Intramuscular mitochondria transplantation ameliorates paclitaxel-induced peripheral neuropathy by restoring neuronal mitochondrial homeostasis and function.

AIMS: Paclitaxel-induced peripheral neuropathy (PIPN) is a significant, dose-limiting side effect of chemotherapy characterized by neuronal dysfunction stemming from mitochondrial damage. This study investigates the therapeutic potential of mitochondria transplantation for mitigating PIPN.

MATERIALS AND

METHODS

PIPN was induced in rats via intraperitoneal paclitaxel injections (2 mg/kg, four doses). Allogeneic mitochondria from donor soleus muscles were injected into the vastus lateralis muscle of recipient rats. Sensory and motor functions were evaluated using behavioral tests. Mitochondrial biodistribution was tracked utilizing MitoTracker™ dye and lentiviral Mito-GFP labeling. Mechanistic evaluations included mitochondrial complex I-V activity assays, biogenesis marker quantification (TFAM, Nrf2), and histological assessments of sciatic nerve myelination, intraepidermal nerve fibers (IENFs), and neuromuscular junctions (NMJs).

KEY FINDINGS: Exogenous mitochondria successfully underwent retrograde transport from the muscle into the sciatic nerve and spinal cord, significantly alleviating paclitaxel-induced neuropathic pain and motor impairments. Mechanistically, transplantation restored mitochondrial complex activities and biogenesis markers in the peripheral nervous system, improved neuronal redox balance, and reduced microglial infiltration. Furthermore, mitochondrial transplantation promoted sciatic nerve remyelination and normalized target-tissue innervation by rescuing IENF and NMJ densities.

SIGNIFICANCE: Intramuscular mitochondria transplantation effectively counteracts paclitaxel-induced mitochondrial damage, suppresses neuroinflammation, and restores neuronal homeostasis, offering a promising therapeutic strategy for managing PIPN.