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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Available from: Kambiz Alavian, Oct 09, 2015
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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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    ABSTRACT: Mitochondrial function is paramount to energy homeostasis, metabolism, signaling, and apoptosis in cells. Mitochondrial complex V (ATP synthase), a molecular motor, is the ultimate ATP generator and a key determinant of mitochondrial function. ATP synthase catalyzes the final coupling step of oxidative phosphorylation to supply energy in the form of ATP. Alterations at this step will crucially impact mitochondrial respiration and hence cardiac performance. It is well established that cardiac contractility is strongly dependent on the mitochondria, and that myocardial ATP depletion is a key feature of heart failure. ATP synthase dysfunction can cause and exacerbate human diseases, such as cardiomyopathy and heart failure. While ATP synthase has been extensively studied, essential questions related to how the regulation of ATP synthase determines energy metabolism in the heart linger and therapies targeting this important mechanism remain scarce. This review will visit the main findings, identify unsolved issues and provide insights into potential future perspectives related to the regulation of ATP synthase and cardiac pathophysiology.
    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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    ABSTRACT: Accepted features of neurodegenerative disease include mitochondrial and protein folding dysfunction and activation of pro-death factors. Neurons that experience high metabolic demand or those found in organisms with genetic mutations in proteins that control cell stress may be more susceptible to aging and neurodegenerative disease. In neurons, events that normally promote growth, synapse formation, and plasticity are also often deployed to control neurotoxicity. Such protective strategies are coordinated by master stress-fighting proteins. One such specialized protein is the anti-cell death Bcl-2 family member Bcl-xL, whose myriad death-protecting functions include enhancement of bioenergetic efficiency, prevention of mitochondrial permeability transition channel activity, protection from mitochondrial outer membrane permeabilization (MOMP) to pro-apoptotic factors, and improvement in the rate of vesicular trafficking. Synapse formation and normal neuronal activity provide protection from neuronal death. Therefore, Bcl-xL brings about synapse formation as a neuroprotective strategy. In this review we will consider how this multi-functional master regulator protein uses many strategies to enhance synaptic and neuronal function and thus counteracts neurodegenerative stimuli.
    Frontiers in Physiology 09/2014; 5:355. DOI:10.3389/fphys.2014.00355 · 3.53 Impact Factor
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    • "Furthermore, the deficient activities of respiratory chain complexes caused by tRNA mutations often alter mitochondrial membrane potentials, which is a key indicator of cellular viability (44). Indeed, mitochondrial membrane potentials reflect the pumping of hydrogen ions across the inner membrane during the process of electron transport and oxidative phosphorylation (45). In this study, 80% reduction in mitochondrial membrane potential was observed in mutant cell lines carrying the m.12201T>C mutation. "
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    ABSTRACT: In this report, we investigated the molecular genetic mechanism underlying the deafness-associated mitochondrial tRNAHis 12201T>C mutation. The destabilization of a highly conserved base-pairing (5A-68U) by the m.12201T>C mutation alters structure and function of tRNAHis. Using cybrids constructed by transferring mitochondria from lymphoblastoid cell lines derived from a Chinese family into mtDNA-less (ρo) cells, we showed ∼70% decrease in the steady-state level of tRNAHis in mutant cybrids, compared with control cybrids. The mutation changed the conformation of tRNAHis, as suggested by slower electrophoretic mobility of mutated tRNA with respect to the wild-type molecule. However, ∼60% increase in aminoacylated level of tRNAHis was observed in mutant cells. The failure in tRNAHis metabolism was responsible for the variable reductions in seven mtDNA-encoded polypeptides in mutant cells, ranging from 37 to 81%, with the average of ∼46% reduction, as compared with those of control cells. The impaired mitochondrial translation caused defects in respiratory capacity in mutant cells. Furthermore, marked decreases in the levels of mitochondrial ATP and membrane potential were observed in mutant cells. These mitochondrial dysfunctions caused an increase in the production of reactive oxygen species in the mutant cells. The data provide the evidence for a mitochondrial tRNAHis mutation leading to deafness.
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