The novel mitochondria-targeted hydrogen sulfide donors AP39 and AP123 exert anti-photoaging effects on primary dermal fibroblasts and mouse skin exposed to UVA in association with activation of Nrf2-mediated antioxidant response

Ultraviolet A (UVA) radiation plays a role in photodamaged skin through stimulating oxidative stress-induced various matrix metalloproteases (including MMP-1, 3 and 9) leading to degradation of extracellular matrix proteins, in particular, collagen, which are the hallmark of skin aging. Compromised mitochondrial integrity mediated by ROS is also responsible for cellular damage and dysfunction of the skin. Thus, promoting activity of nuclear factor E2-related factor 2 (Nrf2), a transcription factor controlling the antioxidant response, represents a promising strategy for inhibiting photoaging. We aimed to assess whether mitochondria-targeted hydrogen sulfide (H 2 S) donors (AP39 and AP123), having abilities to suppress mitochondrial ROS, exerted anti-photoaging effects via activating Nrf2 in dermal fibroblasts and mouse skin exposed to UVA. At first, AP39 and AP123 were shown to inhibit UVA (8 J/cm 2 )-mediated induction of ROS formation and MMP-1 activity as well as reduction of collagen in primary dermal fibroblasts. Then, we determined anti-photoaging effects of AP39 and AP123 on MMP-1, 3 and 9, collagen, MnSOD and PGC-1α (peroxisome proliferator-activated receptor γ, coactivator 1α; co-transcriptional regulation factor controlling mitochondrial biogenesis) in association with Nrf2 nuclear localization in BALB/c mouse skin exposed to UVA (60 J/cm 2 ). Our finding revealed that topical treatment with AP39 or AP123 dose-dependently protected against UVA-mediated increased MMP-1, 3 and 9 expression and decreased collagen levels as compared to the vehicle-treated group. In addition, both compounds could reverse UVA-dependent reduction of MnSOD and PGC-1α expressions. Application of AP39 and AP123 to mouse skin prior to UVA exposure was also shown to increase Nrf2 nuclear translocation and reduce oxidative DNA damage formation (8-hydroxy-2'-deoxyguanosine; 8-OHdG). In summary, AP39 and AP123 capable of activating Nrf2 and promoting mitochondrial integrity could provide anti-photoaging effects on dermal fibroblasts and mouse skin through suppression of UVA-mediated induction of MMPs and reduction of collagen.