Studies On The Novel Function Of Nuclear Modifier Gene MTO2

Nuclear modifier genes do not induce any pathology per se,but contribute to the pathogenic effect of the mitochondrial mutations.The nuclear modifier could be a common functional polymorphism in a tissue-specific protein,possibly with mitochondrial location.MtDNA mutations were necessary for mitochondrial diseases that caused by mitochondrial dysfunction,but not sufficient to induce the pathology.Nuclear modifier genes,environment factors,also contributes to the pathogenic effect of the mitochondrial mutations.In-depth clarify the interaction between this three factors, has an important social significance for guiding mitochondrial disease diagnosis,early warning and treatment.Nuclear modifier gene MTO2 encoding the mitochondrial 5-methylaminomethyl-2-thiouridylate-methyltransferase. Our laboratory first identified and characterized this gene.MTO2 is a nuclear genes encoding protein,which was highly evolutionarily conserved,mto2 null mutants expressed a respiratory-deficient phenotype when coexisting with the C1409G mutation of mitochondrial 15 S rRNA(paromomycin resistance mutation p₄₅₄^R)at the very conservative site for human deafness-associated 12S rRNA A1555G mutations.In this study,we focus on the interaction between nuclear modifier gene MTO2 and aminoglycosides(mainly neomycin),and have received the following innovations.1,We here report first that the knockout of MTO2 significantly inhibited mtDNA p₄₅₄^R mutant`s sensitivity to aminoglycoside antibiotics.Here are the results:(1)In neomycin GYP medium,when mitochondria genes were wild type,whether MTO2 knockout or not,the growth of yeast strains has no significant difference;when mitochondria genes were complete deletion,whether MTO2 knockout or not,the growth of yeast strains also has no significant difference;Interesting,when mtDNA P₄₅₄^R,wild-type MTO2 strains were hardly survival in neomycin GYP medium,but the growth of MTO2 knockout strains were only partly inhibited,there was a significant difference performance of neomycin sensitivity between them.(2)In the non-neomycin GYP medium,the growth of all strains there is no significant difference.2,from the genome-wide level,we doing some research on the MTO2.The gene chip results showed:under mtDNA p₄₅₄^R mutation,without a treatment with neomycin,the knockout of MTO2,significantly promote the expression of genes involved in rRNA metabolism,but lower expression of genes involved in glucose fermentation.After the treatment with neomycin,there was significantly increased expression of genes involved in glucose fermentation,but rRNA metabolism genes has no significant difference expression.Knockout of MTO2 significantly inhibited p₄₅₄^R associated aminoglycoside antibiotics sensitivity.The molecular mechanism of which was not changed rRNA structure caused by p₄₅₄^R mutation,but enhanced yeast capability of using glucose fermentation to produce more ATP,partly restored mitochondrial defects caused by p₄₅₄^R mutation and the aminoglycoside antibiotics.