A spontaneous mitonuclear epistasis converging on Rieske Fe-S protein exacerbates complex III deficiency in mice

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Purhonen , J , Grigorjev , V , Ekiert , R , Aho , N , Rajendran , J , Pietras , R , Truve , K , Wikström , M , Sharma , V , Osyczka , A , Fellman , V & Kallijärvi , J 2020 , ' A spontaneous mitonuclear epistasis converging on Rieske Fe-S protein exacerbates complex III deficiency in mice ' , Nature Communications , vol. 11 , no. 1 , 322 . https://doi.org/10.1038/s41467-019-14201-2

Title: A spontaneous mitonuclear epistasis converging on Rieske Fe-S protein exacerbates complex III deficiency in mice
Author: Purhonen, Janne; Grigorjev, Vladislav; Ekiert, Robert; Aho, Noora; Rajendran, Jayasimman; Pietras, Rafal; Truve, Katarina; Wikström, Mårten; Sharma, Vivek; Osyczka, Artur; Fellman, Vineta; Kallijärvi, Jukka
Contributor: University of Helsinki, STEMM - Stem Cells and Metabolism Research Program
University of Helsinki, Department of Physics
University of Helsinki, STEMM - Stem Cells and Metabolism Research Program
University of Helsinki, Institute of Biotechnology
University of Helsinki, Department of Physics
University of Helsinki, Clinicum
University of Helsinki, Clinicum
Date: 2020-01-16
Language: eng
Number of pages: 12
Belongs to series: Nature Communications
ISSN: 2041-1723
URI: http://hdl.handle.net/10138/313076
Abstract: We previously observed an unexpected fivefold (35 vs. 200 days) difference in the survival of respiratory chain complex III (CIII) deficient Bcs1/(p.S78G) mice between two congenic backgrounds. Here, we identify a spontaneous homoplasmic mtDNA variant (m.G14904A, mt-Cyb(p.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 Bcs1/(p.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 bc(1) 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.
Subject: IRON-SULFUR PROTEIN
CYTOCHROME BC(1) COMPLEX
GUI MEMBRANE-BUILDER
RESPIRATORY-CHAIN
CRYSTAL-STRUCTURE
GRACILE SYNDROME
MUTATIONS
GENERATION
DYNAMICS
DISEASE
1182 Biochemistry, cell and molecular biology
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