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Matthew Hirschey

Associate Professor of Medicine
Medicine, Endocrinology, Metabolism, and Nutrition
104775, Room 50-201, Durham, NC 27701
300 N. Duke Street, 50-201, Durham, NC 27701

Selected Publications


Optical imaging reveals chemotherapy-induced metabolic reprogramming of residual disease and recurrence.

Journal Article Sci Adv · April 5, 2024 Fewer than 20% of triple-negative breast cancer patients experience long-term responses to mainstay chemotherapy. Resistant tumor subpopulations use alternative metabolic pathways to escape therapy, survive, and eventually recur. Here, we show in vivo, lon ... Full text Link to item Cite

NAD metabolism modulates inflammation and mitochondria function in diabetic kidney disease.

Journal Article J Biol Chem · August 2023 Diabetes mellitus is the leading cause of cardiovascular and renal disease in the United -States. Despite the beneficial interventions available for patients with diabetes, there remains a need for additional therapeutic targets and therapies in diabetic k ... Full text Link to item Cite

In vivo metabolic imaging identifies lipid vulnerability in a preclinical model of Her2+/Neu breast cancer residual disease and recurrence.

Journal Article NPJ Breast Cancer · September 26, 2022 Recurrent cancer cells that evade therapy is a leading cause of death in breast cancer patients. This risk is high for women showing an overexpression of human epidermal growth factor receptor 2 (Her2). Cells that persist can rely on different substrates f ... Full text Link to item Cite

Statin therapy inhibits fatty acid synthase via dynamic protein modifications.

Journal Article Nat Commun · May 10, 2022 Statins are a class of drug widely prescribed for the prevention of cardiovascular disease, with pleiotropic cellular effects. Statins inhibit HMG-CoA reductase (HMGCR), which converts the metabolite HMG-CoA into mevalonate. Recent discoveries have shown H ... Full text Link to item Cite

Deglutarylation of glutaryl-CoA dehydrogenase by deacylating enzyme SIRT5 promotes lysine oxidation in mice.

Journal Article J Biol Chem · April 2022 A wide range of protein acyl modifications has been identified on enzymes across various metabolic processes; however, the impact of these modifications remains poorly understood. Protein glutarylation is a recently identified modification that can be none ... Full text Link to item Cite

Early-life mitochondrial DNA damage results in lifelong deficits in energy production mediated by redox signaling in Caenorhabditis elegans.

Journal Article Redox Biol · July 2021 The consequences of damage to the mitochondrial genome (mtDNA) are poorly understood, although mtDNA is more susceptible to damage resulting from some genotoxicants than nuclear DNA (nucDNA), and many environmental toxicants target the mitochondria. Report ... Full text Link to item Cite

Discovering the landscape of protein modifications.

Journal Article Molecular cell · May 2021 Protein modifications modulate nearly every aspect of cell biology in organisms, ranging from Archaea to Eukaryotes. The earliest evidence of covalent protein modifications was found in the early 20th century by studying the amino acid composition of prote ... Full text Cite

Sirtuin 5 Is Regulated by the SCFCyclin F Ubiquitin Ligase and Is Involved in Cell Cycle Control.

Journal Article Mol Cell Biol · January 25, 2021 The ubiquitin-proteasome system is essential for cell cycle progression. Cyclin F is a cell cycle-regulated substrate adapter F-box protein for the Skp1, CUL1, and F-box protein (SCF) family of E3 ubiquitin ligases. Despite its importance in cell cycle pro ... Full text Link to item Cite

Multiple metabolic changes mediate the response of Caenorhabditis elegans to the complex I inhibitor rotenone.

Journal Article Toxicology · January 15, 2021 Rotenone, a mitochondrial complex I inhibitor, has been widely used to study the effects of mitochondrial dysfunction on dopaminergic neurons in the context of Parkinson's disease. Although the deleterious effects of rotenone are well documented, we found ... Full text Link to item Cite

In Vivo Optical Metabolic Imaging of Long-Chain Fatty Acid Uptake in Orthotopic Models of Triple-Negative Breast Cancer.

Journal Article Cancers (Basel) · January 5, 2021 Targeting a tumor's metabolic dependencies is a clinically actionable therapeutic approach; however, identifying subtypes of tumors likely to respond remains difficult. The use of lipids as a nutrient source is of particular importance, especially in breas ... Full text Link to item Cite

A cell-nonautonomous mechanism of yeast chronological aging regulated by caloric restriction and one-carbon metabolism.

