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 organization: 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
Date: 2020-01-16
Language: eng
Number of pages: 12
Belongs to series: Nature Communications
ISSN: 2041-1723
DOI: https://doi.org/10.1038/s41467-019-14201-2
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
Peer reviewed: Yes
Rights: cc_by
Usage restriction: openAccess
Self-archived version: publishedVersion
Funder: Valtion perusrahoitus/hankkeet
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