Cyclosporine A protects mitochondria in an in vitro model of hypoxia/reperfusion injury.
Hypoxia/reperfusion injury is a major clinical problem. One of its hallmarks is an increased cytosolic Ca2+ content and an increased generation of reactive oxygen species in the cytosol and in mitochondria. In the present study of an in vitro model of hypoxia/reperfusion injury, mitochondria are exposed to Ca2+ in combination with extra- and intramitochondrially acting prooxidants. In this model mitochondria are damaged in a Ca(2+)-dependent manner. The extent and the site(s) of damage depend on both the kind of respiratory substrate and prooxidant used. The major damage occurs specifically at site I of the respiratory chain, and is due to hydrolysis of oxidized pyridine nucleotides and Ca2+ release followed by Ca2+ re-uptake (Ca2+ 'cycling'). Cyclosporine A completely protects against this damage. The protection is due to inhibition of pyridine nucleotide hydrolysis, an obligatory step in the sequence of events that links prooxidants to Ca2+ release from intact mitochondria.
Gogvadze
V
V
Laboratory of Biochemistry I, Swiss Federal Institute of Technology (ETH), Zürich.
Richter
C
C
D000244:Adenosine Diphosphate / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology*; D004533:Egtazic Acid / Q000494:pharmacology; D000860:Hypoxia; D007700:Kinetics; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects*; D051381:Rats; D015427:Reperfusion Injury / Q000517:prevention & control*
D004533:Egtazic Acid; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; D000244:Adenosine Diphosphate; D016572:Cyclosporine; D002118:Calcium