Regulation of substrate-linked mitochondrial ROS generation

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DESCRIPTION (provided by applicant): Glucose availability affects cell growth, proliferation and survival. Many of these effects appear to depend on glucose metabolism, and in particular, substrate level control of mitochondrial flux. Glucose sensing in pancreatic beta cells is coupled to insulin secretion via mitochondrial oxidative phosphorylation with direct effects on cellular energy charge. Longer term exposure of multiple cell types, including endothelium and pancreatic beta cells, to high glucose concentrations results in inefficient coupling of substrate supply to oxidative phosphorylation, with formation of superoxide radicals by diversion of reducing equivalents to single electron reduction of molecular oxygen. This application addresses key questions about how cells respond to positive energy balance. Using endothelial cells and islet cell lines as prototypic cell lineages, we will characterize cellular and mitochondrial responses to the availability of a nutrient source, glucose, in excess of metabolic requirements. Specifically, we have found that incubation of primary endothelial cells in 25 mM glucose induces c-myc transcription, activation of NF-KB pro-inflammatory pathways and downregulation of PI3-K/Akt signaling. Each of these pathways is relevant to mitochondrial metabolism and redox homeostasis. The following specific aims are proposed: 1. To test the hypothesis glucose-stimulated oxidative stress is dependent on c-myc transactivation of NRF- 1-dependent mitochondrial gene expression. 2. To test the hypothesis that Bcl-xL, induced by NF-kB transcription factors, reduces glucose-stimulated oxidative stress by modulating the equilibrium between mitochondrial redox carriers. Insights gained from these studies will help us understand how hyperglycemia This information will be important for designing effective prevention and treatment for end organ damage for the growing population in the United States with diabetes.