CYCLOSPORINE A PROTECTS MITOCHONDRIA IN AN IN-VITRO MODEL OF HYPOXIA REPERFUSION INJURY

Hypoxia/reperfusion injury is a major clinical problem. One of its hal lmarks is an increased cytosolic Ca2+ content and an increased generat ion 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 intram itochondrially acting prooxidants. In this model mitochondria are dama ged in a Ca2+-dependent manner. The extent and the site(s) of damage d epend on both the kind of respiratory substrate and prooxidant used. T he major damage occurs specifically at site I of the respiratory chain , and is due to hydrolysis of oxidized pyridine nucleotides and Ca2+ r elease followed by Ca2+ re-uptake (Ca2+ 'cycling'). Cyclosporine A com pletely protects against this damage. The protection is due to inhibit ion of pyridine nucleotide hydrolysis, an obligatory step in the seque nce of events that links prooxidants to Ca2+ release from intact mitoc hondria.