Bax Inhibitor-1-Mediated Inhibition of Mitochondrial Ca2+ Intake Regulates Mitochondrial Permeability Transition Pore Opening and Cell Death

摘要

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 Ca²⁺ 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.