Rosmarinic acid alleviates ultraviolet-mediated skin aging via attenuation of mitochondrial and ER stress responses

Chronic exposure to Ultraviolet B radiation (UV-B) evokes a myriad of toxic signalling events in the irradiated skin. One of such response is ER stress, which is known to exacerbate photodamage responses. Also, recent literature has highlighted the adverse impact of environmental toxicants on mitochondrial dynamics and mitophagy. Impaired mitochondrial dynamics escalates oxidative damage and causes apoptosis. There have been evidences that support crosstalk between ER stress and mitochondrial dysfunction. However, mechanistic clarification is still needed to verify the interactions between UPR responses and mitochondrial dynamics impairment in UV-B-induced photodamage models. Lastly, plant-based natural agents have garnered attention as therapeutic agents against skin photodamage. Thus, gaining mechanistic insights of plant-based natural agents is required for their application and feasibility in clinical settings. With this aim in view, this study was performed in primary human dermal fibroblasts (HDFs) and Balb/C mice. Different parameters regarding mitochondrial dynamics, ER stress, intracellular damage and histological damage were analyzed using western blot, rt-PCR and microscopy. We demonstrated that UV-B exposure leads to induction of UPR responses, upregulation of Drp-1 and inhibition of mitophagy. Further, 4-PBA treatment leads to reversal of these noxious stimuli in irradiated HDF cells, thereby, indicating an upstream role of UPR induction in mitophagy inhibition. Also, we explored the therapeutic effect of Rosmarinic acid (RA) against ER stress and impaired mitophagy in photodamage models. RA prevents intracellular damage via alleviation of ER stress and mitophagic responses in HDFs and irradiated Balb/C mice skin. The current study summarizes the mechanistic insights into UVB-mediated intracellular damage and role of natural plant-based agent (RA) in ameliorating these toxic responses.