Mutations in RHOT1 disrupt ER-mitochondria contact sites interfering with calcium homeostasis and mitochondrial dynamics in Parkinson's disease
| Autor: | Grossmann, Dajana, Berenguer, Clara, Bellet, Marie Estelle, Scheibner, David, Bohler, Jill, Massart, François, Rapaport, Doron, Skupin, Alexander, Fouquier D Hérouël, Aymeric, Sharma, Manu, Ghelfi, Jenny, Rakovic, Aleksandar, Lichtner, Peter, Antony, Paul, Glaab, Enrico, May, Patrick, Dimmer, Kai Stefan, Fitzgerald, Julia Catherine, Anne Grünewald, Krüger, Rejko |
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| Přispěvatelé: | FNR: PEARL (P13/6682797/Krüger), MiRisk-PD (MiRisk‐PD, C17/BM/11676395), CASCAD (7975668), INTER/BMBF/13/04, NCER-PD, FNR9631103. [sponsor], DFG: KR2119/8‐1, DI 1386/2‐1, FOR2488 [sponsor], NIH: P41 GM103426 [sponsor], BMBF: Mito‐PD 031 A 430 A [sponsor], JPND Courage-PD [sponsor], Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Biomedical Data Science (Glaab Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Integrative Cell Signalling (Skupin Group) [research center] |
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| Zdroj: | BASE-Bielefeld Academic Search Engine Antioxidants & redox signaling. United States (2019). |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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