Editing activity for eliminating mischarged tRNAs is essential in mammalian mitochondria

Taru Hilander, Xiao-Long Zhou, Svetlana Konovalova, Fu-Ping Zhang, Liliya Euro, Dmitri Shilov, Matti Poutanen, Joseph Chihade, En-Duo Wang, Henna Tyynismaa

Research output: Contribution to journalArticleScientificpeer-review

Abstract

Accuracy of protein synthesis is enabled by the selection of amino acids for tRNA charging by aminoacyl-tRNA synthetases (ARSs), and further enhanced by the proofreading functions of some of these enzymes for eliminating tRNAs mischarged with noncognate amino acids. Mouse models of editing-defective cytoplasmic alanyl-tRNA synthetase (AlaRS) have previously demonstrated the importance of proofreading for cytoplasmic protein synthesis, with embryonic lethal and progressive neurodegeneration phenotypes. Mammalian mitochondria import their own set of nuclear-encoded ARSs for translating critical polypeptides of the oxidative phosphorylation system, but the importance of editing by the mitochondrial ARSs for mitochondrial proteostasis has not been known. We demonstrate here that the human mitochondrial AlaRS is capable of editing mischarged tRNAs in vitro, and that loss of the proofreading activity causes embryonic lethality in mice. These results indicate that tRNA proofreading is essential in mammalian mitochondria, and cannot be overcome by other quality control mechanisms.
Original languageEnglish
JournalNucleic Acids Research
Volume46
Issue number2
Pages (from-to)849–860
Number of pages12
ISSN0305-1048
DOIs
Publication statusPublished - 2018
MoE publication typeA1 Journal article-refereed

Fields of Science

  • 3111 Biomedicine

Cite this

Hilander, Taru ; Zhou, Xiao-Long ; Konovalova, Svetlana ; Zhang, Fu-Ping ; Euro, Liliya ; Shilov, Dmitri ; Poutanen, Matti ; Chihade, Joseph ; Wang, En-Duo ; Tyynismaa, Henna. / Editing activity for eliminating mischarged tRNAs is essential in mammalian mitochondria. In: Nucleic Acids Research. 2018 ; Vol. 46, No. 2. pp. 849–860.
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title = "Editing activity for eliminating mischarged tRNAs is essential in mammalian mitochondria",
abstract = "Accuracy of protein synthesis is enabled by the selection of amino acids for tRNA charging by aminoacyl-tRNA synthetases (ARSs), and further enhanced by the proofreading functions of some of these enzymes for eliminating tRNAs mischarged with noncognate amino acids. Mouse models of editing-defective cytoplasmic alanyl-tRNA synthetase (AlaRS) have previously demonstrated the importance of proofreading for cytoplasmic protein synthesis, with embryonic lethal and progressive neurodegeneration phenotypes. Mammalian mitochondria import their own set of nuclear-encoded ARSs for translating critical polypeptides of the oxidative phosphorylation system, but the importance of editing by the mitochondrial ARSs for mitochondrial proteostasis has not been known. We demonstrate here that the human mitochondrial AlaRS is capable of editing mischarged tRNAs in vitro, and that loss of the proofreading activity causes embryonic lethality in mice. These results indicate that tRNA proofreading is essential in mammalian mitochondria, and cannot be overcome by other quality control mechanisms.",
keywords = "3111 Biomedicine",
author = "Taru Hilander and Xiao-Long Zhou and Svetlana Konovalova and Fu-Ping Zhang and Liliya Euro and Dmitri Shilov and Matti Poutanen and Joseph Chihade and En-Duo Wang and Henna Tyynismaa",
year = "2018",
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Editing activity for eliminating mischarged tRNAs is essential in mammalian mitochondria. / Hilander, Taru; Zhou, Xiao-Long; Konovalova, Svetlana; Zhang, Fu-Ping; Euro, Liliya; Shilov, Dmitri; Poutanen, Matti; Chihade, Joseph; Wang, En-Duo; Tyynismaa, Henna.

In: Nucleic Acids Research, Vol. 46, No. 2, 2018, p. 849–860.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - Editing activity for eliminating mischarged tRNAs is essential in mammalian mitochondria

AU - Hilander, Taru

AU - Zhou, Xiao-Long

AU - Konovalova, Svetlana

AU - Zhang, Fu-Ping

AU - Euro, Liliya

AU - Shilov, Dmitri

AU - Poutanen, Matti

AU - Chihade, Joseph

AU - Wang, En-Duo

AU - Tyynismaa, Henna

PY - 2018

Y1 - 2018

N2 - Accuracy of protein synthesis is enabled by the selection of amino acids for tRNA charging by aminoacyl-tRNA synthetases (ARSs), and further enhanced by the proofreading functions of some of these enzymes for eliminating tRNAs mischarged with noncognate amino acids. Mouse models of editing-defective cytoplasmic alanyl-tRNA synthetase (AlaRS) have previously demonstrated the importance of proofreading for cytoplasmic protein synthesis, with embryonic lethal and progressive neurodegeneration phenotypes. Mammalian mitochondria import their own set of nuclear-encoded ARSs for translating critical polypeptides of the oxidative phosphorylation system, but the importance of editing by the mitochondrial ARSs for mitochondrial proteostasis has not been known. We demonstrate here that the human mitochondrial AlaRS is capable of editing mischarged tRNAs in vitro, and that loss of the proofreading activity causes embryonic lethality in mice. These results indicate that tRNA proofreading is essential in mammalian mitochondria, and cannot be overcome by other quality control mechanisms.

AB - Accuracy of protein synthesis is enabled by the selection of amino acids for tRNA charging by aminoacyl-tRNA synthetases (ARSs), and further enhanced by the proofreading functions of some of these enzymes for eliminating tRNAs mischarged with noncognate amino acids. Mouse models of editing-defective cytoplasmic alanyl-tRNA synthetase (AlaRS) have previously demonstrated the importance of proofreading for cytoplasmic protein synthesis, with embryonic lethal and progressive neurodegeneration phenotypes. Mammalian mitochondria import their own set of nuclear-encoded ARSs for translating critical polypeptides of the oxidative phosphorylation system, but the importance of editing by the mitochondrial ARSs for mitochondrial proteostasis has not been known. We demonstrate here that the human mitochondrial AlaRS is capable of editing mischarged tRNAs in vitro, and that loss of the proofreading activity causes embryonic lethality in mice. These results indicate that tRNA proofreading is essential in mammalian mitochondria, and cannot be overcome by other quality control mechanisms.

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