Idebenone Protects Photoreceptors Impaired by Oxidative Phosphorylation Disorder in Retinal Detachment

Overview

Journal Invest Ophthalmol Vis Sci

Specialty Ophthalmology

Date 2025 Jan 8

PMID 39774627

Authors

Lisong Wang

Gaocheng Zou

Yuanye Yan

Ronghua Shi

Yue Guo

Mei Zhang

Li Lu

Kai Dong

Affiliations

Soon will be listed here.

Abstract

Purpose: Oxidative phosphorylation (OXPHOS) is an aerobic metabolic mechanism, and its dysfunction plays an important role in the pathological changes of ischemic diseases. However, systematic studies on the occurrence of retinal detachment (RD) are lacking.

Methods: Single-cell RNA sequencing (scRNA-seq) of the human retina was performed to detect the metabolic changes of various retinal cells after RD. In this study, animal experiments were conducted to explore the OXPHOS activity after RD. In addition, idebenone, a coenzyme Q10 (CoQ10) analog currently used to treat Leber hereditary optic neuropathy (LHON), was used to improve the OXPHOS disorder in experimental RD model.

Results: ScRNA-seq revealed abnormal energy metabolism and OXPHOS pathways in retinal cells after RD. Adenosine triphosphate (ATP) and reactive oxygen species (ROS) are the main products of OXPHOS, the mouse RD model indicated that the rise in ROS levels may have a greater impact on photoreceptors in the early stage, whereas decreased ATP synthesis was observed in the later stage; these changes threaten the function and morphology of the retina. Idebenone was administered to model mice intragastrically, leading to reduced ROS levels in the early stage post-RD and improved ATP synthesis in the later stage, which was closely related to the maintenance of mitochondrial morphology.

Conclusions: OXPHOS disorder leads to photoreceptor degeneration after RD, which can be alleviated by improving OXPHOS function.

References

Lin J, Narayanan R, Philippakis E, Yonekawa Y, Apte R . Retinal detachment. Nat Rev Dis Primers. 2024; 10(1):18. DOI: 10.1038/s41572-024-00501-5. View

Aleo S, Del Dotto V, Romagnoli M, Fiorini C, Capirossi G, Peron C . Genetic variants affecting NQO1 protein levels impact the efficacy of idebenone treatment in Leber hereditary optic neuropathy. Cell Rep Med. 2024; 5(2):101383. PMC: 10897523. DOI: 10.1016/j.xcrm.2023.101383. View

Qureshi M, Steel D . Retinal detachment following cataract phacoemulsification-a review of the literature. Eye (Lond). 2019; 34(4):616-631. PMC: 7093479. DOI: 10.1038/s41433-019-0575-z. View

Lyseng-Williamson K . Idebenone: A Review in Leber's Hereditary Optic Neuropathy. Drugs. 2016; 76(7):805-13. DOI: 10.1007/s40265-016-0574-3. View

Borrelli E, Berni A, Cascavilla M, Barresi C, Battista M, Lari G . Visual Outcomes and Optical Coherence Tomography Biomarkers of Vision Improvement in Patients With Leber Hereditary Optic Neuropathy Treated With Idebenone. Am J Ophthalmol. 2022; 247:35-41. DOI: 10.1016/j.ajo.2022.11.004. View

Millman J, Doggett T, Thebeau C, Zhang S, Semenkovich C, Rajagopal R . Measurement of Energy Metabolism in Explanted Retinal Tissue Using Extracellular Flux Analysis. J Vis Exp. 2019; (143). PMC: 6417428. DOI: 10.3791/58626. View

Zhuang J, Qin Y, Feng Y, Su Z, He X, Li W . A Novel Hexokinases Inhibitor Based on Molecularly Imprinted Polymer for Combined Starvation and Enhanced Photothermal Therapy of Malignant Tumors. ACS Appl Mater Interfaces. 2023; 15(21):25898-25908. DOI: 10.1021/acsami.3c00079. View

