This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Joza, N.
Right arrow Articles by Penninger, J. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Joza, N.
Right arrow Articles by Penninger, J. M.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, December 2005, p. 10261-10272, Vol. 25, No. 23
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.23.10261-10272.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Muscle-Specific Loss of Apoptosis-Inducing Factor Leads to Mitochondrial Dysfunction, Skeletal Muscle Atrophy, and Dilated Cardiomyopathy

Nicholas Joza,1,2,3* Gavin Y. Oudit,4 Doris Brown,5 Paule Bénit,6 Zamaneh Kassiri,3 Nicola Vahsen,7 Loralyn Benoit,2 Mikin M. Patel,4 Karin Nowikovsky,8 Anne Vassault,7 Peter H. Backx,4 Teiji Wada,1 Guido Kroemer,7 Pierre Rustin,6 and Josef M. Penninger1,2,3*

Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Dr. Bohrgasse 7, 1030 Vienna, Austria,1 Departments of Immunology,2 Medical Biophysics, University of Toronto, Toronto, Ontario, Canada,3 Departments of Physiology and Medicine, Division of Cardiology, University Health Network, and Heart and Stroke Richard Lewar Centre, University of Toronto, Toronto, Ontario, Canada,4 Department of Anatomy, University of California at San Francisco, San Francisco, California 94143-2711,5 INSERM U676, Hopital Robert Debre, 75019 Paris, France,6 Centre National de la Recherche Scientifique, UMR1599, Institut Gustave Roussy, Villejuif, France,7 Max F. Perutz Laboratories, Departments of Microbiology and Genetics, University of Vienna, Campus Vienna Biocenter, A-1030 Vienna, Austria8

Received 16 August 2005/ Accepted 17 August 2005

Cardiac and skeletal muscle critically depend on mitochondrial energy metabolism for their normal function. Recently, we showed that apoptosis-inducing factor (AIF), a mitochondrial protein implicated in programmed cell death, plays a role in mitochondrial respiration. However, the in vivo consequences of AIF-regulated mitochondrial respiration resulting from a loss-of-function mutation in Aif are not known. Here, we report tissue-specific deletion of Aif in the mouse. Mice in which Aif has been inactivated specifically in cardiac and skeletal muscle exhibit impaired activity and protein expression of respiratory chain complex I. Mutant animals develop severe dilated cardiomyopathy, heart failure, and skeletal muscle atrophy accompanied by lactic acidemia consistent with defects in the mitochondrial respiratory chain. Isolated hearts from mutant animals exhibit poor contractile performance in response to a respiratory chain-dependent energy substrate, but not in response to glucose, supporting the notion that impaired heart function in mutant animals results from defective mitochondrial energy metabolism. These data provide genetic proof that the previously defined cell death promoter AIF has a second essential function in mitochondrial respiration and aerobic energy metabolism required for normal heart function and skeletal muscle homeostasis.

* Corresponding author. Mailing address: Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Dr. Bohrgasse 3-5, 1030 Vienna, Austria. Phone: (43-1)79730454. Fax: (43-1)79730459. E-mail for Nicholas Joza: nicholas.joza@imba.oeaw.ac.at. E-mail for Josef M. Penninger: josef.penninger{at}imba.oeaw.ac.at.

Molecular and Cellular Biology, December 2005, p. 10261-10272, Vol. 25, No. 23
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.23.10261-10272.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Choudhury, S., Bae, S., Kumar, S. R., Ke, Q., Yalamarti, B., Choi, J. H., Kirshenbaum, L. A., Kang, P. M. (2009). Role of AIF in cardiac apoptosis in hypertrophic cardiomyocytes from Dahl salt-sensitive rats. Cardiovasc Res 0: cvp261v2-cvp261 [Abstract] [Full Text]  
  • Ishimura, R., Martin, G. R., Ackerman, S. L. (2008). Loss of Apoptosis-Inducing Factor Results in Cell-Type-Specific Neurogenesis Defects. J. Neurosci. 28: 4938-4948 [Abstract] [Full Text]  
  • Zwaferink, H., Stockinger, S., Reipert, S., Decker, T. (2008). Stimulation of Inducible Nitric Oxide Synthase Expression by Beta Interferon Increases Necrotic Death of Macrophages upon Listeria monocytogenes Infection. Infect. Immun. 76: 1649-1656 [Abstract] [Full Text]  
  • Churbanova, I. Y., Sevrioukova, I. F. (2008). Redox-dependent Changes in Molecular Properties of Mitochondrial Apoptosis-inducing Factor. J. Biol. Chem. 283: 5622-5631 [Abstract] [Full Text]  
  • Gustafsson, A. B., Gottlieb, R. A. (2008). Heart mitochondria: gates of life and death. Cardiovasc Res 77: 334-343 [Abstract] [Full Text]  
  • Wilkinson, J. C., Wilkinson, A. S., Galban, S., Csomos, R. A., Duckett, C. S. (2008). Apoptosis-Inducing Factor Is a Target for Ubiquitination through Interaction with XIAP. Mol. Cell. Biol. 28: 237-247 [Abstract] [Full Text]  
  • Muller, F. L., Song, W., Jang, Y. C., Liu, Y., Sabia, M., Richardson, A., Van Remmen, H. (2007). Denervation-induced skeletal muscle atrophy is associated with increased mitochondrial ROS production. Am. J. Physiol. Regul. Integr. Comp. Physiol. 293: R1159-R1168 [Abstract] [Full Text]  
  • Cao, G., Xing, J., Xiao, X., Liou, A. K. F., Gao, Y., Yin, X.-M., Clark, R. S. B., Graham, S. H., Chen, J. (2007). Critical Role of Calpain I in Mitochondrial Release of Apoptosis-Inducing Factor in Ischemic Neuronal Injury. J. Neurosci. 27: 9278-9293 [Abstract] [Full Text]  
  • Fernando, P., Megeney, L. A. (2007). Is caspase-dependent apoptosis only cell differentiation taken to the extreme?. FASEB J. 21: 8-17 [Abstract] [Full Text]  
  • Delettre, C., Yuste, V. J., Moubarak, R. S., Bras, M., Robert, N., Susin, S. A. (2006). Identification and Characterization of AIFsh2, a Mitochondrial Apoptosis-inducing Factor (AIF) Isoform with NADH Oxidase Activity. J. Biol. Chem. 281: 18507-18518 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»