Mechanisms Underlying Mitrochondrial Dysfunction in the Diabetic Heart

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DESCRIPTION (provided by applicant): The mitochondrial network, as a source and victim of oxidative stress has become a dominant player at the origin of many important diseases, among which cardiomyopathy in diabetic and obese patients ranks as one of the most relevant. Our long-term goal is to identify the critical mechanistic steps involved in the production of mitochondrially-derived reactive oxygen (ROS) and nitrogen (RNS) species in common diseases, such as diabetes, obesity, and heart failure. In the emerging view of the mitochondrion as a key signaling organelle in which ROS and RNS fulfill critical physiological roles, we aim to achieve a more comprehensive and quantitative understanding of its role in the (patho)physiology of diabetes related metabolic, contractile, and electrical dysfunction. The main hypotheses of the current proposal are that: 1) Cardiac myocytes from diabetic animals are more susceptible to mitochondrial dysfunction caused by oxidative/nitrosative stress in response to hyperglycemia, and 2) the diabetic heart is more susceptible to the incidence of conduction disturbances, arrhythmias and contractile dysfunction because of its compromised metabolic status. We base our hypotheses on the following observations: 1) the mitochondrial network of a cardiomyocyte is extremely sensitive to environmental perturbations once a threshold level of ROS is attained, leading to a cell-wide collapse of the mitochondrial membrane potential (??m) and myocyte inexcitability; 2) ROS and RNS bioavailability are regulated through common mechanisms; 3) oscillations of ??m can be readily prevented by exogenous or endogenous ROS scavengers, or nitric oxide production inhibitors; 4) oscillations of mitochondrial energetics drive oscillations of surface KATP current and action potentials, affecting the incidence of post-ischemic arrhythmias and contractile dysfunction in the intact heart. PUBLIC HEALTH RELEVANCE: Diabetes is caused by a deficiency in the secretion or action of insulin, affecting >150 million individuals worldwide and nearly 6% of the US population. A recent study by the World Health Organization estimates that those numbers will grow to 366 million by 2030. Achieving the aims of the present study will lead to a better understanding of how mitochondrial dysfunction affects the incidence and severity of cardiac complications among diabetics, and will identify novel targets for therapeutic strategies against this common disease.