PUBLICATION

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

Authors
Zhang, Q., Zhang, L., Chen, D., He, X., Yao, S., Zhang, Z., Chen, Y., Guan, M.X.
ID
ZDB-PUB-180824-10
Date
2018
Source
Nucleic acids research   46(20): 10930-10945 (Journal)
Registered Authors
Keywords
none
MeSH Terms
  • Animals
  • Deafness/genetics*
  • Deafness/metabolism
  • Deafness/physiopathology
  • Female
  • Gene Expression Profiling
  • Hair Cells, Auditory/metabolism
  • In Situ Hybridization
  • Larva/genetics
  • Larva/metabolism
  • Male
  • Mitochondrial Proteins/genetics*
  • Mitochondrial Proteins/metabolism
  • Organelle Biogenesis*
  • RNA, Transfer/genetics*
  • RNA, Transfer/metabolism
  • Sequence Deletion
  • Zebrafish
  • Zebrafish Proteins/genetics*
  • Zebrafish Proteins/metabolism
  • tRNA Methyltransferases/genetics*
  • tRNA Methyltransferases/metabolism
(all 22)
PubMed
30137487 Full text @ Nucleic Acids Res.
Abstract
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.
Genes / Markers
Marker Marker Type Name
kars1GENElysyl-tRNA synthetase 1
lars2GENEleucyl-tRNA synthetase 2, mitochondrial
mt-co2GENEcytochrome c oxidase II, mitochondrial
mt-cybGENEcytochrome b, mitochondrial
mt-nd1GENENADH dehydrogenase 1, mitochondrial
mt-nd6GENENADH dehydrogenase 6, mitochondrial
mt-teTRNAGtRNA glutamic acid, mitochondrial
mt-thTRNAGtRNA histidine, mitochondrial
mt-tkTRNAGtRNA lysine, mitochondrial
mt-tmTRNAGtRNA methionine, mitochondrial
1 - 10 of 16
Show
Figures
Figure Gallery (8 images)
Show all Figures
Expression
Phenotype
Fish Conditions Stage Phenotype Figure
trmuzf3047/zf3047standard conditionsProtruding-mouth
trmuzf3047/zf3047standard conditionsDay 5
trmuzf3047/zf3047standard conditionsDay 5
trmuzf3047/zf3047standard conditionsDay 5
trmuzf3047/zf3047standard conditionsDay 5
trmuzf3047/zf3047standard conditionsDay 5
trmuzf3047/zf3047standard conditionsDay 5
trmuzf3047/zf3047standard conditionsDay 5
trmuzf3047/zf3047standard conditionsDay 5
trmuzf3047/zf3047standard conditionsDay 5
1 - 10 of 39
Show
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
zf3047
    		Insertion
    1 - 1 of 1
    Show
    Human Disease / Model
    Human Disease Fish Conditions Evidence
    inner ear diseasetrmuzf3047/zf3047standard conditionsTAS
    1 - 1 of 1
    Show
    Sequence Targeting Reagents
    Target Reagent Reagent Type
    trmuCRISPR1-trmuCRISPR
    1 - 1 of 1
    Show
    Fish
    Fish
    trmuzf3047/zf3047
    WT
    1 - 2 of 2
    Show
    Antibodies
    Orthology
    Engineered Foreign Genes
    No data available
    Mapping
    Your Input Welcome
    We welcome your input and comments. Please use this form to recommend updates to the information in ZFIN. We appreciate as much detail as possible and references as appropriate. We will review your comments promptly.
    Citation
    Zhang, Q., Zhang, L., Chen, D., He, X., Yao, S., Zhang, Z., Chen, Y., Guan, M.X. (2018) Deletion of Mtu1 (Trmu) in zebrafish revealed the essential role of tRNA modification in mitochondrial biogenesis and hearing function. Nucleic acids research. 46(20):10930-10945.