Mitofusin-2 is a major determinant of oxidative stress-mediated heart muscle cell apoptosis.
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.
Shen
Tao
T
Institute of Cardiovascular Sciences, Peking University, Beijing 100083, China.
Zheng
Ming
M
Cao
Chunmei
C
Chen
Chunlei
C
Tang
Jian
J
Zhang
Wanrui
W
Cheng
Heping
H
Chen
Kuang-Hueih
KH
Xiao
Rui-Ping
RP
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
D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D006861:Hydrogen Peroxide; D048049:Extracellular Signal-Regulated MAP Kinases; D020169:Caspases; D020558:GTP Phosphohydrolases; C489710:Mfn2 protein, rat