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

Cell reports (2023-12-07)
Vinita Bharat, Aarooran S Durairaj, Roeland Vanhauwaert, Li Li, Colin M Muir, Sujyoti Chandra, Chulhwan S Kwak, Yann Le Guen, Pawan Nandakishore, Chung-Han Hsieh, Stefano E Rensi, Russ B Altman, Michael D Greicius, Liang Feng, Xinnan Wang
RÉSUMÉ

Dysregulated iron or Ca2+ 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 Ca2+ overflow, through an interaction of Fe2+ with mitochondrial calcium uniporter (MCU). 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 Food and Drug Administration-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.

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