Pathogenic mechanism of a human mitochondrial tRNA Phe mutation associated with myoclonic epilepsy with ragged red fibers syndrome

Ling, Jiqiang; Roy, Hervé; Qin, Daoming; Rubio, Mary Anne T.; Alfonzo, Juan D.; Fredrick, Kurt; Ibba, Michael

doi:10.1073/pnas.0704441104

Cited by 45RNA and protein synthesis mechanismsMitochondrial Function and PathologyRNA modifications and cancer

Pathogenic mechanism of a human mitochondrial tRNA Phe mutation associated with myoclonic epilepsy with ragged red fibers syndrome

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Ling, Jiqiang, Roy, Hervé, Qin, Daoming, Rubio, Mary Anne T., Alfonzo, Juan D., Fredrick, Kurt, Ibba, Michael·2007·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.0704441104PMC PMC2000536

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Abstract

Human mitochondrial tRNA (hmt-tRNA) mutations are associated with a variety of diseases including mitochondrial myopathies, diabetes, encephalopathies, and deafness. Because the current understanding of the precise molecular mechanisms of these mutations is limited, there is no efficient method to treat their associated mitochondrial diseases. Here, we use a variety of known mutations in hmt-tRNA(Phe) to investigate the mechanisms that lead to malfunctions. We tested the impact of hmt-tRNA(Phe) mutations on aminoacylation, structure, and translation elongation-factor binding. The majority of the mutants were pleiotropic, exhibiting defects in aminoacylation, global structure, and elongation-factor binding. One notable exception was the G34A anticodon mutation of hmt-tRNA(Phe) (mitochondrial DNA mutation G611A), which is associated with MERRF (myoclonic epilepsy with ragged red fibers). In vitro, the G34A mutation decreases aminoacylation activity by 100-fold, but does not affect global folding or recognition by elongation factor. Furthermore, G34A hmt-tRNA(Phe) does not undergo adenosine-to-inosine (A-to-I) editing, ruling out miscoding as a possible mechanism for mitochondrial malfunction. To improve the aminoacylation state of the mutant tRNA, we modified the tRNA binding domain of the nucleus-encoded human mitochondrial phenylalanyl-tRNA synthetase, which aminoacylates hmt-tRNA(Phe) with cognate phenylalanine. This variant enzyme displayed significantly improved aminoacylation efficiency for the G34A mutant, suggesting a general strategy to treat certain classes of mitochondrial diseases by modification of the corresponding nuclear gene.

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m.611G N A decreases aminoacylation activity 100-fold in vitro.
“Recent examples include the mt-tRNA Phe m.611G N A mutation, which decreases aminoacylation activity 100-fold in vitro [203]”
From Mitochondrial DNA mutations and human disease (2010) · cites this paper as [203]
Aminoacylation efficiency of mutant mt-tRNA Phe with m.611G N A was significantly improved by modifying the mt-tRNA binding domain of cognate phenylalanyl-tRNA synthetase.
“Aminoacylation efficiency of mutant mt-tRNA Phe , carrying the m.611G N A MERRF mutation, was significantly improved following modification of the mt-tRNA binding domain of the cognate phenylalanyl-tRNA synthetase [203].”
From Mitochondrial DNA mutations and human disease (2010) · cites this paper as [203]

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“611GNA mutation, which decreases aminoacylation activity 100-fold in vitro [203], and the mt-tRNA m.”
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Authors: Ling, J., Roy, H., Qin, D., Rubio, M. A. T., Alfonzo, J. D., Fredrick, K., & Ibba, M.
Affiliations: The Ohio State University (US)
ORCID: Ling, Jiqiang
Roy, Hervé
Rubio, Mary Anne T.
Alfonzo, Juan D.
Fredrick, Kurt
Ibba, Michael
Venue: Proceedings of the National Academy of Sciences
Publisher: National Academy of Sciences
Published: 2007-09-25
Volume: 104
Issue: 39
Pages: 15299-15304
ISSN: 0027-8424 (ISSN-L)
1091-6490
DOI: 10.1073/pnas.0704441104
PMC: PMC2000536
OpenAlex: W2040369986
Cited by: 45
References: 72
Citations by year: 2026: 2 · 2025: 4 · 2023: 1 · 2022: 1 · 2020: 2 · 2019: 2 · 2017: 3 · 2016: 1 · 2015: 5 · 2013: 1 · 2012: 3
FWCI: 1.72
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Proceedings of the National Academy of Sciences (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Chapman University Digital Commons (Chapman University) (submittedVersion)
Funders: National Science Foundation (0344002, 0620707)
American Heart Association
United States-Israel Binational Science Foundation
National Institutes of Health (GM 072528)
National Institute of General Medical Sciences (GM072528, R01GM072528)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA modifications and cancer
Keywords: myoclonic epilepsy with ragged-red fibers, MERRF, aminoacylation, phenylalanyl-tRNA synthetase, tRNA structure, A-to-I RNA editing, mitochondrial disease, pleiotropic mutations
MeSH terms: RNA, Mitochondrial, Anticodon, Base Sequence, Epilepsies, Myoclonic, Humans, Kinetics, Mitochondria, Molecular Conformation, Molecular Sequence Data, Mutation, Nucleic Acid Conformation, Peptide Elongation Factor Tu, Phenylalanine, RNA, RNA, Transfer, Phe, MERRF Syndrome

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Pathogenic mechanism of a human mitochondrial tRNA Phe mutation associated with myoclonic epilepsy with ragged red fibers syndrome

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