Redox Biology of Melatonin: Discriminating Between Circadian and Noncircadian Functions

Melatonin has not only to be seen as a regulator of circadian clocks. In addition to its chronobiotic functions, it displays other actions, especially in cell protection. This includes antioxidant, anti-inflammatory, and mitochondria-protecting effects. Although protection is also modulated by the circadian system, the respective actions of melatonin can be distinguished and differ with regard to dose requirements in therapeutic settings. It is the aim of this article to outline these differences in terms of function, signaling, and dosage. Focus has been placed on both the nexus and the dissecting properties between circadian and noncircadian mechanisms. This has to consider details beyond the classic view of melatonin's role, such as widespread synthesis in extrapineal tissues, formation in mitochondria, effects on the mitochondrial permeability transition pore, and secondary signaling, for example, via upregulation of sirtuins and by regulating noncoding RNAs, especially microRNAs. The relevance of these findings, the differences and connections between circadian and noncircadian functions of melatonin shed light on the regulation of inflammation, including macrophage/microglia polarization, damage-associated molecular patterns, avoidance of cytokine storms, and mitochondrial functions, with numerous consequences to antioxidative protection, that is, aspects of high actuality with regard to deadly viral and bacterial diseases. Antioxid. Redox Signal. 37, 704-725.