ArticleThe Journal of biological chemistry2020
Complex I mutations synergize to worsen the phenotypic expression of Leber's hereditary optic neuropathy.
Article in The Journal of biological chemistry, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 39 citations in OpenAlex.
- [Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences · 2026Review
- Mitochondrial complex I deficiency-associated diseases and models.Cellular and molecular life sciences : CMLS · 2026Review
- Modifier variants in metabolic pathways are associated with an increased penetrance of Leber's Hereditary Optic Neuropathy.European journal of human genetics : EJHG · 2026Article
- Molecular Mechanism of Mitochondrial Complex I Disruption by m.14484T>C Underlying Leber Hereditary Optic Neuropathy.bioRxiv : the preprint server for biology · 2026Article
- Relationship between Cellular Oxygen Consumption and Atherosclerosis-associated Mitochondrial Mutations (Variants of the Mitochondrial Genome).Current medicinal chemistry · 2026Article
- Article
- Vitamin A treatment restores vision failures arising from Leber's hereditary optic neuropathy-linked mtDNA mutation.JCI insight · 2025Article
- The Role of mtDNA Mutations in Atherosclerosis: The Influence of Mitochondrial Dysfunction on Macrophage Polarization.International journal of molecular sciences · 2025Review
- Mutation of CRYAB encoding a conserved mitochondrial chaperone and antiapoptotic protein causes hereditary optic atrophy.JCI insight · 2024Article
- Mitochondrial tRNAAdvanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Mitochondrial complex I subunitHeliyon · 2024Review
- Maternally inherited non-syndromic hearing loss is linked with a novel mitochondrial ND6 gene mutation.Irish journal of medical science · 2024Article
- Deficient tRNA posttranscription modification dysregulated the mitochondrial quality controls and apoptosis.iScience · 2024Article
- Two mitochondrial DNA polymorphisms modulate cardiolipin binding and lead to synthetic lethality.Nature communications · 2024Article
- Induced pluripotent stem cells: ex vivo models for human diseases due to mitochondrial DNA mutations.Journal of biomedical science · 2023Review
- Optimized allotopic expression of mitochondrial ND6 transgene restored complex I and apoptosis deficiencies caused by LHON-linked ND6 14484T > C mutation.Journal of biomedical science · 2023Article
- Creation of Mitochondrial Disease Models Using Mitochondrial DNA Editing.Biomedicines · 2023Review
- Abnormal morphology and function in retinal ganglion cells derived from patients-specific iPSCs generated from individuals with Leber's hereditary optic neuropathy.Human molecular genetics · 2023Article
- Pathological and Therapeutic Advances in Parkinson's Disease: Mitochondria in the Interplay.Journal of Alzheimer's disease : JAD · 2023Review
- Article
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Authors and funding
12 authors at 5 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Leber's hereditary optic neuropathy (LHON) is a maternal inheritance of eye disease because of the mitochondrial DNA (mtDNA) mutations. We previously discovered a 3866T>C mutation within the gene for the ND1 subunit of complex I as possibly amplifying disease progression for patients bearing the disease-causing 11778G>A mutation within the gene for the ND4 subunit of complex I. However, whether and how the ND1 mutation exacerbates the ND4 mutation were unknown. In this report, we showed that four Chinese families bearing both m.3866T>C and m.11778G>A mutations exhibited higher penetrances of LHON than 6 Chinese pedigrees carrying only the m.3866T>C mutation or families harboring only the m.11778G>A mutation. The protein structure analysis revealed that the m.3866T>C (I187T) and m.11778G>A (R340H) mutations destabilized the specific interactions with other residues of ND1 and ND4, thereby altering the structure and function of complex I. Cellular data obtained using cybrids, constructed by transferring mitochondria from the Chinese families into mtDNA-less (ρ°) cells, demonstrated that the mutations perturbed the stability, assembly, and activity of complex I, leading to changes in mitochondrial ATP levels and membrane potential and increasing the production of reactive oxygen species. These mitochondrial dysfunctions promoted the apoptotic sensitivity of cells and decreased mitophagy. Cybrids bearing only the m.3866T>C mutation displayed mild mitochondrial dysfunctions, whereas those harboring both m.3866T>C and m.11778G>A mutations exhibited greater mitochondrial dysfunctions. These suggested that the m.3866T>C mutation acted in synergy with the m.11778G>A mutation, aggravating mitochondrial dysfunctions and contributing to higher penetrance of LHON in these families carrying both mtDNA mutations.
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