Mitochondrial dynamics in diabetic cardiomyopathy

Diabetic cardiomyopathy (DCM) is associated with metabolic changes and oxidative stress, indicating abnormalities in mitochondrial function. Mitochondrial morphology is now recognized as an important factor in regulating mitochondrial function. However, the role of mitochondrial morphology in DCM pathology is not understood. Mitochondrial morphology is mainly controlled by fission and fusion. DLP1/Drp1 mediates fission, whereas mitofusin and OPA1 mediate fusion of the outer and inner membranes, respectively. OPA1 is also known to function in inner membrane maintenance and thus energetic activity. OPA1 exists in full length, L-OPA1, and proteolytically cleaved forms, S-OPA1. However, the respective roles of L- and S-OPA1 in regulating mitochondrial fusion and energetic activity are ill-defined. We observed a delay in the appearance of dysfunctional mitochondria in diabetic hearts, suggesting a pathological transition in DCM progression. We also observed that mitochondrial dysfunction accompanies increased cleavage of OPA1 in diabetic hearts. We hypothesize that mitochondrial dynamics is an integral component of DCM progression, in which increased OPA1 cleavage exacerbates DCM pathology. Two specific aims of this proposal are: (1) To identify the pathological transition point at which dysfunctional mitochondria emerge during DCM progression and demonstrate mitochondrial fission as a novel target for ameliorating DCM pathology, and (2) to test the hypothesis that OPA1 cleavage during pathological transition sensitizes cardiac cells to further damage, exacerbating DCM pathology. These studies will use the mouse model of type 1 diabetes in normal and fission inhibitory transgenic mice, as well as cell culture models differentially expressing L- and S-OPA1. By examining changes in mitochondrial structure and energetics in diabetic hearts, this proposal will identify pathological transition point in DCM progression, which can be a useful marker for determining the effective therapeutic window. This proposal will also provide better understanding and mechanistic insight as to the function of OPA1 in structural and energetic regulation of mitochondria and its contribution to DCM pathology. (AHA Program: Grant-in-Aid)