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

Purhonen, Janne ; Grigorjev, Vladislav ; Ekiert, Robert ; Aho, Noora ; Rajendran, Jayasimman ; Pietras, Rafał ; Truvé, Katarina ; Wikström, Mårten ; Sharma, Vivek and Osyczka, Artur , et al. (2020) In Nature Communications 11(1).
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... (More)

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.

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publishing date
type
Contribution to journal
publication status
published
subject
in
Nature Communications
volume
11
issue
1
article number
322
publisher
Nature Publishing Group
external identifiers
  • scopus:85077941342
  • pmid:31949167
ISSN
2041-1723
DOI
10.1038/s41467-019-14201-2
language
English
LU publication?
yes
id
eb78568a-3335-47f8-9126-30e402321b8b
date added to LUP
2020-02-03 10:57:06
date last changed
2024-03-04 11:57:28
@article{eb78568a-3335-47f8-9126-30e402321b8b,
  abstract     = {{<p>We previously observed an unexpected fivefold (35 vs. 200 days) difference in the survival of respiratory chain complex III (CIII) deficient Bcs1l<sup>p.S78G</sup> mice between two congenic backgrounds. Here, we identify a spontaneous homoplasmic mtDNA variant (m.G14904A, mt-Cyb<sup>p.D254N</sup>), 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 Bcs1l<sup>p.S78G</sup> 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<sub>1</sub> 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.</p>}},
  author       = {{Purhonen, Janne and Grigorjev, Vladislav and Ekiert, Robert and Aho, Noora and Rajendran, Jayasimman and Pietras, Rafał and Truvé, Katarina and Wikström, Mårten and Sharma, Vivek and Osyczka, Artur and Fellman, Vineta and Kallijärvi, Jukka}},
  issn         = {{2041-1723}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Communications}},
  title        = {{A spontaneous mitonuclear epistasis converging on Rieske Fe-S protein exacerbates complex III deficiency in mice}},
  url          = {{http://dx.doi.org/10.1038/s41467-019-14201-2}},
  doi          = {{10.1038/s41467-019-14201-2}},
  volume       = {{11}},
  year         = {{2020}},
}