Document Detail

Bid-induced release of AIF from mitochondria causes immediate neuronal cell death.
MedLine Citation:
PMID:  18535584     Owner:  NLM     Status:  MEDLINE    
Mitochondrial dysfunction and release of pro-apoptotic factors such as cytochrome c or apoptosis-inducing factor (AIF) from mitochondria are key features of neuronal cell death. The precise mechanisms of how these proteins are released from mitochondria and their particular role in neuronal cell death signaling are however largely unknown. Here, we demonstrate by fluorescence video microscopy that 8-10 h after induction of glutamate toxicity, AIF rapidly translocates from mitochondria to the nucleus and induces nuclear fragmentation and cell death within only a few minutes. This markedly fast translocation of AIF to the nucleus is preceded by increasing translocation of the pro-apoptotic bcl-2 family member Bid (BH3-interacting domain death agonist) to mitochondria, perinuclear accumulation of Bid-loaded mitochondria, and loss of mitochondrial membrane integrity. A small molecule Bid inhibitor preserved mitochondrial membrane potential, prevented nuclear translocation of AIF, and abrogated glutamate-induced neuronal cell death, as shown by experiments using Bid small interfering RNA (siRNA). Cell death induced by truncated Bid was inhibited by AIF siRNA, indicating that caspase-independent AIF signaling is the main pathway through which Bid mediates cell death. This was further supported by experiments showing that although caspase-3 was activated, specific caspase-3 inhibition did not protect neuronal cells against glutamate toxicity. In conclusion, Bid-mediated mitochondrial release of AIF followed by rapid nuclear translocation is a major mechanism of glutamate-induced neuronal death.
S Landshamer; M Hoehn; N Barth; S Duvezin-Caubet; G Schwake; S Tobaben; I Kazhdan; B Becattini; S Zahler; A Vollmar; M Pellecchia; A Reichert; N Plesnila; E Wagner; C Culmsee
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2008-06-06
Journal Detail:
Title:  Cell death and differentiation     Volume:  15     ISSN:  1350-9047     ISO Abbreviation:  Cell Death Differ.     Publication Date:  2008 Oct 
Date Detail:
Created Date:  2008-09-16     Completed Date:  2008-10-27     Revised Date:  2014-09-18    
Medline Journal Info:
Nlm Unique ID:  9437445     Medline TA:  Cell Death Differ     Country:  England    
Other Details:
Languages:  eng     Pagination:  1553-63     Citation Subset:  IM    
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MeSH Terms
Apoptosis Inducing Factor / genetics,  metabolism*
BH3 Interacting Domain Death Agonist Protein / antagonists & inhibitors,  genetics,  metabolism*
Caspases / metabolism
Cell Death / physiology*
Enzyme Activation
Gene Silencing
Glutamic Acid / toxicity
Microscopy, Fluorescence
Microscopy, Video
Mitochondria / metabolism*
Neurons / cytology,  drug effects,  physiology*
RNA, Small Interfering / genetics,  metabolism
Recombinant Fusion Proteins / genetics,  metabolism
Grant Support
Reg. No./Substance:
0/Apoptosis Inducing Factor; 0/BH3 Interacting Domain Death Agonist Protein; 0/Bid protein, mouse; 0/Pdcd8 protein, mouse; 0/RNA, Small Interfering; 0/Recombinant Fusion Proteins; 3KX376GY7L/Glutamic Acid; EC 3.4.22.-/Caspases

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