limitations, an international task force of 180 scientists was assembled to explore the concept of a low-toxicity "broad-spectrum" therapeutic approach that could simultaneously target many key pathways and mechanisms. Using cancer hallmark phenotypes and the tumor microenvironment to account for the various aspects of relevant cancer biology, interdisciplinary teams reviewed each hallmark area and nominated a wide range of high-priority targets (74 in total) that could be modified to improve patient outcomes. For these targets, corresponding low-toxicity therapeutic approaches were then suggested, many of which were phytochemicals. Proposed actions on each target and all of the approaches were further reviewed for known effects on other hallmark areas and the tumor microenvironment. Potential contrary or procarcinogenic effects were found for 3.9% of the relationships between targets and hallmarks, and mixed evidence of complementary and contrary relationships was found for 7.1%. Approximately 67% of the relationships revealed potentially complementary effects, and the remainder had no known relationship. Among the approaches, 1.1% had contrary, 2.8% had mixed and 62.1% had complementary relationships. These results suggest that a broad-spectrum approach should be feasible from a safety standpoint. This novel approach has potential to be relatively inexpensive, it should help us address stages and types of cancer that lack conventional treatment, and it may reduce relapse risks. A proposed agenda for future research is offered.

Authors
Block, KI; Gyllenhaal, C; Lowe, L; Amedei, A; Amin, ARMR; Amin, A; Aquilano, K; Arbiser, J; Arreola, A; Arzumanyan, A; Ashraf, SS; Azmi, AS; Benencia, F; Bhakta, D; Bilsland, A; Bishayee, A; Blain, SW; Block, PB; Boosani, CS; Carey, TE; Carnero, A; Carotenuto, M; Casey, SC; Chakrabarti, M; Chaturvedi, R; Chen, GZ; Chen, H; Chen, S; Chen, YC; Choi, BK; Ciriolo, MR; Coley, HM; Collins, AR; Connell, M; Crawford, S; Curran, CS; Dabrosin, C; Damia, G; Dasgupta, S; DeBerardinis, RJ; Decker, WK et al.
MLA Citation
Block, KI, Gyllenhaal, C, Lowe, L, Amedei, A, Amin, ARMR, Amin, A, Aquilano, K, Arbiser, J, Arreola, A, Arzumanyan, A, Ashraf, SS, Azmi, AS, Benencia, F, Bhakta, D, Bilsland, A, Bishayee, A, Blain, SW, Block, PB, Boosani, CS, Carey, TE, Carnero, A, Carotenuto, M, Casey, SC, Chakrabarti, M, Chaturvedi, R, Chen, GZ, Chen, H, Chen, S, Chen, YC, Choi, BK, Ciriolo, MR, Coley, HM, Collins, AR, Connell, M, Crawford, S, Curran, CS, Dabrosin, C, Damia, G, Dasgupta, S, DeBerardinis, RJ, and Decker, WK et al. "Designing a broad-spectrum integrative approach for cancer prevention and treatment." Seminars in cancer biology 35 Suppl (December 2015): S276-S304. (Review)
PMID
26590477
Source
epmc
Published In
Seminars in Cancer Biology
Volume
35 Suppl
Publish Date
2015
Start Page
S276
End Page
S304
DOI
10.1016/j.semcancer.2015.09.007

Sirtuins

© 2015 by John Wiley & Sons, Ltd. All rights reserved.The mammalian sirtuins are a family of seven NAD+-dependent deacetylase enzymes that regulate a wide range of hepatic functions. Altered sirtuin expression in model organisms results in pleiotropic hepatic dysfunction. Furthermore, altered sirtuin expression in humans is associated with hepatic diseases including NAFLD, NASH, and HCC. In this chapter, we review the known biology of the seven sirtuins and the areas of emerging interest in this exciting field.

Authors
Huynh, FK; Mcdonnell, E; Anderson, KA; Hirschey, MD
MLA Citation
Huynh, FK, Mcdonnell, E, Anderson, KA, and Hirschey, MD. "Sirtuins." Signaling Pathways in Liver Diseases: Third Edition. September 28, 2015. 374-384.
Source
scopus
Publish Date
2015
Start Page
374
End Page
384
DOI
10.1002/9781118663387.ch27

SIRT3 regulates progression and development of diseases of aging.

The mitochondrial sirtuin SIRT3 is a protein deacylase that influences almost every major aspect of mitochondrial biology, including nutrient oxidation, ATP generation, reactive oxygen species (ROS) detoxification, mitochondrial dynamics, and the mitochondrial unfolded protein response (UPR). Interestingly, mice lacking SIRT3 (SIRT3KO), either spontaneously or when crossed with mouse models of disease, develop several diseases of aging at an accelerated pace, such as cancer, metabolic syndrome, cardiovascular disease, and neurodegenerative diseases, and, thus, might be a valuable model of accelerated aging. In this review, we discuss functions of SIRT3 in pathways involved in diseases of aging and how the lack of SIRT3 might accelerate the aging process. We also suggest that further studies on SIRT3 will help uncover important new pathways driving the aging process.

Authors
McDonnell, E; Peterson, BS; Bomze, HM; Hirschey, MD
MLA Citation
McDonnell, E, Peterson, BS, Bomze, HM, and Hirschey, MD. "SIRT3 regulates progression and development of diseases of aging." Trends in endocrinology and metabolism: TEM 26.9 (September 2015): 486-492. (Review)
PMID
26138757
Source
epmc
Published In
Trends in Endocrinology and Metabolism
Volume
26
Issue
9
Publish Date
2015
Start Page
486
End Page
492
DOI
10.1016/j.tem.2015.06.001

Long-chain Acylcarnitines Reduce Lung Function by Inhibiting Pulmonary Surfactant.

The role of mitochondrial energy metabolism in maintaining lung function is not understood. We previously observed reduced lung function in mice lacking the fatty acid oxidation enzyme long-chain acyl-CoA dehydrogenase (LCAD). Here, we demonstrate that long-chain acylcarnitines, a class of lipids secreted by mitochondria when metabolism is inhibited, accumulate at the air-fluid interface in LCAD(-/-) lungs. Acylcarnitine accumulation is exacerbated by stress such as influenza infection or by dietary supplementation with l-carnitine. Long-chain acylcarnitines co-localize with pulmonary surfactant, a unique film of phospholipids and proteins that reduces surface tension and prevents alveolar collapse during breathing. In vitro, the long-chain species palmitoylcarnitine directly inhibits the surface adsorption of pulmonary surfactant as well as its ability to reduce surface tension. Treatment of LCAD(-/-) mice with mildronate, a drug that inhibits carnitine synthesis, eliminates acylcarnitines and improves lung function. Finally, acylcarnitines are detectable in normal human lavage fluid. Thus, long-chain acylcarnitines may represent a risk factor for lung injury in humans with dysfunctional fatty acid oxidation.

Authors
Otsubo, C; Bharathi, S; Uppala, R; Ilkayeva, OR; Wang, D; McHugh, K; Zou, Y; Wang, J; Alcorn, JF; Zuo, YY; Hirschey, MD; Goetzman, ES
MLA Citation
Otsubo, C, Bharathi, S, Uppala, R, Ilkayeva, OR, Wang, D, McHugh, K, Zou, Y, Wang, J, Alcorn, JF, Zuo, YY, Hirschey, MD, and Goetzman, ES. "Long-chain Acylcarnitines Reduce Lung Function by Inhibiting Pulmonary Surfactant." The Journal of biological chemistry 290.39 (September 2015): 23897-23904.
PMID
26240137
Source
epmc
Published In
The Journal of biological chemistry
Volume
290
Issue
39
Publish Date
2015
Start Page
23897
End Page
23904
DOI
10.1074/jbc.m115.655837

Metabolic Regulation by Lysine Malonylation, Succinylation, and Glutarylation.

Protein acetylation is a well-studied regulatory mechanism for several cellular processes, ranging from gene expression to metabolism. Recent discoveries of new post-translational modifications, including malonylation, succinylation, and glutarylation, have expanded our understanding of the types of modifications found on proteins. These three acidic lysine modifications are structurally similar but have the potential to regulate different proteins in different pathways. The deacylase sirtuin 5 (SIRT5) catalyzes the removal of these modifications from a wide range of proteins in different subcellular compartments. Here, we review these new modifications, their regulation by SIRT5, and their emerging role in cellular regulation and diseases.

Authors
Hirschey, MD; Zhao, Y
MLA Citation
Hirschey, MD, and Zhao, Y. "Metabolic Regulation by Lysine Malonylation, Succinylation, and Glutarylation." Molecular & cellular proteomics : MCP 14.9 (September 2015): 2308-2315. (Review)
PMID
25717114
Source
epmc
Published In
Molecular & cellular proteomics : MCP
Volume
14
Issue
9
Publish Date
2015
Start Page
2308
End Page
2315
DOI
10.1074/mcp.r114.046664

SIRT3 Directs Carbon Traffic in Muscle to Promote Glucose Control.

Authors
Huynh, FK; Muoio, DM; Hirschey, MD
MLA Citation
Huynh, FK, Muoio, DM, and Hirschey, MD. "SIRT3 Directs Carbon Traffic in Muscle to Promote Glucose Control." Diabetes 64.9 (September 2015): 3058-3060.
PMID
26294425
Source
epmc
Published In
Diabetes
Volume
64
Issue
9
Publish Date
2015
Start Page
3058
End Page
3060
DOI
10.2337/db15-0709

Regulation of mitochondria beta oxidation by non-enzymatic post-translational modifications

Authors
Henriques, BJ; Anderson, KA; Hirschey, MD; Gomes, CM
MLA Citation
Henriques, BJ, Anderson, KA, Hirschey, MD, and Gomes, CM. "Regulation of mitochondria beta oxidation by non-enzymatic post-translational modifications." July 2015.
Source
wos-lite
Published In
FEBS Journal
Volume
282
Publish Date
2015
Start Page
342
End Page
342

High-Resolution Metabolomics with Acyl-CoA Profiling Reveals Widespread Remodeling in Response to Diet.

The availability of acyl-Coenzyme A (acyl-CoA) thioester compounds affects numerous cellular functions including autophagy, lipid oxidation and synthesis, and post-translational modifications. Consequently, the acyl-CoA level changes tend to be associated with other metabolic alterations that regulate these critical cellular functions. Despite their biological importance, this class of metabolites remains difficult to detect and quantify using current analytical methods. Here we show a universal method for metabolomics that allows for the detection of an expansive set of acyl-CoA compounds and hundreds of other cellular metabolites. We apply this method to profile the dynamics of acyl-CoA compounds and corresponding alterations in metabolism across the metabolic network in response to high fat feeding in mice. We identified targeted metabolites (>50) and untargeted features (>1000) with significant changes (FDR < 0.05) in response to diet. A substantial extent of this metabolic remodeling exhibited correlated changes in acyl-CoA metabolism with acyl-carnitine metabolism and other features of the metabolic network that together can lead to the discovery of biomarkers of acyl-CoA metabolism. These findings show a robust acyl-CoA profiling method and identify coordinated changes of acyl-CoA metabolism in response to nutritional stress.

