Contrasting pathophysiological mechanisms of OPA1 mutations in autosomal dominant optic atrophy
Abstract Autosomal dominant optic atrophy (ADOA) caused by mutations in the nuclear-encoded OPA1 gene result in the preferential loss of retinal ganglion cells (RGCs) and progressive optic nerve degeneration. The severity of ADOA can be highly variable. This study compared the pathophysiological con...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-05-01
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| Series: | Cell Death Discovery |
| Online Access: | https://doi.org/10.1038/s41420-025-02442-8 |
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| author | Shi-Qi Yao Jia-Jian Liang Hui Zhou Shaoying Tan Yingjie Cao Chong-Bo Chen Ciyan Xu Ruixi Wang Tai-Ping Li Fang-Fang Zhao Yun Wang Han-Jie He Dan Zhang Meng Wang Lifang Liu Patrick Yu-Wai-Man Shihui Wei Ling-Ping Cen |
| author_facet | Shi-Qi Yao Jia-Jian Liang Hui Zhou Shaoying Tan Yingjie Cao Chong-Bo Chen Ciyan Xu Ruixi Wang Tai-Ping Li Fang-Fang Zhao Yun Wang Han-Jie He Dan Zhang Meng Wang Lifang Liu Patrick Yu-Wai-Man Shihui Wei Ling-Ping Cen |
| author_sort | Shi-Qi Yao |
| collection | DOAJ |
| description | Abstract Autosomal dominant optic atrophy (ADOA) caused by mutations in the nuclear-encoded OPA1 gene result in the preferential loss of retinal ganglion cells (RGCs) and progressive optic nerve degeneration. The severity of ADOA can be highly variable. This study compared the pathophysiological consequences of the c.1034 G > A OPA1 missense mutation and the c.1305+2delGT OPA1 deletion. There was a significant correlation between the severity of visual loss and the extent of macular RGC loss as determined by optical coherence tomography imaging. In cells transfected with the c.1034 G > A mutant, the percentage of fragmented mitochondria was greater than 60% with cytochrome c (cyt c) overflow, and significantly elevated levels of reactive oxygen species (ROS) and apoptosis. In contrast, the c.1305+2delGT mutant caused mitochondrial fragmentation in ~ 20% of HeLa cells, resulting in less cyt c overflow and apoptosis. The extent of mitochondrial network fragmentation and apoptosis increased with decreasing WT OPA1 mRNA expression levels. The c.1034 G > A OPA1 missense mutation is likely to induce a dominant-negative effect compared with haploinsufficiency with the c.1305+2delGT OPA1 deletion. These contrasting pathophysiological mechanisms could influence disease severity in ADOA through their differential consequences on mitochondrial structure and function. The small drug molecule Paromomycin was able to rescue the mitochondrial fragmentation induced by the c.1034 G > A mutation, providing proof-of-concept for further therapeutic validation in ADOA. |
| format | Article |
| id | doaj-art-5d818e9692604d379eef0be2d10e1fdf |
| institution | OA Journals |
| issn | 2058-7716 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death Discovery |
| spelling | doaj-art-5d818e9692604d379eef0be2d10e1fdf2025-08-20T02:00:13ZengNature Publishing GroupCell Death Discovery2058-77162025-05-0111111310.1038/s41420-025-02442-8Contrasting pathophysiological mechanisms of OPA1 mutations in autosomal dominant optic atrophyShi-Qi Yao0Jia-Jian Liang1Hui Zhou2Shaoying Tan3Yingjie Cao4Chong-Bo Chen5Ciyan Xu6Ruixi Wang7Tai-Ping Li8Fang-Fang Zhao9Yun Wang10Han-Jie He11Dan Zhang12Meng Wang13Lifang Liu14Patrick Yu-Wai-Man15Shihui Wei16Ling-Ping Cen17Joint Shantou International Eye Center of Shantou University and The Chinese University of Hong KongJoint Shantou International Eye Center of Shantou University and The Chinese University of Hong KongJoint Shantou International Eye Center of Shantou University and The Chinese University of Hong KongSchool of Optometry, The Hong Kong Polytechnic UniversityJoint Shantou International Eye Center of Shantou University and The Chinese University of Hong KongJoint Shantou International Eye Center of Shantou University and The Chinese University