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CO(2)-sensitive tRNA modification associated with human mitochondrial disease
It has been generally thought that tRNA modifications are stable and static, and their frequencies are rarely regulated. N(6)-threonylcarbamoyladenosine (t(6)A) occurs at position 37 of five mitochondrial (mt-)tRNA species. We show that YRDC and OSGEPL1 are responsible for t(6)A37 formation, utilizi...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5951830/ https://www.ncbi.nlm.nih.gov/pubmed/29760464 http://dx.doi.org/10.1038/s41467-018-04250-4 |
Sumario: | It has been generally thought that tRNA modifications are stable and static, and their frequencies are rarely regulated. N(6)-threonylcarbamoyladenosine (t(6)A) occurs at position 37 of five mitochondrial (mt-)tRNA species. We show that YRDC and OSGEPL1 are responsible for t(6)A37 formation, utilizing L-threonine, ATP, and CO(2)/bicarbonate as substrates. OSGEPL1-knockout cells exhibit respiratory defects and reduced mitochondrial translation. We find low level of t(6)A37 in mutant mt-tRNA isolated from the MERRF-like patient’s cells, indicating that lack of t(6)A37 results in pathological consequences. Kinetic measurements of t(6)A37 formation reveal that the Km value of CO(2)/bicarbonate is extremely high (31 mM), suggesting that CO(2)/bicarbonate is a rate-limiting factor for t(6)A37 formation. Consistent with this, we observe a low frequency of t(6)A37 in mt-tRNAs isolated from human cells cultured without bicarbonate. These findings indicate that t(6)A37 is regulated by sensing intracellular CO(2)/bicarbonate concentration, implying that mitochondrial translation is modulated in a codon-specific manner under physiological conditions. |
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