Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

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

Copyright © 2003 by the Rockefeller University Press.


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}

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

Biochemical Basis of the Antidiabetic Activity of Oleanolic Acid and Related Pentacyclic Triterpenes.
J. M. Castellano, A. Guinda, T. Delgado, M. Rada, and J. A. Cayuela (2013)
Diabetes 62, 1791-1799
   Abstract »    Full Text »    PDF »
cAMP and Mitochondria.
F. Valsecchi, L. S. Ramos-Espiritu, J. Buck, L. R. Levin, and G. Manfredi (2013)
Physiology 28, 199-209
   Abstract »    Full Text »    PDF »
Molecular chaperone TRAP1 regulates a metabolic switch between mitochondrial respiration and aerobic glycolysis.
S. Yoshida, S. Tsutsumi, G. Muhlebach, C. Sourbier, M.-J. Lee, S. Lee, E. Vartholomaiou, M. Tatokoro, K. Beebe, N. Miyajima, et al. (2013)
PNAS 110, E1604-E1612
   Abstract »    Full Text »    PDF »
Intracellular and Extracellular ATP Coordinately Regulate the Inverse Correlation between Osteoclast Survival and Bone Resorption.
T. Miyazaki, M. Iwasawa, T. Nakashima, S. Mori, K. Shigemoto, H. Nakamura, H. Katagiri, H. Takayanagi, and S. Tanaka (2012)
J. Biol. Chem. 287, 37808-37823
   Abstract »    Full Text »    PDF »
Cardiac mitochondrial matrix and respiratory complex protein phosphorylation.
R. Covian and R. S. Balaban (2012)
Am J Physiol Heart Circ Physiol 303, H940-H966
   Abstract »    Full Text »    PDF »
SH2 Domain-Containing Phosphatase 2 Is a Critical Regulator of Connective Tissue Mast Cell Survival and Homeostasis in Mice.
N. Sharma, V. Kumar, S. Everingham, R. S. Mali, R. Kapur, L.-F. Zeng, Z.-Y. Zhang, G.-S. Feng, K. Hartmann, A. Roers, et al. (2012)
Mol. Cell. Biol. 32, 2653-2663
   Abstract »    Full Text »    PDF »
Nitric Oxide and Calcium Participate in the Fine Regulation of Mitochondrial Biogenesis in Follicular Thyroid Carcinoma Cells.
S. Le Pennec, D. Mirebeau-Prunier, N. Boutet-Bouzamondo, C. Jacques, D. Guillotin, E. Lauret, R. Houlgatte, Y. Malthiery, and F. Savagner (2011)
J. Biol. Chem. 286, 18229-18239
   Abstract »    Full Text »    PDF »
Phosphoproteome Analysis of Functional Mitochondria Isolated from Resting Human Muscle Reveals Extensive Phosphorylation of Inner Membrane Protein Complexes and Enzymes.
X. Zhao, I. R. Leon, S. Bak, M. Mogensen, K. Wrzesinski, K. Hojlund, and O. N. Jensen (2011)
Mol. Cell. Proteomics 10, M110.000299
   Abstract »    Full Text »    PDF »
Mitochondria in heart failure.
M. G. Rosca and C. L. Hoppel (2010)
Cardiovasc Res 88, 40-50
   Abstract »    Full Text »    PDF »
Tyrosine phosphorylation by Src within the cavity of the adenine nucleotide translocase 1 regulates ADP/ATP exchange in mitochondria.
J. Feng, E. Lucchinetti, G. Enkavi, Y. Wang, P. Gehrig, B. Roschitzki, M. C. Schaub, E. Tajkhorshid, K. Zaugg, and M. Zaugg (2010)
Am J Physiol Cell Physiol 298, C740-C748
   Abstract »    Full Text »    PDF »
Epidermal Growth Factor Receptor Translocation to the Mitochondria: REGULATION AND EFFECT.
M. L. Demory, J. L. Boerner, R. Davidson, W. Faust, T. Miyake, I. Lee, M. Huttemann, R. Douglas, G. Haddad, and S. J. Parsons (2009)
J. Biol. Chem. 284, 36592-36604
   Abstract »    Full Text »    PDF »
Modulation of mitochondrial protein phosphorylation by soluble adenylyl cyclase ameliorates cytochrome oxidase defects.
R. Acin-Perez, E. Salazar, S. Brosel, H. Yang, E. A. Schon, and G. Manfredi (2009)
EMBO Mol Med. 1, 392-406
   Abstract »    Full Text »    PDF »
Discrete molecular states in the brain accompany changing responses to a vocal signal.
S. Dong, K. L. Replogle, L. Hasadsri, B. S. Imai, P. M. Yau, S. Rodriguez-Zas, B. R. Southey, J. V. Sweedler, and D. F. Clayton (2009)
PNAS 106, 11364-11369
   Abstract »    Full Text »    PDF »
Localization of PTP-1B, SHP-2, and Src Exclusively in Rat Brain Mitochondria and Functional Consequences.
A. Arachiche, O. Augereau, M. Decossas, C. Pertuiset, E. Gontier, T. Letellier, and J. Dachary-Prigent (2008)
J. Biol. Chem. 283, 24406-24411
   Abstract »    Full Text »    PDF »
