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Vol. 96, Issue 10, 5752-5757, May 11, 1999
Edited by Eugene Roberts, Beckman Research Institute of the City of
Hope, Duarte, CA, and approved March 16, 1999 (received for review January 29, 1999)
Caspase-9 is critical for cytochrome c
(cyto-c)-dependent apoptosis and normal brain development. We
determined that this apical protease in the cyto-c pathway for
apoptosis resides inside mitochondria in several types of
cells, including cardiomyocytes and many neurons. Caspase-9 is released
from isolated mitochondria on treatment with Ca2+ or Bax,
stimuli implicated in ischemic neuronal cell death that are known to
induce cyto-c release from mitochondria. In neuronal cell culture
models, apoptosis-inducing agents trigger translocation of
caspase-9 from mitochondria to the nucleus, which is inhibitable by
Bcl-2. Similarly, in an animal model of transient global cerebral ischemia, caspase-9 release from mitochondria and accumulation in
nuclei was observed in hippocampal and other vulnerable neurons exhibiting early postischemic changes preceding apoptosis. Loss of mitochondrial barrier function during neuronal damage from ischemia
or other insults therefore may play an important role in making certain
caspases available to participate in apoptosis.
Copyright © 1999 by The National Academy of Sciences 0027-8424/99/965752-6$2.00/0
Neurobiology
Release of caspase-9 from mitochondria during neuronal
apoptosis and cerebral ischemia
,,,,,,,,
,,¶
The Burnham Institute, La Jolla, CA 92037;
Department of Emergency Medicine, George Washington University
School of Medicine, Washington, DC 10021; and § Department of
Anesthesiology, University of Maryland School of Medicine, Baltimore,
MD 21201
*
S.K. and M.K. contributed equally to this work.
¶
To whom reprint requests should be addressed at: The
Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037. e-mail: jreed{at}burnham-inst.org.
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