Abstract
The phenotypic manifestations of mitochondrial DNA (mtDNA) mutations are modulated by mitochondrial DNA haplotypes, nuclear modifier genes and environmental factors. The yeast mitochondrial 15S rRNA C1477G (PR or PR 454) mutation corresponds to the human 12S rRNA C1494T and A1555G mutations, which are well known as primary factors for aminoglycoside-induced nonsyndromic deafness. Here we report that the deletion of the nuclear modifier gene MTO2 suppressed the aminoglycoside-sensitivity of mitochondrial 15S rRNA C1477G mutation in Saccharomyces cerevisiae. First, the strain with a single mtDNA C1477G mutation exhibited hypersensitivity to neomycin. Functional assays indicated that the steady-state transcription level of mitochondrial DNA, the mitochondrial respiratory rate, and the membrane potential decreased significantly after neomycin treatment. The impaired mitochondria could not produce sufficient energy to maintain cell viability. Second, when the mto2 null and the mitochondrial C1477G mutations co-existed (mto2(PR)), the oxygen consumption rate in the double mutant decreased markedly compared to that of the control strains (MTO2(PS), mto2(PS) and MTO2(PR)). The expression levels of the key glycolytic genes HXK2, PFK1 and PYK1 in the mto2(PR) strain were stimulated by neomycin and up-regulated by 89%, 112% and 55%, respectively. The enhanced glycolysis compensated for the respiratory energy deficits, and could be inhibited by the glycolytic enzyme inhibitor. Our findings in yeast will provide a new insight into the pathogenesis of human deafness.
Highlights
The phenotypic manifestations of mitochondrial DNA mutations are modulated by mitochondrial DNA haplotypes, nuclear modifier genes and environmental factors [1,2]
We found that the nuclear gene MTO2 could modulate aminoglycoside antibiotic sensitivity induced by the mitochondrial C1477G mutation
To examine the functional consequence of antibiotics on yeast, yeast cells carrying mitochondrial 15S rRNA C1477G and/or nuclear mto2 null mutation were cultured in YPD medium containing neomycin
Summary
The phenotypic manifestations of mitochondrial DNA (mtDNA) mutations are modulated by mitochondrial DNA haplotypes, nuclear modifier genes and environmental factors [1,2]. Individuals carrying the A1555G mutation exhibit diverse clinical phenotypes ranging from normal hearing to severe deafness. This suggests that the clinical symptom may be under the regulation of nuclear genes and environmental factors [3,5,6,7]. The combined effect of mtDNA mutation and nuclear modifier genes have been presented in several studies where environmental influences appear to play a role but remain poorly understood [7,8]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
