ATH (ASX) Stanford scientists: iron-calcium in mitochondrion as target in PD treatment

Originally posted by pivalde: ↑

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.

.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 Bharat¹, Aarooran S Durairaj¹, Roeland Vanhauwaert¹, Li Li¹, Colin M Muir², Sujyoti Chandra¹, Chulhwan S Kwak¹, Yann Le Guen³, Pawan Nandakishore⁴, Chung-Han Hsieh¹, Stefano E Rensi⁵, Russ B Altman⁵, Michael D Greicius⁶, Liang Feng⁷, Xinnan Wang⁸
Affiliations
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.

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Pivalde...Dr. Stamler's U.S. Headquarters Office is located very close to Stanford University. Obviously, I am curious as to whether he is familiar with these scientists, their work, and this paper?! If not, I would think he would be wise to schedule a meeting with them.

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Last updated 15.43pm 29/04/2024 ?

Pivalde...Dr. Stamler's U.S. Headquarters Office is located very...

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