Rab27-dependent mitochondrial extrusion from dopaminergic neurons drives neuroinflammation and neurodegeneration in the MPTP mouse model of Parkinson's disease.

Extrusion of damaged mitochondria is emerging as a trigger of innate immune activation. Parkinson's disease (PD), characterized by profound mitochondrial dysfunction, may involve similar mechanisms. Here, we report that dopaminergic neurons release damaged mitochondria into the extracellular space in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. These neuron-derived mitochondria were subsequently engulfed by glial cells, eliciting robust inflammatory responses. Autophagy inhibition did not affect mitochondrial release, indicating a non-canonical extrusion pathway. Upon mitochondrial damage, Rab27a and Rab27b translocated to the outer mitochondrial membrane, mediating mitochondrial export from dopaminergic neurons. Conditional Rab27 knockdown in dopaminergic neurons reduced extracellular mitochondrial accumulation, microglial activation, antiviral signaling, and dopaminergic neurodegeneration. Together, these findings identify Rab27-dependent mitochondrial extrusion as a critical mechanism coupling dopaminergic neuronal injury to neuroinflammation and neurodegeneration in PD.