TTC19 Plays a Husbandry Role on UQCRFS1 Turnover in the Biogenesis of Mitochondrial Respiratory Complex III.
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Harbour, Michael E
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Bottani, E., Cerutti, R., Harbour, M. E., Ravaglia, S., Dogan, S. A., Giordano, C., Fearnley, I., et al. (2017). TTC19 Plays a Husbandry Role on UQCRFS1 Turnover in the Biogenesis of Mitochondrial Respiratory Complex III.. Molecular cell, 67 (1), 96-105.e4. https://doi.org/10.1016/j.molcel.2017.06.001
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.
Nervous System, Hela Cells, Mitochondria, Animals, Mice, Inbred C57BL, Mice, Knockout, Humans, Mitochondrial Diseases, Disease Models, Animal, Nerve Degeneration, Reactive Oxygen Species, Electron Transport Complex III, Iron-Sulfur Proteins, Membrane Proteins, Mitochondrial Proteins, Behavior, Animal, Motor Activity, Protein Binding, Kinetics, Genotype, Phenotype, Female, Male, Protein Stability, Proteolysis
NRJ-Institut de France (M.Z), Association Francaise contre les Myopathies (AFM) grant 16086 (E.F.-V.).
European Commission FP7 ERC Advanced Investigator Grants (AIG) (322424)
External DOI: https://doi.org/10.1016/j.molcel.2017.06.001
This record's URL: https://www.repository.cam.ac.uk/handle/1810/277561
Attribution-NonCommercial-NoDerivatives 4.0 International
Licence URL: http://creativecommons.org/licenses/by-nc-nd/4.0/
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