Authors
Liu, X; Sadhukhan, S; Sun, S; Wagner, GR; Hirschey, MD; Qi, L; Lin, H; Locasale, JW
MLA Citation
Liu, X, Sadhukhan, S, Sun, S, Wagner, GR, Hirschey, MD, Qi, L, Lin, H, and Locasale, JW. "High-Resolution Metabolomics with Acyl-CoA Profiling Reveals Widespread Remodeling in Response to Diet." Molecular & cellular proteomics : MCP 14.6 (June 2015): 1489-1500.
PMID
25795660
Source
epmc
Published In
Molecular & cellular proteomics : MCP
Volume
14
Issue
6
Publish Date
2015
Start Page
1489
End Page
1500
DOI
10.1074/mcp.m114.044859

Effect of aerobic training on the host systemic milieu in patients with solid tumours: an exploratory correlative study.

Few studies have investigated the effects of exercise on modulation of host factors in cancer patients. We investigated the efficacy of chronic aerobic training on multiple host-related effector pathways in patients with solid tumours.Paired peripheral blood samples were obtained from 44 patients with solid tumours receiving cytotoxic therapy and synthetic erythropoietin (usual care; n=21) or usual care plus supervised aerobic training (n=23) for 12 weeks. Samples were characterised for changes in immune, cytokine and angiogenic factors, and metabolic intermediates. Aerobic training consisted of three supervised cycle ergometry sessions per week at 60% to 100% of peak oxygen consumption (VO2peak), 30-45 min per session, for 12 weeks following a nonlinear prescription.The between-group delta change in cardiopulmonary function was +4.1 ml kg (-1) min(-1), favouring aerobic training (P<0.05). Significant pre-post between-group differences for five cytokine and angiogenic factors (HGF, IL-4, macrophage inflammatory protein-1β (MIP-1β), vascular endothelial growth factor (VEGF), and TNF-α) also favour the aerobic training group (P's<0.05). These reductions occurred in conjunction with nonsignificant group differences for T lymphocytes CD4(+), CD8(+), and CD8(+)/CD45RA (P<0.10). For these factors, circulating concentrations generally increased from baseline to week 12 in the aerobic training group compared with decreases or no change in the usual care group. No significant changes in any metabolic intermediates were observed.Aerobic training alters host availability of select immune-inflammatory effectors in patients with solid tumours; larger confirmatory studies in more homogenous samples are warranted.

Authors
Glass, OK; Inman, BA; Broadwater, G; Courneya, KS; Mackey, JR; Goruk, S; Nelson, ER; Jasper, J; Field, CJ; Bain, JR; Muehlbauer, M; Stevens, RD; Hirschey, MD; Jones, LW
MLA Citation
Glass, OK, Inman, BA, Broadwater, G, Courneya, KS, Mackey, JR, Goruk, S, Nelson, ER, Jasper, J, Field, CJ, Bain, JR, Muehlbauer, M, Stevens, RD, Hirschey, MD, and Jones, LW. "Effect of aerobic training on the host systemic milieu in patients with solid tumours: an exploratory correlative study." British journal of cancer 112.5 (March 2015): 825-831.
PMID
25584487
Source
epmc
Published In
British Journal of Cancer
Volume
112
Issue
5
Publish Date
2015
Start Page
825
End Page
831
DOI
10.1038/bjc.2014.662

Neuronal CRTC-1 governs systemic mitochondrial metabolism and lifespan via a catecholamine signal.

Low energy states delay aging in multiple species, yet mechanisms coordinating energetics and longevity across tissues remain poorly defined. The conserved energy sensor AMP-activated protein kinase (AMPK) and its corresponding phosphatase calcineurin modulate longevity via the CREB regulated transcriptional coactivator (CRTC)-1 in C. elegans. We show that CRTC-1 specifically uncouples AMPK/calcineurin-mediated effects on lifespan from pleiotropic side effects by reprogramming mitochondrial and metabolic function. This pro-longevity metabolic state is regulated cell nonautonomously by CRTC-1 in the nervous system. Neuronal CRTC-1/CREB regulates peripheral metabolism antagonistically with the functional PPARα ortholog, NHR-49, drives mitochondrial fragmentation in distal tissues, and suppresses the effects of AMPK on systemic mitochondrial metabolism and longevity via a cell-nonautonomous catecholamine signal. These results demonstrate that while both local and distal mechanisms combine to modulate aging, distal regulation overrides local contribution. Targeting central perception of energetic state is therefore a potential strategy to promote healthy aging.

Authors
Burkewitz, K; Morantte, I; Weir, HJM; Yeo, R; Zhang, Y; Huynh, FK; Ilkayeva, OR; Hirschey, MD; Grant, AR; Mair, WB
MLA Citation
Burkewitz, K, Morantte, I, Weir, HJM, Yeo, R, Zhang, Y, Huynh, FK, Ilkayeva, OR, Hirschey, MD, Grant, AR, and Mair, WB. "Neuronal CRTC-1 governs systemic mitochondrial metabolism and lifespan via a catecholamine signal." Cell 160.5 (February 2015): 842-855.
PMID
25723162
Source
epmc
Published In
Cell
Volume
160
Issue
5
Publish Date
2015
Start Page
842
End Page
855
DOI
10.1016/j.cell.2015.02.004

Effect of aerobic training on the host systemic milieu in patients with solid tumours: An exploratory correlative study

© 2015 Cancer Research UK. All rights reserved.Background: Few studies have investigated the effects of exercise on modulation of host factors in cancer patients. We investigated the efficacy of chronic aerobic training on multiple host-related effector pathways in patients with solid tumours.Patients and Methods:Paired peripheral blood samples were obtained from 44 patients with solid tumours receiving cytotoxic therapy and synthetic erythropoietin (usual care; n=21) or usual care plus supervised aerobic training (n=23) for 12 weeks. Samples were characterised for changes in immune, cytokine and angiogenic factors, and metabolic intermediates. Aerobic training consisted of three supervised cycle ergometry sessions per week at 60% to 100% of peak oxygen consumption (VO 2peak), 30-45 min per session, for 12 weeks following a nonlinear prescription.Results:The between-group delta change in cardiopulmonary function was +4.1 ml kg-1 min-1, favouring aerobic training (P<0.05). Significant pre-post between-group differences for five cytokine and angiogenic factors (HGF, IL-4, macrophage inflammatory protein-1β (MIP-1β), vascular endothelial growth factor (VEGF), and TNF-) also favour the aerobic training group (P's<0.05). These reductions occurred in conjunction with nonsignificant group differences for T lymphocytes CD4 +, CD8 +, and CD8 +/CD45RA (P<0.10). For these factors, circulating concentrations generally increased from baseline to week 12 in the aerobic training group compared with decreases or no change in the usual care group. No significant changes in any metabolic intermediates were observed.Conclusions:Aerobic training alters host availability of select immune-inflammatory effectors in patients with solid tumours; larger confirmatory studies in more homogenous samples are warranted.

Authors
Glass, OK; Inman, BA; Broadwater, G; Courneya, KS; Mackey, JR; Goruk, S; Nelson, ER; Jasper, J; Field, CJ; Bain, JR; Muehlbauer, M; Stevens, RD; Hirschey, MD; Jones, LW
MLA Citation
Glass, OK, Inman, BA, Broadwater, G, Courneya, KS, Mackey, JR, Goruk, S, Nelson, ER, Jasper, J, Field, CJ, Bain, JR, Muehlbauer, M, Stevens, RD, Hirschey, MD, and Jones, LW. "Effect of aerobic training on the host systemic milieu in patients with solid tumours: An exploratory correlative study." British Journal of Cancer 112.5 (January 1, 2015): 825-831.
Source
scopus
Published In
British Journal of Cancer
Volume
112
Issue
5
Publish Date
2015
Start Page
825
End Page
831
DOI
10.1038/bjc.2014.662

Acyl-CoA thioesterase-2 facilitates mitochondrial fatty acid oxidation in the liver.

Acyl-CoA thioesterase (Acot)2 localizes to the mitochondrial matrix and hydrolyses long-chain fatty acyl-CoA into free FA and CoASH. Acot2 is expressed in highly oxi-dative tissues and is poised to modulate mitochondrial FA oxidation (FAO), yet its biological role is unknown. Using a model of adenoviral Acot2 overexpression in mouse liver (Ad-Acot2), we show that Acot2 increases the utilization of FA substrate during the daytime in ad libitum-fed mice, but the nighttime switch to carbohydrate oxidation is similar to control mice. In further support of elevated FAO in Acot2 liver, daytime serum ketones were higher in Ad-Acot2 mice, and overnight fasting led to minimal hepatic steatosis as compared with control mice. In liver mitochondria from Ad-Acot2 mice, phosphorylating O₂ consumption was higher with lipid substrate, but not with nonlipid substrate. This increase depended on whether FA could be activated on the outer mitochondrial membrane, suggesting that the FA released by Acot2 could be effluxed from mitochondria then taken back up again for oxidation. This circuit would prevent the build-up of inhibitory long-chain fatty acyl-CoA esters. Altogether, our findings indicate that Acot2 can enhance FAO, possibly by mitigating the accumulation of FAO intermediates within the mitochondrial matrix.

Authors
Moffat, C; Bhatia, L; Nguyen, T; Lynch, P; Wang, M; Wang, D; Ilkayeva, OR; Han, X; Hirschey, MD; Claypool, SM; Seifert, EL
MLA Citation
Moffat, C, Bhatia, L, Nguyen, T, Lynch, P, Wang, M, Wang, D, Ilkayeva, OR, Han, X, Hirschey, MD, Claypool, SM, and Seifert, EL. "Acyl-CoA thioesterase-2 facilitates mitochondrial fatty acid oxidation in the liver." Journal of lipid research 55.12 (December 2014): 2458-2470.
PMID
25114170
Source
epmc
Published In
Journal of lipid research
Volume
55
Issue
12
Publish Date
2014
Start Page
2458
End Page
2470
DOI
10.1194/jlr.m046961

Mitochondria, energetics, epigenetics, and cellular responses to stress.

Cells respond to environmental stressors through several key pathways, including response to reactive oxygen species (ROS), nutrient and ATP sensing, DNA damage response (DDR), and epigenetic alterations. Mitochondria play a central role in these pathways not only through energetics and ATP production but also through metabolites generated in the tricarboxylic acid cycle, as well as mitochondria-nuclear signaling related to mitochondria morphology, biogenesis, fission/fusion, mitophagy, apoptosis, and epigenetic regulation.We investigated the concept of bidirectional interactions between mitochondria and cellular pathways in response to environmental stress with a focus on epigenetic regulation, and we examined DNA repair and DDR pathways as examples of biological processes that respond to exogenous insults through changes in homeostasis and altered mitochondrial function.The National Institute of Environmental Health Sciences sponsored the Workshop on Mitochondria, Energetics, Epigenetics, Environment, and DNA Damage Response on 25-26 March 2013. Here, we summarize key points and ideas emerging from this meeting.A more comprehensive understanding of signaling mechanisms (cross-talk) between the mitochondria and nucleus is central to elucidating the integration of mitochondrial functions with other cellular response pathways in modulating the effects of environmental agents. Recent studies have highlighted the importance of mitochondrial functions in epigenetic regulation and DDR with environmental stress. Development and application of novel technologies, enhanced experimental models, and a systems-type research approach will help to discern how environmentally induced mitochondrial dysfunction affects key mechanistic pathways.Understanding mitochondria-cell signaling will provide insight into individual responses to environmental hazards, improving prediction of hazard and susceptibility to environmental stressors.

