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Grossmann, D.* ; Berenguer-Escuder, C.* ; Bellet, M.E.* ; Scheibner, D.* ; Bohler, J.* ; Massart, F.* ; Rapaport, D.* ; Skupin, A.* ; Fouquier d'Hérouël, A.* ; Sharma, M.* ; Ghelfi, J.* ; Rakovic, A.* ; Lichtner, P. ; Antony, P.* ; Glaab, E.* ; May, P.* ; Dimmer, K.S.* ; Fitzgerald, J.C.* ; Gruenewald, A.* ; Krüger, R.*

Mutations in RHOT1 disrupt ER-mitochondria contact sites interfering with calcium homeostasis and mitochondrial dynamics in Parkinson's disease.

Antioxid. Redox Signal. 31, 1213-1234 (2019)
Publ. Version/Full Text Postprint DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Miro1 ; Mitochondria ; Calcium ; Er-mitochondria Contact Site ; Parkinson's Disease ; Patient Fibroblasts; Functional Impact; Miro; Ca2+; Degradation; Pink1; Activation; Transport; Variants
ISSN (print) / ISBN 1523-0864
e-ISSN 1557-7716
Journal Antioxidants & Redox Signaling
Quellenangaben Volume: 31, Issue: 16, Pages: 1213-1234 Article Number: , Supplement: ,
Publisher Mary Ann Liebert
Publishing Place 140 Huguenot Street, 3rd Fl, New Rochelle, Ny 10801 Usa
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Human Genetics (IHG)