ArticleJournal of biomedical science2023
Optimized allotopic expression of mitochondrial ND6 transgene restored complex I and apoptosis deficiencies caused by LHON-linked ND6 14484T > C mutation.
Article in Journal of biomedical science, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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10 citing papers in PubMed, 14 citations in OpenAlex.
- Mitochondria-Targeted Nanotherapeutics: A Promising Strategy in Modulating Mitochondrial Function, Transfer, and Transplantation.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Review
- Emerging therapeutic strategies for mitochondrial DNA-related diseases.Cell reports. Medicine · 2026Review
- Mitochondrial complex I deficiency-associated diseases and models.Cellular and molecular life sciences : CMLS · 2026Review
- Polymer-specific nanoplastics trigger oxidative stress, inflammatory activation, and mitoepigenetic remodeling:Frontiers in toxicology · 2026Article
- Advances in gene therapy for mitochondrial genetic disorders: current status and clinical implementation challenges.Journal of translational medicine · 2025Review
- Vitamin A treatment restores vision failures arising from Leber's hereditary optic neuropathy-linked mtDNA mutation.JCI insight · 2025Article
- Development of a cell-penetrating peptide-based nanocomplex for long-term delivery of intact mitochondrial DNA into epithelial cells.Molecular therapy. Nucleic acids · 2025Article
- Mitochondrial diseases: from molecular mechanisms to therapeutic advances.Signal transduction and targeted therapy · 2025Review
- Mutation of CRYAB encoding a conserved mitochondrial chaperone and antiapoptotic protein causes hereditary optic atrophy.JCI insight · 2024Article
- Poly-(ADP-ribose) polymerases inhibition by olaparib attenuates activities of the NLRP3 inflammasome and of NF-κB in THP-1 monocytes.PloS one · 2024Article
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Authors and funding
8 authors at 5 institutions in 3 countries.
Funding
Abstract
backgroundLeber's hereditary optic neuropathy (LHON) is a maternally inherited eye disease due to mutations in mitochondrial DNA. However, there is no effective treatment for this disease. LHON-linked ND6 14484T > C (p.M64V) mutation caused complex I deficiency, diminished ATP production, increased production of reactive oxygen species (ROS), elevated apoptosis, and impaired mitophagy. Here, we investigated if the allotopic expression of human mitochondrial ND6 transgene corrected the mitochondrial dysfunctions due to LHON-associated m.14484T > C mutation.
methodsNucleus-versions of ND6 was generated by changing 6 non-universal codons with universal codons and added to mitochondrial targeting sequence of COX8. Stable transfectants were generated by transferring human ND6 cDNA expressed in a pCDH-puro vector into mutant cybrids carrying the m.14484T > C mutation and control cybrids. The effect of allotopic expression of ND6 on oxidative phosphorylation (OXPHOS) was evaluated using Blue Native gel electrophoresis and extracellular flux analyzer. Assessment of ROS production in cell lines was performed by flow cytometry with MitoSOX Red reagent. Analyses for apoptosis and mitophagy were undertaken via flow cytometry, TUNEL and immunofluorescence assays.
resultsThe transfer of human ND6 into the cybrids carrying the m.14484T > C mutation raised the levels of ND6, ND1 and ND4L but did not change the levels of other mitochondrial proteins. The overexpression of ND6 led to 20~23% increases in the assembly and activity of complex I, and ~ 53% and ~ 33% increases in the levels of mitochondrial ATP and ΔΨm in the mutant cybrids bearing m.14484T > C mutation. Furthermore, mutant cybrids with overexpression of ND6 exhibited marked reductions in the levels of mitochondrial ROS. Strikingly, ND6 overexpression markedly inhibited the apoptosis process and restored impaired mitophagy in the cells carrying m.14484T > C mutation. However, overexpression of ND6 did not affect the ND6 level and mitochondrial functions in the wild-type cybrids, indicating that this ND6 level appeared to be the maximum threshold level to maintain the normal cell function.
conclusionWe demonstrated that allotopic expression of nucleus-versions of ND6 restored complex I, apoptosis and mitophagy deficiencies caused by the m.14484T > C mutation. The restoration of m.14484T > C mutation-induced mitochondrial dysfunctions by overexpression of ND6 is a step toward therapeutic interventions for LHON and mitochondrial diseases.
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