Authors
Shaughnessy, DT; McAllister, K; Worth, L; Haugen, AC; Meyer, JN; Domann, FE; Van Houten, B; Mostoslavsky, R; Bultman, SJ; Baccarelli, AA; Begley, TJ; Sobol, RW; Hirschey, MD; Ideker, T; Santos, JH; Copeland, WC; Tice, RR; Balshaw, DM; Tyson, FL
MLA Citation
Shaughnessy, DT, McAllister, K, Worth, L, Haugen, AC, Meyer, JN, Domann, FE, Van Houten, B, Mostoslavsky, R, Bultman, SJ, Baccarelli, AA, Begley, TJ, Sobol, RW, Hirschey, MD, Ideker, T, Santos, JH, Copeland, WC, Tice, RR, Balshaw, DM, and Tyson, FL. "Mitochondria, energetics, epigenetics, and cellular responses to stress." Environmental health perspectives 122.12 (December 2014): 1271-1278. (Review)
PMID
25127496
Source
epmc
Published In
Environmental health perspectives
Volume
122
Issue
12
Publish Date
2014
Start Page
1271
End Page
1278
DOI
10.1289/ehp.1408418

SnapShot: Mammalian Sirtuins.

The mammalian sirtuins have emerged as critical regulators of cellular stress resistance, energy metabolism, and tumorigenesis. In some contexts, they delay the onset of age-related diseases and promote a healthy lifespan. The seven mammalian sirtuins, SIRT1-7, share a highly conserved NAD+-binding catalytic core domain although they exhibit distinct expression patterns, catalytic activities, and biological functions. This SnapShot provides an overview of these properties, with an emphasis on their relevance to aging.

Authors
Anderson, KA; Green, MF; Huynh, FK; Wagner, GR; Hirschey, MD
MLA Citation
Anderson, KA, Green, MF, Huynh, FK, Wagner, GR, and Hirschey, MD. "SnapShot: Mammalian Sirtuins." Cell 159.4 (November 2014): 956-956.e1.
PMID
25417168
Source
epmc
Published In
Cell
Volume
159
Issue
4
Publish Date
2014
Start Page
956
End Page
956.e1
DOI
10.1016/j.cell.2014.10.045

Loss of Sirtuin 4 Leads to Insulin Resistance in Mice

Authors
Huynh, FK; Hirschey, MD
MLA Citation
Huynh, FK, and Hirschey, MD. "Loss of Sirtuin 4 Leads to Insulin Resistance in Mice." ENDOCRINE REVIEWS 35.3 (June 2014).
Source
wos-lite
Published In
Endocrine reviews
Volume
35
Issue
3
Publish Date
2014

Lysine glutarylation is a protein posttranslational modification regulated by SIRT5.

We report the identification and characterization of a five-carbon protein posttranslational modification (PTM) called lysine glutarylation (Kglu). This protein modification was detected by immunoblot and mass spectrometry (MS), and then comprehensively validated by chemical and biochemical methods. We demonstrated that the previously annotated deacetylase, sirtuin 5 (SIRT5), is a lysine deglutarylase. Proteome-wide analysis identified 683 Kglu sites in 191 proteins and showed that Kglu is highly enriched on metabolic enzymes and mitochondrial proteins. We validated carbamoyl phosphate synthase 1 (CPS1), the rate-limiting enzyme in urea cycle, as a glutarylated protein and demonstrated that CPS1 is targeted by SIRT5 for deglutarylation. We further showed that glutarylation suppresses CPS1 enzymatic activity in cell lines, mice, and a model of glutaric acidemia type I disease, the last of which has elevated glutaric acid and glutaryl-CoA. This study expands the landscape of lysine acyl modifications and increases our understanding of the deacylase SIRT5.

Authors
Tan, M; Peng, C; Anderson, KA; Chhoy, P; Xie, Z; Dai, L; Park, J; Chen, Y; Huang, H; Zhang, Y; Ro, J; Wagner, GR; Green, MF; Madsen, AS; Schmiesing, J; Peterson, BS; Xu, G; Ilkayeva, OR; Muehlbauer, MJ; Braulke, T; Mühlhausen, C; Backos, DS; Olsen, CA; McGuire, PJ; Pletcher, SD; Lombard, DB; Hirschey, MD; Zhao, Y
MLA Citation
Tan, M, Peng, C, Anderson, KA, Chhoy, P, Xie, Z, Dai, L, Park, J, Chen, Y, Huang, H, Zhang, Y, Ro, J, Wagner, GR, Green, MF, Madsen, AS, Schmiesing, J, Peterson, BS, Xu, G, Ilkayeva, OR, Muehlbauer, MJ, Braulke, T, Mühlhausen, C, Backos, DS, Olsen, CA, McGuire, PJ, Pletcher, SD, Lombard, DB, Hirschey, MD, and Zhao, Y. "Lysine glutarylation is a protein posttranslational modification regulated by SIRT5." Cell metabolism 19.4 (April 2014): 605-617.
PMID
24703693
Source
epmc
Published In
Cell Metabolism
Volume
19
Issue
4
Publish Date
2014
Start Page
605
End Page
617
DOI
10.1016/j.cmet.2014.03.014

Nonenzymatic protein acylation as a carbon stress regulated by sirtuin deacylases.

Cellular proteins are decorated with a wide range of acetyl and other acyl modifications. Many studies have demonstrated regulation of site-specific acetylation by acetyltransferases and deacetylases. Acylation is emerging as a new type of lysine modification, but less is known about its overall regulatory role. Furthermore, the mechanisms of lysine acylation, its overlap with protein acetylation, and how it influences cellular function are major unanswered questions in the field. In this review, we discuss the known roles of acetyltransferases and deacetylases and the sirtuins as a conserved family of a nicotinamide adenine dinucleotide (NAD⁺)-dependent protein deacylases that are important for response to cellular stress and homeostasis. We also consider the evidence for an emerging idea of nonenzymatic protein acylation. Finally, we put forward the hypothesis that protein acylation is a form of protein "carbon stress" that the deacylases evolved to remove as a part of a global protein quality-control network.

Authors
Wagner, GR; Hirschey, MD
MLA Citation
Wagner, GR, and Hirschey, MD. "Nonenzymatic protein acylation as a carbon stress regulated by sirtuin deacylases." Molecular cell 54.1 (April 2014): 5-16. (Review)
PMID
24725594
Source
epmc
Published In
Molecular Cell
Volume
54
Issue
1
Publish Date
2014
Start Page
5
End Page
16
DOI
10.1016/j.molcel.2014.03.027

Protein Acylation Regulates Metabolism

Authors
Hirschey, M
MLA Citation
Hirschey, M. "Protein Acylation Regulates Metabolism." January 28, 2014.
Source
wos-lite
Published In
Biophysical Journal
Volume
106
Issue
2
Publish Date
2014
Start Page
4A
End Page
4A

Measurement of fatty acid oxidation rates in animal tissues and cell lines.

While much oncological research has focused on metabolic shifts in glucose and amino acid oxidation, recent evidence suggests that fatty acid oxidation (FAO) may also play an important role in the metabolic reprogramming of cancer cells. Here, we present a simple method for measuring FAO rates using radiolabeled palmitate, common laboratory reagents, and standard supplies. This protocol is broadly applicable for measuring FAO rates in cultured cancer cells as well as in both malignant and nontransformed animal tissues.

Authors
Huynh, FK; Green, MF; Koves, TR; Hirschey, MD
MLA Citation
Huynh, FK, Green, MF, Koves, TR, and Hirschey, MD. "Measurement of fatty acid oxidation rates in animal tissues and cell lines." Methods in enzymology 542 (January 2014): 391-405.
PMID
24862277
Source
epmc
Published In
Methods in Enzymology
Volume
542
Publish Date
2014
Start Page
391
End Page
405
DOI
10.1016/b978-0-12-416618-9.00020-0

Phosphoproteomic profiling of human myocardial tissues distinguishes ischemic from non-ischemic end stage heart failure.

The molecular differences between ischemic (IF) and non-ischemic (NIF) heart failure are poorly defined. A better understanding of the molecular differences between these two heart failure etiologies may lead to the development of more effective heart failure therapeutics. In this study extensive proteomic and phosphoproteomic profiles of myocardial tissue from patients diagnosed with IF or NIF were assembled and compared. Proteins extracted from left ventricular sections were proteolyzed and phosphopeptides were enriched using titanium dioxide resin. Gel- and label-free nanoscale capillary liquid chromatography coupled to high resolution accuracy mass tandem mass spectrometry allowed for the quantification of 4,436 peptides (corresponding to 450 proteins) and 823 phosphopeptides (corresponding to 400 proteins) from the unenriched and phospho-enriched fractions, respectively. Protein abundance did not distinguish NIF from IF. In contrast, 37 peptides (corresponding to 26 proteins) exhibited a ≥ 2-fold alteration in phosphorylation state (p<0.05) when comparing IF and NIF. The degree of protein phosphorylation at these 37 sites was specifically dependent upon the heart failure etiology examined. Proteins exhibiting phosphorylation alterations were grouped into functional categories: transcriptional activation/RNA processing; cytoskeleton structure/function; molecular chaperones; cell adhesion/signaling; apoptosis; and energetic/metabolism. Phosphoproteomic analysis demonstrated profound post-translational differences in proteins that are involved in multiple cellular processes between different heart failure phenotypes. Understanding the roles these phosphorylation alterations play in the development of NIF and IF has the potential to generate etiology-specific heart failure therapeutics, which could be more effective than current therapeutics in addressing the growing concern of heart failure.

Authors
Schechter, MA; Hsieh, MKH; Njoroge, LW; Thompson, JW; Soderblom, EJ; Feger, BJ; Troupes, CD; Hershberger, KA; Ilkayeva, OR; Nagel, WL; Landinez, GP; Shah, KM; Burns, VA; Santacruz, L; Hirschey, MD; Foster, MW; Milano, CA; Moseley, MA; Piacentino, V; Bowles, DE
MLA Citation
Schechter, MA, Hsieh, MKH, Njoroge, LW, Thompson, JW, Soderblom, EJ, Feger, BJ, Troupes, CD, Hershberger, KA, Ilkayeva, OR, Nagel, WL, Landinez, GP, Shah, KM, Burns, VA, Santacruz, L, Hirschey, MD, Foster, MW, Milano, CA, Moseley, MA, Piacentino, V, and Bowles, DE. "Phosphoproteomic profiling of human myocardial tissues distinguishes ischemic from non-ischemic end stage heart failure." PloS one 9.8 (January 2014): e104157-.
Website
http://hdl.handle.net/10161/13939
PMID
25117565
Source
epmc
Published In
PloS one
Volume
9
Issue
8
Publish Date
2014
Start Page
e104157
DOI
10.1371/journal.pone.0104157

Sirtuin 3 (SIRT3) protein regulates long-chain acyl-CoA dehydrogenase by deacetylating conserved lysines near the active site.

