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In the context of diabetes, mitochondria are sensitive organelles that may play a central role in the development of the disease. Recent advances have placed the pancreatic ß-cell at the center of the picture, since dysfunction and/or loss of these insulin-secreting cells seem to be a prerequisite for any form of diabetes. The liver is another important organ that may adapt to pre-diabetic stage and also contribute to hyperglycemia once diabetes is established through unrepressed gluconeogenesis. How dysfunction of mitochondria in ß-cells and/or in hepatocytes would contribute to diabetes is still unclear. This calls for a better understanding of mitochondrial regulation in metabolically active tissues, in particular pancreatic ß-cells and liver hepatocytes. The present proposal aims at investigating the causality between mitochondrial defects and development of diabetes and will focus on two recently generated mouse models in which Prohibitin-2 and the Mitochondrial Pyruvate Carrier are deleted, targeting mitochondrial dynamics and metabolic activation, respectively.The consortium members will team up to investigate the causal interplay from multiple angles and with multiple approaches that build on the expertise of the partner labs. Specifically, two groups will focus on the mouse models to investigate the systemic response to specific mitochondrial perturbations. A third group will use cell culture systems to perform a thorough characterization in tissue cultures under controlled conditions that will deliver a more detailed description of cellular responses to mitochondrial insults. Numerous interactions between labs are cemented in the specific aims to promote synergistic interactions. The multidisciplinary team brings together all of the experimental and theoretical apparatus necessary to address these general aims, including murine models, appropriate cell lines, wet-lab facilities, biochemical assays, metabolomics, flux analysis with stable isotopes, and mathematical modeling. It should be pointed out that the present consortium brings together complementary expertise in mitochondrial research.As a result of this research, we will obtain a quantitative analysis of the metabolic activity in standard cell lines, MEFs from lethal mouse knockouts, and primary cells isolated from adult mice by metabolomics and 13C metabolic flux analysis. The functional analysis will be complemented with a biochemical analysis of mitochondrial integrity (e.g. respiratory chain, mtDNA content, ROS), with measurements of insulin secretion in isolated pancreatic islets, and with an assessment of gluconeogenesis in murine liver with a perturbed MPC and Phb2 status. These data will be complemented with in vivo measurements of glucose tolerance, insulin sensitivity, diet-induced obesity, and loss of beta-cell mass in mice.The present project should allow us to analyze the pathophysiological consequences of various aspects of mitochondrial dysfunction on the function of beta cells and hepatocytes and how these perturbations may lead to diabetes or obesity. We expect our results to have a major impact in the field of diabetes.