The optimized allotopic expression of ND1 or ND4 genes restores respiratory chain complex I activity in fibroblasts harboring mutations in these genes
Open accessAbstract
Leber's Hereditary Optic Neuropathy (LHON) was the first maternally inherited mitochondrial disease identified and is now considered the most prevalent mitochondrial disorder. LHON patients harbor mutations in mitochondrial DNA (mtDNA). In about 90% of cases, the genes involved encode proteins of the respiratory chain complex I. Even though the molecular bases are known since 20 years almost all remains to be done regarding physiopathology and therapy. In this study, we report a severe decrease of complex I activity in cultured skin fibroblasts isolated from two LHON patients harboring mutations in ND4 or ND1 genes. Most importantly, we were able to restore sustainably (a) the ability to grow on galactose, (b) the ATP synthesis rate and (c) the complex I activity, initially impaired in these cells. Our strategy consisted of forcing mRNAs from nuclearly-encoded ND1 and ND4 genes to localize to the mitochondrial surface. The rescue of the respiratory chain defect observed was possible by discreet amounts of hybrid mRNAs and fusion proteins demonstrating the efficiency of their mitochondrial import. Hence, we confirmed here for two mitochondrial genes located in the organelle that the optimized allotopic expression approach represents a powerful tool that could ultimately be applied in human therapy for LHON.
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Expression of the lenadogene nolparvovec transgene results in the synthesis of a functional human ND4 protein that translocates into the mitochondrial compartment.
“Expression of the transgene results in the synthesis of a functional human ND4 protein that translocates into the mitochondrial compartment.”
From Randomized trial of bilateral gene therapy injection for m.11778G&gt;A <i>MT-ND4</i> Leber optic neuropathy (2023) · cites this paper as [12]
Section 3.2 reports that proteins expressed from the engineered wild-type ND4 plasmid localized to the mitochondrial compartment, and section 3.5 describes the resulting ND4 protein as functional in respiratory-chain complex I. The paper studies a plasmid construct in fibroblasts, not lenadogene nolparvovec specifically, so it does not establish the claim for that transgene. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe allotopic expression strategy has been successfully applied in cell models and safely translated in induced rodent LHON models with preservation of RGCs and visual function.
“This strategy has been successfully applied in cell models and safely translated in induced rodent LHON models with preservation of RGCs and visual function.9–12”
From Randomized trial of bilateral gene therapy injection for m.11778G&gt;A <i>MT-ND4</i> Leber optic neuropathy (2023) · cites this paper as [12]
The Introduction reports restored mitochondrial function in cultured LHON fibroblasts after optimized allotopic expression. The Concluding remarks describe creating and treating an LHON animal model as a future challenge; this paper does not establish safe translation in rodents or preservation of retinal ganglion cells and visual function. (LLM, conf=0.90)
Experimental — accuracy not yet measured
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- Authors
- Bonnet, C., Augustin, S., Ellouze, S., Bénit, P., Bouaita, A., Rustin, P., Sahel, J.-A., & Corral-Debrinski, M.
- Affiliations
- Institut de la Vision (FR)
- Inserm (FR)
- Venue
- Biochimica et Biophysica Acta (BBA) - Molecular Cell Research
- Publisher
- Elsevier BV
- Published
- 2008-10
- Volume
- 1783
- Issue
- 10
- Pages
- 1707-1717
- ISSN
- 0167-4889 (ISSN-L)
- OpenAlex
- W2053558205
- Cited by
- 130
- References
- 49
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 11 · 2023: 13 · 2022: 15 · 2021: 4 · 2020: 8 · 2019: 5 · 2018: 4 · 2017: 5 · 2016: 8 · 2015: 5 · 2014: 8 · 2013: 3 · 2012: 8
- FWCI
- 3.15
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Biochimica et Biophysica Acta (BBA) - Molecular Cell Research (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion, other-oa)
- Funders
- Agence Nationale de la Recherche
- Institut National de la Santé et de la Recherche Médicale
- Institut Carnot Santé Animale
- Retina France
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Coenzyme Q10 studies and effects
- Keywords
- Leber's hereditary optic neuropathy, allotopic expression, ND1 gene, ND4 gene, respiratory chain complex I, mitochondrial DNA mutations, maternally inherited mitochondrial disease, dermal fibroblasts, ATP production, fusion protein, mitochondrial protein import, gene therapy
- MeSH terms
- Adenosine Triphosphate, Adolescent, Adult, Cells, Cultured, Culture Media, Electron Transport, Fibroblasts, Galactose, Humans, Male, Mutation, NADH Dehydrogenase, Protein Binding, RNA, Messenger, Gene Expression Regulation, Enzymologic, Transgenes
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