A Mitochondrial Inside-Out Iron-Calcium Signal Reveals Drug Targets for Parkinson’s Disease

Abstract

Genetic backgrounds and risk factors among individuals with Parkinson 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.

Parkinson’s disease-related Miro1 mutation induces mitochondrial dysfunction and loss of dopaminergic neuronsin vitroandin vivo

“…Of note, the shorter pro-adrenomedullin fragment is implicated in increasing kinesin-mediated mitochondrial velocity [43], in line with our previous findings showing reduced mitochondrial speed in Miro1 p.R272Q dopaminergic neurons [15]. Other ROS-related deregulated genes, such as UBL5 (ubiquitin-related) and FTL (iron-related) have been previously linked to Miro1-mediated mitophagy regulation [8] and to a putative iron-calcium-Miro axis [44], respectively. The Iron-calcium-Miro1 axis hypothesis states that elevated iron levels in PD lead to mitochondrial calcium overflow, which might be preceded by reduced calcium sensing Miro1 capability [44].…”

“…Other ROS-related deregulated genes, such as UBL5 (ubiquitin-related) and FTL (iron-related) have been previously linked to Miro1-mediated mitophagy regulation [8] and to a putative iron-calcium-Miro axis [44], respectively. The Iron-calcium-Miro1 axis hypothesis states that elevated iron levels in PD lead to mitochondrial calcium overflow, which might be preceded by reduced calcium sensing Miro1 capability [44]. Indeed, despite the similar levels of total mitochondrial mass, in the PD-R272Q condition, we observed high levels of ROS and a reduced number of functional mitochondria.…”

“…Indeed, despite the similar levels of total mitochondrial mass, in the PD-R272Q condition, we observed high levels of ROS and a reduced number of functional mitochondria. Miro1 is able to sense both cytosolic calcium [45] and oxidative stress [46,47], with impairments in Miro1 leading to mitophagy alterations and bioenergetics deficits [44,46,47]. A recent study in iPSC-derived dopaminergic neurons, from a healthy individual in which the heterozygous Miro1 p.R272Q mutation had been artificially introduced, showed Ca 2+ deregulation as well as altered mitochondrial morphology and basal respiration [16].…”