Transferrin ameliorates retinal degeneration by mediating the dimerization of all-trans-retinal

Lei Tao; Danxue He; Yuling Chen; Kunhuan Yang; Beiting He; Peixin Cai; Binxiang Cai; Chunyan Liao; Zuguo Liu; Shiying Li; Jingmeng Chen; Yalin Wu

doi:10.1016/j.jbc.2024.108054

Transferrin ameliorates retinal degeneration by mediating the dimerization of all-trans-retinal

J Biol Chem. 2024 Dec 9;301(1):108054. doi: 10.1016/j.jbc.2024.108054. Online ahead of print.

Authors

Lei Tao¹, Danxue He¹, Yuling Chen¹, Kunhuan Yang¹, Beiting He¹, Peixin Cai¹, Binxiang Cai², Chunyan Liao², Zuguo Liu², Shiying Li³, Jingmeng Chen⁴, Yalin Wu⁵

Affiliations

¹ Department of Ophthalmology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China; Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Fujian Engineering and Research Center of Eye Regenerative Medicine, Eye Institute of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China.
² Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Fujian Engineering and Research Center of Eye Regenerative Medicine, Eye Institute of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China.
³ Department of Ophthalmology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China.
⁴ School of Medicine, Xiamen University, Xiamen, Fujian, China; Shenzhen Research Institute of Xiamen University, Shenzhen, Guangdong, China.
⁵ Department of Ophthalmology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China; Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Fujian Engineering and Research Center of Eye Regenerative Medicine, Eye Institute of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China; Shenzhen Research Institute of Xiamen University, Shenzhen, Guangdong, China. Electronic address: [email protected].

PMID: 39653244
DOI: 10.1016/j.jbc.2024.108054

Abstract

High levels of all-trans-retinal (atRAL) in the retina is considered to be responsible for the development of autosomal recessive Stargardt's disease (STGD1) and dry age-related macular degeneration (dAMD). Two bisretinoids, all-trans-retinal dimer (atRAL-dimer) and N-retinyl-N-retinylidene ethanolamine (A2E), form from the dimerization of atRAL in the retina but they possess much lower toxicity and phototoxicity toward retinal pigment epithelium (RPE) cells than atRAL. Here, we introduced a novel function of transferrin (TRF) in mediating the conversion of atRAL into atRAL-dimer and A2E, which effectively protected the retina from damage by atRAL and prevented retinal function decline in mice, and rescued atRAL-loaded RPE cells. Moreover, TRF-mediated conversion of atRAL to atRAL-dimer and A2E required the help of bicarbonate ions (HCO₃^-). atRAL had the capacity to stimulate the expression of TRF in RPE and photoreceptor cells as well as RPE/choroid and neural retina of mice, reflecting that the elevation of TRF levels by atRAL is most likely to help defy level increase and cytotoxicity of atRAL through facilitating its dimerization and thereby serves as a mechanism of retinal self-protection. Our findings offer a promising avenue for the treatment of retinopathies characterized by disrupted clearance of atRAL.

Keywords: all-trans-retinal; dimerization; macular degeneration; retinal function; transferrin.