A mitochondrial inside-out iron-calcium signal reveals drug targets for Parkinson's disease.

Dysregulated iron or Ca homeostasis has been reported in Parkinson's disease (PD) models. Here, we discover a connection between these two metals at the mitochondria. Elevation of iron levels causes inward mitochondrial Ca overflow, through an interaction of Fe with mitochondrial calcium uniporter (MCU). In PD neurons, iron accumulation-triggered Ca influx across the mitochondrial surface leads to spatially confined Ca elevation at the outer mitochondrial membrane, which is subsequently sensed by Miro1, a Ca-binding protein. A Miro1 blood test distinguishes PD patients from controls and responds to drug treatment. Miro1-based drug screens in PD cells discover Food and Drug Administration-approved T-type Ca-channel blockers. Human genetic analysis reveals enrichment of rare variants in T-type Ca-channel subtypes associated with PD status. Our results identify a molecular mechanism in PD pathophysiology and drug targets and candidates coupled with a convenient stratification method.