| Autor: |
Soboll, Sibylle, Brdiczka, Dieter, Jahnke, Dietmar, Schmidt, Anja, Schlattner, Uwe, Wendt, Silke, Wyss, Markus, Wallimann, Theo |
| Zdroj: |
Journal of Molecular and Cellular Cardiology; April 1999, Vol. 31 Issue: 4 p857-866, 10p |
| Abstrakt: |
Mitochondrial creatine kinase (Mi-CK) occurs in dimeric and octameric forms, bothin vitroandin vivo. The Mi-CK octamer, however, is the predominant formin vivoand 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 ratioin vivo, related to ischemia-induced damage, and a similar decrease of octamer stabilityin 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 ischemiain 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 findings, together with recent data showing that the formation of PN is induced in ischemia and that Mi-CK is a prime target of peroxynitrite (PN)-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-CKin vitro, both on dissociation of octamers and reassociation of dimers. At 1 mmPN 66% of Mi-CK octamers dissociated into dimers, whereas octamerization of PN-modified dimers was already completely inhibited at 100μmPN. 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. |
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