Project Summary The insulin-secreting pancreatic beta cell is a highly metabolic cell type and its dysfunction is a main cause of diabetes pathogenesis. The beta cell is reliant on mitochondrial function and energy production for glucose- stimulated insulin secretion. Mitochondrial ATP production is accomplished by 5 multi-subunit complexes of the oxidative phosphorylation (OXPHOS) system. The increase in the ATP:ADP ratio in the beta cell cytosol is the triggering signal for insulin release. Although a net decrease in ATP production would have an impact on beta cell function and insulin secretion, the impact of individual OXPHOS complex defects on beta cell biology and function remains unknown. Indeed, there are a broad spectrum of human diseases caused by defects in individual OXPHOS complexes ranging from neurodegeneration to cardiomyopathies, including maternally- inherited diabetes, suggesting a diverse range of downstream pathomechanisms. Therefore, the objective of this proposal is to elucidate the impact of three individual OXPHOS complexes (Complex I, III, and IV) in the context of the pancreatic beta cell. The hypothesis is that defects in individual OXPHOS complexes will result in distinct signaling pathway changes that will alter beta cell biology. Based on preliminary data, it is also hypothesized that Complex III deficient islets develop a severe hyperglycemic phenotype due to increased production of reactive oxygen species and oxidative stress. This proposal and training plan will provide the applicant with an excellent training environment with two recognized experts in islet physiology and mitochondrial diseases as co-mentors. Being a collaboration between two laboratories will allow the applicant ample opportunities to broaden her knowledge of a new research area, learn new scientific models and technical skills, enhance her critical thinking and rigorous experimental design, and set the stage to translate research questions to human pancreatic samples.