Journal Article J Biol Chem · 2021 Caloric restriction (CR) improves health span and life span of organisms ranging from yeast to mammals. Understanding the mechanisms involved will uncover future interventions for aging-associated diseases. In budding yeast, Saccharomyces cerevisiae, CR is ... Full text Link to item Cite

A cell-nonautonomous mechanism of yeast chronological aging regulated by caloric restriction and one-carbon metabolism.

Journal Article J Biol Chem · December 2, 2020 Caloric restriction (CR) improves health span and life span of organisms ranging from yeast to mammals. Understanding the mechanisms involved will uncover future interventions for aging-associated diseases. In budding yeast, Saccharomyces cerevisiae, CR is ... Full text Link to item Cite

β-Cell-specific ablation of sirtuin 4 does not affect nutrient-stimulated insulin secretion in mice.

Journal Article Am J Physiol Endocrinol Metab · October 1, 2020 Sirtuins are a family of proteins that regulate biological processes such as cellular stress and aging by removing posttranslational modifications (PTMs). We recently identified several novel PTMs that can be removed by sirtuin 4 (SIRT4), which is found in ... Full text Link to item Cite

Making data-driven hypotheses for gene functions by integrating dependency, expression, and literature data

Journal Article · July 17, 2020 AbstractIdentifying the key functions of human genes is a major biomedical research goal. While some genes are well-studied, most human genes we know little about. New tools in data science -- a combination of computer prog ... Full text Cite

NRF2 activation promotes the recurrence of dormant tumour cells through regulation of redox and nucleotide metabolism.

Journal Article Nat Metab · April 2020 The survival and recurrence of dormant tumour cells following therapy is a leading cause of death in cancer patients. The metabolic properties of these cells are likely distinct from those of rapidly growing tumours. Here we show that Her2 down-regulation ... Full text Link to item Cite

In vivo optical metabolic imaging of long-chain fatty acid uptake in orthotopic models of triple negative breast cancer

Journal Article · 2020 Targeting a tumor’s metabolic dependencies is a clinically actionable therapeutic approach, but identifying subtypes of tumors likely to respond remains difficult. The use of lipids as a nutrient source is of particular importance, especially in breast can ... Full text Cite

SIRT6 Promotes Hepatic Beta-Oxidation via Activation of PPARα.

Journal Article Cell Rep · December 17, 2019 The pro-longevity enzyme SIRT6 regulates various metabolic pathways. Gene expression analyses in SIRT6 heterozygotic mice identify significant decreases in PPARα signaling, known to regulate multiple metabolic pathways. SIRT6 binds PPARα and its response e ... Full text Link to item Cite

Investigating RNA expression profiles altered by nicotinamide mononucleotide therapy in a chronic model of alcoholic liver disease.

Journal Article Hum Genomics · December 10, 2019 BACKGROUND: Chronic alcohol consumption is a significant cause of liver disease worldwide. Several biochemical mechanisms have been linked to the initiation and progression of alcoholic liver disease (ALD) such as oxidative stress, inflammation, and metabo ... Full text Link to item Cite

Optical imaging reveals chemotherapy-induced metabolic reprogramming of residual disease and recurrence.

Journal Article Sci Adv · April 5, 2024 Fewer than 20% of triple-negative breast cancer patients experience long-term responses to mainstay chemotherapy. Resistant tumor subpopulations use alternative metabolic pathways to escape therapy, survive, and eventually recur. Here, we show in vivo, lon ... Full text Link to item Cite

NAD metabolism modulates inflammation and mitochondria function in diabetic kidney disease.

Journal Article J Biol Chem · August 2023 Diabetes mellitus is the leading cause of cardiovascular and renal disease in the United -States. Despite the beneficial interventions available for patients with diabetes, there remains a need for additional therapeutic targets and therapies in diabetic k ... Full text Link to item Cite

In vivo metabolic imaging identifies lipid vulnerability in a preclinical model of Her2+/Neu breast cancer residual disease and recurrence.

Journal Article NPJ Breast Cancer · September 26, 2022 Recurrent cancer cells that evade therapy is a leading cause of death in breast cancer patients. This risk is high for women showing an overexpression of human epidermal growth factor receptor 2 (Her2). Cells that persist can rely on different substrates f ... Full text Link to item Cite

Statin therapy inhibits fatty acid synthase via dynamic protein modifications.

