Highlights

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  Iron elevation causes inward mitochondrial Ca²⁺ overflow via an Fe²⁺-MCU interaction (mitochondrial calcium uniporter = MCU).
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  In PD neurons, this Fe²⁺-Ca²⁺ signal causes Ca²⁺ elevation at the OMM (outer mitochondrial membrane)
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  OMM Ca²⁺ levels are sensed by Miro1 (a Ca2+-binding protein.)
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  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.

Cell Rep

. 2023 Dec 6;42(12):113544.

doi: 10.1016/j.celrep.2023.113544. Online ahead of print.

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

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 collapse

Affiliations

• 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].

• PMID: 38060381

DOI: 10.1016/j.celrep.2023.113544Free article

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.