204 - Mitochondria-specific SQR deficiency in mice causes lethal impairment of sulfur respiration

Abstract

Sulfide quinone reductase (SQR) protein is a mitochondrial enzyme highly conserved among species and has been considered as an important enzyme mediating proton transfer in mitochondria during sulfur metabolism (respiration), however, the detailed mechanism and physiological impacts of SQR function are still unknown. We generated SQR genome-edited mice to investigate functions of SQR in sulfur respiration. Deletion of translational start site ATG in mouse Sqr locus caused illegitimate translation and resulted in lack of mitochondrial localization signal in N-terminal region of SQR, we have named this mutant allele as SQRΔN. In SQRΔN mutant mice, SQRΔN protein is expressed at the same level as wild-type mice, but the SQR∆N protein is not localized in mitochondria and remains in cytosol. Pups from SQR∆N heterozygous parents showed mendelian distribution of the genotypes, indicating that the ablation of SQR in mitochondria is not associated with reduced viability in utero. However, SQRΔN homozygous mice showed growth arrest after the third postnatal weeks and they die within tenth week after birth. We quantified the sulfide metabolites in several organs (liver, lung, heart and muscle) of SQRΔN mice and their wild-type littermates via LC-MS/MS analysis and as we expected, SQRΔN mice showed a sulfur metabolite profile different from that of the wild-type littermates. Immortalized embryonic fibroblast derived from SQRΔN homozygous mice showed the decreased mitochondrial membrane potential formation. Mitochondria in soleus muscle and liver of SQRΔN showed markedly altered mitochondrial morphology in transmission electron microscopy analysis. These results indicate that SQR in mitochondria is indeed contribute to the membrane potential formation and energy metabolisms.