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Science 323 (5915): 793-797

Copyright © 2009 by the American Association for the Advancement of Science

Function of Mitochondrial Stat3 in Cellular Respiration

Joanna Wegrzyn,1,2* Ramesh Potla,3* Yong-Joon Chwae,1 Naresh B. V. Sepuri,4 Qifang Zhang,1 Thomas Koeck,5 Marta Derecka,1,6 Karol Szczepanek,1,6 Magdalena Szelag,1,2 Agnieszka Gornicka,1,7 Akira Moh,8 Shadi Moghaddas,9 Qun Chen,9 Santha Bobbili,1 Joanna Cichy,6 Jozef Dulak,2 Darren P. Baker,10 Alan Wolfman,11 Dennis Stuehr,3,5 Medhat O. Hassan,12 Xin-Yuan Fu,8 Narayan Avadhani,13 Jennifer I. Drake,14 Paul Fawcett,14 Edward J. Lesnefsky,9,15 Andrew C. Larner1{dagger}

Abstract: Cytokines such as interleukin-6 induce tyrosine and serine phosphorylation of Stat3 that results in activation of Stat3-responsive genes. We provide evidence that Stat3 is present in the mitochondria of cultured cells and primary tissues, including the liver and heart. In Stat3–/– cells, the activities of complexes I and II of the electron transport chain (ETC) were significantly decreased. We identified Stat3 mutants that selectively restored the protein's function as a transcription factor or its functions within the ETC. In mice that do not express Stat3 in the heart, there were also selective defects in the activities of complexes I and II of the ETC. These data indicate that Stat3 is required for optimal function of the ETC, which may allow it to orchestrate responses to cellular homeostasis.

1 Department of Biochemistry and Molecular Biology and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA.
2 Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics, and Biotechnology, Jagiellonian University, Krakow, Poland.
3 Department of Biology, Cleveland State University, Cleveland, OH 44114, USA.
4 Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad 500 046, India.
5 Department of Pathobiology, Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
6 Department of Immunology, Faculty of Biochemistry, Biophysics, and Biotechnology, Jagiellonian University, Krakow, Poland.
7 Department of Cell Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland.
8 Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
9 Division of Cardiology, Department of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
10 BiogenIdec, 14 Cambridge Center, Cambridge, MA 02142, USA.
11 Department of Cell Biology, Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
12 Pathology and Laboratory Medicine Service, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, OH 44106, USA.
13 Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
14 Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA.
15 Medical Service, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, OH 44106, USA.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: alarner{at}vcu.edu


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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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