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Targeting cytochrome C for optimization of mitochondrial electron transport chain

Defects in the mitochondrial electron transport chain (ETC) underlie the pathogenesis of many diseases ranging from metabolic syndrome to heart failure, and Alzheimer's Disease. Optimization of electron transfer (ET) through ETC provides a unifying therapeutic approach to these diverse disorders. SS‐31 is a synthetic tetrapeptide that selectively targets the inner mitochondrial membrane and has been shown to protect mitochondrial integrity, preserve ATP synthesis, and minimize ROS formation in numerous animal models. We now report that that SS‐31 acts by facilitating ET in the ETC. In isolated mitochondria, SS‐31 potentiated O2 consumption and ATP synthesis initiated by complex I or II substrates, or by direct reduction of cyt C. SS‐31 also promoted ET in cyt C‐deficient mitoplasts, suggesting that SS‐31 facilitates ET through cyt C, especially under rate‐limiting conditions. Circular dichroism and Trp fluorescence verified that SS‐31 interacts directly with cyt C. Photoluminescence and cyclic voltammetry established that SS‐31 increases electron capacity of cyt C and promotes electron diffusion through cyt C. We conclude that SS‐31 minimized the energy barrier for ET through cyt C. This concept represents a novel approach for protecting cellular energy and a paradigm shift in the treatment of a multitude of diseases associated with mitochondrial dysfunction.