Stenton S, Sheremet N, Catarino C, Andreeva N, Assouline Z, Barboni P . Impaired complex I repair causes recessive Leber's hereditary optic neuropathy. J Clin Invest. 2021; 131(6). PMC: 7954600. DOI: 10.1172/JCI138267. View

Van de Sande B, Lee J, Mutasa-Gottgens E, Naughton B, Bacon W, Manning J . Applications of single-cell RNA sequencing in drug discovery and development. Nat Rev Drug Discov. 2023; 22(6):496-520. PMC: 10141847. DOI: 10.1038/s41573-023-00688-4. View

10.

Avci B, Gunaydin C, Guvenc T, Yavuz C, Kuruca N, Bilge S . Idebenone Ameliorates Rotenone-Induced Parkinson's Disease in Rats Through Decreasing Lipid Peroxidation. Neurochem Res. 2020; 46(3):513-522. DOI: 10.1007/s11064-020-03186-w. View

11.

Hisatomi T, Sakamoto T, Murata T, Yamanaka I, Oshima Y, Hata Y . Relocalization of apoptosis-inducing factor in photoreceptor apoptosis induced by retinal detachment in vivo. Am J Pathol. 2001; 158(4):1271-8. PMC: 1891920. DOI: 10.1016/S0002-9440(10)64078-3. View

12.

Trushina E, Trushin S, Hasan M . Mitochondrial complex I as a therapeutic target for Alzheimer's disease. Acta Pharm Sin B. 2022; 12(2):483-495. PMC: 8897152. DOI: 10.1016/j.apsb.2021.11.003. View

13.

Han M, Bushong E, Segawa M, Tiard A, Wong A, Brady M . Spatial mapping of mitochondrial networks and bioenergetics in lung cancer. Nature. 2023; 615(7953):712-719. PMC: 10033418. DOI: 10.1038/s41586-023-05793-3. View

14.

Okoye C, Koren S, Wojtovich A . Mitochondrial complex I ROS production and redox signaling in hypoxia. Redox Biol. 2023; 67:102926. PMC: 10598411. DOI: 10.1016/j.redox.2023.102926. View

15.

Song J, Herrmann J, Becker T . Quality control of the mitochondrial proteome. Nat Rev Mol Cell Biol. 2020; 22(1):54-70. DOI: 10.1038/s41580-020-00300-2. View

16.

Cho H, Loreti E, Shih M, Perata P . Energy and sugar signaling during hypoxia. New Phytol. 2019; 229(1):57-63. DOI: 10.1111/nph.16326. View

17.

Kooragayala K, Gotoh N, Cogliati T, Nellissery J, Kaden T, French S . Quantification of Oxygen Consumption in Retina Ex Vivo Demonstrates Limited Reserve Capacity of Photoreceptor Mitochondria. Invest Ophthalmol Vis Sci. 2016; 56(13):8428-36. PMC: 4699410. DOI: 10.1167/iovs.15-17901. View

18.

Jiang W, Geng H, Lv X, Ma J, Liu F, Lin P . Idebenone Protects against Atherosclerosis in Apolipoprotein E-Deficient Mice Via Activation of the SIRT3-SOD2-mtROS Pathway. Cardiovasc Drugs Ther. 2020; 35(6):1129-1145. DOI: 10.1007/s10557-020-07018-5. View

19.

Sies H, Jones D . Reactive oxygen species (ROS) as pleiotropic physiological signalling agents. Nat Rev Mol Cell Biol. 2020; 21(7):363-383. DOI: 10.1038/s41580-020-0230-3. View

20.

Govers B, van Huet R, Roosing S, Keijser S, Los L, den Hollander A . The genetics and disease mechanisms of rhegmatogenous retinal detachment. Prog Retin Eye Res. 2023; 97:101158. DOI: 10.1016/j.preteyeres.2022.101158. View