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

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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; Osyczka, Artur; Fellman, Vineta; Kallijärvi, Jukka.

In: Nature Communications, Vol. 11, No. 1, 322, 2020.

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Purhonen, J, Grigorjev, V, Ekiert, R, Aho, N, Rajendran, J, Pietras, R, Truvé, 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

APA

Purhonen, J., Grigorjev, V., Ekiert, R., Aho, N., Rajendran, J., Pietras, R., Truvé, 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, 11(1), [322]. https://doi.org/10.1038/s41467-019-14201-2

CBE

Purhonen J, Grigorjev V, Ekiert R, Aho N, Rajendran J, Pietras R, Truvé 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. 11(1):Article 322. https://doi.org/10.1038/s41467-019-14201-2

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Author

Purhonen, Janne ; Grigorjev, Vladislav ; Ekiert, Robert ; Aho, Noora ; Rajendran, Jayasimman ; Pietras, Rafał ; Truvé, Katarina ; Wikström, Mårten ; Sharma, Vivek ; Osyczka, Artur ; Fellman, Vineta ; Kallijärvi, Jukka. / A spontaneous mitonuclear epistasis converging on Rieske Fe-S protein exacerbates complex III deficiency in mice. In: Nature Communications. 2020 ; Vol. 11, No. 1.

RIS

TY - JOUR

T1 - A spontaneous mitonuclear epistasis converging on Rieske Fe-S protein exacerbates complex III deficiency in mice

AU - Purhonen, Janne

AU - Grigorjev, Vladislav

AU - Ekiert, Robert

AU - Aho, Noora

AU - Rajendran, Jayasimman

AU - Pietras, Rafał

AU - Truvé, Katarina

AU - Wikström, Mårten

AU - Sharma, Vivek

AU - Osyczka, Artur

AU - Fellman, Vineta

AU - Kallijärvi, Jukka

PY - 2020

Y1 - 2020

N2 - 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.

AB - 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.

U2 - 10.1038/s41467-019-14201-2

DO - 10.1038/s41467-019-14201-2

M3 - Article

C2 - 31949167

AN - SCOPUS:85077941342

VL - 11

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

IS - 1

M1 - 322

ER -