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

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

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.

Figures
Products