Cardiolipin provides an essential activating platform for caspase-8 on mitochondria.
Cardiolipin is a mitochondria-specific phospholipid known to be intimately involved with apoptosis. However, the lack of appropriate cellular models to date restricted analysis of its role in cell death. The maturation of cardiolipin requires the transacylase tafazzin, which is mutated in the human disorder Barth syndrome. Using Barth syndrome patient-derived cells and HeLa cells in which tafazzin was knocked down, we show that cardiolipin is required for apoptosis in the type II mitochondria-dependent response to Fas stimulation. Cardiolipin provides an anchor and activating platform for caspase-8 translocation to, and embedding in, the mitochondrial membrane, where it oligomerizes and is further activated, steps that are necessary for an efficient type II apoptotic response.
Gonzalvez
Francois
F
Cancer Research UK, The Beatson Institute for Cancer Research, Glasgow, Scotland, UK.
Schug
Zachary T
ZT
Houtkooper
Riekelt H
RH
MacKenzie
Elaine D
ED
Brooks
David G
DG
Wanders
Ronald J A
RJ
Petit
Patrice X
PX
Vaz
Frédéric M
FM
Gottlieb
Eyal
E
D000217:Acyltransferases; D017209:Apoptosis / Q000502:physiology*; D002308:Cardiolipins / Q000235:genetics / Q000378:metabolism*; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008928:Mitochondria / Q000201:enzymology* / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000201:enzymology*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism
D002308:Cardiolipins; C491901:FAS protein, human; D024101:Mitochondrial Proteins; D014157:Transcription Factors; D019014:fas Receptor; D000217:Acyltransferases; C108675:TAFAZZIN protein, human; C505530:CASP8 protein, human; D053181:Caspase 8