Zinc-dependent multi-conductance channel activity in mitochondria isolated from ischemic brain

Laura Bonanni, Mushtaque Chachar, Teresa Jover-Mengual, Hongmei Li, Adrienne Jones, Hidenori Yokota, Dimitry Ofengeim, Richard J. Flannery, Takahiro Miyawaki, Chang Hoon Cho, Brian M. Polster, Marc Pypaert, J. Marie Hardwick, Stefano L. Sensi, R. Suzanne Zukin, Elizabeth A. Jonas

Research output: Contribution to journalArticle

Abstract

Transient global ischemia is a neuronal insult that induces delayed cell death. A hallmark event in the early post-ischemic period is enhanced permeability of mitochondrial membranes. The precise mechanisms by which mitochondrial function is disrupted are, as yet, unclear. Here we show that global ischemia promotes alterations in mitochondrial membrane contact points, a rise in intramitochondrial Zn2+, and activation of large, multi-conductance channels in mitochondrial outer membranes by 1 h after insult. Mitochondrial channel activity was associated with enhanced protease activity and proteolytic cleavage of BCL-xL to generate its pro-death counterpart, ΔN-BCL-xL. The findings implicate ΔN-BCL-xL in large, multi-conductance channel activity. Consistent with this, large channel activity was mimicked by introduction of recombinant ΔN-BCL-xL to control mitochondria and blocked by introduction of a functional BCL-xL antibody to post-ischemic mitochondria via the patch pipette. Channel activity was also inhibited by nicotinamide adenine dinucleotide, indicative of a role for the voltage-dependent anion channel (VDAC) of the outer mitochondrial membrane. In vivo administration of the membrane-impermeant Zn2+ chelator CaEDTA before ischemia or in vitro application of the membrane-permeant Zn2+ chelator tetrakis-(2-pyridylmethyl) ethylenediamine attenuated channel activity, suggesting a requirement for Zn2+. These findings reveal a novel mechanism by which ischemic insults disrupt the functional integrity of the outer mitochondrial membrane and implicate ΔN-BCL-xL and VDAC in the large, Zn2+-dependent mitochondrial channels observed in post-ischemic hippocampal mitochondria.

Original languageEnglish (US)
Pages (from-to)6851-6862
Number of pages12
JournalJournal of Neuroscience
Volume26
Issue number25
DOIs
StatePublished - 2006

Keywords

  • BCL-xL
  • Global ischemia
  • Ion channels
  • Mitochondria
  • Programmed cell death
  • Zinc

ASJC Scopus subject areas

  • Neuroscience(all)

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  • Cite this

    Bonanni, L., Chachar, M., Jover-Mengual, T., Li, H., Jones, A., Yokota, H., Ofengeim, D., Flannery, R. J., Miyawaki, T., Cho, C. H., Polster, B. M., Pypaert, M., Hardwick, J. M., Sensi, S. L., Zukin, R. S., & Jonas, E. A. (2006). Zinc-dependent multi-conductance channel activity in mitochondria isolated from ischemic brain. Journal of Neuroscience, 26(25), 6851-6862. https://doi.org/10.1523/JNEUROSCI.5444-05.2006