PUBLICATION
Deletion of Gtpbp3 in zebrafish revealed the hypertrophic cardiomyopathy manifested by aberrant mitochondrial tRNA metabolism
- Authors
- Chen, D., Zhang, Z., Chen, C., Yao, S., Yang, Q., Li, F., He, X., Ai, C., Wang, M., Guan, M.X.
- ID
- ZDB-PUB-190328-4
- Date
- 2019
- Source
- Nucleic acids research 47(10): 5341-5355 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Aminoacylation
- Animals
- CRISPR-Cas Systems
- Cardiomyopathy, Hypertrophic/genetics
- Cardiomyopathy, Hypertrophic/metabolism*
- GTP-Binding Proteins/genetics*
- GTP-Binding Proteins/metabolism
- Gene Deletion*
- In Situ Hybridization
- Mitochondria/genetics
- Mitochondria/metabolism
- Mitochondrial Proteins/metabolism
- Mutation
- Myocytes, Cardiac/metabolism
- Phenotype
- Protein Conformation
- RNA, Transfer/metabolism*
- Transgenes
- Zebrafish/genetics
- Zebrafish Proteins/genetics*
- Zebrafish Proteins/metabolism
- PubMed
- 30916346 Full text @ Nucleic Acids Res.
Citation
Chen, D., Zhang, Z., Chen, C., Yao, S., Yang, Q., Li, F., He, X., Ai, C., Wang, M., Guan, M.X. (2019) Deletion of Gtpbp3 in zebrafish revealed the hypertrophic cardiomyopathy manifested by aberrant mitochondrial tRNA metabolism. Nucleic acids research. 47(10):5341-5355.
Abstract
GTPBP3 is a highly conserved tRNA modifying enzyme for the biosynthesis of τm5U at the wobble position of mitochondrial tRNAGlu, tRNAGln, tRNALys, tRNATrp and tRNALeu(UUR). The previous investigations showed that GTPBP3 mutations were associated with hypertrophic cardiomyopathy (HCM). However, the pathophysiology of GTPBP3 deficiency remains elusively. Using the gtpbp3 knockout zebrafish generated by CRISPR/Cas9 system, we demonstrated the aberrant mitochondrial tRNA metabolism in gtpbp3 knock-out zebrafish. The deletion of gtpbp3 may alter functional folding of tRNA, indicated by conformation changes and sensitivity to S1-mediated digestion of tRNAGlu, tRNALys, tRNATrp and tRNALeu(UUR). Strikingly, gtpbp3 knock-out zebrafish displayed the global increases in the aminoacylated efficiencies of mitochondrial tRNAs. The aberrant mitochondrial tRNA metabolisms impaired mitochondrial translation, produced proteostasis stress and altered activities of respiratory chain complexes. These mitochondria dysfunctions caused the alterations in the embryonic heart development and reduced fractional shortening of ventricles in mutant zebrafish. Notably, the gtpbp3 knock-out zebrafish exhibited hypertrophy of cardiomyocytes and myocardial fiber disarray in ventricles. These cardiac defects in the gtpbp3 knock-out zebrafish recapitulated the clinical phenotypes in HCM patients carrying the GTPBP3 mutation(s). Our findings highlight the fundamental role of defective nucleotide modifications of tRNAs in mitochondrial biogenesis and their pathological consequences in hypertrophic cardiomyopathy.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping