Source-Dependent Mitochondrial Transplantation Drives Schwann Cell Bioenergetic Reprogramming and Peripheral Nerve Regeneration.

Following peripheral nerve injury (PNI), metabolic reprogramming of Schwann cells (SC) plays a critical role in axonal regeneration and functional recovery. Although mitochondrial transplantation (MT) has been proposed as a potential therapeutic strategy, it remains unclear whether its effect is limited to transient energy supplementation. We systematically compared the differential effects of mitochondria derived from human induced pluripotent stem cells (iPSCs, iP-MT) and induced mesenchymal stem cells (iMSCs, iM-MT) on regulating SC metabolism and promoting peripheral nerve regeneration. The results showed that exogenous mitochondria were efficiently taken up by SCs, not only increasing ATP production and mitochondrial membrane potential but also reshaping the metabolic distribution between glycolysis and oxidative phosphorylation. This remodeling promoted cell proliferation, migration, and neurotrophic function, while enhancing antioxidant capacity. In a rat sciatic nerve injury model, MT significantly improved axonal regeneration, remyelination, and the recovery of sensory and motor functions. Notably, iM-MT demonstrated stronger metabolic adaptability and therapeutic efficacy. MT reduced ROS accumulation, increased ATP production, and attenuated apoptosis under oxidative stress. This study reveals that MT promotes nerve repair by driving metabolic reprogramming rather than merely providing temporary energy, offering a new theoretical basis for optimizing the selection of mitochondrial donors.