title: Cholesterol, cardiolipin, and mitochondria permeabilisation.
abstract: Apoptosis is a form of programmed cell death required for the development and for the proper functioning of multicellular organisms. It is defined by a combination of morphological and biochemical modifications that result from the activation of a family of proteases called caspases. Several pathways can lead to caspase activation and they often involve the release of apoptogenic factors normally sequestered in the mitochondrial intermembrane space. Complete release of mitochondrial pro-apoptotic factors ultimately results in cell death, whether in a caspase-dependent or independent manner. A tight control of mitochondrial permeability is therefore essential. Mutations of regulators of the process, such as proteins of the Bcl-2 family, have indeed been reported in many cancers. In addition, the contributions of lipids, both as regulators of protein activities and as components of the pore itself, are starting to be unravelled. Early on, the role of the mitochondria-specific phospholipid cardiolipin as a targeting signal for pro-apoptotic proteins of the Bcl-2 family was discovered. This role was then expanded since it was shown that cardiolipin also supports conformational changes undergone by proteins of the Bcl-2 family, serves as a docking station for additional pro-apoptotic factors, and is essential for the permeabilisation of synthetic liposomes by activated Bax and Bak. More recently, cholesterol, whose level is increased in most cancer cells, was shown to contribute to their resistance to cytotoxic stresses. Reducing cholesterol levels might therefore represent an interesting novel target to sensitize cancer cells to chemotherapeutic agents.
authors.affiliation: MRC-Laboratory of Molecular Biology, Neurobiology Division, Cambridge, UK. slucken@mrc-lmb.cam.ac.uk
authors.forename: Safa
authors.initials: S
authors.lastname: Lucken-Ardjomande Hasler
mesh_terms: D000818:Animals; D017209:Apoptosis; D002308:Cardiolipins / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism*; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism; D010539:Permeability; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D002308:Cardiolipins; D019253:Proto-Oncogene Proteins c-bcl-2; D002784:Cholesterol; D020169:Caspases