Variants in Miro1 Cause Alterations of ER-Mitochondria Contact Sites in Fibroblasts from Parkinson’s Disease Patients

Berenguer-Escuder, Clara; Großmann, Dajana; Massart, Franҫois; Antony, Paul; Burbulla, Lena F.; Glaab, Enrico; Imhoff, Sophie; Trinh, Joanne; Seibler, Philip; Grünewald, Anne; Krüger, Rejko

doi:10.3390/jcm8122226

Cited by 41 publications

(55 citation statements)

References 45 publications

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“…Our result also raises questions about whether PD is a systemic disease. In fact, mitochondrial molecular defects have been widely reported in fibroblasts from PD patients, 33‐37 but we have not observed skin cell death in PD patients. Why are dopaminergic neurons in the substantia nigra most vulnerable to the impairment of mitochondria?…”

Section: Miro1 Protein: a Linchpin For Mitochondrial Motility And Quacontrasting

confidence: 65%

Precision Neurology for Parkinson’s Disease: Coupling Miro1‐Based Diagnosis With Drug Discovery

Bharat

Wang

2020

Movement Disorders

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Parkinson’s disease (PD) is a debilitating movement disorder, significantly afflicting the aging population. Efforts to develop an effective treatment have been challenged by the lack of understanding of the pathological mechanisms underlying neurodegeneration. We have shown that Miro1, an outer mitochondrial membrane protein, situates at the intersection of the complex genetic and functional network of PD. Removing Miro1 from the surface of damaged mitochondria is a prerequisite for mitochondrial clearance via mitophagy. Parkinson’s proteins PINK1, Parkin, and LRRK2 are the molecular helpers to remove Miro1 from dysfunctional mitochondria destined for mitophagy. We have found a delay in clearing Miro1 and initiating mitophagy in postmortem brains and induced pluripotent stem cell–derived neurons from PD patients harboring mutations in LRRK2, PINK1, or Parkin, or from sporadic PD patients with no known mutations. In addition, we have shown that reducing Miro1 by both genetic and pharmacological approaches can correct this Miro1 phenotype and rescue Parkinson’s‐relevant phenotypes in human neurons and fly PD models. These results suggest that the Miro1 defect may be a common denominator for PD, and compounds that reduce Miro1 promise a new class of drugs to battle PD. We propose to couple this Miro1 phenotype with Miro1‐based drug discovery in future therapeutic studies, which could significantly improve the success of clinical trials. © 2020 International Parkinson and Movement Disorder Society

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Section: Miro1 Protein: a Linchpin For Mitochondrial Motility And Quacontrasting

confidence: 65%

Precision Neurology for Parkinson’s Disease: Coupling Miro1‐Based Diagnosis With Drug Discovery

Bharat

Wang

2020

Movement Disorders

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“…Very recently, four rare missense variants in RHOT1 were identi ed in PD patients from Caucasian populations. Using patient-derived broblasts, the researchers observed that these variants impaired calcium homeostasis and caused alterations of ER-mitochondria contact sites, ultimately affecting energy metabolism and increasing mitophagy [12,13]. The likely pathogenic variant identi ed in our study, p.S95N, is located in the N-GTPase domain, which is different from the location of the four reported variants.…”

Section: Discussioncontrasting

confidence: 60%

“…Importantly, heterozygous pathogenic variants in TRAP1 and HSPA9 were also found in PD patients [10,11]. Very recently, two studies on European ancestry found that mutation of ras homolog family member T1 (RHOT1), which encodes another pivotal mitochondrial transport protein (Miro1) and serves as mitochondrial-endoplasmic reticulum (ER) contact sites, also caused ADPD [12,13]. However, the role of the six Mendelian dominantly inherited mitochondrial function-associated genes is still awaiting con rmation or has not been duplicated in PD patients of different ethnicities.…”

Section: Introductionmentioning

confidence: 99%

Systematic analysis of rare variants in mitochondrial function-associated genes for autosomal-dominant Parkinson’s disease in a Chinese population

