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 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.

Ca2+-associated triphasic pH changes in mitochondria during brown adipocyte activation

“…In mitochondria, TG incubation did not significantly affect Ca 2+ levels over 30 min (Figure S5B), which was in contrast to previous reports that TG treatment induces mitochondrial Ca 2+ increase through mitochondrial calcium uniporter (MCU) [33], [34], [35]. The insignificant Ca 2+ increase in BAs was probably due to a low MCU activity in metabolically active cells [36] (cf.…”

BCL-2 family: integrating stress responses at the ER to control cell demise

“…[92][93][94][95] BI-1 may also modulate apoptosis in part through the induction of mPTP. 96 Thus, members of the TMBIM family regulate cell death indirectly, possibly through the modulation of calcium signaling across different intracellular membranes. It remains to be determined if TMBIM family members antagonize BH3-only proteins or alter the activity of multidomain BCL-2 family members.…”

The Unfolded Protein Response: At the Intersection between Endoplasmic Reticulum Function and Mitochondrial Bioenergetics

“…In this direction, the ER foldase ERp44 is considered to be present at MAMs since it binds to IP 3 R (34, 35); however, no direct evidence for a function of ERp44 in MAMs has been yet reported. Finally, Bax-inhibitor-1 (BI-1), an evolutionary conserved ER-localized protein with wide roles in apoptosis regulation (36), is also located at MAMs, regulating mitochondrial calcium uptake and apoptosis (37). BI-1 has been shown to repress the UPR and regulate autophagy under stress conditions, through the inhibition of the IRE1α signaling pathway and the modulation of calcium signaling (38–40) (Figure 2).…”