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

Summary

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.