Cardiolipin and apoptosis.
Cardiolipin (CL) is recognized to be an essential phospholipid in eukaryotic energy metabolism so that physiological and pathological perturbations in its synthetic and catabolic pathways play key roles in maintaining mitochondrial structure and function, and ultimately cell survival. This review describes potential regulatory mechanisms in CL synthesis and the effects of de-acylation pathways on steady state levels of CL and its interaction with cytochrome c. The latter interaction is significant in the initiation of programmed cell death. Physiological factors that modify CL acylation include ageing, dietary influences and ischemia/reperfusion where the terminal events may be either necrosis or apoptosis. In various pathologies, phospholipase activity increases in response to production of peroxidized CL. The cell may use lysosomal or mitochondrial pathways for CL degradation. However, the manner by which CL and cytochrome c leave the mitochondria is not well understood. The lipid (CL)-bound form of cytochrome c is thought to initiate apoptosis via a lipid transfer step involving mitochondrially targeted Bid. A direct relationship between CL loss and cytochrome c release from the mitochondria has been identified as an initial step in the pathway to apoptosis. An absolute requirement for CL in the function of crucial mitochondrial proteins, e.g., cytochrome oxidase and the adenine nucleotide translocase, are likely additional factors impacting apoptosis and cellular energy homeostasis. This is reflected in the occurrence of both oncotic and apoptotic events in ischemia and reperfusion injury. Other potential clinical manifestations of perturbations of CL synthesis are discussed with particular emphasis on Barth Syndrome where a primary defect can be attributed to CL metabolism and is associated with dilated cardiomyopathy. Finally, the model of fatty acid induced apoptosis is used as a paradigm to our understanding of the temporal relationship between decreased mitochondrial CL, release of cytochrome c, and initiation of apoptosis.
McMillin
Jeanie B
JB
The Department of Pathology and Laboratory Medicine, the University of Texas Medical School at Houston, The University of Texas Health Science Center, 6431 Fannin, Houston, TX 77030, USA.
Dowhan
William
W
D000215:Acylation; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002308:Cardiolipins / Q000096:biosynthesis / Q000502:physiology*; D002311:Cardiomyopathy, Dilated / Q000378:metabolism; D002312:Cardiomyopathy, Hypertrophic / Q000378:metabolism; D002478:Cells, Cultured; D003574:Cytochrome c Group / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism; D008929:Mitochondria, Heart / Q000378:metabolism / Q000502:physiology; D000226:Mitochondrial ADP, ATP Translocases / Q000378:metabolism; D008956:Models, Chemical; D017202:Myocardial Ischemia / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D017855:Transferases (Other Substituted Phosphate Groups) / Q000172:deficiency
D002308:Cardiolipins; D003574:Cytochrome c Group; D005227:Fatty Acids; D000226:Mitochondrial ADP, ATP Translocases; D003576:Electron Transport Complex IV; D017855:Transferases (Other Substituted Phosphate Groups); C020676:CDP-diacylglycerol-glycerol-3-phosphate 3-phosphatidyltransferase