title: Mechanistic study on the nuclear modifier gene MSS1 mutation suppressing neomycin sensitivity of the mitochondrial 15S rRNA C1477G mutation in Saccharomyces cerevisiae.
abstract: The phenotypic manifestation of mitochondrial DNA (mtDNA) mutations can be modulated by nuclear genes and environmental factors. However, neither the interaction among these factors nor their underlying mechanisms are well understood. The yeast Saccharomyces cerevisiae mtDNA 15S rRNA C1477G mutation (PR) corresponds to the human 12S rRNA A1555G mutation. Here we report that a nuclear modifier gene mss1 mutation suppresses the neomycin-sensitivity phenotype of a yeast C1477G mutant in fermentable YPD medium. Functional assays show that the mitochondrial function of the yeast C1477G mutant was impaired severely in YPD medium with neomycin. Moreover, the mss1 mutation led to a significant increase in the steady-state level of HAP5 (heme activated protein), which greatly up-regulated the expression of glycolytic transcription factors RAP1, GCR1, and GCR2 and thus stimulated glycolysis. Furthermore, the high expression of the key glycolytic enzyme genes HXK2, PFK1 and PYK1 indicated that enhanced glycolysis not only compensated for the ATP reduction from oxidative phosphorylation (OXPHOS) in mitochondria, but also ensured the growth of the mss1(PR) mutant in YPD medium with neomycin. This study advances our understanding of the phenotypic manifestation of mtDNA mutations.
authors.affiliation: College of Life Sciences, Zhejiang University, Hangzhou, China.
authors.forename: Qiyin
authors.initials: Q
authors.lastname: Zhou
authors.affiliation: College of Life Sciences, Zhejiang University, Hangzhou, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: College of Life Sciences, Zhejiang University, Hangzhou, China.
authors.forename: Xiangyu
authors.initials: X
authors.lastname: He
authors.affiliation: College of Life Sciences, Zhejiang University, Hangzhou, China.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Zhu
authors.affiliation: College of Life Sciences, Zhejiang University, Hangzhou, China.
authors.forename: Yaoyao
authors.initials: Y
authors.lastname: Shen
authors.affiliation: College of Life Sciences, Zhejiang University, Hangzhou, China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Yu
authors.affiliation: College of Life Sciences, Zhejiang University, Hangzhou, China.
authors.forename: Xuexiang
authors.initials: X
authors.lastname: Wang
authors.affiliation: Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Xuchen
authors.initials: X
authors.lastname: Qi
authors.affiliation: College of Life Sciences, Zhejiang University, Hangzhou, China.
authors.forename: Xuan
authors.initials: X
authors.lastname: Zhang
authors.affiliation: College of Life Sciences, Zhejiang University, Hangzhou, China.
authors.forename: Mingjie
authors.initials: M
authors.lastname: Fan
authors.affiliation: College of Life Sciences, Zhejiang University, Hangzhou, China; The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Dai
authors.affiliation: Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Shuxu
authors.initials: S
authors.lastname: Yang
authors.affiliation: College of Life Sciences, Zhejiang University, Hangzhou, China.
authors.forename: Qingfeng
authors.initials: Q
authors.lastname: Yan
mesh_terms: D001483:Base Sequence; D015152:Blotting, Northern; D017931:DNA Primers; D004272:DNA, Mitochondrial / Q000235:genetics*; D019204:GTP-Binding Proteins / Q000235:genetics*; D006019:Glycolysis; D009154:Mutation; D009355:Neomycin / Q000494:pharmacology*; D012335:RNA, Ribosomal / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics*; D014158:Transcription, Genetic
chemical_list: D017931:DNA Primers; D004272:DNA, Mitochondrial; D012335:RNA, Ribosomal; D029701:Saccharomyces cerevisiae Proteins; D019204:GTP-Binding Proteins; C082241:MSS1 protein, S cerevisiae; D009355:Neomycin