Cardiolipin deficiency releases cytochrome c from the inner mitochondrial membrane and accelerates stimuli-elicited apoptosis.
Cardiolipin (CL) is a mitochondria-specific phospholipid synthesized by CL synthase (CLS). We describe here a human gene for CLS and its analysis via RNAi knockdown on apoptotic progression. Although mitochondrial membrane potential is unchanged in cells containing only 25% of the normal amount of CL, free cytochrome c (cyt. c) is detected in the intermembrane space and the mitochondria exhibit signs of reorganized cristae. However, the release of cyt. c from the mitochondria still requires apoptotic stimulation. Increased sensitivity to apoptotic signals and accelerated rates of apoptosis are observed in CL-deficient cells, followed by elevated levels of secondary necrosis. Apoptosis is thought to progress via binding of truncated Bid (tBid) to mitochondrial CL, followed by CL oxidation which results in cyt. c release. The exaggerated and accelerated apoptosis observed in CL-deficient cells is matched by an accelerated reduction in membrane potential and increased cyt. c release, but not by decreased tBid binding. This study suggests that the CL/cyt. c relationship is important in apoptotic progression and that regulating CL oxidation or/and deacylation could represent a possible therapeutic target.
Choi
S-Y
SY
Graduate Program in Molecular and Cellular Biology, Center for Developmental Genetics, Stony Brook University, Stony Brook, NY 11794, USA.
Gonzalvez
F
F
Jenkins
G M
GM
Slomianny
C
C
Chretien
D
D
Arnoult
D
D
Petit
P X
PX
Frohman
M A
MA
D000818:Animals; D017209:Apoptosis; D002308:Cardiolipins / Q000378:metabolism* / Q000502:physiology; D045304:Cytochromes c / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D053078:Membrane Potential, Mitochondrial; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000378:metabolism*; D041681:NIH 3T3 Cells; D034622:RNA Interference; D017855:Transferases (Other Substituted Phosphate Groups) / Q000235:genetics / Q000378:metabolism*
D002308:Cardiolipins; D008565:Membrane Proteins; D045304:Cytochromes c; D017855:Transferases (Other Substituted Phosphate Groups); C100091:cardiolipin synthetase