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 oct amer/dimer ratio in vivo, related to ischemia-induced damage, and a similar decrease of octamer stability in vitro, induced by peroxynitrite (PN) radi cals. We used animal models to induce ischemia in two different ways: acute ischemia in intact heart (Langendorff perfusion) and chronic ischemia in v ivo (LAD-infarction). In both models, impairment of heart function and mito chondrial energy metabolism was associated with a significant decrease of M i-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 an d that Mi-CK is a prime target of peroxynitrite (PM)-induced damage, sugges t that oxygen radicals generated during ischemia and reoxygenation could be an important factor for the decreased octamer stability. To test this hypo thesis, we studied the effect of PN on pure Mi-CK in vitro, both on dissoci ation of octamers and reassociation of dimers. At 1 mM PN 66% of Mi-CK octa mers 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 hig h energy phosphate out of mitochondria and hence heart function in general. (C) 1999 Academic Press.