Melatonin and mitochondrial protection in cardiac ischemia–reperfusion injury: mechanisms, evidence and translational perspectives

Cardiac ischemia-reperfusion injury (IRI) leads to significant mitochondrial impairment, which contributes to cell death and hampers myocardial recovery. During IRI, mitochondria are subjected to oxidative stress, calcium overload, and altered dynamics, resulting in the opening of the mitochondrial permeability transition pore (mPTP), release of cytochrome c, and activation of apoptotic pathways. Melatonin, a pleiotropic indoleamine produced by the pineal gland and other tissues, has cardioprotective effects through both direct antioxidant activity and receptor-mediated mechanisms. This review explores melatonin's role in maintaining mitochondrial integrity under IRI conditions. Melatonin counteracts oxidative damage by neutralizing reactive oxygen species, stabilizing mitochondrial membrane potential, and preventing mPTP opening, thereby reducing activation of cell death pathways. It also supports mitochondrial biogenesis and dynamics, contributing to energy balance and reduced oxidative burden. In addition, melatonin regulates mitophagy, ensuring mitochondrial quality control and preventing excessive degradation, which collectively contributes to restoring mitochondrial function and cellular metabolism. In rodent preclinical models, melatonin administration before ischemia, during ischemia, or at reperfusion has consistently reduced infarct size and improved cardiac function. While these preclinical findings are encouraging, studies on rabbits or pigs and clinical studies have not consistently replicated these benefits. The variability in outcomes may be attributed to differences in study design, timing and method of melatonin administration, and types of endpoints measured. Comorbidities, risk factors, and comedications further influence mitochondrial biology and melatonin's efficacy in cardiac IRI. A dedicated comparative analysis evaluates melatonin against established and emerging cardioprotective approaches targeting mitochondria, underscoring its potential for combination therapies.