Matthew Hirschey, PhD

Faculty Member, Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center


Associate Professor, Departments of Medicine, Division of Endocrinology, Metabolism, and Nutrition,
and  Pharmacology and Cancer Biology


Carmichael Building

919 479 2315


Matthew Hirschey is an Assistant Professor in the Departments of Medicine (Division of Endocrinology, Metabolism and Nutrition) and Pharmacology & Cancer Biology at Duke University Medical Center and a faculty member of the Sarah W. Stedman Nutrition and Metabolism Center and the newly formed Duke Molecular Physiology Institute. His research focuses on mitochondrial metabolism, with a particular interest in how cells use metabolites and chemical modifications to sense metabolism. He and his lab study the regulation of this process by a family of enzymes called sirtuins, and how sirtuins maintain energy homeostasis. His work has appeared in several leading journals, including Nature, Science, Cell Metabolism and Molecular Cell. He has received several awards including an Innovator Award from the American Heart Association, a New Scholar in Aging Award from the Ellison Medical Foundation, and the Helmholtz Young Investigator in Diabetes (HeIDi) Award. His work is supported by grants from the American Heart Association, the Mallinckrodt Foundation, Friedreich's Ataxia Research Alliance, the Ellison Medical Foundation, and the National Institutes of Health. 

BSc University of Vermont, Burlington, VT
PhD, Chemistry and Biochemistry, University of California, Santa Barbara 

The Hirschey laboratory explores different aspects of mitochondrial function, a crucial sub-cellular organelle that is gaining increasing recognition as a regulator of human health. Mitochondrial dysfunction is correlated with several disease states. However, mitochondria perform several functions, including synthesis, degradation, fission/fusion, signaling and ATP production. Thus, before we can understand how mitochondrial dysfunction contributes to disease, we need to better understand the myriad of processes performed by the mitochondria, and how they are regulated. 

Protein acetylation is a highly abundant post-translational modification in the mitochondria. 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 (1). Mitochondrial protein acetylation levels are primarily regulated by sirtuin 3 (SIRT3), a member of the sirtuin family of NAD+-dependent protein deacetylases. We identified an important regulatory role for SIRT3 as a key modulator of energy homeostasis (2). In the absence of SIRT3, mitochondrial proteins become hyperacetylated, have altered function, and lead to mitochondrial dysfunction (3). We are currently studying acetylated mitochondrial proteins, their regulation by SIRT3, and further defining the role of protein acetylation in mitochondrial function.

In an extension from the above project, we are exploring the regulatory role for novel post-translational modifications (4). We are working to identify mitochondrial proteins that are modified, their regulation, and further defining nutrient integration and signaling into mitochondrial function. In one example, we independently discovered a new protein modification called glutarylation, and its regulation by the sirtuin SIRT5 (5). We found several proteins are glutarlyated, have altered function, and can be rescued by SIRT5-catalyzed deglutarylation. We are working to understand this new modification, and its importance in mitochondrial biology.

Finally, mitochondrial dysfunction is correlated with several types of disease states, including diabetes and obesity, cardiovascular disease, cancer, and other diseases of aging. Leveraging the sirtuins as tools to manipulate metabolism, we are studying how altered mitochondrial metabolism contributes to these disease states the aging process itself.


Kristin Anderson, PhD


Zhihong Lin

Darren Stuart

Postdocs / Fellows

Russell Ericksen, PhD

Derek Zackman, MD

Graduate/Medical Students

Keith Keenan

Alec Trub