Journal Article Nat Commun · May 10, 2022 Statins are a class of drug widely prescribed for the prevention of cardiovascular disease, with pleiotropic cellular effects. Statins inhibit HMG-CoA reductase (HMGCR), which converts the metabolite HMG-CoA into mevalonate. Recent discoveries have shown H ... Full text Link to item Cite

Deglutarylation of glutaryl-CoA dehydrogenase by deacylating enzyme SIRT5 promotes lysine oxidation in mice.

Journal Article J Biol Chem · April 2022 A wide range of protein acyl modifications has been identified on enzymes across various metabolic processes; however, the impact of these modifications remains poorly understood. Protein glutarylation is a recently identified modification that can be none ... Full text Link to item Cite

Early-life mitochondrial DNA damage results in lifelong deficits in energy production mediated by redox signaling in Caenorhabditis elegans.

Journal Article Redox Biol · July 2021 The consequences of damage to the mitochondrial genome (mtDNA) are poorly understood, although mtDNA is more susceptible to damage resulting from some genotoxicants than nuclear DNA (nucDNA), and many environmental toxicants target the mitochondria. Report ... Full text Link to item Cite

Discovering the landscape of protein modifications.

Journal Article Molecular cell · May 2021 Protein modifications modulate nearly every aspect of cell biology in organisms, ranging from Archaea to Eukaryotes. The earliest evidence of covalent protein modifications was found in the early 20th century by studying the amino acid composition of prote ... Full text Cite

Sirtuin 5 Is Regulated by the SCFCyclin F Ubiquitin Ligase and Is Involved in Cell Cycle Control.

Journal Article Mol Cell Biol · January 25, 2021 The ubiquitin-proteasome system is essential for cell cycle progression. Cyclin F is a cell cycle-regulated substrate adapter F-box protein for the Skp1, CUL1, and F-box protein (SCF) family of E3 ubiquitin ligases. Despite its importance in cell cycle pro ... Full text Link to item Cite

Multiple metabolic changes mediate the response of Caenorhabditis elegans to the complex I inhibitor rotenone.

Journal Article Toxicology · January 15, 2021 Rotenone, a mitochondrial complex I inhibitor, has been widely used to study the effects of mitochondrial dysfunction on dopaminergic neurons in the context of Parkinson's disease. Although the deleterious effects of rotenone are well documented, we found ... Full text Link to item Cite

In Vivo Optical Metabolic Imaging of Long-Chain Fatty Acid Uptake in Orthotopic Models of Triple-Negative Breast Cancer.

Journal Article Cancers (Basel) · January 5, 2021 Targeting a tumor's metabolic dependencies is a clinically actionable therapeutic approach; however, identifying subtypes of tumors likely to respond remains difficult. The use of lipids as a nutrient source is of particular importance, especially in breas ... Full text Link to item Cite

A cell-nonautonomous mechanism of yeast chronological aging regulated by caloric restriction and one-carbon metabolism.

Journal Article J Biol Chem · 2021 Caloric restriction (CR) improves health span and life span of organisms ranging from yeast to mammals. Understanding the mechanisms involved will uncover future interventions for aging-associated diseases. In budding yeast, Saccharomyces cerevisiae, CR is ... Full text Link to item Cite

A cell-nonautonomous mechanism of yeast chronological aging regulated by caloric restriction and one-carbon metabolism.

Journal Article J Biol Chem · December 2, 2020 Caloric restriction (CR) improves health span and life span of organisms ranging from yeast to mammals. Understanding the mechanisms involved will uncover future interventions for aging-associated diseases. In budding yeast, Saccharomyces cerevisiae, CR is ... Full text Link to item Cite

β-Cell-specific ablation of sirtuin 4 does not affect nutrient-stimulated insulin secretion in mice.

Journal Article Am J Physiol Endocrinol Metab · October 1, 2020 Sirtuins are a family of proteins that regulate biological processes such as cellular stress and aging by removing posttranslational modifications (PTMs). We recently identified several novel PTMs that can be removed by sirtuin 4 (SIRT4), which is found in ... Full text Link to item Cite

Making data-driven hypotheses for gene functions by integrating dependency, expression, and literature data

Journal Article · July 17, 2020 AbstractIdentifying the key functions of human genes is a major biomedical research goal. While some genes are well-studied, most human genes we know little about. New tools in data science -- a combination of computer prog ... Full text Cite

NRF2 activation promotes the recurrence of dormant tumour cells through regulation of redox and nucleotide metabolism.

