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Mitochondrial cholesterol and cell death

AuthorsFernández-Checa, José C.
cholesterol in cell
cell death
mitochondrial cholesterol
Issue Date21-Jul-2010
CitationBiochimica et Biophysica Acta (BBA) - Bioenergetics 1797(Suppl.): 120 (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). 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.
DescriptionComunicación presentada en la 16th European Bionergetics Conference, celebrada del 17 al 22 de julio de 2010 en Varsovia (Polonia)
Publisher version (URL)http://dx.doi.org/10.1016/j.bbabio.2010.04.358
Identifiersissn: 0006-3002
Appears in Collections:(IIBB) Comunicaciones congresos
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