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Antioxid Redox Signal. 2019 Aug 21. doi: 10.1089/ars.2018.7718. [Epub ahead of print]

Mutations in RHOT1 Disrupt Endoplasmic Reticulum-Mitochondria Contact Sites Interfering with Calcium Homeostasis and Mitochondrial Dynamics in Parkinson's Disease.

Author information

1
Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, Luxembourg.
2
Department of Neurodegenerative Diseases, Center of Neurology and Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
3
Interfaculty Institute of Biochemistry (IFIB), University of Tübingen, Tübingen, Germany.
4
National Biomedical Computation Resource, University of California San Diego, La Jolla, California.
5
Centre for Genetic Epidemiology, Institute for Clinical Epidemiology and Applied Biometry, University of Tübingen, Tübingen, Germany.
6
Institute of Neurogenetics, University of Lübeck, Lübeck, Germany.
7
Institute of Human Genetics, Helmholtz Zentrum München GmbH, Neuherberg, Germany.
8
Parkinson Research Clinic, Centre Hospitalier de Luxembourg (CHL), Luxembourg, Luxembourg.

Abstract

Aims: The outer mitochondrial membrane protein Miro1 is a crucial player in mitochondrial dynamics and calcium homeostasis. Recent evidence indicated that Miro1 mediates calcium-induced mitochondrial shape transition, which is a prerequisite for the initiation of mitophagy. Moreover, altered Miro1 protein levels have emerged as a shared feature of monogenic and sporadic Parkinson's disease (PD), but, so far, no disease-associated variants in RHOT1 have been identified. Here, we aim to explore the genetic and functional contribution of RHOT1 mutations to PD in patient-derived cellular models. Results: For the first time, we describe heterozygous RHOT1 mutations in two PD patients (het c.815G>A; het c.1348C>T) and identified mitochondrial phenotypes with reduced mitochondrial mass in patient fibroblasts. Both mutations led to decreased endoplasmic reticulum-mitochondrial contact sites and calcium dyshomeostasis. As a consequence, energy metabolism was impaired, which in turn caused increased mitophagy. Innovation and Conclusion: Our study provides functional evidence that ROTH1 is a genetic risk factor for PD, further implicating Miro1 in calcium homeostasis and mitochondrial quality control.

KEYWORDS:

ER–mitochondria contact site; Miro1; Parkinson's disease; calcium; mitochondria; patient fibroblasts

PMID:
31303019
DOI:
10.1089/ars.2018.7718

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