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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.<\/jats:p>","DOI":"10.1038\/s41392-025-02450-1","type":"journal-article","created":{"date-parts":[[2025,10,30]],"date-time":"2025-10-30T00:02:56Z","timestamp":1761782576000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Ambient light alleviates retinal neurodegeneration in mice by powering mitochondria via the engineered optoenergetic rhodopsin"],"prefix":"10.1038","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-2038-6568","authenticated-orcid":false,"given":"Run-Zhou","family":"Yang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiting","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuanbin","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dian-Dian","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Zou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youzhi","family":"Liang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia-Kang","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Su","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chun-Ping","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei-Rong","family":"Zeng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Si-Yuan","family":"Chang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sen-Miao","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Yan","family":"Meng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui-Fang","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pei-Pei","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinzhi","family":"Lei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Xiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Gu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3252-2965","authenticated-orcid":false,"given":"Biao","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shi-Qing","family":"Cai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1575-0723","authenticated-orcid":false,"given":"Jiayi","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2603-9718","authenticated-orcid":false,"given":"Jian-Sheng","family":"Kang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,30]]},"reference":[{"key":"2450_CR1","doi-asserted-by":"publisher","first-page":"3873","DOI":"10.1016\/j.jmb.2018.03.025","volume":"430","author":"BJ Berry","year":"2018","unstructured":"Berry, B. 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