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PMID: 10318956 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

Release of caspase-9 from mitochondria during neuronal apoptosis and cerebral ischemia.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 96 ·No. 10 ·1999-05-11 ·Pages 5752-7

Krajewski S, Krajewska M, Ellerby LM, Welsh K, Xie Z, Deveraux QL, Salvesen GS, Bredesen DE, Rosenthal RE, Fiskum G, Reed JC

Abstract

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.

MeSH Terms
Amino Acid Sequence Animals Apoptosis Brain/metabolism Brain Ischemia/metabolism Calcium/pharmacology Caspase 9 Caspases/metabolism Cell Nucleus/enzymology Cytochrome c Group/metabolism Enzyme Precursors/metabolism Immunohistochemistry Mitochondria/enzymology Molecular Sequence Data Myocardium/metabolism Neurons/metabolism PC12 Cells Proto-Oncogene Proteins/pharmacology Proto-Oncogene Proteins c-bcl-2/metabolism Rats Reperfusion Injury/enzymology bcl-2-Associated X Protein
Chemicals
Bax protein, rat Cytochrome c Group Enzyme Precursors Proto-Oncogene Proteins Proto-Oncogene Proteins c-bcl-2 bcl-2-Associated X Protein Casp9 protein, rat Caspase 9 Caspases Calcium
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Krajewski S
The Burnham Institute, La Jolla, CA 92037, USA.
Krajewska M
Ellerby L M
Welsh K
Xie Z
Deveraux Q L
Salvesen G S
Bredesen D E
Rosenthal R E
Fiskum G
Reed J C
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.96.10.5752
Published
1999-05-11
Pages
5752-7
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC21932
Subset
IM
Grants
NIA NIH HHS · R01 AG012282 · United States
NINDS NIH HHS · NS 36821 · United States
NINDS NIH HHS · R01 NS034152 · United States
NINDS NIH HHS · R01 NS033376 · United States
NIA NIH HHS · R01 AG015402 · United States
NINDS NIH HHS · R01 NS036821 · United States
NINDS NIH HHS · NS33376 · United States
NIA NIH HHS · AG 12282 · United States
External Links
PubMed source DOI: 10.1073/pnas.96.10.5752 PMC Full Text View journal details
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