1. TTC19 Plays a Husbandry Role on UQCRFS1 Turnover in the Biogenesis of Mitochondrial Respiratory Complex III
- Author
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Raffaele Cerutti, Carla Giordano, Sabrina Ravaglia, Giulia d'Amati, Erika Fernandez-Vizarra, Massimo Zeviani, Carlo Viscomi, Sukru Anil Dogan, Ian M. Fearnley, Michael E. Harbour, and Emanuela Bottani
- Subjects
0301 basic medicine ,Iron-Sulfur Proteins ,Male ,Mitochondrial Diseases ,Dimer ,Inbred C57BL ,Nervous System ,chemistry.chemical_compound ,Electron Transport Complex III ,Mice ,complex III deficiency ,mitochondrial complex III ,mitochondrial disease ,mitochondrial quality control ,mitochondrial respiratory chain ,mouse model ,Rieske protein ,TTC19 ,UQCRFS1 ,Animals ,Behavior, Animal ,Disease Models, Animal ,Female ,Genotype ,HeLa Cells ,Humans ,Kinetics ,Membrane Proteins ,Mice, Inbred C57BL ,Mice, Knockout ,Mitochondria ,Mitochondrial Proteins ,Motor Activity ,Nerve Degeneration ,Phenotype ,Protein Binding ,Protein Stability ,Proteolysis ,Reactive Oxygen Species ,Respiratory system ,chemistry.chemical_classification ,biology ,Biochemistry ,Knockout ,03 medical and health sciences ,Molecular Biology ,Reactive oxygen species ,Behavior ,Animal ,Cell Biology ,Mitochondrial respiratory chain complex III ,030104 developmental biology ,chemistry ,Coenzyme Q – cytochrome c reductase ,Disease Models ,biology.protein ,rieske protein ,Biogenesis - 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.
- Published
- 2017