Melatonin Preserves Mitochondrial Redox Balance in UVB-Exposed Human Keratinocytes

Melatonin (N-acetyl-5-methoxytryptamine) is an evolutionarily conserved indoleamine with potent antioxidant and cytoprotective properties. Due to its amphiphilic nature, melatonin readily accumulates in mitochondria, where it regulates redox homeostasis and bioenergetic function. Although melatonin has been implicated in cutaneous protection against ultraviolet radiation (UVR), the mitochondrial mechanisms underlying its effects in UVB-exposed keratinocytes remain insufficiently characterized. In this study, we investigated the mitochondrial-centered protective effects of melatonin in human epidermal keratinocytes (NHEKs) subjected to UVB irradiation. UVB exposure induced a dose-dependent decrease in cell viability and proliferation, accompanied by excessive reactive oxygen species (ROS) production, mitochondrial membrane depolarization (ΔΨm), ATP depletion, caspase-3 activation, and increased expression of DNA damage- and senescence-associated markers, including γH2AX, p53, and p16^INK4a. Pre-treatment with melatonin attenuated these alterations by reducing oxidative stress, preserving ΔΨm, maintaining ATP production, suppressing apoptotic signaling, and modulating DNA damage- and senescence-related pathways. Collectively, our findings suggest that mitochondria are a central target of melatonin in UVB-exposed keratinocytes and demonstrate that maintenance of mitochondrial redox balance and bioenergetic integrity is associated with reduced apoptotic and senescence-related changes.