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

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.