CO2 -sensitive tRNA modification associated with human mitochondrial disease

Nature Communications
Huan LinTsutomu Suzuki

Abstract

It has been generally thought that tRNA modifications are stable and static, and their frequencies are rarely regulated. N6-threonylcarbamoyladenosine (t6A) occurs at position 37 of five mitochondrial (mt-)tRNA species. We show that YRDC and OSGEPL1 are responsible for t6A37 formation, utilizing L-threonine, ATP, and CO2/bicarbonate as substrates. OSGEPL1-knockout cells exhibit respiratory defects and reduced mitochondrial translation. We find low level of t6A37 in mutant mt-tRNA isolated from the MERRF-like patient's cells, indicating that lack of t6A37 results in pathological consequences. Kinetic measurements of t6A37 formation reveal that the Km value of CO2/bicarbonate is extremely high (31 mM), suggesting that CO2/bicarbonate is a rate-limiting factor for t6A37 formation. Consistent with this, we observe a low frequency of t6A37 in mt-tRNAs isolated from human cells cultured without bicarbonate. These findings indicate that t6A37 is regulated by sensing intracellular CO2/bicarbonate concentration, implying that mitochondrial translation is modulated in a codon-specific manner under physiological conditions.

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Citations

Jan 31, 2019·Nucleic Acids Research·Valérie de Crécy-LagardJanusz M Bujnicki
Jul 10, 2019·Nucleic Acids Research·Saori ShinodaTsutomu Suzuki
Feb 13, 2020·Nucleic Acids Research·Jing-Bo ZhouXiao-Long Zhou
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Nov 28, 2018·International Journal of Molecular Sciences·Marisa PereiraAna Raquel Soares
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Jul 6, 2019·Nucleic Acids Research·Lindsey Van HauteMichal Minczuk
Jan 29, 2019·Frontiers in Genetics·Ya-Ming HouHoward Gamper
Dec 6, 2020·Nature Communications·Jonah BeenstockFrank Sicheri
Jan 30, 2021·The FEBS Journal·Takeshi Chujo, Kazuhito Tomizawa
Feb 24, 2021·Critical Reviews in Biochemistry and Molecular Biology·Yasemin YoluçStefanie Kellner
Mar 5, 2021·Nature Reviews. Molecular Cell Biology·Tsutomu Suzuki
Jul 15, 2020·Current Opinion in Microbiology·Satoshi KimuraMatthew K Waldor
Apr 22, 2021·Science China. Life Sciences·Jing LiRu-Juan Liu
Jun 11, 2021·RNA Biology·Huixin LiangQiyi Zhao
Aug 8, 2021·International Journal of Molecular Sciences·Marta Jedynak-SlyvkaRoman J Szczesny
Dec 5, 2018·Biochemistry·Leticia Pollo-Oliveira, Valérie de Crécy-Lagard
Aug 27, 2021·Internal Medicine·Tomoya KawazoeEiji Isozaki
Oct 5, 2021·Cellular and Molecular Life Sciences : CMLS·Jing-Bo ZhouXiao-Long Zhou
Oct 7, 2021·Nucleic Acids Research·Jonah Beenstock, Frank Sicheri

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Methods Mentioned

BETA
aminoacylation
deacylation
in vitro transcription
xenografts
Fluorescence
antisense oligonucleotides
transfections
in
PCR
cochlear implant

Software Mentioned

WoLF PSORT
PSORT
iPSORT

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