title: Mitofusin-2 is a major determinant of oxidative stress-mediated heart muscle cell apoptosis.
abstract: 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 H(2)O(2) 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 H(2)O(2) 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.
authors.affiliation: Institute of Cardiovascular Sciences, Peking University, Beijing 100083, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Shen
authors.forename: Ming
authors.initials: M
authors.lastname: Zheng
authors.forename: Chunmei
authors.initials: C
authors.lastname: Cao
authors.forename: Chunlei
authors.initials: C
authors.lastname: Chen
authors.forename: Jian
authors.initials: J
authors.lastname: Tang
authors.forename: Wanrui
authors.initials: W
authors.lastname: Zhang
authors.forename: Heping
authors.initials: H
authors.lastname: Cheng
authors.forename: Kuang-Hueih
authors.initials: KH
authors.lastname: Chen
authors.forename: Rui-Ping
authors.initials: RP
authors.lastname: Xiao
mesh_terms: D000256:Adenoviridae / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D020558:GTP Phosphohydrolases; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008565:Membrane Proteins / Q000378:metabolism / Q000502:physiology*; D024101:Mitochondrial Proteins / Q000378:metabolism / Q000502:physiology*; D008954:Models, Biological; D009132:Muscles / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction
chemical_list: D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D006861:Hydrogen Peroxide; D048049:Extracellular Signal-Regulated MAP Kinases; D020169:Caspases; D020558:GTP Phosphohydrolases; C489710:Mfn2 protein, rat