Mitochondria transplantation transiently rescues cerebellar neurodegeneration improving mitochondrial function and reducing mitophagy in mice.

Cerebellar ataxia is the primary manifestation of cerebellar degenerative diseases, and mitochondrial dysfunction in Purkinje cells (PCs) plays a critical role in disease progression. In this study, we investigated the feasibility of mitochondria transplantation as a potential therapeutic approach to rescue cerebellar neurodegeneration and elucidate the associated mechanisms. We constructed a conditional Drp1 knockout model in PCs (PCKO mice), characterized by progressive ataxia. Drp1 knockout resulted in pervasive and progressive apoptosis of PCs and significant activation of surrounding glial cells. Mitochondrial dysfunction, which triggers mitophagy, is a key pathogenic factor contributing to morphological and functional damage in PCs. Transplanting liver-derived mitochondria into the cerebellum of 1-month-old PCKO mice improved mitochondrial function, reduced mitophagy, delayed apoptosis of PCs, and alleviated cerebellar ataxia for up to 3 weeks. These findings demonstrate that mitochondria transplantation holds promise as a therapeutic approach for cerebellar degenerative diseases.