Oxidative stress underlies the mechanism for Ca(2+)-induced permeability transition of mitochondria.
Recent studies demonstrated that the generation of intracellular reactive oxygen species (ROS) was enhanced prior to the onset of mitochondrial membrane permeability transition (MPT), a critical step for the induction of DNA fragmentation and apoptosis. Although Ca2+ induces typical MPT that involves depolarization and swelling of mitochondria and finally releases cytochrome c into cytosol, the mechanism by which ROS induce MPT remains unclear. In the presence of inorganic phosphate, Ca2+ increased the oxygen consumption and ROS production by isolated mitochondria as determined by a chemiluminescence (CHL) method using L-012. Ca2+ increased the generation of H2O2 by some mechanism that was inhibited by cyclosporin A but not by superoxide dismutase (SOD) and trifluoperazine. Ca2+ decreased the content of free thiols in adenine nucleotide translocase (ANT) in mitochondrial membranes with concomitant increase in ROS generation. The presence of cyclosporin A, trifluoperazine, or SOD inhibited the Ca(2+)-induced increase of L-012 CHL and decrease in the free thiols of ANT. These results indicate that Ca2+ increases the generation of ROS which oxidize the free thiol groups in mitochondrial ANT, thereby inducing MPT to release cytochrome c.
Kanno
Tomoko
T
Institute of Medical Science, Kurashiki Medical Center, Kurashiki 710-8522, Japan. kanno@mx3.kct.ne.jp
Sato
Eisuke E
EE
Muranaka
Shikibu
S
Fujita
Hirofumi
H
Fujiwara
Takuzo
T
Utsumi
Toshihiko
T
Inoue
Masayasu
M
Utsumi
Kozo
K
D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002118:Calcium / Q000378:metabolism*; D019069:Cell Respiration / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology; D045304:Cytochromes c / Q000378:metabolism; D007425:Intracellular Membranes / Q000187:drug effects / Q000378:metabolism*; D008163:Luminescent Measurements; D008165:Luminol / Q000031:analogs & derivatives* / Q000378:metabolism; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism*; D000226:Mitochondrial ADP, ATP Translocases / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress; D010539:Permeability; D010710:Phosphates / Q000494:pharmacology; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000378:metabolism; D013482:Superoxide Dismutase / Q000494:pharmacology; D014268:Trifluoperazine / Q000494:pharmacology
D010710:Phosphates; D017382:Reactive Oxygen Species; D013438:Sulfhydryl Compounds; C081614:L 012; D014268:Trifluoperazine; D008165:Luminol; D016572:Cyclosporine; D045304:Cytochromes c; D000226:Mitochondrial ADP, ATP Translocases; D013482:Superoxide Dismutase; D002118:Calcium