Mitochondrial dynamics in beta cell function and dysfunction

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DESCRIPTION (provided by applicant): Mitochondria play a key role as b-cell nutrient integrators. One of the manifestations of diabetes is the gradual reduction in mitochondrial capacity to produce signals in response to fuels. The cause of this gradual deterioration is not yet understood. The goal of this study is to determine the mechanism of deterioration in mitochondrial function during development of b-cell dysfunction and diabetes. This study takes advantage of our recent findings in b-cell models of diabetes demonstrating the appearance of an inactive subpopulation of mitochondria within each individual cell accompanied by a drastic reduction in the ability of all mitochondria to interact through fusion and fission. We have found that induction of fusion and fission proteins in b-cells prevents the appearance of inactive units, promotes larger webs and leads to Functional homogeneity. Fusion and fission events, together termed "mitochondrial dynamics" (MtDy), have been shown in other cell types to be essential for bioenergetic performance and Ca2+ delivery throughout the mitochondrial web. Moreover, MtDy has been shown to control the propagation of ROS induced apoptotic signaling across the mitochondria) network. We have developed methods that allow us to label and track individual mitochondria, observe fusion and fission events, and quantify the mitochondrial network, while simultaneously monitoring mitochondrial membrane potential. Our preliminary studies demonstrate that b-cells have high mitochondrial networking activity manifested by frequent fusion and fission. Moreover, following fission, mitochondria with compromised membrane potential are irreversibly segregated, suggesting that MtDy serve as a quality control mechanism. We hypothesize that mitochondrial fusion and fission serve to communicate glucose-induced metabolic signals through the mitochondrial web. Environmental factors that induce diabetes, such as glucolipotoxicity (GLT). impair MtDv. resulting in gradual deterioration of mitochondrial function that is manifested by the generation of a subpopulation of mitochondria with reduced levels of activity. We will: (A) Test the prediction that altering MtDy will affect b-cell responses to glucose and GLT in culture and in cells from diabetic animals; (B) Determine factors that regulate MtDy in b-cells and identify nutrition parameters and metabolic pathways that function as the mediators; and (C) Determine the role of MtDy in calcium delivery to mitochondria during glucose-stimulated insulin secretion, and in damage repair and quality control of the mitochondrial population within the b-cell under GLT. This study explores the mechanism of diabetes. It will test a new hypothesis for its pathophysiology and identify potential new drug targets for diabetes, obesity and metabolic syndrome.