A1 Journal article (refereed)
A spontaneous mitonuclear epistasis converging on Rieske Fe-S protein exacerbates complex III deficiency in mice (2020)


Purhonen, Janne; Grigorjev, Vladislav; Ekiert, Robert; Aho, Noora; Rajendran, Jayasimman; Pietras, Rafał; Truvé, Katarina; Wikström, Mårten; Sharma, Vivek; Osyczka, Artur; Fellman, Vineta et al. (2020). A spontaneous mitonuclear epistasis converging on Rieske Fe-S protein exacerbates complex III deficiency in mice. Nature Communications, 11, 322. DOI: 10.1038/s41467-019-14201-2


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Publication details

All authors or editors: Purhonen, Janne; Grigorjev, Vladislav; Ekiert, Robert; Aho, Noora; Rajendran, Jayasimman; Pietras, Rafał; Truvé, Katarina; Wikström, Mårten; Sharma, Vivek; Osyczka, Artur; et al.

Journal or series: Nature Communications

eISSN: 2041-1723

Publication year: 2020

Volume: 11

Article number: 322

Publisher: Nature Publishing Group

Publication country: United Kingdom

Publication language: English

DOI: http://doi.org/10.1038/s41467-019-14201-2

Open Access: Publication published in an open access channel

Publication is parallel published (JYX): https://jyx.jyu.fi/handle/123456789/67414


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.


Keywords: metabolic disorders; mitochondrial diseases; mitochondrial DNA; survival; animal disease models


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Ministry reporting: Yes

Reporting Year: 2020

Preliminary JUFO rating: 3


Last updated on 2020-18-08 at 13:38