Mitofusin 1 inhibits an apoptosis-associated amino-terminal conformational change in Bax, but not its mitochondrial translocation, in a GTPase-dependent manner

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• 作者：Seung-Wook Ryu^a ; ^b ; ^{ryus@kaist.ac.kr} ; Kyungsun Choi^a ; Jong-Hwan Park^c ; Yeong-Min Park^d ; Sunchang Kim^b ; ^e ; Chulhee Choi^a ; ^b ; ^{cchoi@kaist.ac.kr}
• 关键词：Apoptosis ; Bax ; Mitochondria ; Mitofusin ; Mfn1 ; Mfn2 ; Outer mitochondrial membrane
• 刊名：Cancer Letters
• 出版年：2012
• 期刊代码：44_03043835
• 类别：med
• 出版时间：1 October, 2012
• 卷：323
• 期：1
• 页码：62-68
• 文件大小：715 K

摘要

Mitochondrial fusion and fission are dynamically regulated during apoptotic cell death, and mitofusin (Mfn) and related proteins have been shown to be involved in apoptosis-associated changes in mitochondrial morphology and function. Here, we investigated the involvement of Mfn proteins in the conformational activation and mitochondrial translocation of Bax, a key molecule responsible for apoptosis-associated mitochondrial changes. When ectopically expressed, Mfn1 inhibited the amino-terminal activation, but not the mitochondrial translocation, of Bax during staurosporine-induced apoptosis; overexpression of Mfn2 had no effect. Overexpression of Mfn1 mutants carrying point mutations in the GTPase domain (Mfn1-K88T and Mfn1-T109A) did not inhibit the amino-terminal activation of Bax. Furthermore, staurosporine-induced amino-terminal activation of Bax was significantly delayed in Mfn1-shRNA transfected (Mfn1-depleted) HeLa cells compared to cells transfected with control shRNA. These results collectively suggest a role for Mfn1 in regulating the activation of Bax on the outer mitochondrial membrane in a GTPase-dependent manner.