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

Laboratory of Mitochondrial Biology and Metabolism

Michael N. Sack, M.D., Ph.D.
Branch Chief
Laboratory of Mitochondrial Biology and Metabolism


Building 10-CRC Room 5-3150
10 Center Dr
Bethesda, MD 20892
P: +1 301 402 9259
F: +1 301 402 0888
ms761k@nih.gov


Background

Michael Sack graduated with his M.B.B.Ch. and M.Sc. from the University of Witwatersrand and earned his Ph.D. in 2000 from the University of Cape Town in South Africa. He did his internship at Johannesburg General Hospital and his internal medicine residency at Georgetown University Medical Center. He conducted cardiology research and did a clinical fellowship at Washington University Medical Center from 1994 to 1997. Dr. Sack joined the NHLBI in 2003. In 2012, he received the NHLBI’s Star Award for Excellence in Clinical Care for work at the Cardoza Community Clinic. Dr. Sack has authored or coauthored more than 80 papers, editorials, reviews, and book chapters. He currently sits on the editorial boards of the Journal of Molecular and Cellular Cardiology, American Journal of Physiology, Journal of Gerontology, and Drug Discovery Today. Dr. Sack is also a member of the American Society for Clinical Investigation and is a fellow with the American College of Physicians.

Research Interests

Dr. Sack’s laboratory focuses on modifications of proteins that play pivotal roles in metabolism and mitochondrial function to understand how these modifications affect disease risk. Perturbations in mitochondrial activity and energy balance can lead to diabetes and obesity, which influence cardiovascular disease (CVD) risk, as well as other disorders including Early Onset Parkinson Disease (EOPD).  

A relationship between metabolic homeostasis and neurodegenerative disorders has been proposed in several contexts and perturbed lipid metabolism has long been associated with Parkinson Disease. Dr. Sack has found that the E3-ubiquitin ligase Parkin—a product of the gene PARK2 which is frequently mutated in people  with EOPD —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 team is actively screening for and recruiting patients with EOPD to explore the mechanisms whereby PARK2 mutations can increase the susceptibility of individuals to Parkinson Disease. 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.

Additionally, as many mitochondrial proteins are modified by the addition of acetyl groups that are a product of fat and glucose metabolism, his laboratory explores acetyl modification in the context of diabetes and obesity. In the liver, mitochondrial proteins are acetylated and deacetylated depending on nutrient levels and the mitochondrial “acetylome” is being explored to 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’s laboratory has identified new targets of SIRT3 deacetylation and has identified an important regulatory component of the counter-regulatory acetyltransferase program. His group is actively exploring the role of these regulatory proteins in nutrient-excess associated disease.

Ultimately, Dr. Sack’s goal is for his work on metabolic and mitochondrial homeostasis programs to understand how these intracellular pathways modify disease susceptibility and to identify new ‘targets’ to modify in the prevention and reversal of disease.

 

Selected Publications

Identification of a molecular component of the mitochondrial acetyltransferase programme: a novel role for GCN5L1.
Scott I, Webster BR, Li JH, Sack MN.
Biochem. J. 2012 May 1;443(3):655-61.
[Text Abstract on PubMed]

Platelet mitochondrial dysfunction is evident in type 2 diabetes in association with modifications of mitochondrial anti-oxidant stress proteins.
Avila C, Huang RJ, Stevens MV, Aponte AM, Tripodi D, Kim KY, Sack MN.
Exp. Clin. Endocrinol. Diabetes. 2012 Apr;120(4):248-51.
[Text Abstract on PubMed]

Parkin is a lipid-responsive regulator of fat uptake in mice and mutant human cells.
Kim KY, Stevens MV, Akter MH, Rusk SE, Huang RJ, Cohen A, Noguchi A, Springer D, Bocharov AV, Eggerman TL, Suen DF, Youle RJ, Amar M, Remaley AT, Sack MN.
J. Clin. Invest. 2011 Sep;121(9):3701-12.
[Text Abstract on PubMed]

SIRT3-dependent deacetylation exacerbates acetaminophen hepatotoxicity.
Lu Z, Bourdi M, Li JH, Aponte AM, Chen Y, Lombard DB, Gucek M, Pohl LR, Sack MN.
EMBO Rep. 2011 Aug;12(8):840-6.
[Text Abstract on PubMed]

Characterization of the murine SIRT3 mitochondrial localization sequence and comparison of mitochondrial enrichment and deacetylase activity of long and short SIRT3 isoforms.
Bao J, Lu Z, Joseph JJ, Carabenciov D, Dimond CC, Pang L, Samsel L, McCoy, Leclerc J, Nguyen P, Gius D, Sack MN.
J. Cell. Biochem. 2010 May;110(1):238-47.
[Text Abstract on PubMed]

Michael N. Sack's Full List of Publications

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December 23, 2013
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AAAS council elects 388 new AAAS FellowsExternal link Disclaimer
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Last Updated: February 14, 2014

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