Cholesterol and peroxidized cardiolipin in mitochondrial membrane properties, permeabilization and cell death.
Mitochondria are known to actively regulate cell death with the final phenotype of demise being determined by the metabolic and energetic status of the cell. Mitochondrial membrane permeabilization (MMP) is a critical event in cell death, as it regulates the degree of mitochondrial dysfunction and the release of intermembrane proteins that function in the activation and assembly of caspases. In addition to the crucial role of proapoptotic members of the Bcl-2 family, the lipid composition of the mitochondrial membranes is increasingly recognized to modulate MMP and hence cell death. The unphysiological accumulation of cholesterol in mitochondrial membranes regulates their physical properties, facilitating or impairing MMP during Bax and death ligand-induced cell death depending on the level of mitochondrial GSH (mGSH), which in turn regulates the oxidation status of cardiolipin. Cholesterol-mediated mGSH depletion stimulates TNF-induced reactive oxygen species and subsequent cardiolipin peroxidation, which destabilizes the lipid bilayer and potentiates Bax-induced membrane permeabilization. These data suggest that the balance of mitochondrial cholesterol to peroxidized cardiolipin regulates mitochondrial membrane properties and permeabilization, emerging as a rheostat in cell death.
Liver Unit and Centro de Investigaciones Biomédicas Esther Koplowitz, IMDiM, Hospital Clínic i Provincial and CIBEREHD, IDIBAPS, and Department of Cell Death and Proliferation, Instituto Investigaciones Biomédicas de Barcelona, Consejo Superior de Investigaciones Científicas, Barcelona, Spain.
Joan
J
Montero
Montserrat
M
Mari
Anna
A
Colell
Albert
A
Morales
Gorka
G
Basañez
Carmen
C
Garcia-Ruiz
Jose C
JC
Fernández-Checa
D000818:Animals; D002308:Cardiolipins / Q000378:metabolism*; D016923:Cell Death / Q000502:physiology*; D002784:Cholesterol / Q000378:metabolism*; D045304:Cytochromes c / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D008054:Lipid Peroxides / Q000378:metabolism; D008107:Liver Diseases / Q000378:metabolism; D008563:Membrane Lipids / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000378:metabolism*; D008954:Models, Biological; D009369:Neoplasms / Q000378:metabolism / Q000628:therapy; D009410:Nerve Degeneration / Q000378:metabolism; D010539:Permeability
D002308:Cardiolipins; D008054:Lipid Peroxides; D008563:Membrane Lipids; D045304:Cytochromes c; D002784:Cholesterol; D005978:Glutathione