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J. Biol. Chem., Vol. 282, Issue 32, 23354-23361, August 10, 2007

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Mitofusin-2 Is a Major Determinant of Oxidative Stress-mediated Heart Muscle Cell Apoptosis^*

Tao Shen¹, Ming Zheng¹, Chunmei Cao, Chunlei Chen, Jian Tang, Wanrui Zhang, Heping Cheng, Kuang-Hueih Chen^¶2, and Rui-Ping Xiao^¶3

From the Institute of Cardiovascular Sciences, Peking University, Beijing 100083, China, the Institute of Molecular Medicine, Peking University, Beijing 100 871, China; and the ^¶Laboratory of Cardiovascular Science, NIA, National Institutes of Health, Baltimore, Maryland 21224

An inexorable loss of terminally differentiated heart muscle cells is a crucial causal factor for heart failure. Here, we have provided several lines of evidence to demonstrate that mitofusin-2 (Mfn-2; also called hyperplasia suppressor gene), a member of the mitofusin family, is a major determinant of oxidative stress-mediated cardiomyocyte apoptosis. First, oxidative stress with H₂O₂ led to concurrent increases in Mfn-2 expression and apoptosis in cultured neonatal rat cardiomyocytes. Second, overexpression of Mfn-2 to a level similar to that induced by H₂O₂ was sufficient to trigger myocyte apoptosis, which is associated with profound inhibition of Akt activation without altering ERK1/2 signaling. Third, Mfn-2 silencing inhibited oxidative stress-induced apoptosis in H9C2 cells, a cardiac muscle cell line. Furthermore, Mfn-2-induced myocyte apoptosis was abrogated by inhibition of caspase-9 (but not caspase-8) and by overexpression of Bcl-x_L or enhanced activation of phosphatidylinositol 3-kinase-Akt, suggesting that inhibition of Akt signaling and activation of the mitochondrial death pathway are essentially involved in Mfn-2-induced heart muscle cell apoptosis. These results indicate that increased cardiac Mfn-2 expression is both necessary and sufficient for oxidative stress-induced heart muscle cell apoptosis, suggesting that Mfn-2 deregulation may be a crucial pathogenic element and a potential therapeutic target for heart failure.

Received for publication, March 28, 2007 , and in revised form, June 4, 2007.

^* This work was supported by Chinese Young Investigator Award 30225036, National Natural Science Foundation of China Grant 30500182, and Peking University 985 Project and in part by the National Institutes of Health intramural research program (to R.-P. X. and K.-H. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this work.

² To whom correspondence may be addressed: Lab. of Cardiovascular Science, Gerontology Research Center, NIA, NIH, 5600 Nathan Shock Dr., Baltimore, MD 21224. Tel.: 410-558-8662; Fax: 410-558-8150; E-mail: chenku{at}grc.nia.nih.gov. ³ To whom correspondence may be addressed: Lab. of Cardiovascular Science, Gerontology Research Center, NIA, NIH, 5600 Nathan Shock Dr., Baltimore, MD 21224. Tel.: 410-558-8662; Fax: 410-558-8150; E-mail: Xiaor{at}grc.nia.nih.gov.

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