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

• DOI: 10.1089/ars.2018.7718
• Publication Date: 2019-07-15T07:19:00Z
• Authors: Dajana Grossmann; Clara Berenguer-E...; Marie Estelle Bellet; David Scheibner; Jill Bohler; Francois Massart; Doron Rapaport; Alexander Skupin; Aymeric Fouquier ...; Manu Sharma; Jenny Ghelfi; Aleksandar Raković; Peter Lichtner; Paul Antony; Enrico Glaab; Patrick May; Kai Stefan Dimmer; Julia Catherine F...; Anne Grünewald; Rejko Krüger
• Keywords: rho GTP-Binding Proteins; 0301 basic medicine; 0303 health sciences; Parkinson Disease; Middle Aged; Endoplasmic Reticulum; Mitochondria; Mitochondrial Proteins; Original Research Communications; 03 medical and health sciences; Mutation; Homeostasis; Humans; Calcium; Aged

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.