Ischemia/reperfusion impairs mitochondrial energy conservation and triggers O2.- release as a byproduct of respiration.

The aim of the present study was to elucidate the role of mitochondria in the development of heart failure following ischemia/reperfusion. Although mitochondria were increasingly assumed to be responsible for the establishment of an oxidative stress situation the lack of suitable methods to prove it required new concepts for an evaluation of the validity of this hypothesis. The principal idea was to expose isolated mitochondria to metabolic conditions which are developed during ischemia/reperfusion in the cell (anoxia, lactogenesis) and study how they respond. Heart mitochondria treated in that way responded with an incomplete collapse of the transmembraneous proton gradient, thereby impairing respiration-linked ATP generation. The membrane effect affected also the proper control of e- transfer through redox-cycling ubisemiquinone. Electrons were found to leak at this site from its normal pathway to O2 suggesting that ubisemiquinone becomes an active O2.- generator. It was concluded from these observations that mitochondria are likely to play a pathogenetic role in the reperfusion injury of the heart both, by an impairment of energy conservation and their transition to a potent O2.(-)-radical generator. Furthermore, there is considerable evidence that the exogenous NADH-dehydrogenase of heart mitochondria is mainly responsible for functional changes of these organelles during ischemia/reperfusion.