Mtu1-Mediated Thiouridine Formation of Mitochondrial tRNAs Is Required for Mitochondrial Translation and Is Involved in Reversible Infantile Liver Injury

Wu, Yong; Wei, Fan Yan; Kawarada, Layla; Suzuki, Tsutomu; Araki, Kimi; Komohara, Yoshihiro; Fujimura, Akiko; Kaitsuka, Taku; Takeya, Motohiro; Oike, Yuichi; Tomizawa, Kazuhito

doi:10.1371/journal.pgen.1006355

Cited by 31 publications

(32 citation statements)

References 36 publications

(56 reference statements)

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“…Mutations in both MTO1 and GTPBP3 cause mitochondrial translation defects and hypertrophic cardiomyopathy, lactic acidosis, and encephalopathy [ 128 – 130 ], whereas defects in the 2-thiouridylase MTU1 are implicated in reversible infantile liver injury (Fig. 2 ) [ 131 ].…”

Section: Mt-trna Modificationsmentioning

confidence: 99%

The mitochondrial epitranscriptome: the roles of RNA modifications in mitochondrial translation and human disease

Bohnsack

Sloan

2017

Cell. Mol. Life Sci.

115

109

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Mitochondrial protein synthesis is essential for the production of components of the oxidative phosphorylation system. RNA modifications in the mammalian mitochondrial translation apparatus play key roles in facilitating mitochondrial gene expression as they enable decoding of the non-conventional genetic code by a minimal set of tRNAs, and efficient and accurate protein synthesis by the mitoribosome. Intriguingly, recent transcriptome-wide analyses have also revealed modifications in mitochondrial mRNAs, suggesting that the concept of dynamic regulation of gene expression by the modified RNAs (the “epitranscriptome”) extends to mitochondria. Furthermore, it has emerged that defects in RNA modification, arising from either mt-DNA mutations or mutations in nuclear-encoded mitochondrial modification enzymes, underlie multiple mitochondrial diseases. Concomitant advances in the identification of the mitochondrial RNA modification machinery and recent structural views of the mitochondrial translation apparatus now allow the molecular basis of such mitochondrial diseases to be understood on a mechanistic level.

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Section: Mt-trna Modificationsmentioning

confidence: 99%

The mitochondrial epitranscriptome: the roles of RNA modifications in mitochondrial translation and human disease

Bohnsack

Sloan

2017

Cell. Mol. Life Sci.

115

109

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“…Dysregulation of genes encoding enzymes involved in intermediary metabolism has been reported from cell and murine models of the GTPBP3 and TRMU defects respectively [ 18 , 21 ]. Therefore, we examined the mRNA expression of genes relevant for metabolic processes related to mitochondrial function.…”

Section: Resultsmentioning

confidence: 99%

“…coli and S . cerevisiae [ 32 , 67 , 68 ], and more recently in GTPBP3-silenced cells [ 18 ] and in a liver-specific Mtu1-deficient mouse [ 21 ]. In addition, our results suggest that the C .…”

Section: Discussionmentioning

confidence: 99%

“…It should be pointed out, however, that, since limited material is available, precise quantification of the level of these modifications in mt-tRNAs from patient cells has not been conducted to date. In any case, defects in GTPBP3, or MTO1, or TRMU compromises mitochondrial translation to some extent and lead to OXPHOS dysfunction, proteostasis stress, and activation of retrograde signaling pathways [ 8 , 11 , 18 – 21 ]. Presently, however, it is very unclear how TRMU mutations lead to liver disease while those in GTPBP3 and MTO1 lead to heart failure [ 8 – 11 ].…”

Section: Introductionmentioning

confidence: 99%

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Mutations in the Caenorhabditis elegans orthologs of human genes required for mitochondrial tRNA modification cause similar electron transport chain defects but different nuclear responses

