Revisiting the role of melatonin in human melanocyte physiology: A skin context perspective

Abstract

The evolutionarily ancient methoxyindoleamine, melatonin, has long perplexed investigators by its versatility of functions and mechanisms of action, which include the regulation of vertebrate pigmentation. Although first discovered through its potent skin‐lightening effects in amphibians, melatonin's role in human skin and hair follicle pigmentation and its impact on melanocyte physiology remain unclear. Synthesizing our limited current understanding of this role, we specifically examine its impact on melanogenesis, oxidative biology, mitochondrial function, melanocyte senescence, and pigmentation‐related clock gene activity, with emphasis on human skin, yet without ignoring instructive pointers from nonhuman species. Given the strict dependence of melanocyte functions on the epithelial microenvironment, we underscore that melanocyte responses to melatonin are best interrogated in a physiological tissue context. Current evidence suggests that melatonin and some of its metabolites inhibit both, melanogenesis (via reducing tyrosinase activity) and melanocyte proliferation by stimulating melatonin membrane receptors (MT1, MT2). We discuss whether putative melanogenesis‐inhibitory effects of melatonin may occur via activation of Nrf2‐mediated PI3K/AKT signaling, estrogen receptor‐mediated and/or melanocortin‐1 receptor‐ and cAMP‐dependent signaling, and/or via melatonin‐regulated changes in peripheral clock genes that regulate human melanogenesis, namely Bmal1 and Per1. Melatonin and its metabolites also accumulate in melanocytes where they exert net cyto‐ and senescence‐protective as well as antioxidative effects by operating as free radical scavengers, stimulating the synthesis and activity of ROS scavenging enzymes and other antioxidants, promoting DNA repair, and enhancing mitochondrial function. We argue that it is clinically and biologically important to definitively clarify whether melanocyte cell culture‐based observations translate into melatonin‐induced pigmentary changes in a physiological tissue context, that is, in human epidermis and hair follicles ex vivo, and are confirmed by clinical trial results. After defining major open questions in this field, we close by suggesting how to begin answering them in clinically relevant, currently available preclinical in situ research models.

Recognition of Melanocytes in Immuno-Neuroendocrinology and Circadian Rhythms: Beyond the Conventional Melanin Synthesis

“…Melatonin (MT), an evolutionary ancient hormone, has been found in almost all organisms, ranging from animals, plants, and microorganisms [52,53]. Increasing studies have revealed that melanocytes can endogenously produce melatonin and its precursor serotonin (5 hydroxytryptamines: 5-HT) [54][55][56].…”

“…Well established as the guardian of the genome and cellular and tissue in humans, melatonin exerts pleiotropic functions via melatonin receptor-dependent or non-receptor-dependent pathways such as potent antioxidative, free radical scavenging, anti-inflammatory, and mitochondrial protective activities [52,53]. It has been reported that melatonin and its metabolites, such as 6-hydroxymelatonin (6(OH)M), N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK), can inhibit proliferation, pigmentation, and DNA synthesis in a dose-dependent manner in melanocytes [58].…”

“…In addition, accumulating evidence suggests that they can also mediate phenotypic actions, including regulating keratinocyte proliferation and differentiation, enhancing epidermal barrier formation, regulating hair growth cycling, and counteracting UVB-induced skin damage [60,[63][64][65]. Hence, the topical application of these multifunctional molecules is promising and attractive in the treatment of pigmentary disorders and other skin diseases, such as atopic dermatitis [52,53,61].…”

Essential Oils and Melatonin as Functional Ingredients in Dogs

“…Additionally, in an open-label study of women and men with androgenetic alopecia, melatonin (33 ppm) topical application reduced the alopecia degree, and the TrichoScan technique showed a 29.2% increase in the hair count in 54.8% of patients after 3 months, and a 42.7% increase in 58.1% of patients after 6 months, demonstrating improvements in hair texture, decreased hair loss, and a reduction in seborrheic dermatitis, in safety and tolerant topical application of a cosmetic melatonin solution [ 117 ]. An exhaustive and recent revision of melatonin action in melanocyte physiology in humans and other mammals can be consulted [ 118 ].…”

Evolutionary Genomics Reveals Multiple Functions of Arylalkylamine N-Acetyltransferase in Fish

“…Therefore, melatonin was previously reported to be mainly synthesized in pinealocytes and then released into the bloodstream to reach central and peripheral organs for diverse roles. However, recent reports indicate that a majority of melatonin is synthesized in other tissues such as gut and skin rather than the pineal gland ( Yasmin et al, 2021 ; Sevilla et al, 2022 ), suggesting that it can also regulate biological activities by binding to its specific receptors in target tissues ( Shi et al, 2004 ; Isorna et al, 2009 ; Kuz’mina, 2020 ).…”