Long-chain acyl-CoA dehydrogenase (LCAD) is a key mitochondrial fatty acid oxidation enzyme. We previously demonstrated increased LCAD lysine acetylation in SIRT3 knockout mice concomitant with reduced LCAD activity and reduced fatty acid oxidation. To study the effects of acetylation on LCAD and determine sirtuin 3 (SIRT3) target sites, we chemically acetylated recombinant LCAD. Acetylation impeded substrate binding and reduced catalytic efficiency. Deacetylation with recombinant SIRT3 partially restored activity. Residues Lys-318 and Lys-322 were identified as SIRT3-targeted lysines. Arginine substitutions at Lys-318 and Lys-322 prevented the acetylation-induced activity loss. Lys-318 and Lys-322 flank residues Arg-317 and Phe-320, which are conserved among all acyl-CoA dehydrogenases and coordinate the enzyme-bound FAD cofactor in the active site. We propose that acetylation at Lys-318/Lys-322 causes a conformational change which reduces hydride transfer from substrate to FAD. Medium-chain acyl-CoA dehydrogenase and acyl-CoA dehydrogenase 9, two related enzymes with lysines at positions equivalent to Lys-318/Lys-322, were also efficiently deacetylated by SIRT3 following chemical acetylation. These results suggest that acetylation/deacetylation at Lys-318/Lys-322 is a mode of regulating fatty acid oxidation. The same mechanism may regulate other acyl-CoA dehydrogenases.

Authors
Bharathi, SS; Zhang, Y; Mohsen, A-W; Uppala, R; Balasubramani, M; Schreiber, E; Uechi, G; Beck, ME; Rardin, MJ; Vockley, J; Verdin, E; Gibson, BW; Hirschey, MD; Goetzman, ES
MLA Citation
Bharathi, SS, Zhang, Y, Mohsen, A-W, Uppala, R, Balasubramani, M, Schreiber, E, Uechi, G, Beck, ME, Rardin, MJ, Vockley, J, Verdin, E, Gibson, BW, Hirschey, MD, and Goetzman, ES. "Sirtuin 3 (SIRT3) protein regulates long-chain acyl-CoA dehydrogenase by deacetylating conserved lysines near the active site." J Biol Chem 288.47 (November 22, 2013): 33837-33847.
PMID
24121500
Source
pubmed
Published In
The Journal of biological chemistry
Volume
288
Issue
47
Publish Date
2013
Start Page
33837
End Page
33847
DOI
10.1074/jbc.M113.510354

Targeting sirtuins for the treatment of diabetes.

Sirtuins are a class of NAD(+)-dependent deacetylases, such as deacetylases, that have a wide array of biological functions. Recent studies have suggested that reduced sirtuin action is correlated with Type 2 diabetes. Both overnutrition and aging, which are two major risk factors for diabetes, lead to decreased sirtuin function and result in abnormal glucose and lipid metabolism. Therefore, restoring normal levels of sirtuin action in Type 2 diabetes may be a promising method of treating diabetes. This article reviews the biological functions of three of the seven mammalian sirtuins - SIRT1, SIRT3 and SIRT6 - that have demonstrated prominent metabolic roles and early potential for drug targeting. Clinical trials investigating the use of sirtuin activators for treating diabetes are already underway and show promise as alternatives to current diabetes therapies. Thus, further research into sirtuin activators is warranted and may lead to a new class of safe, effective diabetes treatments.

Authors
Huynh, FK; Hershberger, KA; Hirschey, MD
MLA Citation
Huynh, FK, Hershberger, KA, and Hirschey, MD. "Targeting sirtuins for the treatment of diabetes." Diabetes management (London, England) 3.3 (May 2013): 245-257.
PMID
25067957
Source
epmc
Published In
Diabetes Management
Volume
3
Issue
3
Publish Date
2013
Start Page
245
End Page
257
DOI
10.2217/dmt.13.6

HINT2 and fatty liver disease: mitochondrial protein hyperacetylation gives a hint?

Authors
Anderson, KA; Wang, D; Hirschey, MD
MLA Citation
Anderson, KA, Wang, D, and Hirschey, MD. "HINT2 and fatty liver disease: mitochondrial protein hyperacetylation gives a hint?." Hepatology 57.5 (May 2013): 1681-1683.
PMID
22991239
Source
pubmed
Published In
Hepatology
Volume
57
Issue
5
Publish Date
2013
Start Page
1681
End Page
1683
DOI
10.1002/hep.26085

Suppression of oxidative stress by β-hydroxybutyrate, an endogenous histone deacetylase inhibitor.

Concentrations of acetyl-coenzyme A and nicotinamide adenine dinucleotide (NAD(+)) affect histone acetylation and thereby couple cellular metabolic status and transcriptional regulation. We report that the ketone body d-β-hydroxybutyrate (βOHB) is an endogenous and specific inhibitor of class I histone deacetylases (HDACs). Administration of exogenous βOHB, or fasting or calorie restriction, two conditions associated with increased βOHB abundance, all increased global histone acetylation in mouse tissues. Inhibition of HDAC by βOHB was correlated with global changes in transcription, including that of the genes encoding oxidative stress resistance factors FOXO3A and MT2. Treatment of cells with βOHB increased histone acetylation at the Foxo3a and Mt2 promoters, and both genes were activated by selective depletion of HDAC1 and HDAC2. Consistent with increased FOXO3A and MT2 activity, treatment of mice with βOHB conferred substantial protection against oxidative stress.

Authors
Shimazu, T; Hirschey, MD; Newman, J; He, W; Shirakawa, K; Le Moan, N; Grueter, CA; Lim, H; Saunders, LR; Stevens, RD; Newgard, CB; Farese, RV; de Cabo, R; Ulrich, S; Akassoglou, K; Verdin, E
MLA Citation
Shimazu, T, Hirschey, MD, Newman, J, He, W, Shirakawa, K, Le Moan, N, Grueter, CA, Lim, H, Saunders, LR, Stevens, RD, Newgard, CB, Farese, RV, de Cabo, R, Ulrich, S, Akassoglou, K, and Verdin, E. "Suppression of oxidative stress by β-hydroxybutyrate, an endogenous histone deacetylase inhibitor." Science 339.6116 (January 11, 2013): 211-214.
PMID
23223453
Source
pubmed
Published In
Science
Volume
339
Issue
6116
Publish Date
2013
Start Page
211
End Page
214
DOI
10.1126/science.1227166

SIRT3 weighs heavily in the metabolic balance: A new role for SIRT3 in metabolic syndrome

Eating a "Western diet" high in fat and sugars is associated with accelerated development of age-related metabolic diseases such as obesity, insulin resistance, and diabetes while incidences of these diseases are decreased on a low-calorie diet. The mitochondrial NAD(+)-dependent protein deacetylase SIRT3 has previously been shown to be important in adapting to metabolic stress brought on by fasting and calorie restriction. During times of metabolic stress, SIRT3 is upregulated and maintains homeostasis following nutrient deprivation by turning on pathways such as fatty acid oxidation, antioxidant production, and the urea cycle. New studies now demonstrate that SIRT3 is regulated during nutrient excess. During high-fat diet feeding, SIRT3 is downregulated leading to mitochondrial protein hyperacetylation. The consequence of this hyperacetylation is the accelerated development of metabolic syndrome. Thus, SIRT3 is emerging as an important metabolic sensor working to restore metabolic homeostasis during times of stress. © 2012 The Author. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved.

Authors
Green, MF; Hirschey, MD
MLA Citation
Green, MF, and Hirschey, MD. "SIRT3 weighs heavily in the metabolic balance: A new role for SIRT3 in metabolic syndrome." Journals of Gerontology - Series A Biological Sciences and Medical Sciences 68.2 (2013): 105-107.
PMID
22562958
Source
scival
Published In
Journals of Gerontology: Series A
Volume
68
Issue
2
Publish Date
2013
Start Page
105
End Page
107
DOI
10.1093/gerona/gls132

Whole-organism screening for gluconeogenesis identifies activators of fasting metabolism

Improving the control of energy homeostasis can lower cardiovascular risk in metabolically compromised individuals. To identify new regulators of whole-body energy control, we conducted a high-throughput screen in transgenic reporter zebrafish for small molecules that modulate the expression of the fasting-inducible gluconeogenic gene pck1. We show that this in vivo strategy identified several drugs that affect gluconeogenesis in humans as well as metabolically uncharacterized compounds. Most notably, we find that the translocator protein ligands PK 11195 and Ro5-4864 are glucose-lowering agents despite a strong inductive effect on pck1 expression. We show that these drugs are activators of a fasting-like energy state and, notably, that they protect high-fat diet-induced obese mice from hepatosteatosis and glucose intolerance, two pathological manifestations of metabolic dysregulation. Thus, using a whole-organism screening strategy, this study has identified new small-molecule activators of fasting metabolism. © 2013 Nature America, Inc. All rights reserved.

Authors
Gut, P; Baeza-Raja, B; Andersson, O; Hasenkamp, L; Hsiao, J; Hesselson, D; Akassoglou, K; Verdin, E; Hirschey, MD; Stainier, DYR
MLA Citation
Gut, P, Baeza-Raja, B, Andersson, O, Hasenkamp, L, Hsiao, J, Hesselson, D, Akassoglou, K, Verdin, E, Hirschey, MD, and Stainier, DYR. "Whole-organism screening for gluconeogenesis identifies activators of fasting metabolism." Nature Chemical Biology 9.2 (2013): 97-104.
Source
scival
Published In
Nature Chemical Biology
Volume
9
Issue
2
Publish Date
2013
Start Page
97
End Page
104
DOI
10.1038/nchembio.1136

Suppression of oxidative stress by β-hydroxybutyrate, an endogenous histone deacetylase inhibitor

Concentrations of acetyl-coenzyme A and nicotinamide adenine dinucleotide (NAD+) affect histone acetylation and thereby couple cellular metabolic status and transcriptional regulation. We report that the ketone body D-β-hydroxybutyrate (βOHB) is an endogenous and specific inhibitor of class I histone deacetylases (HDACs). Administration of exogenous βOHB, or fasting or calorie restriction, two conditions associated with increased βOHB abundance, all increased global histone acetylation in mouse tissues. Inhibition of HDAC by βOHB was correlated with global changes in transcription, including that of the genes encoding oxidative stress resistance factors FOXO3A and MT2. Treatment of cells with βOHB increased histone acetylation at the Foxo3a and Mt2 promoters, and both genes were activated by selective depletion of HDAC1 and HDAC2. Consistent with increased FOXO3A and MT2 activity, treatment of mice with βOHB conferred substantial protection against oxidative stress.