et al. 2017

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Several oxidative phosphorylation (OXPHOS) diseases are caused by defects in the post-transcriptional modification of mitochondrial tRNAs (mt-tRNAs). Mutations in MTO1 or GTPBP3 impair the modification of the wobble uridine at position 5 of the pyrimidine ring and cause heart failure. Mutations in TRMU affect modification at position 2 and cause liver disease. Presently, the molecular basis of the diseases and why mutations in the different genes lead to such different clinical symptoms is poorly understood. Here we use Caenorhabditis elegans as a model organism to investigate how defects in the TRMU, GTPBP3 and MTO1 orthologues (designated as mttu-1, mtcu-1, and mtcu-2, respectively) exert their effects. We found that whereas the inactivation of each C. elegans gene is associated with a mild OXPHOS dysfunction, mutations in mtcu-1 or mtcu-2 cause changes in the expression of metabolic and mitochondrial stress response genes that are quite different from those caused by mttu-1 mutations. Our data suggest that retrograde signaling promotes defect-specific metabolic reprogramming, which is able to rescue the OXPHOS dysfunction in the single mutants by stimulating the oxidative tricarboxylic acid cycle flux through complex II. This adaptive response, however, appears to be associated with a biological cost since the single mutant worms exhibit thermosensitivity and decreased fertility and, in the case of mttu-1, longer reproductive cycle. Notably, mttu-1 worms also exhibit increased lifespan. We further show that mtcu-1; mttu-1 and mtcu-2; mttu-1 double mutants display severe growth defects and sterility. The animal models presented here support the idea that the pathological states in humans may initially develop not as a direct consequence of a bioenergetic defect, but from the cell’s maladaptive response to the hypomodification status of mt-tRNAs. Our work highlights the important association of the defect-specific metabolic rewiring with the pathological phenotype, which must be taken into consideration in exploring specific therapeutic interventions.

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“…From studies of their bacterial and yeast orthologs, proteins GTPBP3 and MTO1 are predicted to jointly catalyze the addition of the taurinomethyl group at position 5 of the anticodon wobble uridine (U34) in mt-tRNAs decoding for Lys, Glu, Gln, Leu (UUR) , and Trp 10 , 11 . A third nuclear-encoded protein named TRMU or MTU1 (which is also conserved from bacteria to humans) thiolates position 2 of U34 in a subset of these mt-tRNAs (those decoding for Lys, Glu and Gln) 12 – 16 . Curiously, mutations in TRMU (MIM #610230), although also leading to OXPHOS dysfunction, cause liver failure 12 , 14 .…”

Section: Introductionmentioning

confidence: 99%

Defects in the mitochondrial-tRNA modification enzymes MTO1 and GTPBP3 promote different metabolic reprogramming through a HIF-PPARγ-UCP2-AMPK axis

Boutoual

Meseguer

Villarroya

et al. 2018

Sci Rep

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Human proteins MTO1 and GTPBP3 are thought to jointly catalyze the modification of the wobble uridine in mitochondrial tRNAs. Defects in each protein cause infantile hypertrophic cardiomyopathy with lactic acidosis. However, the underlying mechanisms are mostly unknown. Using fibroblasts from an MTO1 patient and MTO1 silenced cells, we found that the MTO1 deficiency is associated with a metabolic reprogramming mediated by inactivation of AMPK, down regulation of the uncoupling protein 2 (UCP2) and transcription factor PPARγ, and activation of the hypoxia inducible factor 1 (HIF-1). As a result, glycolysis and oxidative phosphorylation are uncoupled, while fatty acid metabolism is altered, leading to accumulation of lipid droplets in MTO1 fibroblasts. Unexpectedly, this response is different from that triggered by the GTPBP3 defect, as GTPBP3-depleted cells exhibit AMPK activation, increased levels of UCP2 and PPARγ, and inactivation of HIF-1. In addition, fatty acid oxidation and respiration are stimulated in these cells. Therefore, the HIF-PPARγ-UCP2-AMPK axis is operating differently in MTO1- and GTPBP3-defective cells, which strongly suggests that one of these proteins has an additional role, besides mitochondrial-tRNA modification. This work provides new and useful information on the molecular basis of the MTO1 and GTPBP3 defects and on putative targets for therapeutic intervention.

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Mtu1-Mediated Thiouridine Formation of Mitochondrial tRNAs Is Required for Mitochondrial Translation and Is Involved in Reversible Infantile Liver Injury

Cited by 31 publications

References 36 publications

The mitochondrial epitranscriptome: the roles of RNA modifications in mitochondrial translation and human disease

The mitochondrial epitranscriptome: the roles of RNA modifications in mitochondrial translation and human disease

Mutations in the Caenorhabditis elegans orthologs of human genes required for mitochondrial tRNA modification cause similar electron transport chain defects but different nuclear responses

Defects in the mitochondrial-tRNA modification enzymes MTO1 and GTPBP3 promote different metabolic reprogramming through a HIF-PPARγ-UCP2-AMPK axis

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