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The Department of Biomedicine

BBB seminar: Michael N. Sack

The divergent regulation of mitochondrial function in modulating cardiac resistance to ischemic stress and in the development of skeletal muscle insulin resistance

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Michael N. Sack
Cardiology Branch, NHLBI, National Institutes of Health, Bethesda, MD, USA

The resurgence of investigation into mitochondrial biology stems, in part, from the realization that the regulation of mitochondrial content, turnover and function to maintain diverse homeostatic demands are driven by exquisite biochemical and molecular control. Globally, this regulatory control can be termed the mitochondrial biogenesis regulatory program. ‘Fine-tuning' of this biogenesis promotes resilience of mitochondria and hence cellular susceptibility to ischemia-reperfusion injury and to oxidative stress. Conversely, disruption of mitochondrial homeostasis is proposed to orchestrate the development of insulin-resistance, thereby increasing risk of cardiovascular disease.

The focus of this seminar will be to present data from our laboratory investigating the molecular and cellular mechanisms governing mitochondrial biology that result in the augmentation of cardiac ischemia-tolerance and to delay/reverse the effects of the cardio-metabolic syndrome. The biological insights obtained in the laboratory are then translated to evaluate their potential roles in human disease.

In the heart, the predominant roles of mitochondria pertain to oxidative phosphorylation, calcium homeostasis, reactive radical species biology and intrinsic apoptosis. Collectively, these functions would support a central role of mitochondria in modifying cardiac tolerance to ischemic injury. This is exemplified in ‘ischemic preconditioning', the cell-survival program initiated by non-lethal ischemic or oxidative stress signaling, where mitochondria show enhanced resilient to ischemia-reperfusion. We are ‘exploiting' ischemic preconditioning to identify signaling and molecular regulatory events modulating cellular tolerance to ischemia-reperfusion injury with specific focus on the regulatory control of mitochondrial biogenesis, oxidative phosphorylation and on the control of reactive radical biology. Our work on the uncoupling proteins and electron transfer functional modulation will be discussed in this context.

In stark contrast to the ‘optimized' mitochondrial function intrinsic to ischemic preconditioning, insulin-resistance associated with diabetes and obesity, is accompanied by the disruption of mitochondrial biology, at least in part, due to perturbed regulatory control of mitochondrial biogenesis. Diabetes and obesity in-turn are the fastest growing cardiac risk factors. We have begun to evaluate mitochondria in insulin-resistance as a strategy to identify novel modulators of mitochondrial dysregulation. Our work on the regulation of the mitochondrial biogenesis program in insulin resistance muscle cells as well as its relevance in human diabetic subjects will be discussed.

Host: Anne Jonassen, Department of Biomedicine