Melatonin and mitochondrial function during ischemia/reperfusion injury

Abstract

Ischemia/reperfusion (IR) injury occurs in many organs and tissues, and contributes to morbidity and mortality worldwide. Melatonin, an endogenously produced indolamine, provides a strong defense against IR injury. Mitochondrion, an organelle for ATP production and a decider for cell fate, has been validated to be a crucial target for melatonin to exert its protection against IR injury. In this review, we first clarify the mechanisms underlying mitochondrial dysfunction during IR and melatonin's protection of mitochondria under this condition. Thereafter, special focus is placed on the protective actions of melatonin against IR injury in brain, heart, liver, and others. Finally, we explore several potential future directions of research in this area. Collectively, the information compiled here will serve as a comprehensive reference for the actions of melatonin in IR injury identified to date and will hopefully aid in the design of future research and increase the potential of melatonin as a therapeutic agent.

Keywords: Ischemia/reperfusion injury; Melatonin; Mitochondria; Oxidative stress.

Fig. 1

The mechanisms underlying mitochondrial dysfunction in IR and melatonin’s protection of mitochondria under this condition. IR leads to electron leakage and excessive free radical production in mitochondria. The excessive free radical directly causes oxidative damage to mitochondrial respiratory chain and EME further leading to a burst of electron leakage and free radical production. Moreover, free radical also damages mitochondrial membrane structure (TOM complex reduction and mitochondrial membrane lipid peroxidation) and increases MPTP opening, resulting in membrane potential loss and pro-apoptosis factor release. Apart from directly scavenging free radical, melatonin also activates STAT3, a transcription factor for antioxidant enzymes, by activating SAFE pathway and JAK2. Melatonin activates AMPK–PGC-1α–SIRT3 axis to reduce mitochondrial oxidative stress and enhances its biogenesis. By activating PGC-1α, melatonin also upregulates TOM complex, the entry gate for the majority of precursor proteins that are imported into the mitochondria. As a result, melatonin exerts protective effects on diverse organs enduring IR injury. Red arrows damaging processes. Green arrows promotion or amelioration. Blue arrows inhibitory effects (AMPK adenosine monophosphate-activated protein kinase, EME energy metabolism enzymes, IR ischemia/reperfusion, JAK2 Janus kinase 2, MPTP mitochondrial permeability transition pore, SAFE survivor activating factor enhancement, SIRT3 silent information regulator 3, STAT3 signal transducer and activator of transcription 3, PGC-1α peroxisome proliferator-activated receptor-gamma coactivator-1α, TOM translocases in the outer membrane)