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The Diabetic Heart: Examination of the Inner Mitochondrial Membrane Tara L. Croston Cardiovascular complications, such as diabetic cardiomyopathy, are the primary cause of morbidity and mortality in patients with diabetes mellitus. The hyperglycemic environment associated with diabetes mellitus has been shown to induce the mitochondrial dysfunction contributing to diabetic cardiomyopathy. The examination of mitochondrial function is further complicated by the existence of two spatially and functionally distinct cardiac mitochondrial subpopulations, the subsarcolemmal (SSM) interfibrillar (IFM) mitochondria. These two pools of mitochondria respond differently to pathologic stimuli, such as diabetes mellitus. Targeted by the deleterious effects of diabetes mellitus, the inner mitochondrial membrane (IMM) is composed of a specific lipid environment that houses many critical processes and machinery required for proper mitochondrial function. The impact of diabetes mellitus on the IMM, including the lipids and processes housed within, is not completely understood in type 1 diabetic setting, and has not been assessed in mitochondrial subpopulations from type 2 diabetic human heart. The goal of the studies included in this dissertation was to understand the importance of IMM preservation during diabetes mellitus and to translate rodent mitochondrial dysfunction that occurs during diabetic cardiomyopathy to the human diabetic heart. FVB mice (20-25 grams) were made type 1 diabetic through multiple low dose injections of streptozotocin (STZ) for five consecutive days. Five weeks post diabetic onset, hearts were excised and mitochondrial subpopulations were isolated. For the type 2 diabetic human population, right atrial appendages were excised during coronary artery bypass grafting or valve replacement surgery, from which mitochondrial subpopulations were isolated. Cardiolipin, an essential phospholipid contained within the IMM, was shown to be decreased during a type 1 diabetic insult; however the mechanism attributing to this decrease in unknown; therefore, the cardiolipin biosynthetic pathway was evaluated in the type 1 diabetic mouse model. Results indicated decreased cardiolipin synthase protein content and activity in the diabetic IFM. The data also revealed a decrease in two critical cardiolipin-ATP synthase associations, which could potentially contribute to the observed decreased ATP synthase activity in the diabetic IFM, all of which are located in the IMM. Within the type 1 diabetic mouse model, a key constituent involved in protein import, glucose regulated protein 75, has been reported to be decreased and when overexpressed, preliminary data depicted mitochondrial functional restoration in the diabetic IFM. Mitochondrial dysfunction, as evidenced by decreased state 3 mitochondrial respiration, as well as decreased electron transport chain complex I and complex IV activity was observed in the SSM of type 2 diabetic human heart, compared to the non-diabetic heart. These results suggest for the first time, that mitochondrial dysfunction is present in the type 2 diabetic human heart and that SSM impacted to a greater extent than IFM. Taken together, the results of these studies demonstrate the importance of preserving the IMM structure to alleviate mitochondrial dysfunction associated with the diabetic heart, as well as understanding the effect of diabetes mellitus on human cardiac mitochondrial subpopulations. Further, the preliminary results highlight therapeutic strategies involving protein import constituents on the ability to attenuate mitochondrial dysfunction that occurred during a diabetic insult.