Mitochondrial permeability transition and cytochrome c release in ischemia-reperfusion injury of the rat liver.
BACKGROUND
We investigated whether ischemia-reperfusion causes activation of caspases and whether this activation is related to cytochrome c release from the mitochondria into the cytosol as a result of the mitochondrial inner membrane permeability transition.


METHODS
Rats were subjected to 30 min to 120 min of hepatic ischemia followed by 6 h of reperfusion. Cyclosporin A or ruthenium red (inhibitors of the mitochondrial inner membrane permeability transition) was given intravenously at 60 and 30 min before ischemia, respectively.


RESULTS
Reperfusion after ischemia caused the release of liver enzymes accompanied by mitochondrial membrane depolarization, DNA fragmentation, and translocation of cytochrome c from the mitochondria into the cytosol. Accumulation of cytochrome c in the cytosol and activation of caspase-3-like protease was already detected during ischemia and before reperfusion. Pretreatment with cyclosporin A or ruthenium red significantly ameliorated the loss of the mitochondrial membrane potential, the increase of plasma membrane permeability, the cytosolic accumulation of cytochrome c, DNA fragmentation, and caspase-3-like protease activation.


CONCLUSIONS
The mitochondrial inner membrane permeability transition occurs during ischemia and/or after reperfusion, resulting in translocation of cytochrome c and activation of caspases.
Hirakawa
Akihiko
A
Department of Emergency and Critical Care Medicine, Kansai Medical University, Moriguchi, Osaka, Japan. takeyama@takii.kmu.ac.jp
Takeyama
Naoshi
N
Nakatani
Toshio
T
Tanaka
Takaya
T
D000818:Animals; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002463:Cell Membrane Permeability / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology; D003574:Cytochrome c Group / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D053938:DNA Fragmentation; D004789:Enzyme Activation; D007425:Intracellular Membranes / Q000502:physiology; D008099:Liver / Q000098:blood supply* / Q000201:enzymology / Q000648:ultrastructure; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008930:Mitochondria, Liver / Q000378:metabolism* / Q000648:ultrastructure; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000378:metabolism*; D012430:Ruthenium Red / Q000494:pharmacology
D003574:Cytochrome c Group; D012430:Ruthenium Red; D016572:Cyclosporine; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases