Aims: Oxidative stress and mitochondrial dysfunction play a role in the process of skin photoaging via activation of matrix metalloproteases (MMPs) and the subsequent degradation of collagen. The activation of nuclear factor E2-related factor 2 (Nrf2), a transcription factor controlling antioxidant and cytoprotective defense systems, might offer a pharmacological approach to prevent skin photoaging. We therefore investigated a pharmacological approach to prevent skin photoaging, and also investigated a protective effect of the novel mitochondria-targeted hydrogen sulfide (H2S) delivery molecules AP39 and AP123, and nontargeted control molecules, on ultraviolet A light (UVA)-induced photoaging in normal human dermal fibroblasts (NHDFs) in vitro and the skin of BALB/c mice in vivo. Results: In NHDFs, AP39 and AP123 (50-200 nM) but not nontargeted controls suppressed UVA (8 J/cm2)-mediated cytotoxicity and induction of MMP-1 activity, preserved cellular bioenergetics, and increased the expression of collagen and nuclear levels of Nrf2. In in vivo experiments, topical application of AP39 or AP123 (0.3-1 μM/cm2; but not nontargeted control molecules) to mouse skin before UVA (60 J/cm2) irradiation prevented skin thickening, MMP induction, collagen loss of oxidative stress markers 8-hydroxy-2'-deoxyguanosine (8-OHdG), increased Nrf2-dependent signaling, as well as increased manganese superoxide dismutase levels and levels of the mitochondrial biogenesis marker peroxisome proliferator-activated receptor-gamma coactivator (PGC-1α). Innovation and Conclusion: Targeting H2S delivery to mitochondria may represent a novel approach for the prevention and treatment of skin photoaging, as well as being useful tools for determining the role of mitochondrial H2S in skin disorders and aging. Antioxid. Redox Signal. 36, 1268-1288.
Keywords: Nrf2; ROS; bioenergetics; disulfide; hydrogen sulfide (H2S); longevity; mitochondria; persulfide; photoaging.