RT Journal Article SR Electronic T1 An Iron-Calcium-Miro Axis Influences Parkinson’s Risk and Neurodegeneration JF bioRxiv FD Cold Spring Harbor Laboratory SP 2022.10.30.513580 DO 10.1101/2022.10.30.513580 A1 Vinita Bharat A1 Roeland Vanhauwaert A1 Li Li A1 Colin M. Muir A1 Aarooran Sivakumaran Durairaj A1 Sujyoti Chandra A1 Yann Le Guen A1 Pawan Nandakishore A1 Chung-Han Hsieh A1 Stefano E. Rensi A1 Russ B. Altman A1 Michael D. Greicius A1 Liang Feng A1 Xinnan Wang YR 2023 UL http://biorxiv.org/content/early/2023/01/12/2022.10.30.513580.abstract AB Genetic backgrounds and risk factors among individuals with Parkinson’s disease (PD) are highly heterogenous, limiting our ability to effectively detect and treat PD. Here we connect several potential PD risk genes and elements to one biological pathway. Elevation of Fe2+-levels causes Ca2+-overflow into the mitochondria, through an interaction of Fe2+ with mitochondrial calcium uniporter (MCU), the Ca2+-import channel in the inner mitochondrial membrane, and resultant MCU oligomerization. This mechanism acts in PD neuron models and postmortem brains. Miro, a Ca2+-binding protein, functions downstream of Ca2+-dysregulation, and holds promise to classify PD status and monitor drug efficacy in human blood cells. Polygenetic enrichment of rare, non-synonymous variants in this iron-calcium-Miro axis influences PD risk. This axis can be targeted by multiple ways to prevent neurodegeneration in PD models. Our results show a linear pathway linking several PD risk factors, which can be leveraged for genetic counseling, risk evaluation, and therapeutic strategies.Competing Interest StatementThe authors declare the following competing interests: X.W. is a co-founder, adviser, and shareholder of AcureX Therapeutics, and a shareholder of Mitokinin Inc. V.B., L.L., C.-H.H., and R.V. are shareholders of AcureX Therapeutics. P.N. is employed by Vroom Inc. Patents based on this study were filed by Stanford University with X.W., R.V., V.B., L.L., C.-H.H. as inventors. The remaining authors declare no competing interests.