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

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

Cell Reports (Dec 2023)

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

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

Affiliations

Vinita Bharat: Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA 94305, USA
Aarooran S. Durairaj: Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA 94305, USA
Roeland Vanhauwaert: Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA 94305, USA
Li Li: Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA 94305, USA
Colin M. Muir: 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
Sujyoti Chandra: Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA 94305, USA
Chulhwan S. Kwak: Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA 94305, USA
Yann Le Guen: 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
Pawan Nandakishore: Vroom Inc., Houston, TX 77042, USA
Chung-Han Hsieh: Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA 94305, USA
Stefano E. Rensi: Department of Bioengineering, Stanford University, Stanford, CA 94305, USA
Russ B. Altman: Department of Bioengineering, Stanford University, Stanford, CA 94305, USA
Michael D. Greicius: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA
Liang Feng: Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA
Xinnan Wang: Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA 94305, USA; Corresponding author

Journal volume & issue: Vol. 42, no. 12
p. 113544

Abstract

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Summary: 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.

CP: Neuroscience

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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