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.
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3 March 2003
Article|
March 03 2003
Regulation of cytochrome c oxidase activity by c-Src in osteoclasts
Tsuyoshi Miyazaki,
Tsuyoshi Miyazaki
1Department of Cell Biology, Yale University School of Medicine, New Haven, CT 06520
2Department of Orthopaedics and Rehabilitation, Yale University School of Medicine, New Haven, CT 06520
3Department of Orthopaedic Surgery, Faculty of Medicine, The University of Tokyo, Tokyo 113-0033, Japan
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Lynn Neff,
Lynn Neff
2Department of Orthopaedics and Rehabilitation, Yale University School of Medicine, New Haven, CT 06520
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Sakae Tanaka,
Sakae Tanaka
3Department of Orthopaedic Surgery, Faculty of Medicine, The University of Tokyo, Tokyo 113-0033, Japan
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William C. Horne,
William C. Horne
1Department of Cell Biology, Yale University School of Medicine, New Haven, CT 06520
2Department of Orthopaedics and Rehabilitation, Yale University School of Medicine, New Haven, CT 06520
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Roland Baron
Roland Baron
1Department of Cell Biology, Yale University School of Medicine, New Haven, CT 06520
2Department of Orthopaedics and Rehabilitation, Yale University School of Medicine, New Haven, CT 06520
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Tsuyoshi Miyazaki
1Department of Cell Biology, Yale University School of Medicine, New Haven, CT 06520
2Department of Orthopaedics and Rehabilitation, Yale University School of Medicine, New Haven, CT 06520
3Department of Orthopaedic Surgery, Faculty of Medicine, The University of Tokyo, Tokyo 113-0033, Japan
Lynn Neff
2Department of Orthopaedics and Rehabilitation, Yale University School of Medicine, New Haven, CT 06520
Sakae Tanaka
3Department of Orthopaedic Surgery, Faculty of Medicine, The University of Tokyo, Tokyo 113-0033, Japan
William C. Horne
1Department of Cell Biology, Yale University School of Medicine, New Haven, CT 06520
2Department of Orthopaedics and Rehabilitation, Yale University School of Medicine, New Haven, CT 06520
Roland Baron
1Department of Cell Biology, Yale University School of Medicine, New Haven, CT 06520
2Department of Orthopaedics and Rehabilitation, Yale University School of Medicine, New Haven, CT 06520
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: [email protected]
*
Abbreviations used in this paper: Cox, cytochrome c oxidase; Csk, COOH-terminal Src family kinase; CT, calcitonin; ERK, extracellular signal-regulated kinase; MEK, MAPK/ERK kinase; MOI, multiplicity of infection; OCL, osteoclast-like cell; TRAP, tartrate-resistant acid phosphatase.
Received:
September 20 2002
Revision Received:
January 21 2003
Accepted:
January 21 2003
Online ISSN: 1540-8140
Print ISSN: 0021-9525
The Rockefeller University Press
2003
J Cell Biol (2003) 160 (5): 709–718.
Article history
Received:
September 20 2002
Revision Received:
January 21 2003
Accepted:
January 21 2003
Citation
Tsuyoshi Miyazaki, Lynn Neff, Sakae Tanaka, William C. Horne, Roland Baron; Regulation of cytochrome c oxidase activity by c-Src in osteoclasts . J Cell Biol 3 March 2003; 160 (5): 709–718. doi: https://doi.org/10.1083/jcb.200209098
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