Endoplasmic reticulum protein BI-1 regulates Ca²⁺-mediated bioenergetics to promote autophagy.

Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA.
Genes & development (Impact Factor: 12.64). 05/2012; 26(10):1041-54. DOI: 10.1101/gad.184325.111
Source: PubMed

ABSTRACT Autophagy is a lysosomal degradation pathway that converts macromolecules into substrates for energy production during nutrient-scarce conditions such as those encountered in tumor microenvironments. Constitutive mitochondrial uptake of endoplasmic reticulum (ER) Ca²⁺ mediated by inositol triphosphate receptors (IP₃Rs) maintains cellular bioenergetics, thus suppressing autophagy. We show that the ER membrane protein Bax inhibitor-1 (BI-1) promotes autophagy in an IP₃R-dependent manner. By reducing steady-state levels of ER Ca²⁺ via IP₃Rs, BI-1 influences mitochondrial bioenergetics, reducing oxygen consumption, impacting cellular ATP levels, and stimulating autophagy. Furthermore, BI-1-deficient mice show reduced basal autophagy, and experimentally reducing BI-1 expression impairs tumor xenograft growth in vivo. BI-1's ability to promote autophagy could be dissociated from its known function as a modulator of IRE1 signaling in the context of ER stress. The results reveal BI-1 as a novel autophagy regulator that bridges Ca²⁺ signaling between ER and mitochondria, reducing cellular oxygen consumption and contributing to cellular resilience in the face of metabolic stress.

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    ABSTRACT: Bax inhibitor-1 (BI-1) is an evolutionarily-conserved endoplasmic reticulum protein. The expression of BI-1 in mammalian cells suppresses apoptosis induced by Bax, a pro-apoptotic member of the Bcl-2 family. BI-1 has been shown to be associated with calcium (Ca2+) levels, reactive oxygen species (ROS) production, cytosolic acidification, and autophagy as well as endoplasmic reticulum stress signaling pathways. According to both in vitro and clinical studies, BI-1 promotes the characteristics of cancers. In other diseases, BI-1 has also been shown to regulate insulin resistance, adipocyte differentiation, hepatic dysfunction and depression. However, the roles of BI-1 in these disease conditions are not fully consistent among studies. Until now, the molecular mechanisms of BI-1 have not directly explained with regard to how these conditions can be regulated. Therefore, this review investigates the physiological role of BI-1 through molecular mechanism studies and its application in various diseases.
    Current Molecular Medicine 07/2014; 14(5). DOI:10.2174/1566524014666140603101113 · 3.61 Impact Factor
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    ABSTRACT: A recently studied endoplasmic reticulum (ER) stress regulator, Bax inhibitor-1 (BI-1) plays a regulatory role in mitochondrial Ca(2+) levels. In this study, we identified ER-resident and mitochondria-associated ER membrane (MAM)-resident populations of BI-1. ER stress increased mitochondrial Ca(2+) to a lesser extent in BI-1-overexpressing cells (HT1080/BI-1) than in control cells, most likely as a result of impaired mitochondrial Ca(2+) intake ability and lower basal levels of intra-ER Ca(2+). Moreover, opening of the Ca(2+)-induced mitochondrial permeability transition pore (PTP) and cytochrome c release were regulated by BI-1. In HT1080/BI-1, the basal mitochondrial membrane potential was low and also resistant to Ca(2+) compared with control cells. The activity of the mitochondrial membrane potential-dependent mitochondrial Ca(2+) intake pore, the Ca(2+) uniporter, was reduced in the presence of BI-1. This study also showed that instead of Ca(2+), other cations including K(+) enter the mitochondria of HT1080/BI-1 through mitochondrial Ca(2+)-dependent ion channels, providing a possible mechanism by which mitochondrial Ca(2+) intake is reduced, leading to cell protection. We propose a model in which BI-1-mediated sequential regulation of the mitochondrial Ca(2+) uniporter and Ca(2+)-dependent K(+) channel opening inhibits mitochondrial Ca(2+) intake, thereby inhibiting PTP function and leading to cell protection.
    Scientific Reports 06/2014; 4:5194. DOI:10.1038/srep05194 · 5.08 Impact Factor
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    ABSTRACT: Calcium homeostasis balances passive calcium leak and active calcium uptake. Human Bax inhibitor-1 (hBI-1) is an antiapoptotic protein that mediates a calcium leak and is representative of a highly conserved and widely distributed family, the transmembrane Bax inhibitor motif (TMBIM) proteins. Here, we present crystal structures of a bacterial homolog and characterize its calcium leak activity. The structure has a seven-transmembrane-helix fold that features two triple-helix sandwiches wrapped around a central C-terminal helix. Structures obtained in closed and open conformations are reversibly interconvertible by change of pH. A hydrogen-bonded, pKa (where Ka is the acid dissociation constant)-perturbed pair of conserved aspartate residues explains the pH dependence of this transition, and biochemical studies show that pH regulates calcium influx in proteoliposomes. Homology models for hBI-1 provide insights into TMBIM-mediated calcium leak and cytoprotective activity.
    Science 06/2014; 344(6188):1131-5. DOI:10.1126/science.1252043 · 31.48 Impact Factor

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