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

Shira Weisthal, Nurit Keinan, Danya Ben-Hail, Tasleem Arif, Varda Shoshan-Barmatz

Research output: Contribution to journalArticlepeer-review

70 Scopus citations

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.

Original languageEnglish
Pages (from-to)2270-2281
Number of pages12
JournalBiochimica et Biophysica Acta - Molecular Cell Research
Volume1843
Issue number10
DOIs
StatePublished - 1 Jan 2014

Keywords

  • Apoptosis
  • Calcium
  • Oligomerization
  • VDAC1 over-expression

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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