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

Janne Purhonen, Vladislav Grigorjev, Robert Ekiert, Noora Aho, Jayasimman Rajendran, Rafał Pietras, Katarina Truvé, Mårten Wikström, Vivek Sharma, Artur Osyczka, Vineta Fellman and Jukka Kallijärvi ()
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Janne Purhonen: Folkhälsan Research Center
Vladislav Grigorjev: Folkhälsan Research Center
Robert Ekiert: Jagiellonian University
Noora Aho: University of Helsinki
Jayasimman Rajendran: Folkhälsan Research Center
Rafał Pietras: Jagiellonian University
Katarina Truvé: University of Gothenburg
Mårten Wikström: University of Helsinki
Vivek Sharma: University of Helsinki
Artur Osyczka: Jagiellonian University
Vineta Fellman: Folkhälsan Research Center
Jukka Kallijärvi: Folkhälsan Research Center

Nature Communications, 2020, vol. 11, issue 1, 1-12

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-019-14201-2

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