Purhonen 2020 Nat Commun

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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. Nat Commun 11:322.

» PMID: 31949167 Open Access

Purhonen J, Grigorjev V, Ekiert R, Aho N, Rajendran J, Pietras R, Truve K, Wikstroem M, Sharma Vivek, Osyczka A, Fellman V, Kallijaervi J (2020) Nat Commun

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.


Bioblast editor: Plangger M O2k-Network Lab: FI Helsinki Mervaala E


Labels: MiParea: Respiration, mtDNA;mt-genetics 

Stress:Mitochondrial disease  Organism: Mouse  Tissue;cell: Liver, Kidney  Preparation: Isolated mitochondria  Enzyme: Complex III 

Coupling state: LEAK, OXPHOS, ET  Pathway: N, NS, ROX  HRR: Oxygraph-2k, O2k-Fluorometer 

Labels, 2020-01, AmR