1. A spontaneous mitonuclear epistasis converging on Rieske Fe-S protein exacerbates complex III deficiency in mice
- Author
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Noora Aho, Mårten Wikström, Vladislav Grigorjev, Vineta Fellman, Vivek Sharma, Janne Purhonen, Artur Osyczka, Robert Ekiert, Jukka Kallijärvi, Rafał Pietras, Katarina Truvé, Jayasimman Rajendran, 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, and Children's Hospital
- Subjects
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 - Abstract
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.
- Published
- 2020