Journal Article Nat Metab · April 2020 The survival and recurrence of dormant tumour cells following therapy is a leading cause of death in cancer patients. The metabolic properties of these cells are likely distinct from those of rapidly growing tumours. Here we show that Her2 down-regulation ... Full text Link to item Cite

In vivo optical metabolic imaging of long-chain fatty acid uptake in orthotopic models of triple negative breast cancer

Journal Article · 2020 Targeting a tumor’s metabolic dependencies is a clinically actionable therapeutic approach, but identifying subtypes of tumors likely to respond remains difficult. The use of lipids as a nutrient source is of particular importance, especially in breast can ... Full text Cite

SIRT6 Promotes Hepatic Beta-Oxidation via Activation of PPARα.

Journal Article Cell Rep · December 17, 2019 The pro-longevity enzyme SIRT6 regulates various metabolic pathways. Gene expression analyses in SIRT6 heterozygotic mice identify significant decreases in PPARα signaling, known to regulate multiple metabolic pathways. SIRT6 binds PPARα and its response e ... Full text Link to item Cite

Investigating RNA expression profiles altered by nicotinamide mononucleotide therapy in a chronic model of alcoholic liver disease.

Journal Article Hum Genomics · December 10, 2019 BACKGROUND: Chronic alcohol consumption is a significant cause of liver disease worldwide. Several biochemical mechanisms have been linked to the initiation and progression of alcoholic liver disease (ALD) such as oxidative stress, inflammation, and metabo ... Full text Link to item Cite

Loss of BCAA Catabolism during Carcinogenesis Enhances mTORC1 Activity and Promotes Tumor Development and Progression.

Journal Article Cell Metab · May 7, 2019 Tumors display profound changes in cellular metabolism, yet how these changes aid the development and growth of tumors is not fully understood. Here we use a multi-omic approach to examine liver carcinogenesis and regeneration, and find that progressive lo ... Full text Link to item Cite

Quantifying Competition among Mitochondrial Protein Acylation Events Induced by Ethanol Metabolism.

Journal Article J Proteome Res · April 5, 2019 Mitochondrial dysfunction is one of many key factors in the etiology of alcoholic liver disease (ALD). Lysine acetylation is known to regulate numerous mitochondrial metabolic pathways, and recent reports demonstrate that alcohol-induced protein acylation ... Full text Link to item Cite

Cellular energetics and mitochondrial uncoupling in canine aging.

Journal Article Geroscience · April 2019 The first domesticated companion animal, the dog, is currently represented by over 190 unique breeds. Across these numerous breeds, dogs have exceptional variation in lifespan (inversely correlated with body size), presenting an opportunity to discover lon ... Full text Link to item Cite

Respiratory Phenomics across Multiple Models of Protein Hyperacylation in Cardiac Mitochondria Reveals a Marginal Impact on Bioenergetics.

Journal Article Cell Rep · February 5, 2019 Acyl CoA metabolites derived from the catabolism of carbon fuels can react with lysine residues of mitochondrial proteins, giving rise to a large family of post-translational modifications (PTMs). Mass spectrometry-based detection of thousands of acyl-PTMs ... Full text Link to item Cite

Sensing Mitochondrial Acetyl-CoA to Tune Respiration.

Journal Article Trends Endocrinol Metab · January 2019 Fatty acid synthesis (FAS) in mitochondria produces a key metabolite called lipoic acid. However, a new study by Van Vranken et al.[1] (Mol. Cell 2018;71:567-580) shows that mitochondrial FAS regulates the assembly of oxidative phosphorylation complexes, t ... Full text Link to item Cite

Ablation of Sirtuin5 in the postnatal mouse heart results in protein succinylation and normal survival in response to chronic pressure overload.

Journal Article J Biol Chem · July 6, 2018 Mitochondrial Sirtuin 5 (SIRT5) is an NAD+-dependent demalonylase, desuccinylase, and deglutarylase that controls several metabolic pathways. A number of recent studies point to SIRT5 desuccinylase activity being important in maintaining cardiac function a ... Full text Link to item Cite

Remodeling of the Acetylproteome by SIRT3 Manipulation Fails to Affect Insulin Secretion or β Cell Metabolism in the Absence of Overnutrition.

