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

Area of Science:

• Mitochondrial genetics
• Cellular respiration
• Mitochondrial disease

Background:

• Mice with respiratory chain complex III (CIII) deficiency due to Bcs1l^p.S78G mutation showed a fivefold difference in survival between congenic backgrounds.
• This unexpected variation suggested genetic modifiers influencing the disease phenotype.

Purpose of the Study:

• To identify the genetic factor responsible for the differential survival observed in CIII-deficient mice.
• To investigate the role of mitochondrial DNA (mtDNA) variation in modulating mitochondrial disease severity.

Main Methods:

• Identification of a spontaneous homoplasmic mtDNA variant (m.G14904A, mt-Cyb^p.D254N) in the short-survival mouse background.
• Utilizing maternal inheritance of mtDNA to confirm the variant's causative role.
• Employing molecular dynamics simulations to predict the structural and functional impact of the mt-Cyb^p.D254N variant.

Main Results:

• The mt-Cyb^p.D254N variant was confirmed as the causative factor, further reducing CIII activity below the survival threshold in Bcs1l^p.S78G mice.
• Molecular dynamics simulations indicated that the D254N substitution restricts MT-CYB ef loop flexibility, potentially impacting RISP dynamics.
• Comparison with Rhodobacter cytochrome bc1 complex suggested a kinetics defect associated with the equivalent substitution.

Conclusions:

• This study presents a unique instance of spontaneous mitonuclear epistasis, where a mtDNA variant modifies a nuclear gene-induced mitochondrial disease.
• mtDNA variation plays a critical role in modifying the phenotypic expression of mitochondrial disorders.