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

Nat Commun. 2020 Jan 16;11(1):322. doi: 10.1038/s41467-019-14201-2.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATPases Associated with Diverse Cellular Activities / genetics
  • ATPases Associated with Diverse Cellular Activities / metabolism
  • Animals
  • Cytochrome b Group / chemistry
  • Cytochrome b Group / genetics
  • Cytochromes b
  • DNA, Mitochondrial
  • Electron Transport Complex III / chemistry
  • Electron Transport Complex III / genetics*
  • Electron Transport Complex III / metabolism*
  • Energy Metabolism
  • Epistasis, Genetic / genetics*
  • Female
  • Male
  • Metabolism, Inborn Errors / genetics*
  • Metabolism, Inborn Errors / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria / genetics*
  • Mitochondrial Diseases / genetics*
  • Molecular Chaperones / genetics
  • Molecular Chaperones / metabolism
  • Molecular Dynamics Simulation
  • Oxidation-Reduction


  • BCS1L protein, mouse
  • Cytochrome b Group
  • DNA, Mitochondrial
  • Molecular Chaperones
  • Rieske iron-sulfur protein
  • Cytochromes b
  • ATPases Associated with Diverse Cellular Activities
  • Electron Transport Complex III