Ischemic preconditioning blocks BAD translocation, Bcl-xL cleavage, and large channel activity in mitochondria of postischemic hippocampal neurons

Takahiro Miyawaki, Toshihiro Mashiko, Dimitry Ofengeim, Richard J. Flannery, Kyung Min Noh, Sho Fujisawa, Laura Bonanni, Michael V.L. Bennett, R. Suzanne Zukin, Elizabeth A. Jonas

Research output: Contribution to journalArticle

71 Scopus citations

Abstract

Transient forebrain or global ischemia induces delayed neuronal death in vulnerable CA1 pyramidal cells with many features of apoptosis. A brief period of ischemia, i.e., ischemic preconditioning, affords robust protection of CA1 neurons against a subsequent more prolonged ischemic challenge. Here we show that preconditioning acts via PI3K/Akt signaling to block the ischemia-induced cascade involving mitochondrial translocation of Bad, assembly of Bad with Bcl-xL, cleavage of Bcl-xL to form its prodeath fragment, ΔN-Bcl-xL, activation of large-conductance channels in the mitochondrial outer membrane, mitochondrial release of cytochrome c and Smac/DIABLO (second mitochondria-derived activator of caspases/direct IAP-binding protein with low pI), caspase activation, and neuronal death. These findings show how preconditioning acts to prevent the release of cytochrome c and Smac/DIABLO from mitochondria and to preserve the integrity of the mitochondrial membrane. The specific PI3K inhibitor LY294002 administered in vivo 1 h before or immediately after ischemia or up to 120 h later significantly reverses preconditioning-induced protection, indicating a requirement for sustained PI3K signaling in ischemic tolerance. These findings implicate PI3K/Akt signaling in maintenance of the integrity of the mitochondrial outer membrane.

Original languageEnglish (US)
Pages (from-to)4892-4897
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number12
DOIs
StatePublished - Mar 25 2008

Keywords

  • Akt
  • Ischemic tolerance
  • PI3K
  • Postischemic neurodegeneration

ASJC Scopus subject areas

  • General

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