Matthew Hirschey

Overview:

The Hirschey Lab in the Duke Molecular Physiology Institute, and the Departments of Medicine and Pharmacology & Cancer Biology at Duke University studies different aspects of metabolic control, mitochondrial signaling, and cellular processes regulating human health and disease.

Positions:

Associate Professor of Medicine

Medicine, Endocrinology, Metabolism, and Nutrition
School of Medicine

Associate Professor in Pharmacology and Cancer Biology

Pharmacology & Cancer Biology
School of Medicine

Member of Sarah W. Stedman Nutrition and Metabolism Center

Sarah Stedman Nutrition & Metabolism Center
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 2006

University of California - Santa Barbara

Grants:

The role of NRF2 in breast cancer dormancy and recurrence

Administered By
Pharmacology & Cancer Biology
Awarded By
National Institutes of Health
Role
Collaborator
Start Date
End Date

The Role of Acetylation in Regulating Iron-Sulfur Cluster Biogenesis

Administered By
Sarah Stedman Nutrition & Metabolism Center
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

In Vivo Modeling of Mitochondrial Complex I Deficiency in Retinal Ganglion Cells

Administered By
Ophthalmology
Awarded By
National Institutes of Health
Role
Advisor
Start Date
End Date

Glenn Award for Research in Biological Mechanisms of Aging

Administered By
Duke Molecular Physiology Institute
Awarded By
Glenn Foundation for Medical Research
Role
Principal Investigator
Start Date
End Date

Systemic, maternal and transgenerational effects of nutrient stress

Administered By
Biology
Awarded By
National Institutes of Health
Role
Collaborator
Start Date
End Date

Publications:

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

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. Reports from the toxicological literature suggest that exposure to early-life mitochondrial damage could lead to deleterious consequences later in life (the "Developmental Origins of Health and Disease" paradigm), but reports from other fields often report beneficial ("mitohormetic") responses to such damage. Here, we tested the effects of low (causing no change in lifespan) levels of ultraviolet C (UVC)-induced, irreparable mtDNA damage during early development in Caenorhabditis elegans. This exposure led to life-long reductions in mtDNA copy number and steady-state ATP levels, accompanied by increased oxygen consumption and altered metabolite profiles, suggesting inefficient mitochondrial function. Exposed nematodes were also developmentally delayed, reached smaller adult size, and were rendered more susceptible to subsequent exposure to chemical mitotoxicants. Metabolomic and genetic analysis of key signaling and metabolic pathways supported redox and mitochondrial stress-response signaling during early development as a mechanism for establishing these persistent alterations. Our results highlight the importance of early-life exposures to environmental pollutants, especially in the context of exposure to chemicals that target mitochondria.
Authors
Hershberger, KA; Rooney, JP; Turner, EA; Donoghue, LJ; Bodhicharla, R; Maurer, LL; Ryde, IT; Kim, JJ; Joglekar, R; Hibshman, JD; Smith, LL; Bhatt, DP; Ilkayeva, OR; Hirschey, MD; Meyer, JN
MLA Citation
Hershberger, Kathleen A., et al. “Early-life mitochondrial DNA damage results in lifelong deficits in energy production mediated by redox signaling in Caenorhabditis elegans.Redox Biol, vol. 43, July 2021, p. 102000. Pubmed, doi:10.1016/j.redox.2021.102000.
URI
https://scholars.duke.edu/individual/pub1482924
PMID
33993056
Source
pubmed
Published In
Redox Biology
Volume
43
Published Date
Start Page
102000
DOI
10.1016/j.redox.2021.102000

Discovering the landscape of protein modifications.

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 proteins by chemical hydrolysis. These discoveries challenged what defined a canonical amino acid. The advent and rapid adoption of mass-spectrometry-based proteomics in the latter part of the 20th century enabled a veritable explosion in the number of known protein modifications, with more than 500 discrete modifications counted today. Now, new computational tools in data science, machine learning, and artificial intelligence are poised to allow researchers to make significant progress in discovering new protein modifications and determining their function. In this review, we take an opportunity to revisit the historical discovery of key post-translational modifications, quantify the current landscape of covalent protein adducts, and assess the role that new computational tools will play in the future of this field.
Authors
Keenan, EK; Zachman, DK; Hirschey, MD
MLA Citation
Keenan, E. Keith, et al. “Discovering the landscape of protein modifications.Mol Cell, vol. 81, no. 9, May 2021, pp. 1868–78. Pubmed, doi:10.1016/j.molcel.2021.03.015.
URI
https://scholars.duke.edu/individual/pub1478130
PMID
33798408
Source
pubmed
Published In
Mol Cell
Volume
81
Published Date
Start Page
1868
End Page
1878
DOI
10.1016/j.molcel.2021.03.015

