Ambient light alleviates retinal neurodegeneration in mice by powering mitochondria via the engineered optoenergetic rhodopsin

The mitochondrial proton motive force (pmf) is a critical driver of cellular energy production and influences various cellular processes. Dysregulation of pmf is implicated in a range of diseases, including neurodegenerative diseases, mitochondrial diseases, cancer and aging-related pathologies. Currently, an efficient strategy to rescue ATP production and mitigate reactive oxygen species (ROS) generation under conditions of energy deprivation is lacking. Here, we engineered a light-sensitive, mitochondria-targeting proton-pumping rhodopsin (PPR), mt-EcGAPR, capable of generating an efficient pmf for ATP synthesis while simultaneously mitigating reactive oxygen species (ROS) generation during stress and decreasing DNA double-strand breaks (DSBs). Owing to its transparency to visible light, eye is the ideal candidate for the noninvasive application of mt-EcGAPR in the treatment of mitochondria-related retinal degenerative diseases. Using a silicone oil-induced ocular hypertension glaucoma mouse model, we demonstrate that ambient light activation of mt-EcGAPR significantly increased ATP production, suppressed ROS accumulation, and protected retinal ganglion cells (RGCs) from degeneration. Mechanistically, mt-EcGAPR inhibited endoplasmic reticulum (ER) stress-ATF6-gasdermin D (GSDMD)-mediated pyroptosis, thereby preserving retinal structure and function. This intervention ultimately led to improved visual acuity in glaucomatous eyes of mice. Collectively, our findings establish mt-EcGAPR as a promising therapeutic strategy for glaucoma and potentially other neurodegenerative diseases associated with mitochondrial dysfunction and impaired bioenergetics.

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Publication Details

Journal
Signal Transduction and Targeted Therapy
Published
2025-10-30
DOI
https://doi.org/10.1038/s41392-025-02450-1
Primary Topic
Mitochondrial Function and Pathology
Type
article
Field-Weighted Citation Impact
0.00

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article

Ambient light alleviates retinal neurodegeneration in mice by powering mitochondria via the engineered optoenergetic rhodopsin

Biao Yan, Jian‐Sheng Kang, Zhuanbin Wu, Yumei Liang et al.
Signal Transduction and Targeted Therapy
Mitochondrial Function and Pathology
article

Ambient light alleviates retinal neurodegeneration in mice by powering mitochondria via the engineered optoenergetic rhodopsin

Biao Yan, Jian‐Sheng Kang, Zhuanbin Wu, Yumei Liang, Huifang Sun, Yun Zou, Siyuan Chang, Shi‐Qing Cai, Run‐Zhou Yang, Dian‐Dian Wang, Yun Luo, Qun‐Ying Lei, Wen Zeng, Jiayi Zhang, Yang Xiang, Yi‐Ting Wang, Sen‐Miao Li, Chunping Huang, Yu Gu, Xiao-Yan Meng, Peipei Liu, Su Zhang
article en

Abstract

The mitochondrial proton motive force (pmf) is a critical driver of cellular energy production and influences various cellular processes. Dysregulation of pmf is implicated in a range of diseases, including neurodegenerative diseases, mitochondrial diseases, cancer and aging-related pathologies. Currently, an efficient strategy to rescue ATP production and mitigate reactive oxygen species (ROS) generation under conditions of energy deprivation is lacking. Here, we engineered a light-sensitive, mitochondria-targeting proton-pumping rhodopsin (PPR), mt-EcGAPR, capable of generating an efficient pmf for ATP synthesis while simultaneously mitigating reactive oxygen species (ROS) generation during stress and decreasing DNA double-strand breaks (DSBs). Owing to its transparency to visible light, eye is the ideal candidate for the noninvasive application of mt-EcGAPR in the treatment of mitochondria-related retinal degenerative diseases. Using a silicone oil-induced ocular hypertension glaucoma mouse model, we demonstrate that ambient light activation of mt-EcGAPR significantly increased ATP production, suppressed ROS accumulation, and protected retinal ganglion cells (RGCs) from degeneration. Mechanistically, mt-EcGAPR inhibited endoplasmic reticulum (ER) stress-ATF6-gasdermin D (GSDMD)-mediated pyroptosis, thereby preserving retinal structure and function. This intervention ultimately led to improved visual acuity in glaucomatous eyes of mice. Collectively, our findings establish mt-EcGAPR as a promising therapeutic strategy for glaucoma and potentially other neurodegenerative diseases associated with mitochondrial dysfunction and impaired bioenergetics.

Signal Transduction and Targeted TherapyVol. 10(1)
Shanghai Academy of Social Sciences (CN), Allen Institute for Brain Science (US), Tiangong University (CN), Chinese Academy of Sciences (CN), Southern University of Science and Technology (CN), Zhengzhou University (CN), Center for Excellence in Brain Science and Intelligence Technology (CN), Eye & ENT Hospital of Fudan University (CN), Shanghai Academy of Environmental Sciences (CN), Institute of Aging (CA), First Affiliated Hospital of Zhengzhou University (CN), Shanghai Model Organisms (China) (CN), Shenzhen Third People’s Hospital (CN)
National Science Foundation, National Natural Science Foundation of China, Science and Technology Commission of Shanghai Municipality, Zhengzhou University, Natural Science Foundation of Henan Province, First Affiliated Hospital of Zhengzhou University, Key Research and Development Program of Ningxia, National Key Research and Development Program of China
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Mitochondrial Function and Pathology
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