The defective expression of gtpbp3 related to tRNA modification alters the mitochondrial function and development of zebrafish

Chen, Danni; Li, Feng; Yang, Qingxian; Tian, Miao; Zhang, Zengming; Zhang, Qinghai; Chen, Ye; Guan, Min‐Xin

doi:10.1016/j.biocel.2016.05.012

Cited by 23 publications

(16 citation statements)

References 55 publications

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“…Several groups studied the physiological impact of GTPBP3 and MTO1 using genetic approaches, and observed mitochondrial dysfunction when either protein was depleted ( 81–83 ). However, none of these studies provided direct evidence that these genes are actually involved in τm 5 U34 formation.…”

Section: Discussionmentioning

confidence: 99%

Metabolic and chemical regulation of tRNA modification associated with taurine deficiency and human disease

Asano

Suzuki

Saito

et al. 2018

Nucleic Acids Research

119

123

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Modified uridine containing taurine, 5-taurinomethyluridine (τm5U), is found at the anticodon first position of mitochondrial (mt-)transfer RNAs (tRNAs). Previously, we reported that τm5U is absent in mt-tRNAs with pathogenic mutations associated with mitochondrial diseases. However, biogenesis and physiological role of τm5U remained elusive. Here, we elucidated τm5U biogenesis by confirming that 5,10-methylene-tetrahydrofolate and taurine are metabolic substrates for τm5U formation catalyzed by MTO1 and GTPBP3. GTPBP3-knockout cells exhibited respiratory defects and reduced mitochondrial translation. Very little τm5U34 was detected in patient’s cells with the GTPBP3 mutation, demonstrating that lack of τm5U results in pathological consequences. Taurine starvation resulted in downregulation of τm5U frequency in cultured cells and animal tissues (cat liver and flatfish). Strikingly, 5-carboxymethylaminomethyluridine (cmnm5U), in which the taurine moiety of τm5U is replaced with glycine, was detected in mt-tRNAs from taurine-depleted cells. These results indicate that tRNA modifications are dynamically regulated via sensing of intracellular metabolites under physiological condition.

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Section: Discussionmentioning

confidence: 99%

Metabolic and chemical regulation of tRNA modification associated with taurine deficiency and human disease

Asano

Suzuki

Saito

et al. 2018

Nucleic Acids Research

119

123

View full text Add to dashboard Cite

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“…Thus, the other genetic, epigenetic, and environmental modifier factors may be involved in the phenotypic manifestation of m.14692A3 G mutation in these Chinese pedigrees (13,60,68,70). Alternatively, tissue-specific differences in tRNA metabolism may also contribute to the development of deafness and diabetes (71,72).…”

Section: Discussionmentioning

confidence: 99%

A Deafness- and Diabetes-associated tRNA Mutation Causes Deficient Pseudouridinylation at Position 55 in tRNAGlu and Mitochondrial Dysfunction

Wang

Líu

Zheng

et al. 2016

Journal of Biological Chemistry

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Several mitochondrial tRNA mutations have been associated with maternally inherited diabetes and deafness. However, the pathophysiology of these tRNA mutations remains poorly understood. In this report, we identified the novel homoplasmic 14692A→G mutation in the mitochondrial tRNA gene among three Han Chinese families with maternally inherited diabetes and deafness. The m.14692A→G mutation affected a highly conserved uridine at position 55 of the TΨC loop of tRNA The uridine is modified to pseudouridine (Ψ55), which plays an important role in the structure and function of this tRNA. Using lymphoblastoid cell lines derived from a Chinese family, we demonstrated that the m.14692A→G mutation caused loss of Ψ55 modification and increased angiogenin-mediated endonucleolytic cleavage in mutant tRNA The destabilization of base-pairing (18A-Ψ55) caused by the m.14692A→G mutation perturbed the conformation and stability of tRNA An approximately 65% decrease in the steady-state level of tRNA was observed in mutant cells compared with control cells. A failure in tRNA metabolism impaired mitochondrial translation, especially for polypeptides with a high proportion of glutamic acid codons such as ND1, ND6, and CO2 in mutant cells. An impairment of mitochondrial translation caused defective respiratory capacity, especially reducing the activities of complexes I and IV. Furthermore, marked decreases in the levels of mitochondrial ATP and membrane potential were observed in mutant cells. These mitochondrial dysfunctions caused an increasing production of reactive oxygen species in the mutant cells. Our findings may provide new insights into the pathophysiology of maternally inherited diabetes and deafness, which is primarily manifested by the deficient nucleotide modification of mitochondrial tRNA.

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“…Mtu1 homologue in zebrafish was obtained from databases of NCBI using the human MTU1 amino acid sequences as queries ( 40 ). The BLAST homology analyses were performed with the available web-based programs of NCBI.…”

Section: Methodsmentioning

confidence: 99%

“…ATP generation was measured using an ATP analysis kit (Beyotime) and a microplate reader (Syneregy H1, Bio-Tek) according to the manufacturer's instructions with minor modifications ( 40 ). Briefly, 20 embryos (per genotypes) were treated with the ATP synthase inhibitor oligomycin to determine cytosolic ATP generation, and same number of embryos (from same batch) were incubated in E3 medium for total cellular ATP levels measurement.…”

Section: Methodsmentioning

confidence: 99%

Deletion of Mtu1 (Trmu) in zebrafish revealed the essential role of tRNA modification in mitochondrial biogenesis and hearing function

Zhang

Chen

et al. 2018

Nucleic Acids Research

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Mtu1(Trmu) is a highly conserved tRNA modifying enzyme responsible for the biosynthesis of τm5s2U at the wobble position of tRNAGln, tRNAGlu and tRNALys. Our previous investigations showed that MTU1 mutation modulated the phenotypic manifestation of deafness-associated mitochondrial 12S rRNA mutation. However, the pathophysiology of MTU1 deficiency remains poorly understood. Using the mtu1 knock-out zebrafish generated by CRISPR/Cas9 system, we demonstrated the abolished 2-thiouridine modification of U34 of mitochondrial tRNALys, tRNAGlu and tRNAGln in the mtu1 knock-out zebrafish. The elimination of this post-transcriptional modification mediated mitochondrial tRNA metabolisms, causing the global decreases in the levels of mitochondrial tRNAs. The aberrant mitochondrial tRNA metabolisms led to the impairment of mitochondrial translation, respiratory deficiencies and reductions of mitochondrial ATP production. These mitochondria dysfunctions caused the defects in hearing organs. Strikingly, mtu1−/– mutant zebrafish displayed the abnormal startle response and swimming behaviors, significant decreases in the sizes of saccular otolith and numbers of hair cells in the auditory and vestibular organs. Furthermore, mtu1−/– mutant zebrafish exhibited the significant reductions in the hair bundle densities in utricle, saccule and lagena. Therefore, our findings may provide new insights into the pathophysiology of deafness, which was manifested by the deficient modifications at wobble position of mitochondrial tRNAs.

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The defective expression of gtpbp3 related to tRNA modification alters the mitochondrial function and development of zebrafish

Cited by 23 publications

References 55 publications

Metabolic and chemical regulation of tRNA modification associated with taurine deficiency and human disease

Metabolic and chemical regulation of tRNA modification associated with taurine deficiency and human disease

A Deafness- and Diabetes-associated tRNA Mutation Causes Deficient Pseudouridinylation at Position 55 in tRNAGlu and Mitochondrial Dysfunction

Deletion of Mtu1 (Trmu) in zebrafish revealed the essential role of tRNA modification in mitochondrial biogenesis and hearing function

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