Journal Article Cell Rep · July 3, 2018 SIRT3 is a nicotinamide adenine dinucleotide (NAD+)-dependent mitochondrial protein deacetylase purported to influence metabolism through post-translational modification of metabolic enzymes. Fuel-stimulated insulin secretion, which involves mitochondrial ... Full text Link to item Cite

Reactive Acyl-CoA Species Modify Proteins and Induce Carbon Stress.

Journal Article Trends Biochem Sci · May 2018 In recent years, our understanding of the scope and diversity of protein post-translational modifications (PTMs) has rapidly expanded. In particular, mitochondrial proteins are decorated with an array of acyl groups that can occur non-enzymatically. Intere ... Full text Link to item Cite

Reactive Acyl-CoA Species and Deacylation by the Mitochondrial Sirtuins

Chapter · April 25, 2018 The sirtuins are a family of nicotinamide adenine dinucleotide (NAD+)-dependent enzymes that remove acyl-lysine modifications from a variety of proteins, thereby controlling a myriad of cellular processes. In mitochondria, reactive acyl-CoA species lead to ... Full text Cite

Fructose and glucose can regulate mammalian target of rapamycin complex 1 and lipogenic gene expression via distinct pathways.

Journal Article J Biol Chem · February 9, 2018 Although calorically equivalent to glucose, fructose appears to be more lipogenic, promoting dyslipidemia, fatty liver disease, cardiovascular disease, and diabetes. To better understand how fructose induces lipogenesis, we compared the effects of fructose ... Full text Link to item Cite

Loss of sirtuin 4 leads to elevated glucose- and leucine-stimulated insulin levels and accelerated age-induced insulin resistance in multiple murine genetic backgrounds.

Journal Article J Inherit Metab Dis · January 2018 Several inherited metabolic disorders are associated with an accumulation of reactive acyl-CoA metabolites that can non-enzymatically react with lysine residues to modify proteins. While the role of acetylation is well-studied, the pathophysiological relev ... Full text Link to item Cite

Dietary Restriction and AMPK Increase Lifespan via Mitochondrial Network and Peroxisome Remodeling.

Journal Article Cell Metab · December 5, 2017 Mitochondrial network remodeling between fused and fragmented states facilitates mitophagy, interaction with other organelles, and metabolic flexibility. Aging is associated with a loss of mitochondrial network homeostasis, but cellular processes causally ... Full text Link to item Cite

Sirtuin 5 is required for mouse survival in response to cardiac pressure overload.

Journal Article J Biol Chem · December 1, 2017 In mitochondria, the sirtuin SIRT5 is an NAD+-dependent protein deacylase that controls several metabolic pathways. Although a wide range of SIRT5 targets have been identified, the overall function of SIRT5 in organismal metabolic homeostasis remains uncle ... Full text Link to item Cite

Metabolic control by sirtuins and other enzymes that sense NAD+, NADH, or their ratio.

Journal Article Biochim Biophys Acta Bioenerg · December 2017 NAD+ is a dinucleotide cofactor with the potential to accept electrons in a variety of cellular reduction-oxidation (redox) reactions. In its reduced form, NADH is a ubiquitous cellular electron donor. NAD+, NADH, and the NAD+/NADH ratio have long been kno ... Full text Link to item Cite

Mechanism-Based Inhibitors of the Human Sirtuin 5 Deacylase: Structure-Activity Relationship, Biostructural, and Kinetic Insight.

Journal Article Angew Chem Int Ed Engl · November 20, 2017 The sirtuin enzymes are important regulatory deacylases in a variety of biochemical contexts and may therefore be potential therapeutic targets through either activation or inhibition by small molecules. Here, we describe the discovery of the most potent i ... Full text Link to item Cite

daf-16/FoxO promotes gluconeogenesis and trehalose synthesis during starvation to support survival.

Journal Article Elife · October 24, 2017 daf-16/FoxO is required to survive starvation in Caenorhabditis elegans, but how daf-16IFoxO promotes starvation resistance is unclear. We show that daf-16/FoxO restructures carbohydrate metabolism by driving carbon flux through the glyoxylate shunt and gl ... Full text Link to item Cite

Chronic Ethanol Metabolism Inhibits Hepatic Mitochondrial Superoxide Dismutase via Lysine Acetylation.

