Mitochondria-targeted hydrogen sulfide delivery molecules protect against uva-induced photoaging in dermal fibroblasts, and in mouse skin in vivo

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 might offer a pharmacological approach to prevent skin photoaging. We therefore investigated protective effect of the novel mitochondria-targeted hydrogen sulfide (H(2)S) delivery molecules AP39 and AP123, and non-targeted control molecules on UVA-induced photoaging in normal human dermal fibroblasts (NDHFs) in vitro and the skin of BALB/c mice in vivo. Results In NDHFs AP39 and AP123 (50-200 nM) but not non-targeted 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/cm(2); but not non-targeted control molecules) to mouse skin prior to UVA (60 J/cm(2)) irradiation prevented skin thickening, MMP induction, collagen loss oxidative stress markers 8-hydroxy-2'-deoxyguanosine (8-OHdG), increased Nrf2-dependent signaling as well as increased manganese superoxide dismutase (MnSOD) levels and levels of the mitochondrial biogenesis marker peroxisome proliferator-activated receptor-gamma coactivator (PGC-1?). Innovation and Conclusion Targeting H(2)S 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 H(2)S in skin disorders and aging.Not heldPublished version, accepted version (12 month embargo