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

Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
The Journal of Cell Biology (Impact Factor: 9.83). 10/2011; 195(2):263-76. DOI: 10.1083/jcb.201108059
Source: PubMed


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 F(1)F(O)-ATP synthase directly affects mitochondrial membrane potential and having identified the mitochondrial ATP synthase β subunit in a screen for Bcl-x(L)-binding partners, we tested and found that Bcl-x(L) failed to protect β 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.

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    • "Cyclophilin D OSCP, subunit d, and subunit b mPTP [88] [118] [119] Bcl-xL F1α, F1β Membrane potential, mPTP and apoptosis [91] [120] p53 OSCP Apoptosis, mPTP [43] [121] [122] S100A1 F1α, F1β Increase of ATP synthase activity [53] Factor B F1α, OSCP Component for ATP synthase complex formation [82] [123] Strap F1β Modulator for cellular energy metabolism [124] PKCδ subunit d Inhibited ATP synthase activity [86] [87] Shown is a list of well-characterized interacting proteins of the mitochondrial ATP synthase along with information of the corresponding interacting subunits of ATP synthase and the related functions. ATP synthesis in heart 24 Am J Cardiovasc Dis 2015;5(1):19-32 "
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    American Journal of Cardiovascular Disease 06/2015; 5(1):19-32.
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    • "A link between synaptic alterations and metabolism produced by Bcl-xL was provided by studies on cultured hippocampal neurons overexpressing or depleted of Bcl-xL (Alavian et al., 2011; Chen et al., 2011). Overexpression of Bcl-xL in resting neurons led to a large (almost 100%) increase in cytoplasmic ATP levels. "
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