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Cardiolipin provides an essential activating platform for caspase-8 on mitochondria

¹ Cancer Research UK, The Beatson Institute for Cancer Research, Glasgow G61 1BD, Scotland, UK
² Department of Clinical Chemistry and ³ Department of Pediatrics, Laboratory Genetic Metabolic Diseases, University of Amsterdam, Academic Medical Center, Amsterdam 1105 AZ, Netherlands
⁴ Division of Medical Genetics, Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104
⁵ Institut Cochin, Départment de Génétique et Dévelopement, Centre National de la Recherche Scientifique UMR 8104, Institut National de la Santé et de la Recherche Médicale U567 et Université Paris-Descartes, Paris 75014, France

Correspondence to Eyal Gottlieb: e.gottlieb{at}beatson.gla.ac.uk

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.

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