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J. Cell Biol. 160 (5): 709-718

Copyright © 2003 by the Rockefeller University Press.


Article

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

Tsuyoshi Miyazaki1,2,3, Lynn Neff2, Sakae Tanaka3, William C. Horne1,2, and Roland Baron1,2

1 Department of Cell Biology, Yale University School of Medicine, New Haven, CT 06520
2 Department of Orthopaedics and Rehabilitation, Yale University School of Medicine, New Haven, CT 06520
3 Department of Orthopaedic Surgery, Faculty of Medicine, The University of Tokyo, Tokyo 113-0033, Japan

Address correspondence to Roland Baron, Dept. of Orthopaedics and Rehabilitation, Yale University School of Medicine, PO Box 208044, New Haven, CT 06520-8044. Tel.: (203) 785-5986. Fax: (203) 785-2744. E-mail: roland.baron{at}yale.edu

Abstract: 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.

Key Words: oxidative phosphorylation; mitochondria; calcitonin; bone resorption; apoptosis


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