MITOCHONDRIAL DYSFUNCTION IN DIABETIC CARDIOMYOPATHY

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Diabetic cardiomyopathy is a leading cause of death among diabetics. Mechanistically, loss of mitochondrial function likely plays a role in the progression of the disease due to bioenergetic deficits and increased free radical production. Oxidative stress can be further exacerbated by metabolic conditions that result from diabetes. For example, elevated free fatty acids inhibit glycolysis and mitochondrial oxidative phosphorylation by non fatty acid carbon sources (Randle cycle). A constant, rigid, utilization of fatty acids may promote sustained increased free radical production during hyperglycemic conditions because fatty acid oxidation generates more free radicals relative to other oxidizable substrates. Importantly, the Randle cycle may be disrupted by activation of cAMP-dependent protein kinase (PKA), suggesting endogenous means of alleviating metabolic stress that are present may be compromised. Using a genetic model of type 1 diabetes (OVE26 mice), we have begun examining the longitudinal effects of the disease on cardiac mitochondria and PKA signaling. Our results indicate a rigid reliance of cardiac mitochondria from OVE26 mice on fatty acid oxidation for supporting energy production. Importantly, we have also found that PKA protein levels and activity are decreased in hearts of OVE26 mice. Based on these observations we hypothesize: Under hyperglycemic conditions, mitochondrial reliance on fatty acid oxidation increases oxidative stress. Reliance on fatty acids as an energy source is exacerbated by oxidative inactivation and loss of PKA signaling. Prolonged oxidative stress, coupled with loss of PKA activity, contributes to diabetic cardiomyopathy. This hypothesis will be tested using a genetic model of type 1 diabetes (OVE26 mice), cell culture, and protein biochemistry by the following specific aims. Aim 1. Mechanistically determine the alterations in mitochondrial function that occur with the progression of diabetic cardiomyopathy. The hypothesis is that increased oxidative stress associated with hyperglycemia is a function, in part, of rigid utilization of fatty acids with concomitant decreases respiratory activity. Biochemical studies, proteomic analysis, and cardiac structure/function analysis using MRI will be performed to test this hypothesis. Aim 2. Define the molecular mechanisms that lead to deficits in PKA activity and content as induced by hyperglycemia. We hypothesize that the increased oxidative stress promotes PKA oxidation, inactivation, and degradation. This loss of PKA activity then contributes to further oxidative stress via sustained and rigid utilization of fatty acid oxidation. Aim 3. The goal of this aim is to define the causal link between decreased PKA signaling, diminished mitochondrial function, increased oxidative stress, and diabetic cardiomyopathy. Studies will be performed to determine how insulin supplementation or activation of PKA restores metabolic pliability. It is hypothesized that sustaining PKA signaling will sustain mitochondrial function and attenuate the progression of diabetic cardiomyopathy.