Authors
Shimazu, T; Hirschey, MD; Newman, J; He, W; Shirakawa, K; Moan, NL; Grueter, CA; Lim, H; Saunders, LR; Stevens, RD; Newgard, CB; Jr, RVF; Cabo, RD; Ulrich, S; Akassoglou, K; Verdin, E
MLA Citation
Shimazu, T, Hirschey, MD, Newman, J, He, W, Shirakawa, K, Moan, NL, Grueter, CA, Lim, H, Saunders, LR, Stevens, RD, Newgard, CB, Jr, RVF, Cabo, RD, Ulrich, S, Akassoglou, K, and Verdin, E. "Suppression of oxidative stress by β-hydroxybutyrate, an endogenous histone deacetylase inhibitor." Science 339.6116 (2013): 211-214.
Source
scival
Published In
Science
Volume
339
Issue
6116
Publish Date
2013
Start Page
211
End Page
214
DOI
10.1126/science.1227166

The sirtuins, oxidative stress and aging: An emerging link

Reactive oxygen species (ROS) are a family of compounds that can oxidatively damage cellular macromolecules and may influence lifespan. Sirtuins are a conserved family of nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylases that regulate lifespan in many model organisms including yeast and mice. Recent work suggests that sirtuins can modulate ROS levels notably during a dietary regimen known as calorie restriction which enhances lifespan for several organisms. Although both sirtuins and ROS have been implicated in the aging process, their precise roles remain unknown. In this review, we summarize current thinking about the oxidative stress theory of aging, discuss some of the compelling data linking the sirtuins to ROS and aging, and propose a conceptual model placing the sirtuins into an ROSdriven mitochondria-mediated hormetic response. © Merksameret al.

Authors
Merksamer, PI; Liu, Y; He, W; Hirschey, MD; Chen, D; Verdin, E
MLA Citation
Merksamer, PI, Liu, Y, He, W, Hirschey, MD, Chen, D, and Verdin, E. "The sirtuins, oxidative stress and aging: An emerging link." Aging 5.3 (2013): 144-150.
PMID
23474711
Source
scival
Published In
Aging
Volume
5
Issue
3
Publish Date
2013
Start Page
144
End Page
150

Oxygen flux analysis to understand the biological function of sirtuins.

The sirtuins are a family of highly conserved NAD(+)-dependent lysine deacylases with important roles in metabolic regulation. Of the seven mammalian sirtuins, three localize to the mitochondria: SIRT3, SIRT4, and SIRT5. Mitochondrial sirtuins are crucial regulators of the metabolic network that controls energy homeostasis and impacts cancer, obesity, diabetes, mitochondrial diseases, metabolic disorders, and many other human diseases of aging. To best study the mitochondrial function of the sirtuins, we have employed an oxygen flux analyzer as a tool to track and record the extracellular oxygen consumption rate and acidification rate that reflects mitochondrial respiration and glycolysis, respectfully. Here we described the methods using this assay to study the substrate utilization and mitochondrial function in a human hepatocellular carcinoma cell line, Huh7. Additionally, we have generated a stable SIRT4 knocked-down Huh7 cell line. With this cell line, we evaluated how the absence of SIRT4 affects mitochondrial function, glucose utilization, glutamine oxidation, and fatty acid oxidation in these cells.

Authors
Wang, D; Green, MF; McDonnell, E; Hirschey, MD
MLA Citation
Wang, D, Green, MF, McDonnell, E, and Hirschey, MD. "Oxygen flux analysis to understand the biological function of sirtuins." Methods Mol Biol 1077 (2013): 241-258.
PMID
24014411
Source
pubmed
Published In
Methods in molecular biology (Clifton, N.J.)
Volume
1077
Publish Date
2013
Start Page
241
End Page
258
DOI
10.1007/978-1-62703-637-5_16

Generating mammalian sirtuin tools for protein-interaction analysis.

The sirtuins are a family of NAD(+)-dependent deacylases with important effects on aging, cancer, and metabolism. Sirtuins exert their biological effects by catalyzing deacetylation and/or deacylation reactions in which Acyl groups are removed from lysine residues of specific proteins. A current challenge is to identify specific sirtuin target proteins against the high background of acetylated proteins recently identified by proteomic surveys. New evidence indicates that bona fide sirtuin substrate proteins form stable physical associations with their sirtuin regulator. Therefore, identification of sirtuin interacting proteins could be a useful aid in focusing the search for substrates. Described here is a method for identifying sirtuin protein interactors. Employing basic techniques of molecular cloning and immunochemistry, the method describes the generation of mammalian sirtuin protein expression plasmids and their use to overexpress and immunoprecipitate sirtuins with their interacting partners. Also described is the use of the Database for Annotation, Visualization, and Integrated Discovery for interpreting the sirtuin protein-interaction data obtained.

Authors
Hershberger, KA; Motley, J; Hirschey, MD; Anderson, KA
MLA Citation
Hershberger, KA, Motley, J, Hirschey, MD, and Anderson, KA. "Generating mammalian sirtuin tools for protein-interaction analysis." Methods Mol Biol 1077 (2013): 69-78.
PMID
24014400
Source
pubmed
Published In
Methods in molecular biology (Clifton, N.J.)
Volume
1077
Publish Date
2013
Start Page
69
End Page
78
DOI
10.1007/978-1-62703-637-5_5

Ethanol metabolism modifies hepatic protein acylation in mice.

Mitochondrial protein acetylation increases in response to chronic ethanol ingestion in mice, and is thought to reduce mitochondrial function and contribute to the pathogenesis of alcoholic liver disease. The mitochondrial deacetylase SIRT3 regulates the acetylation status of several mitochondrial proteins, including those involved in ethanol metabolism. The newly discovered desuccinylase activity of the mitochondrial sirtuin SIRT5 suggests that protein succinylation could be an important post-translational modification regulating mitochondrial metabolism. To assess the possible role of protein succinylation in ethanol metabolism, we surveyed hepatic sub-cellular protein fractions from mice fed a control or ethanol-supplemented diet for succinyl-lysine, as well as acetyl-, propionyl-, and butyryl-lysine post-translational modifications. We found mitochondrial protein propionylation increases, similar to mitochondrial protein acetylation. In contrast, mitochondrial protein succinylation is reduced. These mitochondrial protein modifications appear to be primarily driven by ethanol metabolism, and not by changes in mitochondrial sirtuin levels. Similar trends in acyl modifications were observed in the nucleus. However, comparatively fewer acyl modifications were observed in the cytoplasmic or the microsomal compartments, and were generally unchanged by ethanol metabolism. Using a mass spectrometry proteomics approach, we identified several candidate acetylated, propionylated, and succinylated proteins, which were enriched using antibodies against each modification. Additionally, we identified several acetyl and propionyl lysine residues on the same sites for a number of proteins and supports the idea of the overlapping nature of lysine-specific acylation. Thus, we show that novel post-translational modifications are present in hepatic mitochondrial, nuclear, cytoplasmic, and microsomal compartments and ethanol ingestion, and its associated metabolism, induce specific changes in these acyl modifications. These data suggest that protein acylation, beyond protein acetylation, contributes to the overall metabolic regulatory network and could play an important role in the pathogenesis of alcoholic liver disease.

Authors
Fritz, KS; Green, MF; Petersen, DR; Hirschey, MD
MLA Citation
Fritz, KS, Green, MF, Petersen, DR, and Hirschey, MD. "Ethanol metabolism modifies hepatic protein acylation in mice. (Published online)" PLoS One 8.9 (2013): e75868-.
PMID
24073283
Source
pubmed
Published In
PloS one
Volume
8
Issue
9
Publish Date
2013
Start Page
e75868
DOI
10.1371/journal.pone.0075868

Preface

Authors
Hirschey, MD
MLA Citation
Hirschey, MD. "Preface." Methods in Molecular Biology 1077 (2013): v-.
Source
scival
Published In
Methods in molecular biology (Clifton, N.J.)
Volume
1077
Publish Date
2013
Start Page
v

Hepatic insulin signaling is required for obesity-dependent expression of SREBP-1c mRNA but not for feeding-dependent expression.

Dissecting the role of insulin in the complex regulation of triglyceride metabolism is necessary for understanding dyslipidemia and steatosis. Liver insulin receptor knockout (LIRKO) mice show that in the physiological context of feeding, hepatic insulin signaling is not required for the induction of mTORC1, an upstream activator of the lipogenic regulator, SREBP-1c. Feeding induces SREBP-1c mRNA in LIRKO livers, though not to the extent observed in controls. A high fructose diet also partially induces SREBP-1c and lipogenic gene expression in LIRKO livers. Insulin signaling becomes more important in the pathological context of obesity, as knockdown of the insulin receptor in ob/ob mice, a model of Type 2 diabetes, using antisense oligonucleotides, abolishes the induction of SREBP-1c and its targets by obesity and ameliorates steatosis. Thus, insulin-independent signaling pathways can partially compensate for insulin in the induction of SREBP-1c by feeding but the further induction by obesity/Type 2 diabetes is entirely dependent upon insulin.

Authors
Haas, JT; Miao, J; Chanda, D; Wang, Y; Zhao, E; Haas, ME; Hirschey, M; Vaitheesvaran, B; Farese, RV; Kurland, IJ; Graham, M; Crooke, R; Foufelle, F; Biddinger, SB
MLA Citation
Haas, JT, Miao, J, Chanda, D, Wang, Y, Zhao, E, Haas, ME, Hirschey, M, Vaitheesvaran, B, Farese, RV, Kurland, IJ, Graham, M, Crooke, R, Foufelle, F, and Biddinger, SB. "Hepatic insulin signaling is required for obesity-dependent expression of SREBP-1c mRNA but not for feeding-dependent expression." Cell Metab 15.6 (June 6, 2012): 873-884.
PMID
22682225
Source
pubmed
Published In
Cell Metabolism
Volume
15
Issue
6
Publish Date
2012
Start Page
873
End Page
884
DOI
10.1016/j.cmet.2012.05.002

Whole-organism screening for gluconeogenesis identifies activators of fasting metabolism

Improving the control of energy homeostasis can lower cardiovascular risk in metabolically compromised individuals. To identify new regulators of whole-body energy control, we conducted a high-throughput screen in transgenic reporter zebrafish for small molecules that modulate the expression of the fasting-inducible gluconeogenic gene pck1. We show that this in vivo strategy identified several drugs that affect gluconeogenesis in humans as well as metabolically uncharacterized compounds. Most notably, we find that the translocator protein ligands PK 11195 and Ro5-4864 are glucose-lowering agents despite a strong inductive effect on pck1 expression. We show that these drugs are activators of a fasting-like energy state and, notably, that they protect high-fat diet-induced obese mice from hepatosteatosis and glucose intolerance, two pathological manifestations of metabolic dysregulation. Thus, using a whole-organism screening strategy, this study has identified new small-molecule activators of fasting metabolism.

