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.
Highlights
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
whole-genome sequencing (WGS) (n = 3 for Lund C57BL/6JBomTac and n = 2 for Helsinki C57BL/6JCrl) revealed 844 homozygous single-nucleotide polymorphisms and 3655 small insertion/deletions between the strains, only 8 of which were in coding regions of genes (Supplementary Table 1)
Genotyping of approximately 80 mice throughout past generations using archived genomic DNA from ear biopsies revealed that the variant was introduced from wild-type (WT) C57BL/6JBomTac females repeatedly after 2008, when congenization of the Bcs1lc.A232G knock-in allele was started (Supplementary Fig. 1a)
Summary
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. In Rhodobacter cytochrome bc[1] 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. Homozygous Bcs1lc.A232G (Bcs1lp.S78G) knock-in mice[8], carrying a GRACILE syndrome[9,10] patient mutation[3], recapitulate many manifestations of human CIII deficiency They display postweaning growth failure, hepatopathy, renal tubulopathy, and, in a C57BL/6JBomTac-derived genetic background (Lund colony), deterioration due to metabolic crisis with extreme hypoglycemia by 35 days of age (P35)[11,12,13]. Computational, and spectroscopic data to show how the effects of this non-pathogenic variant and the disease-causing Bcs1l mutation converge to exacerbate CIII deficiency and disease progression
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