Abstract

Background Peripheral nerve injury (PNI) often leads to sensory and motor dysfunction. This study investigated the promoting effect of hypoxia-preconditioned mitochondrial transplantation on the structural and functional reconstruction of peripheral nerves and the molecular mechanisms involved. Methods We explored the effects of hypoxia-preconditioned mitochondrial transplantation on Schwann cell (SC) phenotypes, including proliferation, migration, cellular senescence, and mitochondrial membrane potential, and explored the underlying molecular mechanism through Western blotting. We assessed axonal and myelin regeneration, as well as motor function recovery, in injured rats through behavioral tests, morphological analysis, and electrophysiological detection. Results Hypoxia preconditioning significantly increased the mitochondrial membrane potential in SCs without altering their ultrastructure or the normal expression of the COX IV and TOMM20 proteins. The uptake efficiency of SCs for exogenous mitochondria was significantly greater than that of neurons, endothelial cells, fibroblasts, and other cells. Hypoxia-preconditioned mitochondrial transplantation activated the MAPK (Ras-ERK-c-Fos/c-Jun) pathway; promoted SC proliferation, migration, and dedifferentiation; inhibited H 2 O 2 -induced cellular senescence; and partially restored the mitochondrial membrane potential. Hypoxia-preconditioned mitochondrial transplantation significantly accelerated axonal growth, promoted axonal remyelination, led to significant recovery of electrophysiological function, and improved motor function. Conclusion Hypoxia preconditioning enhances the mitochondrial membrane potential of SC-derived mitochondria. Mitochondrial transplantation modulates SC functions by activating the Ras-ERK-c-Fos/c-Jun pathway, significantly increases nerve fiber density and myelin thickness, alleviates gastrocnemius muscle atrophy, and promotes motor function recovery, providing a new strategy for the clin