A spontaneous mitonuclear epistasis converging on Rieske Fe-S protein exacerbates complex III deficiency in mice
| Autor: | Noora Aho, Mårten Wikström, Vladislav Grigorjev, Vineta Fellman, Vivek Sharma, Janne Purhonen, Artur Osyczka, Robert Ekiert, Jukka Kallijärvi, Rafał Pietras, Katarina Truvé, Jayasimman Rajendran |
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| Přispěvatelé: | STEMM - Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Research Programs Unit, Department of Physics, Institute of Biotechnology, Materials Physics, Clinicum, HUS Children and Adolescents, Children's Hospital |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
DYNAMICS
epistasis Male 0301 basic medicine Non-Mendelian inheritance Mitochondrial Diseases Metabolic disorders Respiratory chain General Physics and Astronomy DISEASE mitokondriotaudit Electron Transport Complex III Mice 0302 clinical medicine energy metabolism CRYSTAL-STRUCTURE IRON-SULFUR PROTEIN lcsh:Science Mice Knockout Genetics mitokondrio-DNA Multidisciplinary CYTOCHROME BC(1) COMPLEX Cytochrome b Cytochromes b Mitochondria 3. Good health Female RESPIRATORY-CHAIN GRACILE SYNDROME henkiinjääminen Oxidation-Reduction Mitochondrial DNA Mitochondrial disease Science Congenic Molecular Dynamics Simulation Biology DNA Mitochondrial Article General Biochemistry Genetics and Molecular Biology 03 medical and health sciences aineenvaihduntahäiriöt medicine metabolic disorders Animals MUTATIONS Epistasis Genetic Energy metabolism General Chemistry Cytochrome b Group medicine.disease Mice Inbred C57BL 030104 developmental biology Coenzyme Q – cytochrome c reductase Epistasis 1182 Biochemistry cell and molecular biology ATPases Associated with Diverse Cellular Activities lcsh:Q GUI MEMBRANE-BUILDER koe-eläinmallit Metabolism Inborn Errors 030217 neurology & neurosurgery GENERATION Molecular Chaperones |
| Zdroj: | Nature Communications, Vol 11, Iss 1, Pp 1-12 (2020) Nature Communications |
| ISSN: | 2041-1723 |
| Popis: | We previously observed an unexpected fivefold (35 vs. 200 days) difference in the survival of respiratory chain complex III (CIII) deficient Bcs1lp.S78G mice between two congenic backgrounds. Here, we identify a spontaneous homoplasmic mtDNA variant (m.G14904A, mt-Cybp.D254N), affecting the CIII subunit cytochrome b (MT-CYB), in the background with short survival. We utilize maternal inheritance of mtDNA to confirm this as the causative variant and show that it further decreases the low CIII activity in Bcs1lp.S78G tissues to below survival threshold by 35 days of age. Molecular dynamics simulations predict D254N to restrict the flexibility of MT-CYB ef loop, potentially affecting RISP dynamics. In Rhodobacter cytochrome bc1 complex the equivalent substitution causes a kinetics defect with longer occupancy of RISP head domain towards the quinol oxidation site. These findings represent a unique case of spontaneous mitonuclear epistasis and highlight the role of mtDNA variation as modifier of mitochondrial disease phenotypes. A difference in the survival of respiratory chain complex III deficient Bcs1lp.S78G mice was observed between two congenic mouse strains. Here the authors show how in one of the strains the combined effects of a spontaneously arising non-pathogenic variant and the disease-causing Bcs1lp.S78G mutation exacerbate CIII deficiency and disease progression. |
| Databáze: | OpenAIRE |
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