Glia maturation factor-β induces ferroptosis by impairing chaperone-mediated autophagic degradation of ACSL4 in early diabetic retinopathy
Caiying Liu,
Wan Sun,
Tong Zhu,
Si Shi,
Jieping Zhang,
Juan Wang,
Furong Gao,
Qingjian Ou,
Caixia Jin,
Jiao Li,
Jing-Ying Xu,
Jingfa Zhang,
Haibin Tian,
Guo-Tong Xu,
Lixia Lu
Affiliations
Caiying Liu
Department of Ophthalmology of Tongji Hospital and Laboratory of Clinical and Visual Sciences of Tongji Eye Institute, Tongji University School of Medicine, Shanghai, 200065, China; Department of Biochemistry and Molecular Biology, School of Medicine, Tongji University, Shanghai, 200092, China
Wan Sun
Department of Ophthalmology of Tongji Hospital and Laboratory of Clinical and Visual Sciences of Tongji Eye Institute, Tongji University School of Medicine, Shanghai, 200065, China; Department of Biochemistry and Molecular Biology, School of Medicine, Tongji University, Shanghai, 200092, China
Tong Zhu
Department of Ophthalmology of Tongji Hospital and Laboratory of Clinical and Visual Sciences of Tongji Eye Institute, Tongji University School of Medicine, Shanghai, 200065, China; Department of Biochemistry and Molecular Biology, School of Medicine, Tongji University, Shanghai, 200092, China
Si Shi
Department of Ophthalmology of Tongji Hospital and Laboratory of Clinical and Visual Sciences of Tongji Eye Institute, Tongji University School of Medicine, Shanghai, 200065, China; Department of Biochemistry and Molecular Biology, School of Medicine, Tongji University, Shanghai, 200092, China
Jieping Zhang
Department of Ophthalmology of Tongji Hospital and Laboratory of Clinical and Visual Sciences of Tongji Eye Institute, Tongji University School of Medicine, Shanghai, 200065, China; Department of Biochemistry and Molecular Biology, School of Medicine, Tongji University, Shanghai, 200092, China
Juan Wang
Department of Ophthalmology of Tongji Hospital and Laboratory of Clinical and Visual Sciences of Tongji Eye Institute, Tongji University School of Medicine, Shanghai, 200065, China; Department of Biochemistry and Molecular Biology, School of Medicine, Tongji University, Shanghai, 200092, China
Furong Gao
Department of Ophthalmology of Tongji Hospital and Laboratory of Clinical and Visual Sciences of Tongji Eye Institute, Tongji University School of Medicine, Shanghai, 200065, China; Department of Biochemistry and Molecular Biology, School of Medicine, Tongji University, Shanghai, 200092, China
Qingjian Ou
Department of Ophthalmology of Tongji Hospital and Laboratory of Clinical and Visual Sciences of Tongji Eye Institute, Tongji University School of Medicine, Shanghai, 200065, China; Department of Biochemistry and Molecular Biology, School of Medicine, Tongji University, Shanghai, 200092, China
Caixia Jin
Department of Ophthalmology of Tongji Hospital and Laboratory of Clinical and Visual Sciences of Tongji Eye Institute, Tongji University School of Medicine, Shanghai, 200065, China; Department of Biochemistry and Molecular Biology, School of Medicine, Tongji University, Shanghai, 200092, China
Jiao Li
Department of Ophthalmology of Tongji Hospital and Laboratory of Clinical and Visual Sciences of Tongji Eye Institute, Tongji University School of Medicine, Shanghai, 200065, China; Department of Biochemistry and Molecular Biology, School of Medicine, Tongji University, Shanghai, 200092, China
Jing-Ying Xu
Department of Ophthalmology of Tongji Hospital and Laboratory of Clinical and Visual Sciences of Tongji Eye Institute, Tongji University School of Medicine, Shanghai, 200065, China; Department of Biochemistry and Molecular Biology, School of Medicine, Tongji University, Shanghai, 200092, China
Jingfa Zhang
Department of Ophthalmology, Shanghai General Hospital (Shanghai First People’s Hospital), Shanghai Jiao Tong University, Shanghai, China
Haibin Tian
Department of Ophthalmology of Tongji Hospital and Laboratory of Clinical and Visual Sciences of Tongji Eye Institute, Tongji University School of Medicine, Shanghai, 200065, China; Department of Biochemistry and Molecular Biology, School of Medicine, Tongji University, Shanghai, 200092, China; Corresponding Author. Department of Ophthalmology of Tongji Hospital and Laboratory of Clinical and Visual Sciences of Tongji Eye Institute, Tongji University School of Medicine, Shanghai 200065, China
Guo-Tong Xu
Department of Ophthalmology of Tongji Hospital and Laboratory of Clinical and Visual Sciences of Tongji Eye Institute, Tongji University School of Medicine, Shanghai, 200065, China; Department of Biochemistry and Molecular Biology, School of Medicine, Tongji University, Shanghai, 200092, China; The Collaborative Innovation Center for Brain Science, Tongji University, Shanghai, China; Corresponding Author. Department of Ophthalmology of Tongji Hospital and Laboratory of Clinical and Visual Sciences of Tongji Eye Institute, Tongji University School of Medicine, Shanghai 200065, China
Lixia Lu
Department of Ophthalmology of Tongji Hospital and Laboratory of Clinical and Visual Sciences of Tongji Eye Institute, Tongji University School of Medicine, Shanghai, 200065, China; Department of Biochemistry and Molecular Biology, School of Medicine, Tongji University, Shanghai, 200092, China; Corresponding Author. Department of Ophthalmology of Tongji Hospital and Laboratory of Clinical and Visual Sciences of Tongji Eye Institute, Tongji University School of Medicine, Shanghai 200065, China
Diabetic retinopathy (DR) is one of the leading causes of blindness in the world, and timely prevention and treatment are very important. Previously, we found that a neurodegenerative factor, Glia maturation factor-β (GMFB), was upregulated in the vitreous at a very early stage of diabetes, which may play an important role in pathogenesis. Here, we found that in a high glucose environment, large amounts of GMFB protein can be secreted in the vitreous, which translocates the ATPase ATP6V1A from the lysosome, preventing its assembly and alkalinizing the lysosome in the retinal pigment epithelial (RPE) cells. ACSL4 protein can be recognized by HSC70, the receptor for chaperone-mediated autophagy, and finally digested in the lysosome. Abnormalities in the autophagy–lysosome degradation process lead to its accumulation, which catalyzes the production of lethal lipid species and finally induces ferroptosis in RPE cells. GMFB antibody, lysosome activator NKH477, CMA activator QX77, and ferroptosis inhibitor Liproxstatin-1 were all effective in preventing early diabetic retinopathy and maintaining normal visual function, which has powerful clinical application value. Our research broadens the understanding of the relationship between autophagy and ferroptosis and provides a new therapeutic target for the treatment of DR.
