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: 10.8). 05/2012; 26(10):1041-54. DOI: 10.1101/gad.184325.111
Source: PubMed


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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    • "Even in the absence of ER membrane-localized BI-1, mitochondria membranes from HT1080/BI-1 showed resistance against the loaded Ca2+, suggesting that mitochondrial characteristics might be changed as a result of MAM-localized BI-1. Recently, Sano et al reported a role for BI-1 as a regulator of Ca2+ transfer from the ER to mitochondria, thereby changing mitochondrial bioenergetics37. We have also reported that BI-1 modulates ATP levels, lactate production, and mitochondrial O2 consumption18. "
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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 · 5.58 Impact Factor
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    • "BI-1 has recently been found to be overexpressed in several human carcinomas (5, 23, 24). It was also reported that the expression of BI-1 leads to changes in molecular mechanisms governing normal cellular growth; and consequently, contributes to malignant cell transformation and tumorigenesis (25). Based on this study, we assume that cancer cells that endogenously express BI-1 will show high susceptibility to programmed cell death induced by anti-Fas antibody or Fas ligand, especially in high glucose conditions. "
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    ABSTRACT: Although the role of Bax inhibitor-1 (BI-1) in the protective mechanism against apoptotic stimuli has been studied, little is known about its role in death receptor-mediated cell death. This study was designed to investigate the effect of BI-1 on Fas-induced cell death and the underlying mechanisms. HT1080 adenocarcinoma cells were transfected with vector alone (Neo cells) or BI-1-vector (BI-1 cells) and treated with Fas. The BI-1 cells showed enhanced sensitivity to Fas in cell viability, apoptosis, and caspase-3 analyses. Fas significantly decreased cytosolic pH in BI-1 cells, which correlated with BI-1 oligomerization, mitochondrial Ca(2+) accumulation, and significant inhibition of sodium-hydrogen exchanger (NHE) activity compared with Neo cells. A single treatment with the NHE inhibitor EIPA or siRNA against NHE significantly increased cell death in BI-1 compared with Neo cells, suggesting that the viability of BI-1 cells is affected by the maintenance of intracellular pH homeostasis through NHE.
    BMB reports 12/2013; 47(7). DOI:10.5483/BMBRep.2014.47.7.194 · 2.60 Impact Factor
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    • "The BI-1 protein has recently been established as a regulator of ER stress2930. The ER is a critical site for intracellular Ca2+ storage as well as protein synthesis, folding and trafficking. "
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    ABSTRACT: The anti-apoptotic protein Bax inhibitor-1 (BI-1) is a regulator of apoptosis linked to endoplasmic reticulum (ER) stress. It has been hypothesized that BI-1 protects against neuron degenerative diseases. In this study, BI-1(-/-) mice showed increased vulnerability to chronic mild stress accompanied by alterations in the size and morphology of the hippocampi, enhanced ROS accumulation and an ER stress response compared with BI-1(+/+) mice. BI-1(-/-) mice exposed to chronic mild stress showed significant activation of monoamine oxidase A (MAO-A), but not MAO-B, compared with BI-1(+/+) mice. To examine the involvement of BI-1 in the Ca(2+)-sensitive MAO activity, thapsigargin-induced Ca(2+) release and MAO activity were analyzed in neuronal cells overexpressing BI-1. The in vitro study showed that BI-1 regulates Ca(2+) release and related MAO-A activity. This study indicates an endogenous protective role of BI-1 under conditions of chronic mild stress that is primarily mediated through Ca(2+)-associated MAO-A regulation.
    Scientific Reports 12/2013; 3:3398. DOI:10.1038/srep03398 · 5.58 Impact Factor
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