The Emerging Role of RHOT1/Miro1 in the Pathogenesis of Parkinson's Disease

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.

Mitochondrial dynamics in health and disease

“…Defects in Miro1 (encoded by RHOT1) have been implicated in the pathogenesis of Parkinson's disease (PD) [113]. Four PD patients carrying heterozygous mutations in Miro1 (p.R272Q, p.R450C, p.T351A, p.T610A) were recently identified [114,115]: fibroblasts isolated from these patients displayed changes in mitochondrial-ER contact sites resulting in impaired calcium handling and potential for increased mitophagy, leading the authors to conclude that that Miro1 variants are genetic risk factors for PD.…”

Human microsporidian pathogen Encephalitozoon intestinalis impinges on enterocyte membrane trafficking and signaling

“…Furthermore, TEM-revealed recruitment of mitochondria by E. intestinalis was also reflected at the molecular level. Encephalitozoon intestinalis appeared to activate genes encoding RHOT1, which aids the anterograde transport of mitochondria (Grossmann et al, 2020), and MGARP, which facilitates kinesindependent mitochondrial trafficking along microtubules in infected cells (Li et al, 2009) (Fig. 3I).…”

A nanobody-based toolset to monitor and modify the mitochondrial GTPase Miro1

“…This was further confirmed by the identification of mutations in the Miro1 gene RHOT1 causing an altered mitophagy response [26,27].Although not yet demonstrated at the molecular level, dysregulated cellular levels of Miro1 have been described in ALS animal models and in patients [28,29]. These results, in combination with recent data describing aberrant peroxisomal metabolism in PD patients [27,30], strongly suggest a multifactorial link between Miro1 and neurological diseases. Consequently, Miro1 is considered as an emerging biomarker and potential drug target in neuropathology [25,31].Despite previously conducted in vitro and in vivo studies on Miro1, detailed information about its structure-related function and cellular dynamics are still lacking [32].…”

“…[24,25]. This was further confirmed by the identification of mutations in the Miro1 gene RHOT1 causing an altered mitophagy response [26,27].Although not yet demonstrated at the molecular level, dysregulated cellular levels of Miro1 have been described in ALS animal models and in patients [28,29]. These results, in combination with recent data describing aberrant peroxisomal metabolism in PD patients [27,30], strongly suggest a multifactorial link between Miro1 and neurological diseases.…”