Michael N. Sack, M.D., Ph.D.

Michael N. Sack, M.D., Ph.D.
Senior Investigator
Laboratory of Mitochondrial Biology and Metabolism

P: +1 301 402 9259
F: +1 301 402 0888
ms761k@nih.gov

In response to caloric intake, exertion, and stress, cells exquisitely regulate their energy production by controlling the content, turnover, and activity of their energy-generating organelles, mitochondria. To understand this facet of metabolic homeostasis, Dr. Sack is focusing on modifications of proteins that play pivotal roles in mitochondrial function, using approaches ranging from basic biochemistry to whole-animal physiology in transgenic mouse models. He is particularly interested in the maladaptive stress effects of excess caloric intake on mitochondrial function.

Many mitochondrial proteins are modified by the addition of acetyl groups that are a product of fat and glucose metabolism. In the liver, mitochondrial proteins are acetylated and deacetylated depending on nutrient levels. Dr. Sack is studying the mitochondrial “acetylome” to characterize the process of acetylation and deacetylation, identify key target proteins, and understand how they affect mitochondrial function. He and his colleagues have identified and functionally characterized the mitochondrial localization sequence of SIRT3 deacetylase, which protects against oxidative stress, and are extending their efforts to the counter-regulatory mitochondrial acetyltransferase molecular machinery. Using proteomic analyses, Dr. Sack has identified new targets of SIRT3 deacetylation and explored the effects of this modification on a novel target protein, mitochondrial aldehyde dehydrogenase 2.

A relationship between metabolic homeostasis and neurodegenerative disorders has been proposed in several contexts; perturbed lipid metabolism has long been associated with Parkinson's Disease. Dr. Sack has found that the E3-ubiquitin ligase Parkin—a product of the gene PARK2 which is associated with premature onset Parkinson's Disease—plays an unexpected and pivotal function in metabolic regulation through stabilization of the fatty acid translocase CD36. He and his colleagues have shown that deletion of Parkin impairs lipid uptake, resulting in fatty liver, insulin resistance, and reduced fat accumulation during adipogenesis.

Dr. Sack’s laboratory is now actively engaged in studying the mechanism by which Parkin modulates lipid biology, mitochondrial homeostasis, and stress susceptibility. Through the NIH Clinical Center, he is part of a clinical trial to study the effect of Parkin mutations on lipid biology, insulin sensitivity, and mitochondrial homeostasis. As part of the study, Dr. Sack and his colleagues use biopsy samples donated by clinical trial participants to develop cellular models of disease through induced pluripotent stem (iPS) cell technology. These models are not only important for testing mechanistic hypotheses, but also for testing candidate therapeutic interventions.

Ultimately, Dr. Sack’s goal is for his work on mitochondrial regulation to have an impact on the diseases that are part of the cascade caused by excess caloric intake leading to metabolic dysfunction in cells.