Abstract
The expected increase in prevalence of Parkinson's disease (PD) as the most common neurodegenerative movement disorder over the next years underscores the need for a better understanding of the underlying molecular pathogenesis. Here, first insights provided by genetics over the last two decades, such as dysfunction of molecular and organellar quality control, are described. The mechanisms involved relate to impaired intracellular calcium homeostasis and mitochondrial dynamics, which are tightly linked to the cross talk between the endoplasmic reticulum (ER) and mitochondria. A number of proteins related to monogenic forms of PD have been mapped to these pathways, i.e., PINK1, Parkin, LRRK2, and α-synuclein. Recently, Miro1 was identified as an important player, as several studies linked Miro1 to mitochondrial quality control by PINK1/Parkin-mediated mitophagy and mitochondrial transport. Moreover, Miro1 is an important regulator of mitochondria-ER contact sites (MERCs), where it acts as a sensor for cytosolic calcium levels. The involvement of Miro1 in the pathogenesis of PD was recently confirmed by genetic evidence based on the first PD patients with heterozygous mutations in RHOT1/Miro1. Patient-based cellular models from RHOT1/Miro1 mutation carriers showed impaired calcium homeostasis, structural alterations of MERCs, and increased mitochondrial clearance. To account for the emerging role of Miro1, we present a comprehensive overview focusing on the role of this protein in PD-related neurodegeneration and highlighting new developments in our understanding of Miro1, which provide new avenues for neuroprotective therapies for PD patients.
Highlights
The mitochondrial Rho GTPase Miro1 was first described in yeast, and these studies already reported a link of Miro1 to calcium homeostasis
Our results showed that Miro1-mutant lines with an unchanged number of “wide” mitochondria-ER contact sites (MERCs) compared to controls displayed the FIGURE 2 | are not disassembled upon mitochondrial dysfunction, hampering the initiation of mitophagy
Ability to induce mitophagy after CCCP treatment [13, 14], while mutants with reduced amount of “wide” MERCs revealed a deficit to initiate mitophagy after treatment with CCCP [14]. These findings suggest that the regulation of mitochondrial quality control by Miro1 might crucially depend on the structure of MERCs
Summary
The mitochondrial Rho GTPase Miro was first described in yeast, and these studies already reported a link of Miro to calcium homeostasis. Neurons derived from flies and patients carrying mutations in PINK1 and Parkin displayed increased amounts of MERCs and a disturbed exchange of the phospholipid PS, resulting in an impaired synthesis of dense core vesicles from the ER (Figure 4B) [88] These findings argue in favor of an important role of Miro in lipid homeostasis at MERCs and an impairment of this function in conditions linked to neurodegeneration. PD patient-derived Miro1-mutant fibroblasts and iPSC-derived Miro1-R272Q neurons demonstrated an increased mitochondrial fragmentation after treatment compared to control cells This finding was not surprising given the delayed buffering of calcium transients and resulting retained high levels of calcium in the cytosol [13, 14, 67]. Our findings imply that mutations in Miro cause an impairment of calcium homeostasis, resulting in decreased ATP production and increased calcium-dependent mitochondrial fragmentation, thereby contributing to the pathogenesis of PD
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