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The janus faces of mitochondrial cholesterol in cell death

AuthorsGarcía-Ruiz, Carmen ; Marí, Montserrat ; Morales, Albert ; Colell Riera, Anna ; Fernández-Checa, José C.
Issue DateAug-2010
CitationChemistry and Physics of Lipids 163(Supl.): S13 (2010)
AbstractCholesterol is a critical component of biological membranes, which determines their structural and biophsycial properties. Its distribution within membranes is heterogeneous, partitioning in specialized domains called rafts, where modulate signaling pathways. Due to this fundamental role cholesterol levels are highly regulated. Cholesterol distributes to different subcellular compartments by vesicular dependent and independent mechanisms. Compared to plasma membranes, mitochondria are cholesterol-poor organelles, with estimates of 0.5–3% of the total cholesterol pool. While hepatic mitochondrial cholesterol plays an important physiological role such as in the synthesis of bile acids, its accumulation contributes to liver diseases, such as alcoholic (ASH) and non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC) or neurodegeneration including Alzheimer's disease. Mitochondrial cholesterol loading in ASH and NASH models sensitizes hepatocytes to oxidative stress and inflammatory cytokines, contributing to fatty liver disease by a mechanism that involves mitochondrial GSH (mGSH) depletion due to changes in mitochondrial membrane dynamics. mGSH depletion protects cardiolipin from oxidation to peroxidized cardiolipin, which determines mitochondrial membrane permeabilization by proapoptotic bcl-2 family members, such as Bax. Interestingly, mitochondrial cholesterol accumulation also occurs in HCC, which contributes to chemotherapy resistance. However, despite cholesterol loading, HCC cells exhibit unimpaired transport of GSH into mitochondrial matrix due to the overexpression of mGSH carriers, 2-OG and DIC. This maintenance of mGSH prevents cardiolipin peroxidation. Peroxidized cardiolipin, however, overcomes the resistance to mitochondrial membrane permeabilization induced by Bax. These results characterize mitochondrial cholesterol/peroxidized cardiolipin as a rheostat in cell death regulation, underlying the paradoxical role of cholesterol in cell death regulation.
DescriptionTrabajo presentado a la 51st International Conference on the Bioscience of Lipids (ICBL) celebrada en Bilbao del 7 al 11 de septiembre de 2010.
Identifiersdoi: 10.1016/j.chemphyslip.2010.05.043
issn: 0009-3084
e-issn: 1873-2941
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