Mitophagy upregulates WNT5A/Ca2+ signalling to accelerate fibroblast migration and wound healing

Abstract

In the event of dysregulated wound healing, hard-to-heal chronic wounds form and can place a significant burden on healthcare systems, yet gaps in knowledge surrounding the cellular and molecular processes involved have resulted in a lack of effective treatments. Here, we show that ubiquitin-independent mitophagy is upregulated in the early- and mid-wound healing stages. Additionally, enhancing mitophagy through Urolithin A treatment improved wound healing, in particular by accelerating fibroblast migration. RNAseq analysis demonstrated an upregulation of non-canonical WNT5A signalling in Urolithin A-treated fibroblasts, which was underpinned by elevated cytosolic Ca2+ buffering and CREB phosphorylation, ultimately leading to enhanced actin polymerisation and fibroblast migration. This study is thus the first to elucidate a role for mitophagy specifically in fibroblasts during wound healing; to demonstrate an important role for mitophagy in Ca2+-mediated WNT5A signalling cascades; and indicate the potential therapeutic benefits of treating non-healing wounds with mitophagy inducers such as Urolithin A.