Chen

et al. 2020

Preprint

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Background Mitochondrial dysfunction is involved in the pathogenicity of Parkinson’s disease (PD). However, the genetic roles of mitochondrial function-associated genes responsible for PD need to be replicated in different cohorts. Methods Whole-exome and Sanger sequencing were used to identify the genetic etiology of 400 autosomal dominant-inherited PD (ADPD) patients. Variants in six dominant inherited mitochondrial function-associated genes, including HTRA2, CHCHD2, CHCHD10, TRAP1, HSPA9 and RHOT1, were analyzed. Results A total of 12 rare variants identified in the five genes accounted for 3% of ADPD cases, including 0.5% in HTRA2, 0.8% in CHCHD2, 1% in TRAP1, 0.3% in RHOT1 and 0.5% in HSPA9. Among them, five novel variants, p.E4A, p.R13Cfs*107 and p.R449X in TRAP1, p.S95N in RHOT1 and p.N180I in HSPA9, were identified in ADPD patients. Evidence of a founder event that occurred exclusively in Asia was identified in two probands with p.P53Afs*37 in CHCHD2, which was further observed in one patient from 300 sporadic cases. Based on burden analysis, CHCHD2 tended to be slightly enriched in ADPD. Clinically, all patients carrying mutations in the genes presented typical motor symptoms and a good response to L-DOPA. Most of them had slower disease progression (8/12) and mild cognitive impairment (9/12), but the age of onset varied. No rare variant was detected in CHCHD10. Conclusion Our study expands the mutation spectra and enhances the understanding of the clinical phenotype of PD patients with mitochondrial function-related gene variants. Additionally, the CHCHD2 gene should be given more attention in PD originating in the Chinese population.

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“…Swelling of mitochondria, in turn, may impair the action of the fission machinery. As Miro is a substrate for Parkin(Wang et al, 2011; Shlevkov et al, 2016), and is itself a target of Parkinson’s Disease-associated mutations(Berenguer-Escuder et al, 2019), our results may also be relevant to pathogenetic mechanisms of Parkinson’s diseases.…”

Section: Resultsmentioning

confidence: 87%

VPS13D bridges the ER to Miro containing membranes

Guillén-Samander

Leonzino

Hanna

et al. 2020

Preprint

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Mitochondria, which are excluded from the secretory pathway, depend on lipid transport proteins for their lipid supply from the ER, where most lipids are synthesized. In yeast, the outer membrane GTPase Gem1 is an accessory factor of ERMES, an ER-mitochondria tethering complex that contains lipid transport domains and plays a function, partially redundant with VPS13, in lipid transfer between the two organelles. In metazoa, where VPS13, but not ERMES, is present, the Gem1 orthologue Miro has been linked to mitochondrial motility but not to lipid transport. Here we show that Miro recruits to mitochondria the lipid transport protein VPS13D which, like Miro, is an essential protein in mammals, and whose localization had remained elusive. We also show that VPS13D can tether mitochondria to the ER in a Miro- and VAP-dependent way. These findings reveal a so far missing link between function(s) of Gem1/Miro in yeast and higher eukaryotes, where Miro is a Parkin substrate, with potential implications for Parkinson’s disease pathogenesis.SummaryProtein-mediated ER-mitochondria lipid transfer is critical for eukaryotic cells. However, the underlying machinery is not well conserved. Guillén-Samander et al, show that Gem1/Miro is an evolutionary conserved link between the yeast ERMES complex and the mammalian lipid transfer protein VPS13D.

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Variants in Miro1 Cause Alterations of ER-Mitochondria Contact Sites in Fibroblasts from Parkinson’s Disease Patients

Cited by 41 publications

References 45 publications

Precision Neurology for Parkinson’s Disease: Coupling Miro1‐Based Diagnosis With Drug Discovery

Precision Neurology for Parkinson’s Disease: Coupling Miro1‐Based Diagnosis With Drug Discovery

Systematic analysis of rare variants in mitochondrial function-associated genes for autosomal-dominant Parkinson’s disease in a Chinese population

VPS13D bridges the ER to Miro containing membranes

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