A Mitochondrial Inside-Out Iron-Calcium Signal Reveals Drug Targets for Parkinsons Disease

Abstract

Dysregulated iron or Ca2+ homeostasis has been reported in Parkinsons disease (PD) models. Here we discover a connection between these two metals at the mitochondria. Elevation of iron levels causes inward mitochondrial Ca2+ overflow, through an interaction of Fe2+ with Mitochondrial Calcium Uniporter. In PD neurons, iron accumulation-triggered Ca2+ influx across the mitochondrial surface leads to spatially confined Ca2+ elevation at the outer mitochondrial membrane, which is subsequently sensed by Miro1, a Ca2+-binding protein. A Miro1 blood test distinguishes PD patients from controls and responds to drug treatment. Miro1-based drug screens in PD cells discover FDA-approved T-type Ca2+-channel blockers. Human genetic analysis reveals enrichment of rare variants in T-type Ca2+-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.