Contrasting pathophysiological mechanisms of OPA1 mutations in autosomal dominant optic atrophy

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.

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Publication Details

Journal
Cell Death Discovery
Published
2025-05-30
DOI
https://doi.org/10.1038/s41420-025-02442-8
Citations
2
Primary Topic
Mitochondrial Function and Pathology
Type
article
Field-Weighted Citation Impact
1.61

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article

Contrasting pathophysiological mechanisms of OPA1 mutations in autosomal dominant optic atrophy

Ling‐Ping Cen, Hanjie He, Ruixi Wang, Dan Zhang et al.
2 citations
Cell Death Discovery
Mitochondrial Function and Pathology
1.61
article

Contrasting pathophysiological mechanisms of OPA1 mutations in autosomal dominant optic atrophy

Ling‐Ping Cen, Hanjie He, Ruixi Wang, Dan Zhang, Patrick Yu‐Wai‐Man, Taiping Li, Chong‐Bo Chen, Yingjie Cao, Shaoying Tan, Meng Wang, Yun Wang, Lifang Liu, Jiajian Liang, Hui Zhou, Shihui Wei, Shiqi Yao, Ciyan Xu, Fang-Fang Zhao
article en
2 citations

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.

Cell Death DiscoveryVol. 11(1)
Moorfields Eye Hospital NHS Foundation Trust (GB), Hong Kong Polytechnic University (HK), Guangdong Medical College (CN), Chinese University of Hong Kong (HK), Cambridge University Hospitals NHS Foundation Trust (GB), Chinese PLA General Hospital (CN), Southern University of Science and Technology (CN), Shantou University (CN), Shantou University Medical College (CN), Dongguan People’s Hospital (CN), Moorfields Eye Hospital (GB), Shenzhen Technology University (CN), University College London (GB), MRC Mitochondrial Biology Unit (GB)
National Institute for Health and Care Research, Sight Research UK, National Natural Science Foundation of China, Natural Science Foundation of Guangdong Province, Isaac Newton Trust, Moorfields Eye Hospital NHS Foundation Trust, Moorfields Eye Charity, NIHR Cambridge Biomedical Research Centre
Openalex Percentile: Top 17%
Mitochondrial Function and Pathology
1.61
DOIOpen Access PDFOpenAlex
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