Highlights
- •
Iron elevation causes inward mitochondrial Ca2+ overflow via an Fe2+-MCU interaction (mitochondrial calcium uniporter = MCU).- •
In PD neurons, this Fe2+-Ca2+ signal causes Ca2+ elevation at the OMM (outer mitochondrial membrane)- •
OMM Ca2+ levels are sensed by Miro1 (a Ca2+-binding protein.)- •
Miro1-based drug screens in PD cells identify Ca2+-channel blockers
This is a free paper and I think this is also very important to ATH: The paper demonstrates how the increased iron will do on the mitochondrial level. And even more about how iron chelation will help: "Chelating iron, reducing Ca2+ entry into the cell, or blocking Miro1’s binding to Ca2+ is each neuroprotective". IMO, this was seen in the primate study. Miro1 can be used as a measure of treatment efficacy.
Here is the abstract, but better to read the free paper.A mitochondrial inside-out iron-calcium signal reveals drug targets for Parkinson's disease
AffiliationsAffiliations
- 1Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA 94305, USA.
- 2Department 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.
- 3Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA; Institut du Cerveau - Paris Brain Institute - ICM, 75013 Paris, France.
- 4Vroom Inc., Houston, TX 77042, USA.
- 5Department of Bioengineering, Stanford University, Stanford, CA 94305, USA.
- 6Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA.
- 7Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
- 8Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: [email protected].
DOI: 10.1016/j.celrep.2023.113544Free article
- PMID: 38060381
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.
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