Oligomeric states of the voltage-dependent anion channel and cytochrome c release from mitochondria

Ran Zalk, Adrian Israelson, Erez S. Garty, Heftsi Azoulay-Zohar, Varda Shoshan-Barmatz

Research output: Contribution to journalArticlepeer-review

170 Scopus citations

Abstract

The VDAC (voltage-dependent anion channel) plays a central role in apoptosis, participating in the release of apoptogenic factors including cytochrome c. The mechanisms by which VDAC forms a protein-conducting channel for the passage of cytochrome c are not clear. The present study approaches this problem by addressing the oligomeric status of VDAC and its role in the induction of the permeability transition pore and cytochrome c release. Chemical cross-linking of isolated mitochondria or purified VDAC with five different reagents proved that VDAC exists as dimers, trimers or tetramers. Fluorescence resonance energy transfer between fluorescently labelled VDACs supports the concept of dynamic VDAC oligomerization. Mitochondrial cross-linking prevented both permeability transition pore opening and release of cytochrome c, yet had no effect on electron transport or Ca2+ uptake. Bilayer-reconstituted purified cross-linked VDAC showed decreased conductance and voltage-independent channel activity. In the dithiobis(succinimidyl propionate)-cross-linked VDAC, these channel properties could be reverted to those of the native VDAC by cleavage of the cross-linking. Cross-linking of VDAC reconstituted into liposomes inhibited the release of the proteoliposome-encapsulated cytochrome c. Moreover, encapsulated, but not soluble cytochrome c induced oligomerization of liposome-reconstituted VDAC. Thus the results indicate that VDAC exists in a dynamic equilibrium between dimers and tetramers and suggest that oligomeric VDAC may be involved in mitochondria-mediated apoptosis.

Original languageEnglish
Pages (from-to)73-83
Number of pages11
JournalBiochemical Journal
Volume386
Issue number1
DOIs
StatePublished - 15 Feb 2005

Keywords

  • Apoptosis
  • Cytochrome c
  • Mitochondria
  • Oligomerization
  • Permeability transition pore
  • Voltage-dependent anion channel (VDAC)

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