RT Journal Article SR Electronic T1 Zinc-Dependent Multi-Conductance Channel Activity in Mitochondria Isolated from Ischemic Brain JF The Journal of Neuroscience JO J. Neurosci. FD Society for Neuroscience SP 6851 OP 6862 DO 10.1523/JNEUROSCI.5444-05.2006 VO 26 IS 25 A1 Laura Bonanni A1 Mushtaque Chachar A1 Teresa Jover-Mengual A1 Hongmei Li A1 Adrienne Jones A1 Hidenori Yokota A1 Dimitry Ofengeim A1 Richard J. Flannery A1 Takahiro Miyawaki A1 Chang-Hoon Cho A1 Brian M. Polster A1 Marc Pypaert A1 J. Marie Hardwick A1 Stefano L. Sensi A1 R. Suzanne Zukin A1 Elizabeth A. Jonas YR 2006 UL http://www.jneurosci.org/content/26/25/6851.abstract AB 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.