FUNDC1-dependent mitophagy determines axon regeneration capacity

Neuronal axon regeneration is a complex and coordinated reorganization process that requires the involvement of mitochondria. Here, we demonstrated that FUNDC1 (FUN14 domain containing 1)-mediated mitophagy played a crucial role in determining the intrinsic capacity for axonal regrowth and peripheral nerve recovery. We found that acute nerve injury resulted in the accumulation of impaired mitochondria at the axonal injury site, accompanied by an increase in the expression of the mitophagy receptor FUNDC1. Strikingly, overexpression of FUNDC1 enhanced axonal regeneration both in vitro and in vivo, likely by maintaining a healthy mitochondrial population through mitophagy. Similarly, treatment with urolithin A (UA), a natural mitophagy inducer, promoted axon regrowth after injury. Conversely, <i>fundc1</i> deletion impaired regeneration, an effect reversed by reintroducing wild type (WT) FUNDC1 in neurons but not an MAP1LC3B/LC3 (microtubule associated protein 1 light chain 3 beta)-interacting region (LIR) mutant. Metabolic profiling further demonstrated that FUNDC1-mediated mitophagy drives dorsal root ganglion (DRG) neurons regeneration through enhanced carnosine biosynthesis. Mechanistically, sciatic nerve injury (SNI) in <i>Fundc1</i> transgenic (TG) mice upregulated NRF1 (nuclear respiratory factor 1) and PPARGC1A/PGC-1α (PPARG coactivator 1 alpha), which stimulated mitochondrial biogenesis and activated <i>Carns1</i> (carnosine synthase 1) transcription. This increased carnosine biosynthesis, aiding peripheral nerve recovery through its antioxidant effects. Our findings highlighted FUNDC1-mediated mitophagy as a key mechanism in nerve regeneration, linking mitochondrial quality control, metabolic adaptation, and nerve regeneration.<b>Abbreviations</b>: Δψm: mitochondrial membrane potential; DIV: days in vitro; DRG: dorsal root ganglion; KO: knockout; LIR: LC3-interacting region; P60: postnatal day 60; PNS: peripheral nervous system; PSI: post sciatic nerve injury; ROS: reactive oxygen species; SD: standard deviation; SNI: sciatic nerve injury; TEM: transmission electron microscopy; TG: transgenic; TMRE: tetramethylrhodamine ethylester; UA: urolithin A; WT: wild type.