Bax inhibitor-1-mediated inhibition of mitochondrial Ca2+ intake regulates mitochondrial permeability transition pore opening and cell death

Abstract

A recently studied endoplasmic reticulum (ER) stress regulator, Bax inhibitor-1 (BI-1) plays a regulatory role in mitochondrial Ca2+ levels. In this study, we identified ER-resident and mitochondria-associated ER membrane (MAM)-resident populations of BI-1. ER stress increased mitochondrial Ca2+ 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 Ca2+. Moreover, opening of the Ca2+-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 Ca2+ compared with control cells. The activity of the mitochondrial membrane potential-dependent mitochondrial Ca2+ intake pore, the Ca2+ uniporter, was reduced in the presence of BI-1. This study also showed that instead of Ca2+, other cations including K+ enter the mitochondria of HT1080/BI-1 through mitochondrial Ca2+-dependent ion channels, providing a possible mechanism by which mitochondrial Ca2+ intake is reduced, leading to cell protection. We propose a model in which BI-1-mediated sequential regulation of the mitochondrial Ca2+ uniporter and Ca2+-dependent K + channel opening inhibits mitochondrial Ca2+ intake, thereby inhibiting PTP function and leading to cell protection.