Authors
Gut, P; Baeza-Raja, B; Andersson, O; Hasenkamp, L; Hsiao, J; Hesselson, D; Akassoglou, K; Verdin, E; Hirschey, MD; Stainier, DYR
MLA Citation
Gut, P, Baeza-Raja, B, Andersson, O, Hasenkamp, L, Hsiao, J, Hesselson, D, Akassoglou, K, Verdin, E, Hirschey, MD, and Stainier, DYR. "Whole-organism screening for gluconeogenesis identifies activators of fasting metabolism." Nature Chemical Biology (2012).
PMID
23201900
Source
scival
Published In
Nature Chemical Biology
Publish Date
2012
DOI
10.1038/nchembio.1136

Mitochondrial acetylome analysis in a mouse model of alcohol-induced liver injury utilizing SIRT3 knockout mice

Mitochondrial protein hyperacetylation is a known consequence of sustained ethanol consumption and has been proposed to play a role in the pathogenesis of alcoholic liver disease (ALD). The mechanisms underlying this altered acetylome, however, remain unknown. The mitochondrial deacetylase sirtuin 3 (SIRT3) is reported to be the major regulator of mitochondrial protein deacetylation and remains a central focus for studies on protein acetylation. To investigate the mechanisms underlying ethanol-induced mitochondrial acetylation, we employed a model for ALD in both wild-type (WT) and SIRT3 knockout (KO) mice using a proteomics and bioinformatics approach. Here, WT and SIRT3 KO groups were compared in a mouse model of chronic ethanol consumption, revealing pathways relevant to ALD, including lipid and fatty acid metabolism, antioxidant response, amino acid biosynthesis and the electron-transport chain, each displaying proteins with altered acetylation. Interestingly, protein hyperacetylation resulting from ethanol consumption and SIRT3 ablation suggests ethanol-induced hyperacetylation targets numerous biological processes within the mitochondria, the majority of which are known to be acetylated through SIRT3-dependent mechanisms. These findings reveal overall increases in 91 mitochondrial targets for protein acetylation, identifying numerous critical metabolic and antioxidant pathways associated with ALD, suggesting an important role for mitochondrial protein acetylation in the pathogenesis of ALD. © 2012 American Chemical Society.

Authors
Fritz, KS; Galligan, JJ; Hirschey, MD; Verdin, E; Petersen, DR
MLA Citation
Fritz, KS, Galligan, JJ, Hirschey, MD, Verdin, E, and Petersen, DR. "Mitochondrial acetylome analysis in a mouse model of alcohol-induced liver injury utilizing SIRT3 knockout mice." Journal of Proteome Research 11.3 (2012): 1633-1643.
PMID
22309199
Source
scival
Published In
Journal of Proteome Research
Volume
11
Issue
3
Publish Date
2012
Start Page
1633
End Page
1643
DOI
10.1021/pr2008384

Mitochondrial protein acetylation regulates metabolism.

Changes in cellular nutrient availability or energy status induce global changes in mitochondrial protein acetylation. Over one-third of all proteins in the mitochondria are acetylated, of which the majority are involved in some aspect of energy metabolism. Mitochondrial protein acetylation is regulated by SIRT3 (sirtuin 3), a member of the sirtuin family of NAD+-dependent protein deacetylases that has recently been identified as a key modulator of energy homoeostasis. In the absence of SIRT3, mitochondrial proteins become hyperacetylated, have altered function, and contribute to mitochondrial dysfunction. This chapter presents a review of the functional impact of mitochondrial protein acetylation, and its regulation by SIRT3.

Authors
Anderson, KA; Hirschey, MD
MLA Citation
Anderson, KA, and Hirschey, MD. "Mitochondrial protein acetylation regulates metabolism." Essays Biochem 52 (2012): 23-35. (Review)
PMID
22708561
Source
pubmed
Published In
Essays in biochemistry
Volume
52
Publish Date
2012
Start Page
23
End Page
35
DOI
10.1042/bse0520023

Deficiency of the lipid synthesis enzyme, DGAT1, extends longevity in mice

Calorie restriction results in leanness, which is linked to metabolic conditions that favor longevity. We show here that deficiency of the triglyceride synthesis enzyme acyl CoA:diacylglycerol acyltransferase 1 (DGAT1), which promotes leanness, also extends longevity without limiting food intake. Female DGAT1-deficient mice were protected from agerelated increases in body fat, tissue triglycerides, and inflammation in white adipose tissue. This protection was accompanied by increased mean and maximal life spans of ~25% and ~10%, respectively. Middle-aged Dgat1 -/- mice exhibited several features associated with longevity, including decreased levels of circulating insulin growth factor 1 (IGF1) and reduced fecundity. Thus, deletion of DGAT1 in mice provides a model of leanness and extended lifespan that is independent of calorie restriction. © Streeper e et al.

Authors
Streeper, RS; Grueter, CA; Salomonis, N; Cases, S; Levin, MC; Koliwad, SK; Zhou, P; Hirschey, MD; Verdin, E; Jr, RVF
MLA Citation
Streeper, RS, Grueter, CA, Salomonis, N, Cases, S, Levin, MC, Koliwad, SK, Zhou, P, Hirschey, MD, Verdin, E, and Jr, RVF. "Deficiency of the lipid synthesis enzyme, DGAT1, extends longevity in mice." Aging 4.1 (2012): 13-27.
PMID
22291164
Source
scival
Published In
Aging
Volume
4
Issue
1
Publish Date
2012
Start Page
13
End Page
27

SIRT3 deficiency and mitochondrial protein hyperacetylation accelerate the development of the metabolic syndrome.

Acetylation is increasingly recognized as an important metabolic regulatory posttranslational protein modification, yet the metabolic consequence of mitochondrial protein hyperacetylation is unknown. We find that high-fat diet (HFD) feeding induces hepatic mitochondrial protein hyperacetylation in mice and downregulation of the major mitochondrial protein deacetylase SIRT3. Mice lacking SIRT3 (SIRT3KO) placed on a HFD show accelerated obesity, insulin resistance, hyperlipidemia, and steatohepatitis compared to wild-type (WT) mice. The lipogenic enzyme stearoyl-CoA desaturase 1 is highly induced in SIRT3KO mice, and its deletion rescues both WT and SIRT3KO mice from HFD-induced hepatic steatosis and insulin resistance. We further identify a single nucleotide polymorphism in the human SIRT3 gene that is suggestive of a genetic association with the metabolic syndrome. This polymorphism encodes a point mutation in the SIRT3 protein, which reduces its overall enzymatic efficiency. Our findings show that loss of SIRT3 and dysregulation of mitochondrial protein acetylation contribute to the metabolic syndrome.

Authors
Hirschey, MD; Shimazu, T; Jing, E; Grueter, CA; Collins, AM; Aouizerat, B; Stančáková, A; Goetzman, E; Lam, MM; Schwer, B; Stevens, RD; Muehlbauer, MJ; Kakar, S; Bass, NM; Kuusisto, J; Laakso, M; Alt, FW; Newgard, CB; Farese, RV; Kahn, CR; Verdin, E
MLA Citation
Hirschey, MD, Shimazu, T, Jing, E, Grueter, CA, Collins, AM, Aouizerat, B, Stančáková, A, Goetzman, E, Lam, MM, Schwer, B, Stevens, RD, Muehlbauer, MJ, Kakar, S, Bass, NM, Kuusisto, J, Laakso, M, Alt, FW, Newgard, CB, Farese, RV, Kahn, CR, and Verdin, E. "SIRT3 deficiency and mitochondrial protein hyperacetylation accelerate the development of the metabolic syndrome." Mol Cell 44.2 (October 21, 2011): 177-190.
PMID
21856199
Source
pubmed
Published In
Molecular Cell
Volume
44
Issue
2
Publish Date
2011
Start Page
177
End Page
190
DOI
10.1016/j.molcel.2011.07.019

SIRT3 regulates mitochondrial protein acetylation and intermediary metabolism

The sirtuins are a family of nicotinamide adenine dinucleotide (NAD +)-dependent protein deacetylases that regulate cell survival, metabolism, and longevity. Humans have seven sirtuins (SIRT1-SIRT7) with distinct subcellular locations and functions. SIRT3 is localized to the mitochondrial matrix and its expression is selectively activated during fasting and calorie restriction. Activated SIRT3 deacetylates several key metabolic enzymes-acetyl-coenzyme A synthetase, long-chain acylcoenzyme A (acyl-CoA) dehydrogenase (LCAD), and 3-hydroxy-3-methylglutaryl CoA synthase 2-and enhances their enzymatic activity. Disruption of SIRT3 activity in mice, either by genetic ablation or during high-fat feeding, is associated with accelerated development of metabolic abnormalities similar to the metabolic syndrome in humans. SIRT3 is therefore emerging as a metabolic sensor that responds to change in the energy status of the cell and modulates the activity of key metabolic enzymes via protein deacetylation. © 2011 Cold Spring Harbor Laboratory Press.

Authors
Hirschey, MD; Shimazu, T; Huang, J-Y; Schwer, B; Verdin, E
MLA Citation
Hirschey, MD, Shimazu, T, Huang, J-Y, Schwer, B, and Verdin, E. "SIRT3 regulates mitochondrial protein acetylation and intermediary metabolism." Cold Spring Harbor Symposia on Quantitative Biology 76 (2011): 267-277.
PMID
22114326
Source
scival
Published In
Cold Spring Harbor Laboratory: Symposia on Quantitative Biology
Volume
76
Publish Date
2011
Start Page
267
End Page
277
DOI
10.1101/sqb.2011.76.010850

Old enzymes, new tricks: Sirtuins are NAD +-dependent De-acylases

Seven mammalian sirtuins are nicotinamide adenine dinucleotide (NAD) +-dependent deacetylases and are important modulators of energy metabolism and stress resistance. Two new studies by Du et al. (2011) and Peng et al. (2011) identify a new enzymatic activity for SIRT5, expanding the cellular repertoire of posttranslational modifications targeted by the sirtuins. © 2011 Elsevier Inc.

Authors
Hirschey, MD
MLA Citation
Hirschey, MD. "Old enzymes, new tricks: Sirtuins are NAD +-dependent De-acylases." Cell Metabolism 14.6 (2011): 718-719.
PMID
22100408
Source
scival
Published In
Cell Metabolism
Volume
14
Issue
6
Publish Date
2011
Start Page
718
End Page
719
DOI
10.1016/j.cmet.2011.10.006

Sirtuin-3 (Sirt3) regulates skeletal muscle metabolism and insulin signaling via altered mitochondrial oxidation and reactive oxygen species production

Sirt3 is a member of the sirtuin family of protein deacetylases that is localized in mitochondria and regulates mitochondrial function. Sirt3 expression in skeletal muscle is decreased in models of type 1 and type 2 diabetes and regulated by feeding, fasting, and caloric restriction. Sirt3 knockout mice exhibit decreased oxygen consumption and develop oxidative stress in skeletal muscle, leading to JNK activation and impaired insulin signaling. This effect is mimicked by knockdown of Sirt3 in cultured myoblasts, which exhibit reduced mitochondrial oxidation, increased reactive oxygen species, activation of JNK, increased serine and decreased tyrosine phosphorylation of IRS-1, and decreased insulin signaling. Thus, Sirt3 plays an important role in diabetes through regulation of mitochondrial oxidation, reactive oxygen species production, and insulin resistance in skeletal muscle.

