TY - JOUR
T1 - Mutations in RHOT1 Disrupt Endoplasmic Reticulum-Mitochondria Contact Sites Interfering with Calcium Homeostasis and Mitochondrial Dynamics in Parkinson's Disease
AU - Grossmann, Dajana
AU - Berenguer-Escuder, Clara
AU - Bellet, Marie Estelle
AU - Scheibner, David
AU - Bohler, Jill
AU - Massart, Francois
AU - Rapaport, Doron
AU - Skupin, Alexander
AU - Fouquier D'Hérouël, Aymeric
AU - Sharma, Manu
AU - Ghelfi, Jenny
AU - Raković, Aleksandar
AU - Lichtner, Peter
AU - Antony, Paul
AU - Glaab, Enrico
AU - May, Patrick
AU - Dimmer, Kai Stefan
AU - Fitzgerald, Julia Catherine
AU - Grünewald, Anne
AU - Krüger, Rejko
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85072881741&partnerID=8YFLogxK
U2 - 10.1089/ars.2018.7718
DO - 10.1089/ars.2018.7718
M3 - Journal articles
C2 - 31303019
AN - SCOPUS:85072881741
SN - 1523-0864
VL - 31
SP - 1213
EP - 1234
JO - Antioxidants and Redox Signaling
JF - Antioxidants and Redox Signaling
IS - 16
ER -