Journal Article Alcohol Clin Exp Res · October 2017 BACKGROUND: Chronic ethanol (EtOH) consumption is a major cause of liver disease worldwide. Oxidative stress is a known consequence of EtOH metabolism and is thought to contribute significantly to alcoholic liver disease (ALD). Therefore, elucidating pathw ... Full text Link to item Cite

Nicotinamide mononucleotide requires SIRT3 to improve cardiac function and bioenergetics in a Friedreich's ataxia cardiomyopathy model.

Journal Article JCI Insight · July 20, 2017 Increasing NAD+ levels by supplementing with the precursor nicotinamide mononucleotide (NMN) improves cardiac function in multiple mouse models of disease. While NMN influences several aspects of mitochondrial metabolism, the molecular mechanisms by which ... Full text Link to item Cite

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

Journal Article Cell Metab · April 4, 2017 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 h ... Full text Link to item Cite

A Class of Reactive Acyl-CoA Species Reveals the Non-enzymatic Origins of Protein Acylation.

Journal Article Cell Metab · April 4, 2017 The mechanisms underlying the formation of acyl protein modifications remain poorly understood. By investigating the reactivity of endogenous acyl-CoA metabolites, we found a class of acyl-CoAs that undergo intramolecular catalysis to form reactive interme ... Full text Link to item Cite

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

Journal Article Nat Rev Nephrol · April 2017 The coenzyme nicotinamide adenine dinucleotide (NAD+) has key roles in the regulation of redox status and energy metabolism. NAD+ depletion is emerging as a major contributor to the pathogenesis of cardiac and renal diseases and NAD+ repletion strategies h ... Full text Link to item Cite

A Prob(e)able Route to Lysine Acylation.

Journal Article Cell Chem Biol · February 16, 2017 Non-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 ... Full text Link to item Cite

Progressive mitochondrial protein lysine acetylation and heart failure in a model of Friedreich's ataxia cardiomyopathy.

Journal Article PLoS One · 2017 INTRODUCTION: The childhood heart disease of Friedreich's Ataxia (FRDA) is characterized by hypertrophy and failure. It is caused by loss of frataxin (FXN), a mitochondrial protein involved in energy homeostasis. FRDA model hearts have increased mitochondr ... Full text Link to item Cite

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

Journal Article Cell Rep · November 1, 2016 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 increasi ... Full text Link to item Cite

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

Journal Article Toxicol Sci · August 2016 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 ... Full text Open Access Link to item Cite

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

Journal Article Curr Protoc Toxicol · August 1, 2016 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 ... Full text Link to item Cite

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

Journal Article Anesthesiology · June 2016 BACKGROUND: 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 th ... Full text Link to item Cite

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

Journal Article J Biol Chem · March 25, 2016 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 bo ... Full text Link to item Cite

Dysregulated metabolism contributes to oncogenesis.

Journal Article Semin Cancer Biol · December 2015 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 proce ... Full text Link to item Cite

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

Journal Article Semin Cancer Biol · December 2015 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 ... Full text Link to item Cite

Sirtuins

Chapter · September 28, 2015 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 expressi ... Full text Cite

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

Journal Article J Biol Chem · September 25, 2015 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 lon ... Full text Link to item Cite

SIRT3 regulates progression and development of diseases of aging.

Journal Article Trends Endocrinol Metab · September 2015 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 mitochond ... Full text Link to item Cite

Metabolic Regulation by Lysine Malonylation, Succinylation, and Glutarylation.

Journal Article Mol Cell Proteomics · September 2015 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, hav ... Full text Link to item Cite

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

Journal Article Mol Cell Proteomics · June 2015 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 ... Full text Link to item Cite

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

Journal Article Br J Cancer · March 3, 2015 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 ... Full text Link to item Cite

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

Journal Article British Journal of Cancer · March 3, 2015 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 ... Full text Cite

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

Journal Article Cell · February 26, 2015 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 modu ... Full text Link to item Cite

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

Journal Article J Lipid Res · December 2014 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 biologi ... Full text Link to item Cite

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

Journal Article Environ Health Perspect · December 2014 BACKGROUND: 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 the ... Full text Link to item Cite

SnapShot: Mammalian Sirtuins.

Journal Article Cell · November 6, 2014 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, SIR ... Full text Link to item Cite

Loss of Sirtuin 4 Leads to Insulin Resistance in Mice

Journal Article ENDOCRINE REVIEWS · June 1, 2014 Link to item Cite

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

Journal Article Mol Cell · April 10, 2014 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 modificat ... Full text Link to item Cite

Lysine glutarylation is a protein posttranslational modification regulated by SIRT5.