Authors
Jing, E; Emanuelli, B; Hirschey, MD; Boucher, J; Lee, KY; Lombard, D; Verdin, EM; Kahn, CR
MLA Citation
Jing, E, Emanuelli, B, Hirschey, MD, Boucher, J, Lee, KY, Lombard, D, Verdin, EM, and Kahn, CR. "Sirtuin-3 (Sirt3) regulates skeletal muscle metabolism and insulin signaling via altered mitochondrial oxidation and reactive oxygen species production." Proceedings of the National Academy of Sciences of the United States of America 108.35 (2011): 14608-14613.
PMID
21873205
Source
scival
Published In
Proceedings of the National Academy of Sciences of USA
Volume
108
Issue
35
Publish Date
2011
Start Page
14608
End Page
14613
DOI
10.1073/pnas.1111308108

SIRT1 and SIRT3 deacetylate homologous substrates: AceCS1,2 and HMGCS1,2

SIRT1 and SIRT3 are NAD+-dependent protein deacetylases that are evolutionarily conserved across mammals. These proteins are located in the cytoplasm/nucleus and mitochondria, respectively. Previous reports demonstrated that human SIRT1 deacetylates Acetyl-CoA Synthase 1 (AceCS1) in the cytoplasm, whereas SIRT3 deacetylates the homologous Acetyl-CoA Synthase 2 (AceCS2) in the mitochondria. We recently showed that 3-hydroxy-3-methylglutaryl CoA synthase 2 (HMGCS2) is deacetylated by SIRT3 in mitochondria, and we demonstrate here that SIRT1 deacetylates the homologous 3-hydroxy-3-methylglutaryl CoA synthase 1 (HMGCS1) in the cytoplasm. This novel pattern of substrate homology between cytoplasmic SIRT1 and mitochondrial SIRT3 suggests that considering evolutionary relationships between the sirtuins and their substrates may help to identify and understand the functions and interactions of this gene family. In this perspective, we take a first step by characterizing the evolutionary history of the sirtuins and these substrate families. © Hirschey et al.

Authors
Hirschey, MD; Shimazu, T; Capra, JA; Pollard, KS; Verdin, E
MLA Citation
Hirschey, MD, Shimazu, T, Capra, JA, Pollard, KS, and Verdin, E. "SIRT1 and SIRT3 deacetylate homologous substrates: AceCS1,2 and HMGCS1,2." Aging 3.6 (2011): 635-642.
PMID
21701047
Source
scival
Published In
Aging
Volume
3
Issue
6
Publish Date
2011
Start Page
635
End Page
642

SIRT3 deacetylates mitochondrial 3-hydroxy-3-methylglutaryl CoA synthase 2 and regulates ketone body production.

The mitochondrial sirtuin SIRT3 regulates metabolic homeostasis during fasting and calorie restriction. We identified mitochondrial 3-hydroxy-3-methylglutaryl CoA synthase 2 (HMGCS2) as an acetylated protein and a possible target of SIRT3 in a proteomics survey in hepatic mitochondria from Sirt3(-/-) (SIRT3KO) mice. HMGCS2 is the rate-limiting step in β-hydroxybutyrate synthesis and is hyperacetylated at lysines 310, 447, and 473 in the absence of SIRT3. HMGCS2 is deacetylated by SIRT3 in response to fasting in wild-type mice, but not in SIRT3KO mice. HMGCS2 is deacetylated in vitro when incubated with SIRT3 and in vivo by overexpression of SIRT3. Deacetylation of HMGCS2 lysines 310, 447, and 473 by incubation with wild-type SIRT3 or by mutation to arginine enhances its enzymatic activity. Molecular dynamics simulations show that in silico deacetylation of these three lysines causes conformational changes of HMGCS2 near the active site. Mice lacking SIRT3 show decreased β-hydroxybutyrate levels during fasting. Our findings show SIRT3 regulates ketone body production during fasting and provide molecular insight into how protein acetylation can regulate enzymatic activity.

Authors
Shimazu, T; Hirschey, MD; Hua, L; Dittenhafer-Reed, KE; Schwer, B; Lombard, DB; Li, Y; Bunkenborg, J; Alt, FW; Denu, JM; Jacobson, MP; Verdin, E
MLA Citation
Shimazu, T, Hirschey, MD, Hua, L, Dittenhafer-Reed, KE, Schwer, B, Lombard, DB, Li, Y, Bunkenborg, J, Alt, FW, Denu, JM, Jacobson, MP, and Verdin, E. "SIRT3 deacetylates mitochondrial 3-hydroxy-3-methylglutaryl CoA synthase 2 and regulates ketone body production." Cell Metab 12.6 (December 1, 2010): 654-661.
PMID
21109197
Source
pubmed
Published In
Cell Metabolism
Volume
12
Issue
6
Publish Date
2010
Start Page
654
End Page
661
DOI
10.1016/j.cmet.2010.11.003

Calorie restriction reduces oxidative stress by SIRT3-mediated SOD2 activation.

A major cause of aging and numerous diseases is thought to be cumulative oxidative stress, resulting from the production of reactive oxygen species (ROS) during respiration. Calorie restriction (CR), the most robust intervention to extend life span and ameliorate various diseases in mammals, reduces oxidative stress and damage. However, the underlying mechanism is unknown. Here, we show that the protective effects of CR on oxidative stress and damage are diminished in mice lacking SIRT3, a mitochondrial deacetylase. SIRT3 reduces cellular ROS levels dependent on superoxide dismutase 2 (SOD2), a major mitochondrial antioxidant enzyme. SIRT3 deacetylates two critical lysine residues on SOD2 and promotes its antioxidative activity. Importantly, the ability of SOD2 to reduce cellular ROS and promote oxidative stress resistance is greatly enhanced by SIRT3. Our studies identify a defense program that CR provokes to reduce oxidative stress and suggest approaches to combat aging and oxidative stress-related diseases.

Authors
Qiu, X; Brown, K; Hirschey, MD; Verdin, E; Chen, D
MLA Citation
Qiu, X, Brown, K, Hirschey, MD, Verdin, E, and Chen, D. "Calorie restriction reduces oxidative stress by SIRT3-mediated SOD2 activation." Cell Metab 12.6 (December 1, 2010): 662-667.
PMID
21109198
Source
pubmed
Published In
Cell Metabolism
Volume
12
Issue
6
Publish Date
2010
Start Page
662
End Page
667
DOI
10.1016/j.cmet.2010.11.015

Sirtuin regulation of mitochondria: energy production, apoptosis, and signaling.

Sirtuins are a highly conserved family of proteins whose activity can prolong the lifespan of model organisms such as yeast, worms and flies. Mammals contain seven sirtuins (SIRT1-7) that modulate distinct metabolic and stress response pathways. Three sirtuins, SIRT3, SIRT4 and SIRT5, are located in the mitochondria, dynamic organelles that function as the primary site of oxidative metabolism and play crucial roles in apoptosis and intracellular signaling. Recent findings have shed light on how the mitochondrial sirtuins function in the control of basic mitochondrial biology, including energy production, metabolism, apoptosis and intracellular signaling.

Authors
Verdin, E; Hirschey, MD; Finley, LWS; Haigis, MC
MLA Citation
Verdin, E, Hirschey, MD, Finley, LWS, and Haigis, MC. "Sirtuin regulation of mitochondria: energy production, apoptosis, and signaling." Trends Biochem Sci 35.12 (December 2010): 669-675. (Review)
PMID
20863707
Source
pubmed
Published In
Trends in Biochemical Sciences
Volume
35
Issue
12
Publish Date
2010
Start Page
669
End Page
675
DOI
10.1016/j.tibs.2010.07.003

Mitochondrial sirtuins.

Sirtuins have emerged as important proteins in aging, stress resistance and metabolic regulation. Three sirtuins, SIRT3, 4 and 5, are located within the mitochondrial matrix. SIRT3 and SIRT5 are NAD(+)-dependent deacetylases that remove acetyl groups from acetyllysine-modified proteins and yield 2'-O-acetyl-ADP-ribose and nicotinamide. SIRT4 can transfer the ADP-ribose group from NAD(+) onto acceptor proteins. Recent findings reveal that a large fraction of mitochondrial proteins are acetylated and that mitochondrial protein acetylation is modulated by nutritional status. This and the identification of targets for SIRT3, 4 and 5 support the model that mitochondrial sirtuins are metabolic sensors that modulate the activity of metabolic enzymes via protein deacetylation or mono-ADP-ribosylation. Here, we review and discuss recent progress in the study of mitochondrial sirtuins and their targets.

Authors
Huang, J-Y; Hirschey, MD; Shimazu, T; Ho, L; Verdin, E
MLA Citation
Huang, J-Y, Hirschey, MD, Shimazu, T, Ho, L, and Verdin, E. "Mitochondrial sirtuins." Biochim Biophys Acta 1804.8 (August 2010): 1645-1651. (Review)
PMID
20060508
Source
pubmed
Published In
Biochimica et Biophysica Acta: international journal of biochemistry and biophysics
Volume
1804
Issue
8
Publish Date
2010
Start Page
1645
End Page
1651
DOI
10.1016/j.bbapap.2009.12.021

Acetate metabolism and aging: An emerging connection.

Sirtuins are NAD(+)-dependent protein deacetylases that regulate gene silencing, energy metabolism and aging from bacteria to mammals. SIRT3, a mammalian mitochondrial sirtuin, deacetylates acetyl-CoA synthetase (AceCS2) in the mitochondria. AceCS2 is conserved from bacteria to humans, catalyzes the conversion of acetate to acetyl-CoA and enables peripheral tissues to utilize acetate during fasting conditions. Here, we review the regulation of acetate metabolism by sirtuins, the remarkable conservation of this metabolic regulatory pathway and its emerging role in the regulation of aging and longevity.

Authors
Shimazu, T; Hirschey, MD; Huang, J-Y; Ho, LTY; Verdin, E
MLA Citation
Shimazu, T, Hirschey, MD, Huang, J-Y, Ho, LTY, and Verdin, E. "Acetate metabolism and aging: An emerging connection." Mech Ageing Dev 131.7-8 (July 2010): 511-516.
PMID
20478325
Source
pubmed
Published In
Mechanisms of Ageing and Development
Volume
131
Issue
7-8
Publish Date
2010
Start Page
511
End Page
516
DOI
10.1016/j.mad.2010.05.001

SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation.

