Mitochondria transfer transiently rescues cerebellar neurodegeneration at early stage by alleviating mitophagy

Abstract Cerebellar ataxia is the main manifestation of cerebellar degenerative diseases, and the mitochondrial function of Purkinje cells (PCs) plays a key role in the disease. And treatments targeting the cerebellum need further research. We constructed a model of cerebellar PCs degeneration, characterized by ataxia, through conditional knockout of Drp1 in PCs (PCKO mice). And we further explored the pathogenesis and possible effective treatment of cerebellar degenerative diseases. Drp1 knockout results in pervasive and progressive apoptosis of PCs, accompanied by severe glial cell activation surrounding them. Mitochondrial dysfunction, as a cause of mitophagy, is a key pathogenic factor of PCs morphological damage and dysfunction. Transfer of liver-derived mitochondria into the cerebellum of PCKO mice at 1 month improved mitochondrial function and reduced mitophagy, resulting in a delay of PCs apoptosis and cerebellar ataxia for 3 weeks. This study demonstrates that mitochondria transfer may be an potential treatment for cerebellar degenerative diseases.