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Leber's Hereditary Optic Neuropathy Arising From the Synergy Between ND1 3635G>A Mutation and Mitochondrial YARS2 Mutations
- Source :
- Investigative Ophthalmology & Visual Science
- Publication Year :
- 2021
- Publisher :
- Association for Research in Vision and Ophthalmology (ARVO), 2021.
-
Abstract
- Purpose To investigate the mechanism underlying the synergic interaction between Leber's hereditary optic neuropathy (LHON)-associated ND1 and mitochondrial tyrosyl-tRNA synthetase (YARS2) mutations. Methods Molecular dynamics simulation and differential scanning fluorimetry were used to evaluate the structure and stability of proteins. The impact of ND1 3635G>A and YARS2 p.G191V mutations on the oxidative phosphorylation machinery was evaluated using blue native gel electrophoresis and enzymatic activities assays. Assessment of reactive oxygen species (ROS) production in cell lines was performed by flow cytometry with MitoSOX Red reagent. Analysis of effect of mutations on autophagy was undertaken via flow cytometry for autophagic flux. Results Members of one Chinese family bearing both the YARS2 p.191Gly>Val and m.3635G>A mutations exhibited much higher penetrance of optic neuropathy than those pedigrees carrying only the m.3635G>A mutation. The m.3635G>A (p.Ser110Asn) mutation altered the ND1 structure and function, whereas the p.191Gly>Val mutation affected the stability of YARS2. Lymphoblastoid cell lines harboring both m.3635G>A and p.191Gly>Val mutations revealed more reductions in the levels of mitochondrion-encoding ND1 and CO2 than cells bearing only the m.3635G>A mutation. Strikingly, both m.3635G>A and p.191Gly>Val mutations exhibited decreases in the nucleus-encoding subunits of complex I and IV. These deficiencies manifested greater defects in the stability and activities of complex I and complex IV and overproduction of ROS and promoted greater autophagy in cell lines harboring both m.3635G>A and p.191Gly>Val mutations compared with cells bearing only the m.3635G>A mutation. Conclusions Our findings provide new insights into the pathophysiology of LHON arising from the synergy between ND1 3635G>A mutation and mitochondrial YARS2 mutations.
- Subjects :
- Adult
Male
0301 basic medicine
China
oxidative phosphorylation
Visual Acuity
Optic Atrophy, Hereditary, Leber
Oxidative phosphorylation
030105 genetics & heredity
Mitochondrion
medicine.disease_cause
Severity of Illness Index
Cell Line
Flow cytometry
Mitochondrial Proteins
Optic neuropathy
03 medical and health sciences
Leber's hereditary optic neuropathy
Tyrosine-tRNA Ligase
Autophagy
medicine
Humans
Family
Genetic Testing
Enzyme Assays
Mutation
medicine.diagnostic_test
Chemistry
ND1 gene
mitochondrial tyrosyl-tRNA synthetase
Biochemistry and Molecular Biology
NADH Dehydrogenase
mutations
medicine.disease
Penetrance
Molecular biology
eye diseases
Pedigree
030104 developmental biology
Cell culture
Female
Subjects
Details
- ISSN :
- 15525783
- Volume :
- 62
- Database :
- OpenAIRE
- Journal :
- Investigative Opthalmology & Visual Science
- Accession number :
- edsair.doi.dedup.....de4b588447507520af555e2c8f0e692e