Mutations in RHOT1 Disrupt Endoplasmic Reticulum-Mitochondria Contact Sites Interfering with Calcium Homeostasis and Mitochondrial Dynamics in Parkinson's Disease

Dajana Grossmann*, Clara Berenguer-Escuder, Marie Estelle Bellet, David Scheibner, Jill Bohler, Francois Massart, Doron Rapaport, Alexander Skupin, Aymeric Fouquier D'Hérouël, Manu Sharma, Jenny Ghelfi, Aleksandar Raković, Peter Lichtner, Paul Antony, Enrico Glaab, Patrick May, Kai Stefan Dimmer, Julia Catherine Fitzgerald, Anne Grünewald, Rejko Krüger

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

49 Citations (Scopus)

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 languageEnglish
Pages (from-to)1213-1234
Number of pages22
JournalAntioxidants and Redox Signaling
Volume31
Issue number16
DOIs
Publication statusPublished - 2019
Externally publishedYes

Keywords

  • ER-mitochondria contact site
  • Miro1
  • Parkinson's disease
  • calcium
  • mitochondria
  • patient fibroblasts

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