Purhonen 2020 Nat Commun

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 Marten KF, 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 Bcs1l^p.S78G mice between two congenic backgrounds. Here, we identify a spontaneous homoplasmic mtDNA variant (m.G14904A, mt-Cyb^p.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 Bcs1l^p.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