Neuroprotective effect of astrocytic dopamine Drd2 receptor on mitochondrial complex I in a mouse model of Parkinson's disease through β-arrestin2-NDUFA10 regulation.

Parkinson's disease (PD) is a progressive neurodegenerative disease. Current treatment strategies for PD mainly focus on dopamine replacement and regulation of dopaminergic signaling. Here, we reveal the unique role of the astrocytic dopamine D2 (Drd2) receptor in regulating mitochondrial function, thereby improving Parkinson's disease-like symptoms in a mouse model. Transcriptome sequencing and metabolomics suggest that deletion of astrocytic Drd2 receptor significantly aggravates mitochondrial dysfunction. Mechanistically, we demonstrate that the Drd2 receptor regulates mitochondrial complex I activity by recruiting the scaffold protein β-arrestin2, which facilitates its interaction with NDUFA4 and NDUFA10, two subunits of mitochondrial complex I. Notably, the neuroprotective effect of Drd2 activation in vivo was completely abolished upon selective knockdown of NDUFA10 in mouse astrocytes. The identification of this novel mechanistic axis not only elucidates how astrocytes maintain neuronal mitochondrial homeostasis via dopaminergic signaling but also establishes a transformative framework for the development of targeted combination therapies that concurrently address mitochondrial dysfunction and dopamine receptor dysregulation as a promising avenue for advancing PD treatment strategies.