Calcium binding and translocation by the voltage-dependent anion channel: A possible regulatory mechanism in mitochondrial function

D. Gincel, H. Zaid, V. Shoshan-Barmatz

Research output: Contribution to journalArticlepeer-review

317 Scopus citations

Abstract

Mitochondria play a central role in energy metabolism, Ca2+ signalling, aging and cell death. To control cytosolic or mitochondrial Ca2+ concentration, mitochondria possess several Ca2+-transport systems across the inner membrane. However, the pathway for Ca2+ crossing the outer membrane has not been directly addressed. We report that purified voltage-dependent anion channel (VDAC) reconstituted into lipid bilayers or liposomes is highly permeable to Ca2+. VDAC contains Ca2+-binding sites that bind Ruthenium Red (RuR), La3+ and that RuR completely closed VDACs in single or multichannel experiments. Energized, freshly prepared mitochondria accumulate Ca2+ (500-700 nmol/mg of protein), and subsequently released it. The release of Ca2+ is accompanied by cyclosporin A-inhibited swelling, suggesting activation of permeability transition pore (PTP). RuR and ruthenium amine binuclear complex, when added to mitochondria after Ca2+ accumulation has reached a maximal level and before PTP is activated, prevented the release of Ca2+ and the accompanied mitochondrial swelling. RuR also prevented PTP opening promoted by atractyloside, an adenine nucleotide translocase inhibitor. These results suggest that VDAC, located in the mitochondrial outer membrane, controls Ca2+ transport into and from the mitochondria, and that the inhibition of Ca2+ uptake by RuR and La3+ may result from their interaction with VDAC Ca2+-binding sites. Inhibition of PTP opening or assembly by RuR and ruthenium amine binuclear complex suggest the involvement of VDAC in PTP activity and/or regulation. The permeability of VDAC to Ca2+ and its binding of Ca2+, suggest that VDAC has a role in regulation of the mitochondrial Ca2+ homoeostasis.

Original languageEnglish
Pages (from-to)147-155
Number of pages9
JournalBiochemical Journal
Volume358
Issue number1
DOIs
StatePublished - 15 Aug 2001

Keywords

  • Apoptosis
  • Calcium transport
  • Single channel

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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