Melatonin rescues cell respiration impaired by hypoxia/reoxygenation in aortic endothelial cells and affects the mitochondrial bioenergetics targeting the F1FO-ATPase

Melatonin is evaluated as a potential molecular therapy to counteract mitochondrial dysfunction caused by hypoxia/reoxygenation (H/R) in aortic endothelial cells (pAECs). The mitochondrial permeability transition pore (mPTP) opening undergoes a desensitizing action coupled with a reduction of superoxide anion production in mitochondria treated with melatonin. The effect on mPTP has been attributed to the direct interaction of melatonin with the hydrophilic F1 domain of Ca2+-activated F1FO-ATPase. Mutual exclusion analysis highlights an overlapping binding site between melatonin and the specific F1 inhibitor NBD-Cl. The results are corroborated by melatonin inhibition of ATPase activity of the purified F1 domain in the presence of Ca2+, but not in the presence of natural cofactor Mg2+. Moreover, the impairment of bioenergetics parameters in pAECs metabolism and the increase of oxidative stress arising by H/R injury have been rescued in cells protected by melatonin treatment.