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

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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.


  • Janne Purhonen
  • Vladislav Grigorjev
  • Robert Ekiert
  • Noora Aho
  • Jayasimman Rajendran
  • Rafał Pietras
  • Katarina Truvé
  • Mårten Wikström
  • Vivek Sharma
  • Artur Osyczka
  • Vineta Fellman
  • Jukka Kallijärvi
External organisations
  • Folkhälsan Research Center
  • University of Helsinki
  • Jagellonian University
  • Helsinki University of Technology
  • University of Jyväskylä
  • Sahlgrenska Academy
  • Helsinki University Children's Hospital
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Medical Genetics
Original languageEnglish
Article number322
JournalNature Communications
Issue number1
Publication statusPublished - 2020
Publication categoryResearch