Acetyl-L-carnitine suppresses apoptosis of thioredoxin 2-deficient DT40 cells.
To elucidate the mechanism by which L-carnitine and related metabolites inhibited mitochondria-dependent apoptosis, we used conditional TRX2-knockout DT40 cells (TRX2(-/-)) and compared the properties of signaling pathways leading to apoptosis in the wild and TRX2(-/-) cells. Caspase-3 and 9, but not caspase-8, were strongly activated in TRX2(-/-) cells but not in wild cells. TRX2(-/-) cells generated large amounts of reactive oxygen species that markedly decreased cellular glutathione levels both in cytosol and mitochondria. We found that the critical thiol groups of adenine nucleotide translocator (ANT) were oxidized more easily in TRX2(-/-) cells than in wild cells and that the reduced form, but not oxidized form, of ANT selectively bound to TRX2. Cytochrome c and SOD1 were released from mitochondria more easily in TRX2(-/-) cells than in wild cells. All these phenomena observed with TRX2(-/-) cells were effectively inhibited by acetyl-L-carntine but not L-carnitine. Thus, acetyl-L-carnitine effectively suppressed the oxidative stress in and around mitochondria thereby preventing mitochondrial signaling pathway leading to apoptosis.
Zhu
Xiaoping
X
Department of Biochemistry & Molecular Pathology, Osaka City University Medical School, 1-4-3 Asahimachi, Abeno, Osaka 545-8585, Japan.
Sato
Eisuke F
EF
Wang
Yi
Y
Nakamura
Hajime
H
Yodoi
Junji
J
Inoue
Masayasu
M
D000108:Acetylcarnitine / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology*; D002331:Carnitine / Q000494:pharmacology; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002518:Ceramides / Q000494:pharmacology; D002645:Chickens; D045304:Cytochromes c / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D000226:Mitochondrial ADP, ATP Translocases / Q000378:metabolism; D011485:Protein Binding; D017382:Reactive Oxygen Species / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013482:Superoxide Dismutase / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D013879:Thioredoxins / Q000235:genetics / Q000502:physiology*
D002518:Ceramides; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; D013879:Thioredoxins; D000108:Acetylcarnitine; D045304:Cytochromes c; D000226:Mitochondrial ADP, ATP Translocases; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D020169:Caspases; D005978:Glutathione; D002331:Carnitine