Journal Article Cell Metab · April 1, 2014 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 va ... Full text Link to item Cite

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

Journal Article Methods Enzymol · 2014 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 ... Full text Link to item Cite

Protein Acylation Regulates Metabolism

Conference Biophysical Journal · January 2014 Full text Cite

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

Journal Article PLoS One · 2014 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 fail ... Full text Open Access Link to item Cite

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

Journal Article J Biol Chem · November 22, 2013 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 stu ... Full text Link to item Cite

Preface

Journal Article Methods in Molecular Biology · September 20, 2013 Cite

Targeting sirtuins for the treatment of diabetes.

Journal Article Diabetes Manag (Lond) · May 1, 2013 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 ... Full text Link to item Cite

The sirtuins, oxidative stress and aging: an emerging link.

Journal Article Aging (Albany NY) · March 2013 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 ... Full text Link to item Cite

Whole-organism screening for gluconeogenesis identifies activators of fasting metabolism.

Journal Article Nat Chem Biol · February 2013 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 mo ... Full text Link to item Cite

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

Journal Article J Gerontol A Biol Sci Med Sci · February 2013 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 mitoch ... Full text Link to item Cite

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

Journal Article Science · January 11, 2013 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 endog ... Full text Link to item Cite

Whole-organism screening for gluconeogenesis identifies activators of fasting metabolism

Journal Article Nature Chemical Biology · 2013 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 mo ... Full text Cite

Oxygen flux analysis to understand the biological function of sirtuins.

Journal Article Methods Mol Biol · 2013 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 ... Full text Link to item Cite

Generating mammalian sirtuin tools for protein-interaction analysis.

Journal Article Methods Mol Biol · 2013 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 ... Full text Link to item Cite

Ethanol metabolism modifies hepatic protein acylation in mice.

Journal Article PLoS One · 2013 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 a ... Full text Link to item Cite

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

Journal Article Cell Metab · June 6, 2012 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 s ... Full text Link to item Cite

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

Journal Article J Proteome Res · March 2, 2012 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 unkn ... Full text Link to item Cite

Mitochondrial protein acetylation regulates metabolism.

Journal Article Essays Biochem · 2012 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 ... Full text Link to item Cite

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

Journal Article Aging (Albany NY) · January 2012 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 extend ... Full text Link to item Cite

Old enzymes, new tricks: sirtuins are NAD(+)-dependent de-acylases.

Journal Article Cell Metab · December 7, 2011 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 acti ... Full text Link to item Cite

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

Journal Article Mol Cell · October 21, 2011 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 ... Full text Link to item Cite

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

Journal Article Proc Natl Acad Sci U S A · August 30, 2011 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, fasti ... Full text Link to item Cite

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

Journal Article Aging (Albany NY) · June 2011 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 ... Full text Link to item Cite

SIRT3 regulates mitochondrial protein acetylation and intermediary metabolism.

Journal Article Cold Spring Harb Symp Quant Biol · 2011 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 ... Full text Link to item Cite

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

Journal Article Cell Metab · December 1, 2010 Featured Publication 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 s ... Full text Link to item Cite

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

Journal Article Cell Metab · December 1, 2010 Featured Publication 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 ame ... Full text Link to item Cite

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

Journal Article Trends Biochem Sci · December 2010 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 sirt ... Full text Link to item Cite

Mitochondrial sirtuins.

Journal Article Biochim Biophys Acta · August 2010 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 ... Full text Link to item Cite

Measuring fatty acid oxidation in tissue homogenates

Journal Article Protocol Exchange · April 15, 2010 Full text Cite

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

Journal Article Nature · March 4, 2010 Featured Publication 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 ... Full text Link to item Cite

Acetate metabolism and aging: An emerging connection.

Journal Article Mech Ageing Dev · 2010 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 cons ... Full text Link to item Cite

Acetylation of mitochondrial proteins.

Journal Article Methods Enzymol · 2009 Featured Publication 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, gl ... Full text Link to item Cite

Mammalian Sir2 homolog SIRT3 regulates global mitochondrial lysine acetylation.

Journal Article Mol Cell Biol · December 2007 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 sho ... Full text Link to item Cite

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

Journal Article J Biol Inorg Chem · July 2006 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-v ... Full text Link to item Cite

Preface

Journal Article MDCT: A Practical Approach · January 1, 2006 Full text Cite