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
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.
