Octamer-dimer transitions of mitochondrial creatine kinase in heart disease

Mitochondrial creatine kinase (Mi-CK) occurs in dimeric and octameric forms, both in vitro and in vivo. The Mi-CK octamer, however, is the predominant form in vivo and is important for Various functions of the protein, In the present study we show for the first time a significant decrease of the octamer/dimer ratio in vivo, related to ischemia-induced damage, and a similar decrease of octamer stability in vitro, induced by peroxynitrite (PN) radicals. We used animal models to induce ischemia in two different ways: acute ischemia in intact heart (Langendorff perfusion) and chronic ischemia in vivo (LAD-infarction). In both models, impairment of heart function and mitochondrial energy metabolism was associated with a significant decrease of Mi-CK octamer/dimer ratios and of Mi-CK activities. These Endings, together with recent data showing that the formation of PN is induced in ischemia and that Mi-CK is a prime target of peroxynitrite (PM)-induced damage, suggest that oxygen radicals generated during ischemia and reoxygenation could be an important factor for the decreased octamer stability. To test this hypothesis, we studied the effect of PN on pure Mi-CK in vitro, both on dissociation of octamers and reassociation of dimers. At 1 mM PN 66% of Mi-CK octamers dissociated into dimers, whereas octamerization of PM-modified dimers was already completely inhibited at 100 mu M PN. Our data indicate that PN-induced damage could be responsible for the octamer-dimer transition of Mi-CK in ischemia. A loss of Mi-CK octamers would impair the channeling of high energy phosphate out of mitochondria and hence heart function in general. (C) 1999 Academic Press.