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*,¶, and
- Elizabeth A. Jonas‡
- *Dominick P. Purpura Department of Neuroscience, Rose F. Kennedy Center, Albert Einstein College of Medicine, Bronx, NY 10461;
- ‡Departments of Internal Medicine and Cell Biology, Yale University, New Haven, CT 06520;
- †Department of Neurosurgery, Jichi Medical University, Tochigi 329-0498, Japan; and
- §Neurofisiopatologia, Università degli Studi Gabriele d'Annunzio di Chieti-Pescara, 65124 Pescara, Italy
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Contributed by Michael V. L. Bennett, January 21, 2008 (received for review December 28, 2007)
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.
Footnotes
- ¶To whom correspondence may be addressed at: Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Kennedy Center, Room 602, 1300 Morris Park Avenue, Bronx, NY 10461. E-mail: mbennett{at}aecom.yu.edu or zukin{at}aecom.yu.edu
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Author contributions: T. Miyawaki, T. Mashiko, K.-M.N., R.S.Z., and E.A.J. designed research; T. Miyawaki, T. Mashiko, D.O., R.J.F., K.-M.N., L.B., and E.A.J. performed research; T. Miyawaki, T. Mashiko, D.O., K.-M.N., S.F., M.V.L.B., R.S.Z., and E.A.J. analyzed data; and S.F., M.V.L.B., R.S.Z., and E.A.J. wrote the paper.
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The authors declare no conflict of interest.
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This article contains supporting information online at www.pnas.org/cgi/content/full/0800628105/DC1.
- © 2008 by The National Academy of Sciences of the USA