of Hong KongJoint Shantou International Eye Center of Shantou University and The Chinese University of Hong KongJoint Shantou International Eye Center of Shantou University and The Chinese University of Hong KongJoint Shantou International Eye Center of Shantou University and The Chinese University of Hong KongJoint Shantou International Eye Center of Shantou University and The Chinese University of Hong KongJoint Shantou International Eye Center of Shantou University and The Chinese University of Hong KongJoint Shantou International Eye Center of Shantou University and The Chinese University of Hong KongJoint Shantou International Eye Center of Shantou University and The Chinese University of Hong KongJoint Shantou International Eye Center of Shantou University and The Chinese University of Hong KongJoint Shantou International Eye Center of Shantou University and The Chinese University of Hong KongJohn van Geest Centre for Brain Repair and MRC Mitochondrial Biology Unit, Department of Clinical Neurosciences, University of CambridgeDepartment of Ophthalmology, Third Medical Center of Chinese PLA General HospitalJoint Shantou International Eye Center of Shantou University and The Chinese University of Hong KongAbstract Autosomal dominant optic atrophy (ADOA) caused by mutations in the nuclear-encoded OPA1 gene result in the preferential loss of retinal ganglion cells (RGCs) and progressive optic nerve degeneration. The severity of ADOA can be highly variable. This study compared the pathophysiological consequences of the c.1034 G > A OPA1 missense mutation and the c.1305+2delGT OPA1 deletion. There was a significant correlation between the severity of visual loss and the extent of macular RGC loss as determined by optical coherence tomography imaging. In cells transfected with the c.1034 G > A mutant, the percentage of fragmented mitochondria was greater than 60% with cytochrome c (cyt c) overflow, and significantly elevated levels of reactive oxygen species (ROS) and apoptosis. In contrast, the c.1305+2delGT mutant caused mitochondrial fragmentation in ~ 20% of HeLa cells, resulting in less cyt c overflow and apoptosis. The extent of mitochondrial network fragmentation and apoptosis increased with decreasing WT OPA1 mRNA expression levels. The c.1034 G > A OPA1 missense mutation is likely to induce a dominant-negative effect compared with haploinsufficiency with the c.1305+2delGT OPA1 deletion. These contrasting pathophysiological mechanisms could influence disease severity in ADOA through their differential consequences on mitochondrial structure and function. The small drug molecule Paromomycin was able to rescue the mitochondrial fragmentation induced by the c.1034 G > A mutation, providing proof-of-concept for further therapeutic validation in ADOA.https://doi.org/10.1038/s41420-025-02442-8 |
| spellingShingle | Shi-Qi Yao Jia-Jian Liang Hui Zhou Shaoying Tan Yingjie Cao Chong-Bo Chen Ciyan Xu Ruixi Wang Tai-Ping Li Fang-Fang Zhao Yun Wang Han-Jie He Dan Zhang Meng Wang Lifang Liu Patrick Yu-Wai-Man Shihui Wei Ling-Ping Cen Contrasting pathophysiological mechanisms of OPA1 mutations in autosomal dominant optic atrophy Cell Death Discovery |
| title | Contrasting pathophysiological mechanisms of OPA1 mutations in autosomal dominant optic atrophy |
| title_full | Contrasting pathophysiological mechanisms of OPA1 mutations in autosomal dominant optic atrophy |
| title_fullStr | Contrasting pathophysiological mechanisms of OPA1 mutations in autosomal dominant optic atrophy |
| title_full_unstemmed | Contrasting pathophysiological mechanisms of OPA1 mutations in autosomal dominant optic atrophy |
| title_short | Contrasting pathophysiological mechanisms of OPA1 mutations in autosomal dominant optic atrophy |
| title_sort | contrasting pathophysiological mechanisms of opa1 mutations in autosomal dominant optic atrophy |
| url | https://doi.org/10.1038/s41420-025-02442-8 |
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