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bioRxiv · 10.1101/2022.10.30.513580

An Iron-Calcium-Miro Axis Influences Parkinson Risk and Neurodegeneration

Bharat, V.·Vanhauwaert, R.·Li, L.·Muir, C. M.·Durairaj, A. S.·Chandra, S.·Le Guen, Y.·Nandakishore, P.·Hsieh, C.-H.·Rensi, S. E.·Altman, R.·Greicius, M. D.·Feng, L.·Wang, X.
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Abstract

Dysregulated iron or Ca2+ homeostasis has been reported in Parkinsons 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. 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 FDA-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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Bharat, V., Vanhauwaert, R., Li, L., Muir, C. M., Durairaj, A. S., Chandra, S., Le Guen, Y., Nandakishore, P., Hsieh, C.-H., Rensi, S. E., Altman, R., Greicius, M. D., Feng, L., Wang, X.. 2022-11-01. An Iron-Calcium-Miro Axis Influences Parkinson Risk and Neurodegeneration. https://doi.org/10.1101/2022.10.30.513580

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