Mitophagy promotes metabolic reprogramming to enhance keratinocyte migration via ANGPTL4 during wound healing

Mitochondrial function and quality control is emerging as a key regulator of keratinocyte migration in both wounding and non-wound healing contexts, yet the cellular mechanisms that support this process are incompletely understood. In this study, using single-cell RNA sequencing data of human wounded tissue we identified a distinct population of migrating keratinocytes marked by the high expression of the mitophagy regulator BNIP3 during the proliferative stage of wound healing. Pharmacological induction of mitophagy with Urolithin A accelerated keratinocyte migration in vitro as well as keratinocyte function and regeneration in aged zebrafish, whilst RNA sequencing of primary human keratinocytes revealed the transcriptional upregulation of ANGPTL4 in Urolithin-A treated cells. Mechanistically, Urolithin A increased metabolic switching to a more glycolytic phenotype, leading to AKTGSK3 pathway activity and FOSL1-mediated ANGPTL4 transcription, ultimately promoting keratinocyte migration through enhanced laminin-332 production. Overall, our findings uncover a novel role for mitophagy in promoting keratinocyte migration during wound repair, and demonstrate that pharmacologically enhancing mitophagy promotes regenerative epithelial responses by enhancing FOSL1-mediated ANGPTL4 signalling through the modulation of metabolic switching. These insights significantly expand the understanding of the role of mitophagy on keratinocyte function during wound healing, linking mitophagy to metabolic adaption in keratinocytes, and provide a mechanistic basis for targeting mitophagy or downstream genes in wound healing therapies.