Bcl-x L regulates mitochondrial energetics by stabilizing the inner membrane potential

Ying bei Chen, Miguel A. Aon, Yi Te Hsu, Lucian Soane, Xinchen Teng, J. Michael McCaffery, Wen Chih Cheng, Bing Qi, Hongmei Li, Kambiz N. Alavian, Margaret Dayhoff-Brannigan, Shifa Zou, Fernando J. Pineda, Brian O'Rourke, Young H. Ko, Peter L. Pedersen, Leonard K. Kaczmarek, Elizabeth A. Jonas, J. Marie Hardwick

Research output: Contribution to journalArticle

Abstract

Mammalian Bcl-x L protein localizes to the outer mitochondrial membrane, where it inhibits apoptosis by binding Bax and inhibiting Baxinduced 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 ? subunit in a screen for Bcl-x L-binding partners, we tested and found that Bcl-x L failed to protect ? 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.

Original languageEnglish (US)
Pages (from-to)263-276
Number of pages14
JournalJournal of Cell Biology
Volume195
Issue number2
DOIs
StatePublished - Oct 17 2011

ASJC Scopus subject areas

  • Cell Biology

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    Chen, Y. B., Aon, M. A., Hsu, Y. T., Soane, L., Teng, X., McCaffery, J. M., Cheng, W. C., Qi, B., Li, H., Alavian, K. N., Dayhoff-Brannigan, M., Zou, S., Pineda, F. J., O'Rourke, B., Ko, Y. H., Pedersen, P. L., Kaczmarek, L. K., Jonas, E. A., & Hardwick, J. M. (2011). Bcl-x L regulates mitochondrial energetics by stabilizing the inner membrane potential. Journal of Cell Biology, 195(2), 263-276. https://doi.org/10.1083/jcb.201108059