A spontaneous mitonuclear epistasis converging on Rieske Fe-S protein exacerbates complex III deficiency in mice
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, Article 322. https://doi.org/10.1038/s41467-019-14201-2
Published inNature Communications
© 2020 the Author(s)
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. ...
PublisherNature Publishing Group
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Related funder(s)Academy of Finland
Funding program(s)Academy Project, AoF
Additional information about fundingThis study was supported by grants from Academy of Finland (grant 259296 to V.F., grant 294652 to V.S., grant 311031 to N.A.), Swedish Research Council (grant 521-2011-3877 to V.F.), Finnish Physicians’ Society (to V.F.), Foundation for Pediatric Research in Finland (to V.F.), Folkhälsan Research Center (to V.F. and J.K.), Magnus Ehrnrooth Foundation (to V.F. and V.S.), University of Helsinki (to V.S.), Sigrid Jusélius Foundation (to V.S.), and National Science Centre, Poland (Maestro grant 2015/18/A/NZ1/00046 to A.O.). ...
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