Abstract 2480 Adaptive Mechanisms of Mitochondrial Respiration

The appearance of oxygen in the atmosphere caused evolutionary processes to adapt cells to this new aerobic environment. Eukaryotic cells incorporated mitochondrial organelles and use oxygen in the respiratory chain as final electron acceptor to generate proton motive force to synthesize ATP. In responses to energetic demands, cells (and organisms) respond with different adaptive mechanisms that increase mitochondrial respiration. These responses are conserved processes that maintain cell and organismal fitness and survival by adjusting the mitochondrial respiratory capacity. In these energetic demanding conditions, cells respond through dynamic regulatory mechanisms that cause changes in gene expression, protein translation, assembly of protein complexes, organelle transmembrane transport, activity of metabolic/respiratory enzymes and metabolite allosteric control. In this presentation, the focus will be the regulatory mechanisms of mitochondrial respiration that occurs at the level of protein import at the outer mitochondrial membrane which involves organelle communication with the endoplasmic reticulum. This process largely involves the function of TOM70-dependent mitochondrial protein import through a network of covalent modification and chaperones, a process that is regulated when cells respond to energetic demands. Thus, endoplasmic reticulum proteins including the resident PERK kinase controls a selected set of chaperones and enzymes (including glycosylating enzymes) that signal to mitochondrial outer membranes. A connected process driven by endoplasmic reticulum lipid transfer and mitochondrial protein import that also controls respiration is the formation of cristae invaginations of the inner membrane that harbor respiratory complexes. In addition to OPA-1, the MICOS complex is a main regulatory component of this cristae membrane organelle biogenesis. Finally, selective lipid-dependent membrane remodeling in conditions of energy demands also favor respiratory complex activities through formation of protein assemblies with different structures that favor electron transfer and catalytic activity. These adaptive mechanisms are important for physiological responses to nutrients, temperatures, or physical activity; and failures of these mechanisms lead to metabolic and age-associated diseases and cancer. NIDDK, NIA and NCI.