Mitochondria in apoptosis: past, present and future.
The role of mitochondria in cell death has been increasingly appreciated in the last few years and is now well established in a variety of cellular systems. At present we know that the involvement of mitochondria is regulated by proteins of the Bcl-2 (B-cell lymphocytic-leukaemia proto-oncogene 2) family, which biochemically act by altering the properties of mitochondrial membranes to facilitate the release of apoptogenic proteins like cytochrome c and Smac/Diablo that, once released into the cytosol, are crucial for activating the caspase cascade of cell degradation. The precise mechanism of the pro-apoptotic action is not fully understood yet, but could be clarified in the near future. Instrumental to this clarification is the emerging evidence that CL (cardiolipin), an unusual membrane lipid that is predominantly present in mitochondria, is required for the action of major pro-apoptotic proteins like Bid and Bax. New results obtained in myeloid cells further sustain this possibility and suggest that Bid may be involved in the metabolic cycle of CL re-modelling. In agreement with this postulate, preliminary results indicate a down-regulation of Bid in parallel to the genetic deficiency in CL re-modelling that is associated with a rare human disease, 'Barth Syndrome'. Intriguingly, this disease is characterized by neutropenia, suggesting a link between myeloid differentiation and cell death (and myeloid lymphoma pathogenesis too). I will project current results and trends towards future investigations on the involvement of CL and mitochondrial membranes in myeloid differentiation, cell death and disease.
Degli Esposti
M
M
School of Biological Sciences, University of Manchester, Stopford Building, Oxford Road, Manchester M13 9PT, UK. mauro.esposti@man.ac.uk
D000818:Animals; D017209:Apoptosis; D051023:BH3 Interacting Domain Death Agonist Protein; D002308:Cardiolipins / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D002454:Cell Differentiation; D045304:Cytochromes c / Q000378:metabolism; D006801:Humans; D050356:Lipid Metabolism; D008928:Mitochondria / Q000502:physiology*; D009504:Neutrophils / Q000166:cytology; D000090063:Proto-Oncogene Mas; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D051028:bcl-2-Associated X Protein
C494826:BAX protein, human; D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D002308:Cardiolipins; D002352:Carrier Proteins; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D045304:Cytochromes c