Regulation of cytochrome c oxidase activity by c-Src in osteoclasts

The function of the nonreceptor tyrosine kinase c-Src as a plasma membrane-associated molecular effector of a variety of extracellular stimuli is well known. Here, we show that c-Src is also present within mitochondria, where it phosphorylates cytochrome c oxidase (COX). Deleting the c-src gene reduces COX activity, and this inhibitory effect is restored by expressing exogenous c-Src. Furthermore, reducing endogenous Src kinase activity down-regulates COX activity, whereas activating Src has the opposite effect. Src-induced COX activity is required for normal function of cells that require high levels of ATP, such as mitochondria-rich osteoclasts. The peptide hormone Calcitonin, which inhibits osteoclast function, also down-regulates COX activity. Increasing Src kinase activity prevented the inhibitory effect of Calcitonin on COX activity and osteoclast function. These results suggest that c-Src plays a previously unrecognized role in maintaining cellular energy stores by activating COX in mitochondria.