Abstract
The mechanisms underlying cellular damage induced by the mitochondrially encoded NADH dehydrogenase subunit 4 (MT-ND4) with R340H mutation caused by the variant m.11778G > A in complex I are intricate. Numerous studies indicate that mitochondria play a primary role in cellular death due to this mutation. However, the detailed pathological effects remain incompletely elucidated. To decipher the specific impacts of this mutation on cellular death, mitochondrial dysfunction was investigated in 661 W cells expressing exogenous Mut-ND4 (m.G11778A). Importantly, the oxygen consumption rate (OCR) assessed by Seahorse XF analyzer exhibited a significant decrease under galactose conditions and an excessive production of reactive oxygen species (ROS). Conversely, the activity levels of catalase (CAT), superoxide dismutase (SOD), and glutathione disulfide (GSSG) were decreased, leading to increased cell death in cells expressing Mut-ND4 (m.G11778A) under galactose conditions. In addition, structural disruptions in the optic nerves of mice subjected to Mut-ND4-AAV infection were revealed. These findings suggest that Mut-ND4 (m.G11778A) contributes to cellular injury and an oxidative stress imbalance, characterized by decreased mitochondrial oxygen consumption, increased oxidative products, and reduced antioxidant capacity.
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The datasets used and/or analyzed during the current study available from the corresponding author on reasonable request.
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Acknowledgements
We thank Dr. Linying Zhou and Dr. Xi Lin (Electron Microscopy Lab of Public Technology Service Center, Fujian Medical University) for kindly providing technical assistance in electron microscopy.
Funding
This research received generous support from Joint Funds for the Innovation of Science and Technology, Fujian Province under grant No. 2024Y9336 and No. 2023Y9185. Additionally, it was made possible through the sponsorship of the Fujian Province Natural Science Foundation under grant No. 2022J01739 and the Fujian Provincial Health Technology Project under grant No. 2022GGA018.
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1. Lijun Fang: wrote the main manuscript and performed research. 2. Kangyue Fu, Mengyu Yang, Yiwen Xu and Ezeugwu Sussan Ukamaka: analyzed data and performed research. 3. Dianbo Qu: wrote the manuscript and analyzed data. 4. Tianwen Huang and Jianzhang Hu: wrote the main manuscript text, performed research and designed research. All the authors reviewed the manuscript.
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Fang, L., Fu, K., Yang, M. et al. Oxidative stress imbalance and cellular damage mediated by the ND4 G11778A mutation. Sci Rep (2026). https://doi.org/10.1038/s41598-026-40061-0
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DOI: https://doi.org/10.1038/s41598-026-40061-0
