Proapoptotic Bid binds to monolysocardiolipin, a new molecular connection between mitochondrial membranes and cell death.
Recent evidence indicates that the mitochondrial lipid cardiolipin may be instrumental in the proapoptotic action of Bcl-2 family proteins on mitochondrial membranes, leading to the release of apoptogenic factors. However, contrasting evidence indicates that progressive loss of cardiolipin occurs during apoptosis. Here we show that Bid, a crucial proapoptotic protein that integrates the action of other Bcl-2 family members, exhibits discrete specificity for metabolites of cardiolipin, especially monolysocardiolipin (MCL). MCL, normally present in the remodelling of mitochondrial lipids, progressively increases in mitochondria during Fas-mediated apoptosis as a by-product of cardiolipin degradation, and also enhances Bid binding to membranes. MCL may thus play a crucial role in connecting lipid metabolism, relocation of Bid to mitochondria and integrated action of Bcl-2 proteins on mitochondrial membranes. We propose that Bid interaction with MCL 'primes' the mitochondrial outer membrane via segregation of lipid domains, facilitating membrane discontinuity and leakage of apoptogenic factors.
Esposti
M Degli
MD
School of Biological Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, UK. mauro.esposti@man.ac.uk
Cristea
I M
IM
Gaskell
S J
SJ
Nakao
Y
Y
Dive
C
C
D000818:Animals; D017209:Apoptosis; D051023:BH3 Interacting Domain Death Agonist Protein; D002308:Cardiolipins / Q000737:chemistry* / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism / Q000502:physiology*; D002474:Cell-Free System; D004305:Dose-Response Relationship, Drug; D007425:Intracellular Membranes / Q000378:metabolism*; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism; D008246:Lysophospholipids / Q000737:chemistry* / Q000378:metabolism; D013058:Mass Spectrometry; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D008930:Mitochondria, Liver / Q000378:metabolism; D011485:Protein Binding; D011994:Recombinant Proteins / Q000737:chemistry; D021241:Spectrometry, Mass, Electrospray Ionization
D051023:BH3 Interacting Domain Death Agonist Protein; C494815:Bid protein, mouse; D002308:Cardiolipins; D002352:Carrier Proteins; D008246:Lysophospholipids; D011994:Recombinant Proteins; C067188:monolysocardiolipin