Sirtuins are NAD(+)-dependent protein deacetylases. They mediate adaptive responses to a variety of stresses, including calorie restriction and metabolic stress. Sirtuin 3 (SIRT3) is localized in the mitochondrial matrix, where it regulates the acetylation levels of metabolic enzymes, including acetyl coenzyme A synthetase 2 (refs 1, 2). Mice lacking both Sirt3 alleles appear phenotypically normal under basal conditions, but show marked hyperacetylation of several mitochondrial proteins. Here we report that SIRT3 expression is upregulated during fasting in liver and brown adipose tissues. During fasting, livers from mice lacking SIRT3 had higher levels of fatty-acid oxidation intermediate products and triglycerides, associated with decreased levels of fatty-acid oxidation, compared to livers from wild-type mice. Mass spectrometry of mitochondrial proteins shows that long-chain acyl coenzyme A dehydrogenase (LCAD) is hyperacetylated at lysine 42 in the absence of SIRT3. LCAD is deacetylated in wild-type mice under fasted conditions and by SIRT3 in vitro and in vivo; and hyperacetylation of LCAD reduces its enzymatic activity. Mice lacking SIRT3 exhibit hallmarks of fatty-acid oxidation disorders during fasting, including reduced ATP levels and intolerance to cold exposure. These findings identify acetylation as a novel regulatory mechanism for mitochondrial fatty-acid oxidation and demonstrate that SIRT3 modulates mitochondrial intermediary metabolism and fatty-acid use during fasting.

Authors
Hirschey, MD; Shimazu, T; Goetzman, E; Jing, E; Schwer, B; Lombard, DB; Grueter, CA; Harris, C; Biddinger, S; Ilkayeva, OR; Stevens, RD; Li, Y; Saha, AK; Ruderman, NB; Bain, JR; Newgard, CB; Farese, RV; Alt, FW; Kahn, CR; Verdin, E
MLA Citation
Hirschey, MD, Shimazu, T, Goetzman, E, Jing, E, Schwer, B, Lombard, DB, Grueter, CA, Harris, C, Biddinger, S, Ilkayeva, OR, Stevens, RD, Li, Y, Saha, AK, Ruderman, NB, Bain, JR, Newgard, CB, Farese, RV, Alt, FW, Kahn, CR, and Verdin, E. "SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation." Nature 464.7285 (March 4, 2010): 121-125.
PMID
20203611
Source
pubmed
Published In
Nature
Volume
464
Issue
7285
Publish Date
2010
Start Page
121
End Page
125
DOI
10.1038/nature08778

Acetylation of mitochondrial proteins.

Sirtuins (SIRT1-SIRT7) are a family of NAD(+)-dependent protein deacetylases that regulate cell survival, metabolism, and longevity. SIRT3 is localized to the mitochondria where it deacetylates several key metabolic enzymes: acetylcoenzyme A synthetase, glutamate dehydrogenase, and subunits of complex I and thereby regulates their enzymatic activity. SIRT3 is therefore emerging as a metabolic sensor that responds to change in the energy status of the cell via NAD(+) and that modulates the activity of key metabolic enzymes via protein deacetylation. Here we review experimental approaches that can be used in vitro and in vivo to study the role of acetylation in mitochondrial cell biology.

Authors
Hirschey, MD; Shimazu, T; Huang, J-Y; Verdin, E
MLA Citation
Hirschey, MD, Shimazu, T, Huang, J-Y, and Verdin, E. "Acetylation of mitochondrial proteins." Methods Enzymol 457 (2009): 137-147.
PMID
19426866
Source
pubmed
Published In
Methods in Enzymology
Volume
457
Publish Date
2009
Start Page
137
End Page
147
DOI
10.1016/S0076-6879(09)05008-3

Mammalian Sir2 homolog SIRT3 regulates global mitochondrial lysine acetylation.

Homologs of the Saccharomyces cerevisiae Sir2 protein, sirtuins, promote longevity in many organisms. Studies of the sirtuin SIRT3 have so far been limited to cell culture systems. Here, we investigate the localization and function of SIRT3 in vivo. We show that endogenous mouse SIRT3 is a soluble mitochondrial protein. To address the function and relevance of SIRT3 in the regulation of energy metabolism, we generated and phenotypically characterized SIRT3 knockout mice. SIRT3-deficient animals exhibit striking mitochondrial protein hyperacetylation, suggesting that SIRT3 is a major mitochondrial deacetylase. In contrast, no mitochondrial hyperacetylation was detectable in mice lacking the two other mitochondrial sirtuins, SIRT4 and SIRT5. Surprisingly, despite this biochemical phenotype, SIRT3-deficient mice are metabolically unremarkable under basal conditions and show normal adaptive thermogenesis, a process previously suggested to involve SIRT3. Overall, our results extend the recent finding of lysine acetylation of mitochondrial proteins and demonstrate that SIRT3 has evolved to control reversible lysine acetylation in this organelle.

Authors
Lombard, DB; Alt, FW; Cheng, H-L; Bunkenborg, J; Streeper, RS; Mostoslavsky, R; Kim, J; Yancopoulos, G; Valenzuela, D; Murphy, A; Yang, Y; Chen, Y; Hirschey, MD; Bronson, RT; Haigis, M; Guarente, LP; Farese, RV; Weissman, S; Verdin, E; Schwer, B
MLA Citation
Lombard, DB, Alt, FW, Cheng, H-L, Bunkenborg, J, Streeper, RS, Mostoslavsky, R, Kim, J, Yancopoulos, G, Valenzuela, D, Murphy, A, Yang, Y, Chen, Y, Hirschey, MD, Bronson, RT, Haigis, M, Guarente, LP, Farese, RV, Weissman, S, Verdin, E, and Schwer, B. "Mammalian Sir2 homolog SIRT3 regulates global mitochondrial lysine acetylation." Mol Cell Biol 27.24 (December 2007): 8807-8814.
PMID
17923681
Source
pubmed
Published In
Molecular and Cellular Biology
Volume
27
Issue
24
Publish Date
2007
Start Page
8807
End Page
8814
DOI
10.1128/MCB.01636-07

Imaging Escherichia coli using functionalized core/shell CdSe/CdS quantum dots.

The internalization of a series of water-soluble CdSe/CdS quantum dots (QDs) stabilized by citrate, isocitrate, succinate, and malate by Escherichia coli is established by epifluorescence and confocal fluorescence scanning microscopy, fluorimetry, and UV-vis spectroscopy on whole and lysed bacterial cells. The organic-acid-stabilized QDs span a range in size from 3.8+/-1.1 to 6.0+/-2.4 nm with emission wavelengths from 540 to 630 nm. QDs of different sizes (i.e., 3.8-6 nm) can enter the bacterium and be detected on different fluorescence channels with little interference from other QDs as a result of the distinct emission profiles (i.e., 540-630 nm, respectively). Costaining QD-labeled E. coli with 4',6-diamidino-2-phenylindole dihydrochloride (DAPI) demonstrates that the QDs and DAPI are colocalized within E. coli, whereas costaining QD-labeled E. coli with membrane dye FM4-64 shows that the FM4-64 is localized in the outer bacterial membrane and that the QDs are inside.

Authors
Hirschey, MD; Han, Y-J; Stucky, GD; Butler, A
MLA Citation
Hirschey, MD, Han, Y-J, Stucky, GD, and Butler, A. "Imaging Escherichia coli using functionalized core/shell CdSe/CdS quantum dots." J Biol Inorg Chem 11.5 (July 2006): 663-669.
PMID
16724226
Source
pubmed
Published In
JBIC Journal of Biological Inorganic Chemistry
Volume
11
Issue
5
Publish Date
2006
Start Page
663
End Page
669
DOI
10.1007/s00775-006-0116-7

Preface

Authors
Burton, RM; Forsyth, JD; Obel, B
MLA Citation
Burton, RM, Forsyth, JD, and Obel, B. "Preface." Technovation 8.1-3 (1988): vii-.
Source
scival
Published In
Technovation
Volume
8
Issue
1-3
Publish Date
1988
Start Page
vii
Show More

Research Areas:

  • 3-Hydroxybutyric Acid
  • Acetylation
  • Acyl-CoA Dehydrogenase, Long-Chain
  • Acylation
  • Adenosine Triphosphate
  • Adipose Tissue, Brown
  • Animals
  • Apoptosis
  • Biochemistry
  • Blood Glucose
  • Body Temperature Regulation
  • Caloric Restriction
  • Carbohydrate Metabolism
  • Carbon
  • Cardiovascular Physiological Processes
  • Carnitine
  • Catalase
  • Catecholamines
  • Cell Aging
  • Cell Line
  • Cell Survival
  • Cells, Cultured
  • Clinical Trials as Topic
  • Cold Temperature
  • Combined Modality Therapy
  • DNA Damage
  • Diabetes Mellitus, Type 2
  • Diagnosis, Differential
  • Dietary Carbohydrates
  • Dietary Supplements
  • Dose-Response Relationship, Drug
  • Energy Metabolism
  • Environmental Pollutants
  • Enzyme Activation
  • Ethanol
  • Exercise Test
  • Exercise Therapy
  • Fasting
  • Fatty Acids
  • Fatty Acids, Nonesterified
  • Fatty Liver
  • Feeding Behavior
  • Flow Cytometry
  • Food Deprivation
  • Forkhead Transcription Factors
  • Gene Expression
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Gene Targeting
  • Glutamate Dehydrogenase
  • Glutathione
  • HEK293 Cells
  • Heart Failure
  • Heart Ventricles
  • Hepatocytes
  • Histone Deacetylase Inhibitors
  • Histone Deacetylases
  • Histones
  • Homeostasis
  • Humans
  • Hydroxymethylglutaryl-CoA Synthase
  • Hypoglycemia
  • Immunoblotting
  • Immunoprecipitation
  • Ketone Bodies
  • Ketones
  • Kidney
  • Kinetics
  • Lipid Metabolism
  • Lipid Peroxidation
  • Liver
  • Liver Neoplasms
  • Longevity
  • Lysine
  • Mammals
  • Mass Spectrometry
  • Membrane Proteins
  • Metabolic Networks and Pathways
  • Metabolic Syndrome X
  • Metabolome
  • Metallothionein
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microscopy, Confocal
  • Mitochondria
  • Mitochondria, Liver
  • Mitochondrial Proteins
  • Models, Biological
  • Molecular Dynamics Simulation
  • Molecular Structure
  • Myocardial Ischemia
  • Myocardium
  • NAD
  • Neoplasms
  • Neurons
  • Oxidation-Reduction
  • Oxidative Stress
  • Oxygen
  • Oxygen Consumption
  • Paraquat
  • Phosphopeptides
  • Phosphoproteins
  • Pilot Projects
  • Plasmids
  • Promoter Regions, Genetic
  • Protein Interaction Mapping
  • Proteins
  • Proteome
  • RNA, Small Interfering
  • Reactive Oxygen Species
  • Receptors, Cytoplasmic and Nuclear
  • Recombinant Proteins
  • Reproducibility of Results
  • Sequence Homology, Amino Acid
  • Signal Transduction
  • Silent Information Regulator Proteins, Saccharomyces cerevisiae
  • Sirtuin 2
  • Sirtuin 3
  • Sirtuins
  • Solubility
  • Stress, Physiological
  • Sulfides
  • Superoxide Dismutase
  • Thermogenesis
  • Transcription, Genetic
  • Transcriptional Activation
  • Triglycerides
  • Tumor Cells, Cultured
  • Tumor Markers, Biological
  • Up-Regulation