In their report, Turer and Hill reviewed the pathogenesis of myocardial ischemia-reperfusion injury and rationale for therapy. They discussed the role of mitochondria in reactive oxygen species production. We would like to point out an important aspect of the role of melatonin in mitochondrial permeability transition pore (MPTP) opening.

Mitochondria are considered the main intracellular source of reactive oxygen species as well as the major target of free radical attack. Reactive oxygen species–induced alterations to mitochondrial membrane constituents may lead to a decrease in the bioenergetic function of mitochondria, and this may be a contributory factor in ischemia-reperfusion injury. Growing evidence supports a crucial role of MPTP in cardiomyocyte cell death occurring during ischemia-reperfusion.

Melatonin is a human circadian hormone with well-known antioxidant properties. Melatonin is a highly conserved molecule found in organisms from unicells to vertebrates. Chemically, melatonin and its metabolites can function as endogenous free radical scavengers and broad-spectrum antioxidants. Because of its small size and amphiphilic nature, melatonin easily reaches all cellular and subcellular compartments.

In vitro and in vivo experiments have shown that melatonin can influence mitochondrial homeostasis. Very recently, Petrosillo et al demonstrated that melatonin protects against heart ischemia-reperfusion injury by inhibiting MPTP opening. Melatonin treatment significantly improves the functional recovery of Langendorff hearts on reperfusion, reduces the infarct size, and decreases necrotic damage, as shown by the reduced release of lactate dehydrogenase. All these effects were accompanied by the inhibition of the MPTP opening detected in situ by the mitochondrial release of nicotinamide adenine dinucleotide.

This ability of the mitochondria to accumulate melatonin is of great pharmacologic interest because it means that after exogenous administration in vivo, melatonin enters the mitochondria to exert its beneficial action. Regarding the antioxidant effects of melatonin, which may reduce myocardial damage induced by ischemia-reperfusion, we are assessing, in a prospective trial (Melatonin Adjunct in the Acute Myocardial Infarction Treated With Angioplasty [MARIA]) whether pharmacologic doses of melatonin in patients with ST-segment elevation myocardial infarctions confer cardioprotection against ischemia-reperfusion injury. We wish to finish with success our phase II study, and we await our results with great interest.