PE in modulation of energy flux through OXPHOS

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Project Summary Mitochondrial oxidative phosphorylation (OXPHOS) consists of a series of processes that takes place in the inner mitochondrial membrane (IMM). Energy flux through OXPHOS appears to be intrinsically modulated by the lipid composition of IMM by mechanisms that are not clearly understood. In particular, phosphatidyl- ethanolamine (PE) is a cone-shaped non-bilayer lipid that induces membrane curvature in cristae and binds with high affinity to mitochondrial respiratory complexes and regulate their functions. We found that interventions that induce high OXPHOS flux are accompanied by increases in mitochondrial PE, and such increase was sufficient to increase mitochondrial respiratory capacity. The central premise of this proposal is to provide a comprehensive bioenergetics prognosis for altered mitochondrial PE content. Combining high- resolution respirometry, fluorometry, electrophysiology, and microscopy, we will examine the role of PE in the following processes: 1) Regulation of mitochondrial pyruvate entry at IMM to facilitate the Warburg effect, 2) Origin of electron leak in the electron transport chain to induce oxidative stress, and 3) Efficiency of ATP synthesis to alter cellular fuel economy.