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

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 progression, identifying cyclin F-bound SCF complex (SCFCyclin F) substrates has remained challenging. Since cyclin F overexpression rescues a yeast mutant in the cdc4 gene, we considered the possibility that other genes that genetically modify cdc4 mutant lethality could also encode cyclin F substrates. We identified the mitochondrial and cytosolic deacylating enzyme sirtuin 5 (SIRT5) as a novel cyclin F substrate. SIRT5 has been implicated in metabolic processes, but its connection to the cell cycle is not known. We show that cyclin F interacts with and controls the ubiquitination, abundance, and stability of SIRT5. We show SIRT5 knockout results in a diminished G1 population and a subsequent increase in both S and G2/M. Global proteomic analyses reveal cyclin-dependent kinase (CDK) signaling changes congruent with the cell cycle changes in SIRT5 knockout cells. Together, these data demonstrate that SIRT5 is regulated by cyclin F and suggest a connection between SIRT5, cell cycle regulation, and metabolism.
Authors
Mills, CA; Wang, X; Bhatt, DP; Grimsrud, PA; Matson, JP; Lahiri, D; Burke, DJ; Cook, JG; Hirschey, MD; Emanuele, MJ
MLA Citation
Mills, Christine A., et al. “Sirtuin 5 Is Regulated by the SCFCyclin F Ubiquitin Ligase and Is Involved in Cell Cycle Control.Mol Cell Biol, vol. 41, no. 2, Jan. 2021. Pubmed, doi:10.1128/MCB.00269-20.
URI
https://scholars.duke.edu/individual/pub1464375
PMID
33168699
Source
pubmed
Published In
Molecular and Cellular Biology
Volume
41
Published Date
DOI
10.1128/MCB.00269-20

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

<jats:title>Abstract</jats:title><jats:p>Identifying 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 programming, math &amp; statistics, and topical expertise -- combined with the rapid adoption of open science and data sharing allow scientists to access publicly available datasets and interrogate these data <jats:italic>before</jats:italic> performing any experiments. We present here a new research tool called data-driven hypothesis (DDH) for predicting pathways and functions for thousands of genes across the human genome. Importantly, this method integrates gene essentiality, gene expression, and literature mining to identify candidate molecular functions or pathways of known and unknown genes. Beyond single gene queries, DDH can uniquely handle queries of defined gene ontology pathways or custom gene lists containing multiple genes. The DDH project holds tremendous promise to generate hypotheses, data, and knowledge in order to provide a deep understanding of the dynamic properties of mammalian genes. We present this tool via an intuitive online interface, which will provide the scientific community a platform to query and prioritize experimental hypotheses to test in the lab.</jats:p>
Authors
MLA Citation
Hirschey, Matthew D. Making data-driven hypotheses for gene functions by integrating dependency, expression, and literature data. Cold Spring Harbor Laboratory. Crossref, doi:10.1101/2020.07.17.208751.
URI
https://scholars.duke.edu/individual/pub1465179
Source
crossref
DOI
10.1101/2020.07.17.208751

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

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 that young adult Caenorhabditis elegans showed resistance to 24 and 48 h rotenone exposures. To better understand the response to rotenone in C. elegans, we evaluated mitochondrial bioenergetic parameters after 24 and 48 h exposures to 1 μM or 5 μM rotenone. Results suggested upregulation of mitochondrial complexes II and V following rotenone exposure, without major changes in oxygen consumption or steady-state ATP levels after rotenone treatment at the tested concentrations. We found evidence that the glyoxylate pathway (an alternate pathway not present in higher metazoans) was induced by rotenone exposure; gene expression measurements showed increases in mRNA levels for two complex II subunits and for isocitrate lyase, the key glyoxylate pathway enzyme. Targeted metabolomics analyses showed alterations in the levels of organic acids, amino acids, and acylcarnitines, consistent with the metabolic restructuring of cellular bioenergetic pathways including activation of complex II, the glyoxylate pathway, glycolysis, and fatty acid oxidation. This expanded understanding of how C. elegans responds metabolically to complex I inhibition via multiple bioenergetic adaptations, including the glyoxylate pathway, will be useful in interrogating the effects of mitochondrial and bioenergetic stressors and toxicants.
Authors
Gonzalez-Hunt, CP; Luz, AL; Ryde, IT; Turner, EA; Ilkayeva, OR; Bhatt, DP; Hirschey, MD; Meyer, JN
MLA Citation
Gonzalez-Hunt, Claudia P., et al. “Multiple metabolic changes mediate the response of Caenorhabditis elegans to the complex I inhibitor rotenone.Toxicology, vol. 447, Jan. 2021, p. 152630. Pubmed, doi:10.1016/j.tox.2020.152630.
URI
https://scholars.duke.edu/individual/pub1465328
PMID
33188857
Source
pubmed
Published In
Toxicology
Volume
447
Published Date
Start Page
152630
DOI
10.1016/j.tox.2020.152630

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