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)
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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