Abstract
Caffeine is chemically stable and not readily oxidized under normal physiological conditions but also has antioxidant effects, although the underlying molecular mechanism is not well understood. Superoxide dismutase (SOD) 2 is a manganese-containing enzyme located in mitochondria that protects cells against oxidative stress by scavenging reactive oxygen species (ROS). SOD2 activity is inhibited through acetylation under conditions of stress such as exposure to ultraviolet (UV) radiation. Sirtuin 3 (SIRT3) is the major mitochondrial nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase, which deacetylates two critical lysine residues (lysine 68 and lysine 122) on SOD2 and promotes its antioxidative activity. In this study, we investigated whether the antioxidant effect of caffeine involves modulation of SOD2 by SIRT3 using in vitro and in vivo models. The results show that caffeine interacts with SIRT3 and promotes direct binding of SIRT3 with its substrate, thereby enhancing its enzymatic activity. Mechanistically, caffeine bound to SIRT3 with high affinity (KD = 6.858 × 10–7 M); the binding affinity between SIRT3 and its substrate acetylated p53 was also 9.03 (without NAD+) or 6.87 (with NAD+) times higher in the presence of caffeine. Caffeine effectively protected skin cells from UV irradiation-induced oxidative stress. More importantly, caffeine enhanced SIRT3 activity and reduced SOD2 acetylation, thereby leading to increased SOD2 activity, which could be reversed by treatment with the SIRT3 inhibitor 3-(1H-1,2,3-triazol-4-yl) pyridine (3-TYP) in vitro and in vivo. Taken together, our results show that caffeine targets SIRT3 to enhance SOD2 activity and protect skin cells from UV irradiation-induced oxidative stress. Thus, caffeine, as a small-molecule SIRT3 activator, could be a potential agent to protect human skin against UV radiation.
Highlights
Ultraviolet (UV)A and UVB radiation in sunlight negatively impacts the appearance of human skin
The results showed that 32–4,096 μM caffeine did not reduce free radical levels in vitro (Figure 1B)
It is reported that antioxidant enzyme superoxide dismutase 2 (SOD2) protects against oxidative stress by converting superoxide anion into less toxic hydrogen peroxide (Tao et al, 2010)
Summary
Ultraviolet (UV)A and UVB radiation in sunlight negatively impacts the appearance of human skin. UVA is absorbed by chromophores in dermal cells to induce the generation of ROS that indirectly cause oxidative damage to DNA, leading to mutations and cancer (Farrar et al, 2018; Rybchyn et al, 2018). UVB damages the membranes and proteins of cells on the surface layer of skin and superficial layer of the dermis, leading to sunburn erythema that can result in skin cancer in extreme cases (Khalil and Shebaby, 2017; Raad et al, 2017). The physical and chemical properties of caffeine make it highly stable, and evidence from in vitro and in vivo studies has shown that it can protect cells from oxidative stress and aging (Sutphin et al, 2012; Ma et al, 2015). Caffeine prevented acute ROS-induced necrosis in human skin fibroblasts and inhibited oxidative stress-induced aging by activating autophagy (Li et al, 2018). Caffeine was found to reduce oxidative stress by antioxidant mechanism (Badshah et al, 2019; Nilnumkhum et al, 2019)
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