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

  • Cell Rep. 2023 Dec 6;42(12):113544. doi: 10.1016/j.celrep.2023.113544.
Vinita Bharat  1 ,  Aarooran S Durairaj  1 ,  Roeland Vanhauwaert  1 ,  Li Li  1 ,  Colin M Muir  2 ,  Sujyoti Chandra  1 ,  Chulhwan S Kwak  1 ,  Yann Le Guen  3 ,  Pawan Nandakishore  4 ,  Chung-Han Hsieh  1 ,  Stefano E Rensi  5 ,  Russ B Altman  5 ,  Michael D Greicius  6 ,  Liang Feng  7 ,  Xinnan Wang  8
Affiliations
  • 1. Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • 2. Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA; Graduate Program of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • 3. Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA; Institut du Cerveau - Paris Brain Institute - ICM, 75013 Paris, France.
  • 4. Vroom Inc., Houston, TX 77042, USA.
  • 5. Department of Bioengineering, Stanford University, Stanford, CA 94305, USA.
  • 6. Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • 7. Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • 8. Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: [email protected].
PMID: 38060381 DOI: 10.1016/j.celrep.2023.113544
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.

Keywords
CP: Neuroscience.
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