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.
Miyazaki
Tsuyoshi
T
Department of Cell Biology, Yale University School of Medicine, PO Box 208044, New Haven, CT 06520-8044, USA.
Neff
Lynn
L
Tanaka
Sakae
S
Horne
William C
WC
Baron
Roland
R
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001862:Bone Resorption / Q000235:genetics; D000081247:CSK Tyrosine-Protein Kinase; D019069:Cell Respiration / Q000502:physiology; D002470:Cell Survival / Q000235:genetics; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D003576:Electron Transport Complex IV / Q000378:metabolism*; D004734:Energy Metabolism / Q000502:physiology; D006801:Humans; D007425:Intracellular Membranes / Q000201:enzymology* / Q000648:ultrastructure; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000201:enzymology* / Q000648:ultrastructure; D010010:Osteoclasts / Q000201:enzymology* / Q000648:ultrastructure; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000172:deficiency* / Q000235:genetics; D011993:Recombinant Fusion Proteins; D013347:Subcellular Fractions / Q000201:enzymology / Q000648:ultrastructure; D019061:src-Family Kinases
D011993:Recombinant Fusion Proteins; D003576:Electron Transport Complex IV; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human