Tumor Necrosis Factor {alpha} Inhibits Oxidative Phosphorylation through Tyrosine Phosphorylation at Subunit I of Cytochrome c Oxidase.
L. Samavati, I. Lee, I. Mathes, F. Lottspeich, and M. Huttemann (2008)
J. Biol. Chem. 283, 21134-21144
   Abstract »    Full Text »    PDF »
Survival Signaling by C-RAF: Mitochondrial Reactive Oxygen Species and Ca2+ Are Critical Targets.
A. V. Kuznetsov, J. Smigelskaite, C. Doblander, M. Janakiraman, M. Hermann, M. Wurm, S. F. Scheidl, R. Sucher, A. Deutschmann, and J. Troppmair (2008)
Mol. Cell. Biol. 28, 2304-2313
   Abstract »    Full Text »    PDF »
Role of AMPK{alpha}2 in basal, training-, and AICAR-induced GLUT4, hexokinase II, and mitochondrial protein expression in mouse muscle.
S. B. Jorgensen, J. T. Treebak, B. Viollet, P. Schjerling, S. Vaulont, J. F. P. Wojtaszewski, and E. A. Richter (2007)
Am J Physiol Endocrinol Metab 292, E331-E339
   Abstract »    Full Text »    PDF »
Reactive Oxygen Species-Mediated Mitochondria-to-Nucleus Signaling: A Key to Aging and Radical-Caused Diseases.
P. Storz (2006)
Sci. STKE 2006, re3
   Abstract »    Full Text »    PDF »
Calpain Is Required for Normal Osteoclast Function and Is Down-regulated by Calcitonin.
M. Marzia, R. Chiusaroli, L. Neff, N.-Y. Kim, A. H. Chishti, R. Baron, and W. C. Horne (2006)
J. Biol. Chem. 281, 9745-9754
   Abstract »    Full Text »    PDF »
Mitochondrial AKAP121 Links cAMP and src Signaling to Oxidative Metabolism.
A. Livigni, A. Scorziello, S. Agnese, A. Adornetto, A. Carlucci, C. Garbi, I. Castaldo, L. Annunziato, E. V. Avvedimento, and A. Feliciello (2006)
Mol. Biol. Cell 17, 263-271
   Abstract »    Full Text »    PDF »
Protein Kinase D Mediates Mitochondrion-to-Nucleus Signaling and Detoxification from Mitochondrial Reactive Oxygen Species.
P. Storz, H. Doppler, and A. Toker (2005)
Mol. Cell. Biol. 25, 8520-8530
   Abstract »    Full Text »    PDF »
Mitochondrial Dok-4 Recruits Src Kinase and Regulates NF-{kappa}B Activation in Endothelial Cells.
S. Itoh, S. Lemay, M. Osawa, W. Che, Y. Duan, A. Tompkins, P. S. Brookes, S.-S. Sheu, and J.-i. Abe (2005)
J. Biol. Chem. 280, 26383-26396
   Abstract »    Full Text »    PDF »
Phosphatidylinositol phosphate kinase type I{gamma} regulates dynamics of large dense-core vesicle fusion.
L.-W. Gong, G. Di Paolo, E. Diaz, G. Cestra, M.-E. Diaz, M. Lindau, P. De Camilli, and D. Toomre (2005)
PNAS 102, 5204-5209
   Abstract »    Full Text »    PDF »
cAMP-dependent Tyrosine Phosphorylation of Subunit I Inhibits Cytochrome c Oxidase Activity.
I. Lee, A. R. Salomon, S. Ficarro, I. Mathes, F. Lottspeich, L. I. Grossman, and M. Huttemann (2005)
J. Biol. Chem. 280, 6094-6100
   Abstract »    Full Text »    PDF »
An osteoclastic protein-tyrosine phosphatase may play a role in differentiation and activity of human monocytic U-937 cell-derived, osteoclast-like cells.
M. Amoui, S.-M. Suhr, D. J. Baylink, and K.-H. W. Lau (2004)
Am J Physiol Cell Physiol 287, C874-C884
   Abstract »    Full Text »    PDF »
Phosphorylation of Y845 on the Epidermal Growth Factor Receptor Mediates Binding to the Mitochondrial Protein Cytochrome c Oxidase Subunit II.
J. L. Boerner, M. L. Demory, C. Silva, and S. J. Parsons (2004)
Mol. Cell. Biol. 24, 7059-7071
   Abstract »    Full Text »    PDF »
Tissue-specific Expression and Subcellular Distribution of Murine Glutathione S-transferase Class Kappa.
R. E. Thomson, A. L. Bigley, J. R. Foster, I. R. Jowsey, C. R. Elcombe, T. C. Orton, and J. D. Hayes (2004)
Journal of Histochemistry & Cytochemistry 52, 653-662
   Abstract »    Full Text »    PDF »
Tyrosine Phosphatase Epsilon Is a Positive Regulator of Osteoclast Function in Vitro and In Vivo.
R. Chiusaroli, H. Knobler, C. Luxenburg, A. Sanjay, S. Granot-Attas, Z. Tiran, T. Miyazaki, A. Harmelin, R. Baron, and A. Elson (2004)
Mol. Biol. Cell 15, 234-244
   Abstract »    Full Text »    PDF »
Regulation of osteoclast apoptosis by ubiquitylation of proapoptotic BH3-only Bcl-2 family member Bim.
T. Akiyama, P. Bouillet, T. Miyazaki, Y. Kadono, H. Chikuda, U.-i. Chung, A. Fukuda, A. Hikita, H. Seto, T. Okada, et al. (2003)
EMBO J. 22, 6653-6664
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882