Mitochondrial permeability transition during hypothermic to normothermic reperfusion in rat liver demonstrated by the protective effect of cyclosporin A

The purpose of this study was to test the hypothesis that mitochondrial per meability transition might be implicated in mitochondrial and intact organ dysfunctions associated with damage induced by reperfusion after cold ischa emia. Energetic metabolism was assessed continuously by P-31-NMR on a model system of isolated perfused rat liver; mitochondria were extracted from th e livers and studied by using top-down control analysis. During the tempera ture transition from hypothermic to normothermic perfusion (from 4 to 37 de grees C) the ATP content of the perfused organ fell rapidly, and top-down m etabolic control analysis of damaged mitochondria revealed a specific contr ol pattern characterized by a dysfunction of the phosphorylation subsystem leading to a decreased response to cellular ATP demand. Both dysfunctions w ere fully prevented by cyclosporin A, a specific inhibitor of the mitochond rial transition pore (MTP). These results strongly suggest the involvement of the opening of MTP in vivo during the transition to normothermia on rat liver mitochondrial function and organ energetics.