Background: Mitochondrial respiration is the main source of energy in aerobic animal cells and is adapted to the energy demand by respiratory coupling. Uncoupling proteins (UCPs) perturb respiratory coupling by inducing a proton leak through the mitochondrial inner membrane. Although this could lead to deleterious energy waste, it may prevent the production of oxygen radicals when the rate of phosphorylation of ADP into ATP is low, whereas oxygen and substrate availability to mitochondria is high. The latter conditions are encountered during cardiac reperfusion after ischemia and are highly relevant to heart infarction.
Methods and results: Heart function of 6 transgenic mice expressing high amounts of UCP1 and of 6 littermate controls was compared in isolated perfused hearts in normoxia, after 40-minute global ischemia, and on reperfusion. In normoxia, oxygen consumption, contractility (quantified as the rate-pressure product), and their relationship (energetic yield) were similar in controls and transgenic mice. Although UCP1 expression did not alter the sensitivity to ischemia, it significantly improved functional recovery on reperfusion. After 60 minutes of reperfusion, contractility was 2-fold higher in transgenic mice than in controls. Oxygen consumption remained significantly depressed in controls (53+/-27% of control), whereas it recovered strikingly to preischemic values in transgenic mice, showing uncoupling of respiration by UCP1 activity. Glutathione and aconitase, markers of oxidative damage, indicated lower oxidative stress in transgenic mice.
Conclusions: UCP1 activity is low under normoxia but is induced during ischemia-reperfusion. The presence of UCP1 mitigates reperfusion-induced damage, probably because it lowers mitochondrial hyperpolarization at reperfusion.