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

Antioxid Redox Signal. 2019 Dec 1;31(16):1213-1234. doi: 10.1089/ars.2018.7718. Epub 2019 Aug 21.


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.

Keywords: ER–mitochondria contact site; Miro1; Parkinson's disease; calcium; mitochondria; patient fibroblasts.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Calcium / metabolism*
  • Endoplasmic Reticulum / metabolism*
  • Homeostasis*
  • Humans
  • Middle Aged
  • Mitochondria / metabolism*
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism*
  • Mutation
  • Parkinson Disease / metabolism*
  • rho GTP-Binding Proteins / genetics
  • rho GTP-Binding Proteins / metabolism*


  • Mitochondrial Proteins
  • RHOT1 protein, human
  • rho GTP-Binding Proteins
  • Calcium