Cyclophilin D, a component of the permeability transition-pore, is an apoptosis repressor.
The permeability transition (PT)-pore is an important proapoptotic protein complex in mitochondria. Although it is activated by many signals for apoptosis induction, the role of its various subunits in cell death induction has remained largely unknown. We found that of its components, only the voltage-dependent anion channel in the outer mitochondrial membrane and the adenine nucleotide translocator-1 (ANT-1), a PT-pore subunit of the inner membrane, are apoptosis inducers. We also report that ANT-1's direct interactor, cyclophilin D, can specifically repress ANT-1-induced apoptosis. In addition, cotransfection experiments revealed that for a diverse range of apoptosis inducers, cyclophilin D shows the same repression profile as the compound bongkrekic acid, a specific inhibitor of the PT-pore. This activity seems to be independent of its chaperone activity, the only known function of cyclophilin D to date. Importantly, cyclophilin D is specifically up-regulated in human tumors of the breast, ovary, and uterus, suggesting that inhibition of the PT-pore via up-regulation of cyclophilin D plays a role in tumorigenesis.
Schubert
Alexis
A
Max-Planck-Institute for Biochemistry, Martinsried, Germany.
Grimm
Stefan
S
D033741:Adenine Nucleotide Translocator 1 / Q000502:physiology*; D017209:Apoptosis / Q000502:physiology*; D001865:Bongkrekic Acid / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D003001:Cloning, Molecular; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000502:physiology*; D004272:DNA, Mitochondrial / Q000235:genetics; D005434:Flow Cytometry / Q000379:methods; D006367:HeLa Cells; D006801:Humans; D007473:Ion Channels / Q000037:antagonists & inhibitors / Q000502:physiology*; D007668:Kidney; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D010539:Permeability
D033741:Adenine Nucleotide Translocator 1; D000081406:Peptidyl-Prolyl Isomerase F; D004272:DNA, Mitochondrial; D007473:Ion Channels; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D001865:Bongkrekic Acid; D021983:Cyclophilins