FARS2 deficiency in Drosophila reveals the developmental delay and seizure manifested by aberrant mitochondrial tRNA metabolism.
Nucleic Acids Res
; 49(22): 13108-13121, 2021 12 16.
Article
in En
| MEDLINE
| ID: mdl-34878141
Mutations in genes encoding mitochondrial aminoacyl-tRNA synthetases are linked to diverse diseases. However, the precise mechanisms by which these mutations affect mitochondrial function and disease development are not fully understood. Here, we develop a Drosophila model to study the function of dFARS2, the Drosophila homologue of the mitochondrial phenylalanyl-tRNA synthetase, and further characterize human disease-associated FARS2 variants. Inactivation of dFARS2 in Drosophila leads to developmental delay and seizure. Biochemical studies reveal that dFARS2 is required for mitochondrial tRNA aminoacylation, mitochondrial protein stability, and assembly and enzyme activities of OXPHOS complexes. Interestingly, by modeling FARS2 mutations associated with human disease in Drosophila, we provide evidence that expression of two human FARS2 variants, p.G309S and p.D142Y, induces seizure behaviors and locomotion defects, respectively. Together, our results not only show the relationship between dysfunction of mitochondrial aminoacylation system and pathologies, but also illustrate the application of Drosophila model for functional analysis of human disease-causing variants.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Phenylalanine-tRNA Ligase
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Seizures
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RNA, Transfer
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Developmental Disabilities
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Drosophila Proteins
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Mitochondrial Proteins
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Drosophila melanogaster
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Mutation
Limits:
Animals
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Humans
Language:
En
Journal:
Nucleic Acids Res
Year:
2021
Document type:
Article
Affiliation country:
China
Country of publication:
United kingdom