Identification and functional analysis of novel interacting proteins for regulation of mitochondrial c-Src activity

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Non-receptor-type tyrosine kinase c-Src is implicated in fundamental cellular functions including proliferation, differentiation and survival. Recent studies have suggested that c-Src is also present in mitochondria and involved in the regulatory mechanisms of mitochondrial energy production. Here we have identified novel interaction proteins with c-Src in mitochondria, and investigated their function in the regulation of c-Src kinase activity. Serum starvation exhibits significant reductions of respiration and mitochondrial c-Src activity, and an enhancement of reactive oxygen species production in human T98G cells. Proteome analysis reveals mitochondrial c-Srcinteraction proteins including ATP5A1 of respiratory complex V. Overexpression of ATP5A1 in cells exhibits a significant increase in c-Src kinase activity and respiration in mitochondria. These results suggest that ATP5A1 regulates c-Src kinase activity by its interaction with c-Src complex in mitochondria, and that their interaction is essential for cellular respiration.