This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The Role of Complex I in Mitochondrial Dysfunction and Free Radical Production in Type 1 Diabetes. A leading cause of morbidity and mortality induced by diabetes is heart failure. Diabetes leads to a specific form of heart disease, termed diabetic cardiomyopathy, the causes of which are not completely understood. However, it is known that there are deficiencies in the processes that produce energy for cardiac tissue. These processes occur in distinct subcellular organelles called mitochondria. Loss of mitochondrial function leads to an increase in free radical production, which in turn generates an oxidative stres. The underlying mechanisms of mitochondrial dysfunction, and the role of free radicals in perpetuating diabetic cardiomyopathy are not well understood. The goal of the present project is to assess how mitochondrial function changes as a progression of type 1 diabetes using a genetically modified mouse that develops the disease at birth. Heart mitochondria from two-month-old mice (control and diabetic) are currently being evaluated. While this project is in early stages, the results are quite clear. Specifically, we have found that diabetic mice show no overt decrease in electron transport chain activity (which underlies the fundamental mechanism by which mitochondria produce energy). Furthermore, there is not a diabetes-induced increase in mitochondrial free radical production at this time point. Nevertheless, we have found clear differences in diabetic mitochondria as compared to controls. Specifically, mitochondria from diabetic mice have staggering limitations in the fuel sources they are able to utilize for energy production. They will only produce energy effectively using fatty acids, and have severe deficits in the ability to utilize pyruvate (an end product of glucose breakdown). Provocatively, the diabetic mitochondria also have severe deficits in the ability to produce energy using Krebs cycle intermediates (a central metabolic pathway carried out in the mitochondria). The significance of these findings will become clearer as the study progresses, but indicate significant impairments from an early stage. We anticipate future results of this study to provide important information regarding the molecular basis of the disease progression of type 1 diabetes. Specifically, this study will define the molecular aspects of mitochondrial energy production that are affected by the disease. In turn, this information will be used to determine the cause of increased free radical production and oxidative stress. This will address very fundamental questions. Specifically, how does mitochondrial dysfunction contribute to diabetic cardiomyopathy? Is mitochondrial dysfunction in the heart an early event in the progression of the disease? And, importantly, how can these defects be prevented? Results of this study will provide information about possible therapeutic targets to minimize the onset of diabetic cardiomyopathy and provide insight into improving pharmacological intervention using antioxidant therapy.
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