Locally Activated Mitophagy Contributes to a 'built-in' Protection Against Early Burn-wound Progression in Rats Following a Regulation of HIF-1α

Backgrounds: Deep burn-wounds undergo a dynamic progression in the initial or periburn area after insults. The zone of stasis has a higher risk of deterioration and is considered a salvageable target. Few studies have explored the role of mitochondrial damage in this process and potential “built-in” self-defense within the human body. Methods: A classic “comb” scald rat model was established. Histological and blood-flow observation were processed based on hematoxylin-eosin staining and laser analysis. Oxidative and apoptotic status were analyzed by commercial kits. Transmission electron microscope, immunofluorescence staining, and western blot were applied to detect the mitophagy happened in the zone of stasis and potential regulators. Adenovirus-based gene-silence contributed to determine the role of HIF-1α as a regulatory mediator. Findings: We found that burn insults caused typical ischemia and histological deterioration in the zone of stasis, in parallel with increases in oxidative stress and apoptosis. Mitochondrial damage was also involved in the aforementioned changes. Furthermore, we detected typical mitophagy in burn-wounds, which was contradictory to the burn-wound conversion. HIF-1α expression was closely related to the level of mitophagy, while BNIP3 and PARKIN are involved downstream. Interpretation: Accordingly, burn-induced mitochondrial impairment contributes to the mobilization of injurious mechanisms in the zone of stasis and that mitophagy provides a more beneficial way to protect against burn-wound progression via the elimination of damaged mitochondria. Our findings offer insights into mitochondrial quality control in burn-wound progression and suggest the novel concept that HIF-1α may be a potential therapeutic target due to its possible regulatory effects on BNIP3- or PARKIN-mediated mitophagy. Funding Statement: This work was supported by the following grants: National Natural Science Foundation of China (NSFC) Grants 81671909, 81901958 and Zhejiang Provincial Natural Science Foundation of China Grants: LY18H150004, LY19H150004, LY20H150010. Declaration of Interests: The authors declare no competing financial interests. Ethics Approval Statement: The present study was performed according to protocols approved by the Committee on Animal Care and Use of the Second Affiliated Hospital Zhejiang University School of Medicine (2019-331), and strictly followed the National Institutes of Health Guidelines for the Care and Use of Laboratory Animals.