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A mitochondrial inside-out iron-calcium signal reveals drug targets for Parkinson's disease. Cell reports Bharat, V., Durairaj, A. S., Vanhauwaert, R., Li, L., Muir, C. M., Chandra, S., Kwak, C. S., Le Guen, Y., Nandakishore, P., Hsieh, C. H., Rensi, S. E., Altman, R. B., Greicius, M. D., Feng, L., Wang, X. 2023; 42 (12): 113544

Abstract

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.

View details for DOI 10.1016/j.celrep.2023.113544

View details for PubMedID 38060381