Article (Scientific journals)
Mutations in RHOT1 disrupt ER-mitochondria contact sites interfering with calcium homeostasis and mitochondrial dynamics in Parkinson's disease.
Grossmann, Dajana; Berenguer, Clara; Bellet, Marie Estelle et al.
2019In Antioxidants & redox signaling
Peer reviewed
 

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Keywords :
RHOT1; Miro1; Parkinson's disease; mitochondria; mitochondrial shape transition; ER-mitochondrial contact
Abstract :
[en] OBJECTIVE: 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 (MiST), 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. RESULTS: Here, 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-derived cellular models. Both mutations lead to decreased ER-mitochondrial contact sites and calcium dyshomeostasis. As a consequence, energy metabolism was impaired, which in turn lead to increased mitophagy. CONCLUSION: In summary, our data support the role of Miro1 in maintaining calcium homeostasis and mitochondrial quality control in PD.
Research center :
- Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group)
- Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group)
- Luxembourg Centre for Systems Biomedicine (LCSB): Biomedical Data Science (Glaab Group)
- Luxembourg Centre for Systems Biomedicine (LCSB): Integrative Cell Signalling (Skupin Group)
Disciplines :
Neurology
Genetics & genetic processes
Author, co-author :
Grossmann, Dajana ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
Berenguer, Clara ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
Bellet, Marie Estelle
Scheibner, David
Bohler, Jill
Massart, François  ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
Rapaport, Doron
Skupin, Alexander  ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
Fouquier d'Hérouël, Aymeric ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
Sharma, Manu
Ghelfi, Jenny ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
Rakovic, Aleksandar
Lichtner, Peter
Antony, Paul ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
Glaab, Enrico  ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
May, Patrick  ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
Dimmer, Kai Stefan
Fitzgerald, Julia Catherine
Grünewald, Anne  ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
Krüger, Rejko ;  University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit
More authors (10 more) Less
External co-authors :
yes
Language :
English
Title :
Mutations in RHOT1 disrupt ER-mitochondria contact sites interfering with calcium homeostasis and mitochondrial dynamics in Parkinson's disease.
Publication date :
15 July 2019
Journal title :
Antioxidants & redox signaling
ISSN :
1523-0864
eISSN :
1557-7716
Peer reviewed :
Peer reviewed
Focus Area :
Systems Biomedicine
European Projects :
H2020 - 692320 - CENTRE-PD - TWINNING for a Comprehensive Clinical Centre for the Diagnosis and Treatment of Parkinson's Disease
FnR Project :
FNR11676395 - Mitochondrial Risk Factors In Parkinson's Disease, 2017 (01/03/2018-31/08/2021) - Rejko Krüger
Name of the research project :
MiRisk-PD
Funders :
FNR: PEARL (P13/6682797/Krüger), MiRisk-PD (MiRisk‐PD, C17/BM/11676395), CASCAD (7975668), INTER/BMBF/13/04, NCER-PD, FNR9631103.
DFG: KR2119/8‐1, DI 1386/2‐1, FOR2488
NIH: P41 GM103426
BMBF: Mito‐PD 031 A 430 A
JPND Courage-PD
CE - Commission Européenne [BE]
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