MIRO1 mutation leads to metabolic maladaptation resulting in Parkinson's disease-associated dopaminergic neuron loss.

MIRO1 is a mitochondrial outer membrane protein important for mitochondrial distribution, dynamics and bioenergetics. Over the last decade, evidence has pointed to a link between MIRO1 and Parkinson's disease (PD) pathogenesis. Moreover, a heterozygous MIRO1 mutation (p.R272Q) was identified in a PD patient, from which an iPSC-derived midbrain organoid model was derived, showing MIRO1 mutant-dependent selective loss of dopaminergic neurons. Herein, we use patient-specific iPSC-derived midbrain organoids carrying the MIRO1 p.R272Q mutation to further explore the cellular and molecular mechanisms involved in dopaminergic neuron degeneration. Using single-cell RNA sequencing (scRNAseq) analysis and metabolic modeling we show that the MIRO1 p.R272Q mutation affects the dopaminergic neuron developmental path leading to metabolic deficits and disrupted neuron-astrocyte metabolic crosstalk, which might represent an important pathogenic mechanism leading to their loss.