TRIAP1/PRELI complexes prevent apoptosis by mediating intramitochondrial transport of phosphatidic acid.
Cardiolipin (CL), a mitochondria-specific glycerophospholipid, is required for diverse mitochondrial processes and orchestrates the function of various death-inducing proteins during apoptosis. Here, we identify a complex of the p53-regulated protein TRIAP1 (p53CSV) and PRELI in the mitochondrial intermembrane space (IMS), which ensures the accumulation of CL in mitochondria. TRIAP1/PRELI complexes exert lipid transfer activity in vitro and supply phosphatidic acid (PA) for CL synthesis in the inner membrane. Loss of TRIAP1 or PRELI impairs the accumulation of CL, facilitates the release of cytochrome c, and renders cells vulnerable to apoptosis upon intrinsic and extrinsic stimulation. Survival of TRIAP1- and PRELI-deficient cells is conferred by an excess of exogenously provided phosphatidylglycerol. Our results reveal a p53-dependent cell-survival pathway and highlight the importance of the CL content of mitochondrial membranes in apoptosis.
Institute for Genetics, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, Center for Molecular Medicine, University of Cologne, Germany.
Christoph
C
Potting
Takashi
T
Tatsuta
Tim
T
König
Mathias
M
Haag
Timothy
T
Wai
Mari J
MJ
Aaltonen
Thomas
T
Langer
D000595:Amino Acid Sequence; D017209:Apoptosis; D001692:Biological Transport; D002308:Cardiolipins / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival; D045304:Cytochromes c / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D046912:Multiprotein Complexes / Q000378:metabolism; D010712:Phosphatidic Acids / Q000378:metabolism*; D010715:Phosphatidylglycerols / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D016415:Sequence Alignment; D015398:Signal Transduction
D002308:Cardiolipins; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D046912:Multiprotein Complexes; C102194:PRELID1 protein, human; D010712:Phosphatidic Acids; D010715:Phosphatidylglycerols; D034741:RNA, Small Interfering; C498536:TRIAP1 protein, human; D045304:Cytochromes c