2. Academic Validation
  3. TTC19 Plays a Husbandry Role on UQCRFS1 Turnover in the Biogenesis of Mitochondrial Respiratory Complex III

TTC19 Plays a Husbandry Role on UQCRFS1 Turnover in the Biogenesis of Mitochondrial Respiratory Complex III

  • Mol Cell. 2017 Jul 6;67(1):96-105.e4. doi: 10.1016/j.molcel.2017.06.001.
Emanuela Bottani 1,  Raffaele Cerutti 1,  Michael E Harbour 1,  Sabrina Ravaglia 2,  Sukru Anil Dogan 1,  Carla Giordano 3,  Ian M Fearnley 1,  Giulia D'Amati 3,  Carlo Viscomi 1,  Erika Fernandez-Vizarra 4,  Massimo Zeviani 5
Affiliations

Affiliations

  • 1 MRC Mitochondrial Biology Unit, University of Cambridge, Wellcome Trust/MRC Building Hills Road, Cambridge CB2 0XY, UK.
  • 2 Istituto Neurologico "Casimiro Mondino," via Mondino 2, Pavia 27100, Italy.
  • 3 Department of Radiological, Oncological and Pathological Sciences, Sapienza University of Rome, 00161 Rome, Italy.
  • 4 MRC Mitochondrial Biology Unit, University of Cambridge, Wellcome Trust/MRC Building Hills Road, Cambridge CB2 0XY, UK. Electronic address: [email protected].
  • 5 MRC Mitochondrial Biology Unit, University of Cambridge, Wellcome Trust/MRC Building Hills Road, Cambridge CB2 0XY, UK. Electronic address: [email protected].
PMID: 28673544 DOI: 10.1016/j.molcel.2017.06.001
Abstract

Loss-of-function mutations in TTC19 (tetra-tricopeptide repeat domain 19) have been associated with severe neurological phenotypes and mitochondrial respiratory chain complex III deficiency. We previously demonstrated the mitochondrial localization of TTC19 and its link with complex III biogenesis. Here we provide detailed insight into the mechanistic role of TTC19, by investigating a Ttc19?/? mouse model that shows progressive neurological and metabolic decline, decreased complex III activity, and increased production of Reactive Oxygen Species. By using both the Ttc19?/? mouse model and a range of human cell lines, we demonstrate that TTC19 binds to the fully assembled complex III dimer, i.e., after the incorporation of the iron-sulfur Rieske protein (UQCRFS1). The in situ maturation of UQCRFS1 produces N-terminal polypeptides, which remain bound to holocomplex III. We show that, in normal conditions, these UQCRFS1 fragments are rapidly removed, but when TTC19 is absent they accumulate within complex III, causing its structural and functional impairment.

Keywords

Rieske protein; TTC19; UQCRFS1; complex III deficiency; mitochondrial complex III; mitochondrial disease; mitochondrial quality control; mitochondrial respiratory chain; mouse model.

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