The Molecular Pathogenetic Mechanism Of Mitochondrial TARS2 Mutations Associated With Combined Oxidative Phosphorylation Deficiency

Aminoacyl-t RNA synthetase(aa RS)supplies material for protein biosynthesis by catalyzing the formation of correct aminoacyl-t RNA in cytoplasm and mitochondria.Mitochondria is the power house of the cell,producing ATP responsible for physiological activities of the various organelles through oxidative phosphorylation.Mutations in mitochondrial aa RS genes have been increasing reported in diverse diseases which characterized by early-onset and autosomal recessive transmission with neurological clinical features.However,the molecular pathogenetic mechanism of mitochondrial threonyl-t RNA synthetase(TARS2)remained unclear.Our studies report four novel TARS2 mutations from Chinese patients with combined oxidative phosphorylation deficiency 21.Subjects present with a range of developmental delay,mental retardation and high lactic acid.There are three missense mutations in TARS2: F323 C,G447E,R327 Q.c.775-11(IVS7)T>A mutation,located in intron 7,resulting in alternative splicing,leads to a reduction of TARS2,while the isoform b without the capacity of aminoacylation increases.We reveal that mutations induce a decrease in aminoacylation,leading to decreased levels of mitochondrial respiratory.Additionally,TARS2 mutations cause marked respiratory defects,diminished mitochondrial ATP production and membrane potential,resulting from defective mitochondrial oxidative phosphorylation.In conclusion,our studies investigate thoroughly the molecular pathogenetic mechanism of TARS2 mutations associated with combined oxidative phosphorylation deficiency 21,and provide new insights into the diseases with neurological clinical features.These results also provide theoretical and technical support for further in-depth research on mitochondrial aa RS related recessive disorders.