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The Journal of Neuroscience, June 21, 2006, 26(25):6851-6862; doi:10.1523/JNEUROSCI.5444-05.2006

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Cellular/Molecular
Zinc-Dependent Multi-Conductance Channel Activity in Mitochondria Isolated from Ischemic Brain

Laura Bonanni,¹ Mushtaque Chachar,² Teresa Jover-Mengual,⁴ Hongmei Li,² Adrienne Jones,² Hidenori Yokota,⁴ Dimitry Ofengeim,⁴ Richard J. Flannery,² Takahiro Miyawaki,⁴ Chang-Hoon Cho,² Brian M. Polster,⁵ Marc Pypaert,³ J. Marie Hardwick,⁵ Stefano L. Sensi,¹ R. Suzanne Zukin,⁴ and Elizabeth A. Jonas²

¹Department of Oncology and Neuroscience and Center for Excellence on Aging, d'Annunzio Foundation, Università G. d'Annunzio–Chieti, 66013 Chieti, Italy, Departments of ²Internal Medicine and ³Cell Biology, Yale University, New Haven, Connecticut 06520, ⁴Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461, and ⁵Department of Molecular Microbiology and Immunology, Johns Hopkins University School of Public Health, Baltimore, Maryland 21205

Correspondence should be addressed to Dr. Elizabeth A. Jonas, Department of Internal Medicine (Endocrinology), Yale University School of Medicine, P.O. Box 208020, 333 Cedar Street, New Haven, CT 06520. Email: elizabeth.jonas{at}yale.edu

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, N-BCL-xL. The findings implicate N-BCL-xL in large, multi-conductance channel activity. Consistent with this, large channel activity was mimicked by introduction of recombinant N-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 N-BCL-xL and VDAC in the large, Zn²⁺-dependent mitochondrial channels observed in post-ischemic hippocampal mitochondria.

Key words: global ischemia; zinc; mitochondria; BCL-xL; ion channels; programmed cell death

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Received June 7, 2005; revised May 8, 2006; accepted May 8, 2006.

Correspondence should be addressed to Dr. Elizabeth A. Jonas, Department of Internal Medicine (Endocrinology), Yale University School of Medicine, P.O. Box 208020, 333 Cedar Street, New Haven, CT 06520. Email: elizabeth.jonas{at}yale.edu

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