All organisms have evolved stress response pathways that allow them to switch into an alerted state and protect them from environmental challenges. Skin wounds are acute stresses that can be fatal unless tissue homeostasis is efficiently restored. Wounding of barrier epithelia such as the epidermis causes loss of bodily fluids and can result in opportunistic infection at the wound site. C. elegans is able to tolerate needle wounds such as those inflicted during microinjections, yet the mechanisms that detect and respond epidermal damage have only recently become apparent. Wounding of the worm epidermis by microinjection needle or laser triggers a p38 MAPK dependent innate immune response that defends against opportunistic infection at wounds . In addition to this innate immune response, we previously reported that wounding triggers a cytosolic Ca2+ response which is required for actin polymerization dependent epidermal wound closure. Here we describe an intracellular cytoprotective role for mitochondrial reactive oxygen species (mtROS) in response to wounding in C. elegans epidermis. We show that epidermal mitochondria become fragmented and generate ROS superoxide locally after injury. Reducing mtROS levels by treatment with mitochondrial targeted antioxidants inhibits wound closure. Conversely, genetic or pharmacological elevation of mtROS accelerates wound closure in the wild type, and can rescue the wound closure defects of mutants such as TRPM/gtl-2. mtROS act downstream of wound-triggered Ca2+ influx. We find that the Mitochondrial Calcium Uniporter MCU-1 is essential for rapid mitochondrial Ca2+ uptake and mtROS production after wounding. mtROS can promote actin-based wound closure by local inhibition of Rho GTPase activity via a redox-sensitive motif. Our findings identify mtROS as an important second messenger signal in restoring tissue homeostasis after injury.
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