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Mutations in RHOT1 Disrupt Endoplasmic Reticulum-Mitochondria Contact Sites Interfering with Calcium Homeostasis and
Dajana Grossmann1, Clara Berenguer-Escuder1, Marie Estelle Bellet1
1Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, Luxembourg.
Abstract:
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. 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. Our study provides functional evidence that ROTH1 is a genetic risk factor for PD, further implicating Miro1 in calcium homeostasis and mitochondrial quality control.
Insights
Mutations in the RHOT1 gene, encoding Miro1, are linked to Parkinson's disease (PD). These RHOT1 mutations disrupt calcium balance and mitochondrial function, increasing mitophagy and impacting energy metabolism in PD patients.
Area of Science:
- Neuroscience
- Cell Biology
- Genetics
Background:
- Miro1 (encoded by RHOT1) is vital for mitochondrial dynamics and calcium regulation.
- Miro1's role in calcium-induced mitochondrial shape changes is key to initiating mitophagy.
- Altered Miro1 levels are observed in Parkinson's disease (PD), but RHOT1 mutations were previously unidentified.
Purpose of the Study:
- To investigate the genetic and functional role of RHOT1 mutations in Parkinson's disease.
- To analyze patient-derived cellular models harboring RHOT1 mutations.
Main Methods:
- Genetic sequencing to identify RHOT1 variants in PD patients.
- Analysis of patient-derived fibroblasts to assess mitochondrial phenotypes.
- Evaluation of endoplasmic reticulum-mitochondrial contact sites and calcium homeostasis.
- Assessment of energy metabolism and mitophagy rates.
Main Results:
- First identification of heterozygous RHOT1 mutations (c.815G>A, c.1348C>T) in two PD patients.
- Observed mitochondrial phenotypes, including reduced mitochondrial mass, in patient fibroblasts.
- Demonstrated decreased ER-mitochondrial contact sites and calcium dyshomeostasis.
- Found impaired energy metabolism and consequently increased mitophagy.
Conclusions:
- RHOT1 mutations represent a genetic risk factor for Parkinson's disease.
- Miro1 dysfunction contributes to PD pathogenesis through impaired calcium homeostasis and mitochondrial quality control.