Ca2 +-mediated regulation of VDAC1 expression levels is associated with cell death induction

https://doi.org/10.1016/j.bbamcr.2014.03.021Get rights and content
Under an Elsevier user license
open archive

Highlights

  • VDAC1 oligomerization is coupled to apoptosis induction.

  • Apoptosis inducers raise [Ca2 +]i and induce VDAC1 over-expression, oligomerization and apoptosis.

  • Ca2 +-chelating reagent BAPTA inhibits VDAC1 over-expression and oligomerization and apoptosis.

  • Increased VDAC1 expression and oligomerization, [Ca2 +]i and apoptosis are correlated.

  • Apoptosis inducers are proposed to act by up-regulating Ca2 +-dependent VDAC1 expression.

Abstract

VDAC1, an outer mitochondrial membrane (OMM) protein, is crucial for regulating mitochondrial metabolic and energetic functions and acts as a convergence point for various cell survival and death signals. VDAC1 is also a key player in apoptosis, involved in cytochrome c (Cyto c) release and interactions with anti-apoptotic proteins. Recently, we demonstrated that various pro-apoptotic agents induce VDAC1 oligomerization and proposed that a channel formed by VDAC1 oligomers mediates cytochrome c release. As VDAC1 transports Ca2 + across the OMM and because Ca2 + has been implicated in apoptosis induction, we addressed the relationship between cytosolic Ca2 + levels ([Ca2 +]i), VDAC1 oligomerization and apoptosis induction. We demonstrate that different apoptosis inducers elevate cytosolic Ca2 + and induce VDAC1 over-expression. Direct elevation of [Ca2 +]i by the Ca2 +-mobilizing agents A23187, ionomycin and thapsigargin also resulted in VDAC1 over-expression, VDAC1 oligomerization and apoptosis. In contrast, decreasing [Ca2 +]i using the cell-permeable Ca2 +-chelating reagent BAPTA-AM inhibited VDAC1 over-expression, VDAC1 oligomerization and apoptosis. Correlation between the increase in VDAC1 levels and oligomerization, [Ca2 +]i levels and apoptosis induction, as induced by H2O2 or As2O3, was also obtained. On the other hand, cells transfected to overexpress VDAC1 presented Ca2 +-independent VDAC1 oligomerization, cytochrome c release and apoptosis, suggesting that [Ca2 +]i elevation is not a pre-requisite for apoptosis induction when VDAC1 is over-expressed. The results suggest that Ca2 + promotes VDAC1 over-expression by an as yet unknown signaling pathway, leading to VDAC1 oligomerization, ultimately resulting in apoptosis. These findings provide a new insight into the mechanism of action of existing anti-cancer drugs involving induction of VDAC1 over-expression as a mechanism for inducing apoptosis. This article is part of a Special Issue entitled: Calcium Signaling in Health and Disease. Guest Editors: Geert Bultynck, Jacques Haiech, Claus W. Heizmann, Joachim Krebs, and Marc Moreau

Abbreviations

Cyto c
cytochrome c
EGS
ethylene glycol bis[succinimidylsuccinate]
OMM
outer mitochondrial membrane
VDAC
voltage-dependent anion channel

Keywords

Apoptosis
Calcium
Oligomerization
VDAC1 over-expression

Cited by (0)

This article is part of a Special Issue entitled: Calcium Signaling in Health and Disease.

1

These authors contributed equally to this study.