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

  • Transversal Translational Medicine
December 01, 2019 By:
  • Grossmann D
  • Berenguer-Escuder C
  • Bellet ME
  • Scheibner D
  • Bohler J
  • Massart F
  • Rapaport D
  • Skupin A
  • Fouquier d'Herouel A
  • Sharma M
  • Ghelfi J
  • Rakovic A
  • Lichtner P
  • Antony P
  • Glaab E
  • May P
  • Dimmer KS
  • Fitzgerald JC
  • Grunewald A
  • Kruger R.

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.

2019 Dec. Antioxid Redox Signal.31(16):1213-1234.
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