OPA1 mutations in dominant optic atrophy: domain-specific defects in mitochondrial fusion and apoptotic regulation
Abstract Background Autosomal dominant optic atrophy (ADOA), a leading common inherited optic neuropathy, arises from progressive retinal ganglion cell degeneration, often linked to OPA1 mutations. OPA1, a mitochondrial GTPase, regulates mitochondrial fusion, crista structure, and apoptosis. While G...
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BMC
2025-04-01
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| Series: | Journal of Translational Medicine |
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| Online Access: | https://doi.org/10.1186/s12967-025-06471-w |
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| author | Kexuan Zhang Wenqing Zhang Lin Zhang Xiaorong Hou Runyi Tian Zhengmao Hu Lili Yin Zhonghua Hu |
| author_facet | Kexuan Zhang Wenqing Zhang Lin Zhang Xiaorong Hou Runyi Tian Zhengmao Hu Lili Yin Zhonghua Hu |
| author_sort | Kexuan Zhang |
| collection | DOAJ |
| description | Abstract Background Autosomal dominant optic atrophy (ADOA), a leading common inherited optic neuropathy, arises from progressive retinal ganglion cell degeneration, often linked to OPA1 mutations. OPA1, a mitochondrial GTPase, regulates mitochondrial fusion, crista structure, and apoptosis. While GTPase-related dysfunction is well-studied, the role of other OPA1 domains in ADOA pathology remains unclear. Methods To investigate ADOA-linked OPA1 mutations, we assessed mitochondrial morphology, membrane potential, cytochrome c release, and cell viability in primary cortical neurons and N2a cells expressing OPA1 wild-type or mutant constructs. RNA sequencing and structural predictions (SWISS-MODEL) provided insights into molecular pathways and structural impacts. Results Two ADOA-associated mutations were characterized: V465F (GTPase β-fold) and V560F (BSE α-helix). Both mutations impaired mitochondrial fusion and cell survival under apoptotic stimuli. Notably, the BSE-located V560F mutation caused greater deficits in membrane potential maintenance, earlier apoptosis, and distinct molecular pathway changes compared to V465F. Conclusions This study highlights the domain-specific impacts of OPA1 mutations on mitochondrial function and ADOA pathology, revealing unique roles of the BSE domain in apoptosis regulation and mitochondrial integrity. These findings provide insights into ADOA mechanisms and potential therapeutic targets. |
| format | Article |
| id | doaj-art-911eb7eb10d147b3a713c7e84e2b1ab1 |
| institution | OA Journals |
| issn | 1479-5876 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj-art-911eb7eb10d147b3a713c7e84e2b1ab12025-08-20T02:20:01ZengBMCJournal of Translational Medicine1479-58762025-04-0123112010.1186/s12967-025-06471-wOPA1 mutations in dominant optic atrophy: domain-specific defects in mitochondrial fusion and apoptotic regulationKexuan Zhang0Wenqing Zhang1Lin Zhang2Xiaorong Hou3Runyi Tian4Zhengmao Hu5Lili Yin6Zhonghua Hu7Department of Critical Care Medicine, Institute of Molecular Precision Medicine and Hunan Key Laboratory of Molecular Precision Medicine, Xiangya Hospital, Central South UniversityDepartment of Critical Care Medicine, Institute of Molecular Precision Medicine and Hunan Key Laboratory of Molecular Precision Medicine, Xiangya Hospital, Central South UniversityDepartment of Critical Care Medicine, Institute of Molecular Precision Medicine and Hunan Key Laboratory of Molecular Precision Medicine, Xiangya Hospital, Central South UniversityDepartment of Neurology, The Third Xiangya Hospital, Central South UniversityCenter for Medical Genetics and Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South UniversityCenter for Medical Genetics and Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South UniversityDepartment of Ophthalmology, Shanghai Fourth People’s Hospital, Tongji UniversityDepartment of Critical Care Medicine, Institute of Molecular Precision Medicine and Hunan Key Laboratory of Molecular Precision Medicine, Xiangya Hospital, Central South UniversityAbstract Background Autosomal dominant optic atrophy (ADOA), a leading common inherited optic neuropathy, arises from progressive retinal ganglion cell degeneration, often linked to OPA1 mutations. OPA1, a mitochondrial GTPase, regulates mitochondrial fusion, crista structure, and apoptosis. While GTPase-related dysfunction is well-studied, the role of other OPA1 domains in ADOA pathology remains unclear. Methods To investigate ADOA-linked OPA1 mutations, we assessed mitochondrial morphology, membrane potential, cytochrome c release, and cell viability in primary cortical neurons and N2a cells expressing OPA1 wild-type or mutant constructs. RNA sequencing and structural predictions (SWISS-MODEL) provided insights into molecular pathways and structural impacts. Results Two ADOA-associated mutations were characterized: V465F (GTPase β-fold) and V560F (BSE α-helix). Both mutations impaired mitochondrial fusion and cell survival under apoptotic stimuli. Notably, the BSE-located V560F mutation caused greater deficits in membrane potential maintenance, earlier apoptosis, and distinct molecular pathway changes compared to V465F. Conclusions This study highlights the domain-specific impacts of OPA1 mutations on mitochondrial function and ADOA pathology, revealing unique roles of the BSE domain in apoptosis regulation and mitochondrial integrity. These findings provide insights into ADOA mechanisms and potential therapeutic targets.https://doi.org/10.1186/s12967-025-06471-wAutosomal dominant optic atrophy (ADOA)OPA1 mutationsMitochondrial dynamicsApoptosisGTPase activityBundle signaling element (BSE) |
| spellingShingle | Kexuan Zhang Wenqing Zhang Lin Zhang Xiaorong Hou Runyi Tian Zhengmao Hu Lili Yin Zhonghua Hu OPA1 mutations in dominant optic atrophy: domain-specific defects in mitochondrial fusion and apoptotic regulation Journal of Translational Medicine Autosomal dominant optic atrophy (ADOA) OPA1 mutations Mitochondrial dynamics Apoptosis GTPase activity Bundle signaling element (BSE) |
| title | OPA1 mutations in dominant optic atrophy: domain-specific defects in mitochondrial fusion and apoptotic regulation |
| title_full | OPA1 mutations in dominant optic atrophy: domain-specific defects in mitochondrial fusion and apoptotic regulation |
| title_fullStr | OPA1 mutations in dominant optic atrophy: domain-specific defects in mitochondrial fusion and apoptotic regulation |
| title_full_unstemmed | OPA1 mutations in dominant optic atrophy: domain-specific defects in mitochondrial fusion and apoptotic regulation |
| title_short | OPA1 mutations in dominant optic atrophy: domain-specific defects in mitochondrial fusion and apoptotic regulation |
| title_sort | opa1 mutations in dominant optic atrophy domain specific defects in mitochondrial fusion and apoptotic regulation |
| topic | Autosomal dominant optic atrophy (ADOA) OPA1 mutations Mitochondrial dynamics Apoptosis GTPase activity Bundle signaling element (BSE) |
| url | https://doi.org/10.1186/s12967-025-06471-w |
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