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.
Highlights
The phenotypic expression of mitochondrial DNA mutations can be modulated by nuclear genes and environmental factors [1,2,3,4,5]
We reveal that glycolysis increasingly compensates for the mitochondrial dysfunction of the mss1(PR) mutant and insures its growth, in a similar manner to that of the mto2(PR) mutant [17]
After the cells were cultured in a neomycin-supplemented YPD medium for 16 h, the cell density of the mss1(PR) strain with the overexpression of HAP5 increased significantly (P,0.01) by about 40%, in contrast to that of the mss1(PR) strain (OD600 value 2.384 versus 1.702) (Fig. 7C). These results indicate that HAP5 has a positive effect on the glycolysis of the mss1(PR) strain in neomycinsupplemented medium
Summary
The phenotypic expression of mitochondrial DNA (mtDNA) mutations can be modulated by nuclear genes and environmental factors [1,2,3,4,5]. In the yeast Saccharomyces cerevisiae the mtDNA 15S rRNA C1477G mutation corresponds to the human mtDNA 12S rRNA A1555G mutation [6,7,8,9] In this ideal model of the C1477G mutant, we and others have shown that the presence of additional mutations in the nuclear modifier genes MSS1, or MTO1, or MTO2 causes the double mutant to exhibit a respiratory-deficient phenotype [8,10,11,12,13,14]. We demonstrated that the yeast C1477G mutant was sensitive to aminoglycoside neomycin in a fermentable YPD medium, and that the nuclear modifier gene mto mutation suppressed the C1477G mutant’s phenotypic expression [17]. On the basis of the above evidence, yeast strains with disruption or overexpression of HAP5 were constructed These strains were characterized by examining growth properties and the gene expression of the glycolytic transcription factors. We identified that in the mss1(PR) mutant the increase of glycolysis could be mediated by HAP5
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