A mitochondrial inside-out iron-calcium signal reveals drug targets for Parkinson’s disease
Vinita Bharat, Aarooran S. Durairaj, Roeland Vanhauwaert, Li Li, Colin M. Muir, Sujyoti Chandra, Chulhwan Kwak, Yann Le Guen, Pawan Nandakishore, Chung-Han Hsieh, Stefano Rensi, Russ B. Altman, Michael D. Greicius, Liang Feng, Xinnan Wang
Abstract
Dysregulated iron or Ca 2+ 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 2+ overflow, through an interaction of Fe 2+ with mitochondrial calcium uniporter (MCU). In PD neurons, iron accumulation-triggered Ca 2+ influx across the mitochondrial surface leads to spatially confined Ca 2+ elevation at the outer mitochondrial membrane, which is subsequently sensed by Miro1, a Ca 2+ -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 2+ -channel blockers. Human genetic analysis reveals enrichment of rare variants in T-type Ca 2+ -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.