Mitochondria transplantation preserves retinal ganglion cells and promotes CNS axonal regeneration.

Mitochondrial dysfunction is a central driver of retinal ganglion cell (RGC) loss in glaucoma and other forms of optic neuropathies, leading to irreversible blindness. Here, we demonstrate that replenishing the mitochondrial pool through exogenous mitochondrial transplantation ("mitotherapy") in adult mice not only preserves neuronal survival but also promotes regenerative competence in the central nervous system (CNS). In aging or injured RGCs, we identified profound deficits in mitochondrial biogenesis, fission-fusion balance, and mitophagy. Transplantation of functional mitochondria in in vitro models of trophic deprivation and glutamate excitotoxicity restored mitochondrial homeostasis, improved energy production, reduced reactive oxygen species, enhanced RGC survival, and drove robust neurite outgrowth, with transplanted mitochondria actively trafficking to growth cones. This effect was dampened following inhibition of mitochondrial fusion, indicating a pivotal role of fusion-dependent functional integration of exogenous mitochondria. Strikingly, intravitreal delivery of mitochondria in an optic nerve crush model of adult mice enabled their integration into RGCs, improved survival and electrophysiological responses, and supported axonal regeneration across the lesion site. These findings indicate that mitochondrial transplantation strategy rescues bioenergetic failure and supports a pro-regenerative activity of neurons, highlighting the potential of mitotherapy as a transformative approach for neurodegenerative eye diseases and CNS injuries.