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

非受体型酪氨酸激酶c-Src参与包括增殖、分化和存活在内的基本细胞功能。最近的研究表明，c-Src也存在于线粒体中，并参与线粒体能量产生的调节机制。我们在线粒体中发现了与c-Src相互作用的新蛋白，并研究了它们在调节c-Src激酶活性中的功能。血清饥饿在人T98G细胞中显示呼吸和线粒体c-Src活性显著降低，活性氧产生增强。蛋白质组学分析显示，线粒体c-Src相互作用蛋白包括呼吸复合体v的ATP5A1。细胞中ATP5A1的过表达显示出线粒体中c-Src激酶活性和呼吸的显著增加。这些结果表明，ATP5A1通过与线粒体中c-Src复合物的相互作用来调节c-Src激酶的活性，并且它们的相互作用对细胞呼吸至关重要。

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.