Journal
ANTIOXIDANTS & REDOX SIGNALING
Volume 31, Issue 16, Pages 1213-1234Publisher
MARY ANN LIEBERT, INC
DOI: 10.1089/ars.2018.7718
Keywords
Miro1; mitochondria; calcium; ER-mitochondria contact site; Parkinson's disease; patient fibroblasts
Funding
- Helmholtz Zentrum Munchen-German Research Center for Environmental Health
- German Federal Ministry of Education and Research
- State of Bavaria, Germany
- Munich Center of Health Sciences (MC Health), LudwigMaximilians-Universitat, as part of LMUinnovativ
- Hertie Institute
- DZNE
- Fonds National de la Recherche de Luxembourg (PEARL) [FNR/P13/6682797/Kruger]
- Fonds National de la Recherche de Luxembourg (NCER-PD)
- German Research Council [KR2119/8-1, DI 1386/2-1]
- European Union's (EU) Horizon2020 research and innovation program (WIDESPREAD
- CENTRE-PD) [692320]
- Federal Ministry for Education and Research (BMBF) [Mito-PD 031A 430 A]
- CORE programme of the Fonds National de Recherche de Luxembourg (FNR, MiRisk-PD) [C17/BM/11676395]
- Fonds National de la Recherche [C14/BM/7975668/CaSCAD]
- National Biomedical Computation Resource (NBCR) through the National Institutes of Health [NIH P41 GM103426]
- Fonds Nationale de la Recherche, Luxembourg, as part of the project MitoPD, under bilateral e: Med program by the German Federal Ministry of Education and Research
- FNR [INTER/BMBF/13/04]
- German Federal Ministry of Education and Research (BMBF) [031A 430A]
- University of Tubingen
- EU Joint Programme-Neurodegenerative Disease Research (JPND) project
- Fonds National de la Recherche within the ATTRACT programme (FNR, Model IPD) [FNR9631103]
- EU's Joint Program-Neurodegenerative Diseases Research (JPND
- COURAGE-PD)
- DFG [FOR2488]
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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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