A mitochondrial inside-out iron-calcium signal reveals drug targets for Parkinson's disease
- PMID: 38060381
- PMCID: PMC10804639
- DOI: 10.1016/j.celrep.2023.113544
A mitochondrial inside-out iron-calcium signal reveals drug targets for Parkinson's disease
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.
Keywords: CP: Neuroscience.
Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.
Conflict of interest statement
Declaration of interests The authors declare the following competing interests: X.W. is a co-founder and shareholder of AcureX Therapeutics, and a shareholder of Mitokinin Inc. V.B., L.L., C.-H.H., and R.V. are shareholders of AcureX Therapeutics. P.N. was employed by Vroom Inc. Patents based on this study were filed by Stanford University with X.W., R.V., V.B., L.L., and C.-H.H. as inventors.
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