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.


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Our research focuses on metabolism, with a particular interest in how cells use metabolites and chemical modifications to proteins in order to control these processes.

Our early work on metabolism and metabolic regulation began by looking at a new enzyme in the sirtuin family of NAD+-dependent protein deacetylases called SIRT3. At that time, protein acetylation was becoming increasingly recognized as an important post-translational modification, particularly in metabolic regulation; however, neither the metabolic consequence of mitochondrial protein hyperacetylation nor the specific role of SIRT3 was known. We published a series of papers describing the first biological role of SIRT3, in regulating lipid oxidation; the first mechanism by which acetylation regulated enzyme function, by changing protein conformation; and the consequence of SIRT3 ablation on whole-body metabolism, which accelerated the development of Metabolic Syndrome. Collectively, this body of work has positioned SIRT3 as a primary regulator of mitochondrial metabolism required for energy homeostasis, which continues to be a major focus of research in the sirtuin field today. Read more…

More recently, we have been focused on expanding our understanding of metabolic regulation by post-translational modifications beyond protein acetylation. New types of chemical moieties have been discovered on proteins. Therefore, we began looking for new protein modifications using the rationale that the different sirtuins might regulate different modifications. We recently discovered a new protein modification, never before described in biology, called glutarylation, which is regulated by the mitochondrial sirtuin SIRT5. These concepts are pushing the boundaries of knowledge as the landscape of acylation (referring to multiple ‘acyl’ groups on proteins) is rapidly expanding. Read more…


Different sirtuins with distinct enzymatic activities occupy separate phylogenetic sub-classes. Phylogenetic analysis of the sirtuins could be key to uncovering their enzymology

Acylation is emerging as a new class of lysine modifications, but the mechanisms of lysine acylation and how it influences cellular function are major unanswered questions. We recently identified a class of highly reactive intermediary metabolites that reveals the non-enzymatic mechanisms for wide-spread protein acylation and defines a new concept of endogenous chemical reactivity. Read more...

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An additional way that cells integrate nutrient sensing and metabolism to coordinate proper cellular responses to a particular nutrient source is through the epigenome. For example, glucose drives a gene expression program characterized by activating genes involved in its metabolism, in part, by increasing glucose-derived histone acetylation. Recently, we discovered that lipid-derived acetyl-CoA is a major source of carbon for histone acetylation. We developed a novel method combining 13C-carbon tracing with acetyl-proteomics to show that up to 90% of acetylation on certain histone lysines can be derived from fatty acid carbon. These studies expand the landscape of nutrient sensing and uncover how lipids and metabolism are integrated by epigenetic events that control gene expression. Read more...

Metabolic regulation by protein modifications is important for several physiological states. Dysregulated control of these processes is associated with diabetes and obesity, cardiovascular disease, cancer, inborn errors, and the aging process itself.  We are particularly interested in these disease states, and our overall objective is to better understand how altering metabolism could lead to new therapies to treat these human diseases. Read more… 

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