TTC19 Plays a Husbandry Role on UQCRFS1 Turnover in the Biogenesis of Mitochondrial Respiratory Complex III
| Autor: | 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, Emanuela Bottani |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
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 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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