Abstract
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.
| Original language | English |
|---|---|
| Journal | Antioxidants and Redox Signaling |
| Volume | 31 |
| Issue number | 16 |
| Pages (from-to) | 1213-1234 |
| Number of pages | 22 |
| ISSN | 1523-0864 |
| DOIs | |
| Publication status | Published - 2019 |
Funding
We thank all patients and control individuals for their commitment and support for research. The KORA research platform (KORA, Cooperative Research in the Region of Augsburg) was initiated and financed by the Helmholtz Zentrum München—German Research Center for Environmental Health and funded by the German Federal Ministry of Education and Research and by the State of Bavaria, Germany. KORA research was supported within the Munich Center of Health Sciences (MC Health), Ludwig-Maximilians-Universität, as part of LMUinnovativ. The control fibroblasts were obtained from the Neuro-Biobank of the University of Tübingen, Tübingen, Germany. This biobank is supported by the local University, the Hertie Institute and the DZNE. The Miro1-WT/myc in the pRK5-myc vector was a kind gift of Prof. Pontus Aspenström, Kar-olinska Institute, Sweden. R.K. has received research grants from Fonds National de la Recherche de Luxembourg (PEARL [FNR/P13/6682797/Krüger] and NCER-PD), the German Research Council (KR2119/8-1), the European Union’s (EU) Horizon2020 research and innovation program (WIDESPREAD; CENTRE-PD; grant agreement No. 692320), and the Federal Ministry for Education and Research (BMBF; Mito-PD 031 A 430 A). R.K., A.G., E.G., M.S., and P.M. received funding from the CORE programme of the Fonds National de Recherche de Luxembourg (FNR, MiRisk-PD, C17/BM/11676395). A.S. was supported by the Fonds National de la Recherche through the C14/BM/ 7975668/CaSCAD grant and the National Biomedical Computation Resource (NBCR) through the NIH P41 GM103426 grant from the National Institutes of Health. E.G. received support from the Fonds Nationale de la Recherche, Luxembourg, as part of the project MitoPD, under the auspices of the bilateral e:Med program by the German Federal Ministry of Education and Research and the FNR (INTER/ BMBF/13/04). K.S.D. was supported by the German Research Council (DI 1386/2-1). J.C.F. acknowledges funding from the German Research Council, German Federal Ministry of Education and Research (BMBF) support code 031 A 430 A, DZNE, the University of Tubingen, and the EU Joint Programme—Neurodegenerative Disease Research ( JPND) project. A.G. received funding from the Fonds National de la Recherche within the ATTRACT programme (FNR, Model IPD, FNR9631103). R.K., E.G., and P.M. received funding from the EU’s Joint Program—Neurodegenerative Diseases Research ( JPND; COURAGE-PD). A.R. was supported by the DFG (FOR2488).
Research Areas and Centers
- Academic Focus: Center for Brain, Behavior and Metabolism (CBBM)
