Bcl-xL regulates mitochondrial energetics by stabilizing the inner membrane potential

被引:156
作者
Chen, Ying-bei [1 ]
Aon, Miguel A. [2 ]
Hsu, Yi-Te [5 ]
Soane, Lucian [6 ]
Teng, Xinchen [1 ,6 ]
McCaffery, J. Michael [9 ,10 ]
Cheng, Wen-Chih [6 ]
Qi, Bing [6 ]
Li, Hongmei [11 ]
Alavian, Kambiz N. [11 ]
Dayhoff-Brannigan, Margaret [7 ]
Zou, Shifa [6 ]
Pineda, Fernando J. [6 ,8 ]
O'Rourke, Brian [2 ]
Ko, Young H. [3 ,4 ]
Pedersen, Peter L. [3 ]
Kaczmarek, Leonard K. [12 ]
Jonas, Elizabeth A. [11 ]
Hardwick, J. Marie [1 ,6 ,7 ]
机构
[1] Johns Hopkins Sch Med, Dept Pharmacol & Mol Sci, Baltimore, MD 21205 USA
[2] Johns Hopkins Sch Med, Inst Mol Cardiobiol, Baltimore, MD 21205 USA
[3] Johns Hopkins Sch Med, Dept Biol Chem, Baltimore, MD 21205 USA
[4] Johns Hopkins Sch Med, Russell H Morgan Dept Radiol & Radiol Sci, Baltimore, MD 21205 USA
[5] Med Univ S Carolina, Dept Biochem & Mol Biol, Charleston, SC 29425 USA
[6] Johns Hopkins Bloomberg Sch Publ Hlth, W Harry Feinstone Dept Mol Microbiol & Immunol, Baltimore, MD 21205 USA
[7] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biochem & Mol Biol, Baltimore, MD 21205 USA
[8] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD 21205 USA
[9] Johns Hopkins Univ, Dept Biol, Baltimore, MD 21218 USA
[10] Johns Hopkins Univ, Integrated Imaging Ctr, Baltimore, MD 21218 USA
[11] Yale Univ, Sch Med, Dept Internal Med, New Haven, CT 06520 USA
[12] Yale Univ, Sch Med, Dept Pharmacol, New Haven, CT 06520 USA
基金
美国国家卫生研究院;
关键词
PROGRAMMED CELL-DEATH; BCL-2 FAMILY PROTEINS; ATP SYNTHASE; BRAIN MITOCHONDRIA; MAMMALIAN-CELLS; BAX; APOPTOSIS; INHIBITOR; YEAST; AUTOPHAGY;
D O I
10.1083/jcb.201108059
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Mammalian Bcl-x(L) protein localizes to the outer mitochondrial membrane, where it inhibits apoptosis by binding Bax and inhibiting Bax-induced outer membrane permeabilization. Contrary to expectation, we found by electron microscopy and biochemical approaches that endogenous Bcl-x(L) also localized to inner mitochondrial cristae. Two-photon microscopy of cultured neurons revealed large fluctuations in inner mitochondrial membrane potential when Bcl-x(L) was genetically deleted or pharmacologically inhibited, indicating increased total ion flux into and out of mitochondria. Computational, biochemical, and genetic evidence indicated that Bcl-x(L) reduces futile ion flux across the inner mitochondrial membrane to prevent a wasteful drain on cellular resources, thereby preventing an energetic crisis during stress. Given that F1FO-ATP synthase directly affects mitochondrial membrane potential and having identified the mitochondrial ATP synthase beta subunit in a screen for Bcl-x(L)-binding partners, we tested and found that Bcl-x(L) failed to protect beta subunit-deficient yeast. Thus, by bolstering mitochondrial energetic capacity, Bcl-x(L) may contribute importantly to cell survival independently of other Bcl-2 family proteins.
引用
收藏
页码:263 / 276
页数:14
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