HIF2α activation and mitochondrial deficit due to iron chelation cause retinal atrophy
Abstract Iron accumulation causes cell death and disrupts tissue functions, which necessitates chelation therapy to reduce iron overload. However, clinical utilization of deferoxamine (DFO), an iron chelator, has been documented to give rise to systemic adverse effects, including ocular toxicity. Th...
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| Format: | Article |
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Springer Nature
2023-01-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.202216525 |
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| author | Yang Kong Pei‐Kang Liu Yao Li Nicholas D Nolan Peter M J Quinn Chun‐Wei Hsu Laura A Jenny Jin Zhao Xuan Cui Ya‐Ju Chang Katherine J Wert Janet R Sparrow Nan‐Kai Wang Stephen H Tsang |
| author_facet | Yang Kong Pei‐Kang Liu Yao Li Nicholas D Nolan Peter M J Quinn Chun‐Wei Hsu Laura A Jenny Jin Zhao Xuan Cui Ya‐Ju Chang Katherine J Wert Janet R Sparrow Nan‐Kai Wang Stephen H Tsang |
| author_sort | Yang Kong |
| collection | DOAJ |
| description | Abstract Iron accumulation causes cell death and disrupts tissue functions, which necessitates chelation therapy to reduce iron overload. However, clinical utilization of deferoxamine (DFO), an iron chelator, has been documented to give rise to systemic adverse effects, including ocular toxicity. This study provided the pathogenic and molecular basis for DFO‐related retinopathy and identified retinal pigment epithelium (RPE) as the target tissue in DFO‐related retinopathy. Our modeling demonstrated the susceptibility of RPE to DFO compared with the neuroretina. Intriguingly, we established upregulation of hypoxia inducible factor (HIF) 2α and mitochondrial deficit as the most prominent pathogenesis underlying the RPE atrophy. Moreover, suppressing hyperactivity of HIF2α and preserving mitochondrial dysfunction by α‐ketoglutarate (AKG) protects the RPE against lesions both in vitro and in vivo. This supported our observation that AKG supplementation alleviates visual impairment in a patient undergoing DFO‐chelation therapy. Overall, our study established a significant role of iron deficiency in initiating DFO‐related RPE atrophy. Inhibiting HIF2α and rescuing mitochondrial function by AKG protect RPE cells and can potentially ameliorate patients' visual function. |
| format | Article |
| id | doaj-art-dad16b5228fa4f2aae01a11f4bb1e21e |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2023-01-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-dad16b5228fa4f2aae01a11f4bb1e21e2025-08-24T11:43:51ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842023-01-0115212010.15252/emmm.202216525HIF2α activation and mitochondrial deficit due to iron chelation cause retinal atrophyYang Kong0Pei‐Kang Liu1Yao Li2Nicholas D Nolan3Peter M J Quinn4Chun‐Wei Hsu5Laura A Jenny6Jin Zhao7Xuan Cui8Ya‐Ju Chang9Katherine J Wert10Janet R Sparrow11Nan‐Kai Wang12Stephen H Tsang13Department of Ophthalmology, Vagelos College of Physicians and Surgeons, Columbia UniversityDepartment of Ophthalmology, Vagelos College of Physicians and Surgeons, Columbia UniversityDepartment of Ophthalmology, Vagelos College of Physicians and Surgeons, Columbia UniversityDepartment of Ophthalmology, Vagelos College of Physicians and Surgeons, Columbia UniversityDepartment of Ophthalmology, Vagelos College of Physicians and Surgeons, Columbia UniversityDepartment of Ophthalmology, Vagelos College of Physicians and Surgeons, Columbia UniversityDepartment of Ophthalmology, Vagelos College of Physicians and Surgeons, Columbia UniversityDepartment of Ophthalmology, Vagelos College of Physicians and Surgeons, Columbia UniversityDepartment of Ophthalmology, Vagelos College of Physicians and Surgeons, Columbia UniversityDepartment of Ophthalmology, Vagelos College of Physicians and Surgeons, Columbia UniversityDepartments of Ophthalmology and Molecular Biology, University of Texas Southwestern Medical CenterDepartment of Ophthalmology, Vagelos College of Physicians and Surgeons, Columbia UniversityDepartment of Ophthalmology, Vagelos College of Physicians and Surgeons, Columbia UniversityDepartment of Ophthalmology, Vagelos College of Physicians and Surgeons, Columbia UniversityAbstract Iron accumulation causes cell death and disrupts tissue functions, which necessitates chelation therapy to reduce iron overload. However, clinical utilization of deferoxamine (DFO), an iron chelator, has been documented to give rise to systemic adverse effects, including ocular toxicity. This study provided the pathogenic and molecular basis for DFO‐related retinopathy and identified retinal pigment epithelium (RPE) as the target tissue in DFO‐related retinopathy. Our modeling demonstrated the susceptibility of RPE to DFO compared with the neuroretina. Intriguingly, we established upregulation of hypoxia inducible factor (HIF) 2α and mitochondrial deficit as the most prominent pathogenesis underlying the RPE atrophy. Moreover, suppressing hyperactivity of HIF2α and preserving mitochondrial dysfunction by α‐ketoglutarate (AKG) protects the RPE against lesions both in vitro and in vivo. This supported our observation that AKG supplementation alleviates visual impairment in a patient undergoing DFO‐chelation therapy. Overall, our study established a significant role of iron deficiency in initiating DFO‐related RPE atrophy. Inhibiting HIF2α and rescuing mitochondrial function by AKG protect RPE cells and can potentially ameliorate patients' visual function.https://doi.org/10.15252/emmm.202216525HIF2α upregulationiron deficiencymitochondrial deficitRPE atrophyα‐ketoglutarate |
| spellingShingle | Yang Kong Pei‐Kang Liu Yao Li Nicholas D Nolan Peter M J Quinn Chun‐Wei Hsu Laura A Jenny Jin Zhao Xuan Cui Ya‐Ju Chang Katherine J Wert Janet R Sparrow Nan‐Kai Wang Stephen H Tsang HIF2α activation and mitochondrial deficit due to iron chelation cause retinal atrophy EMBO Molecular Medicine HIF2α upregulation iron deficiency mitochondrial deficit RPE atrophy α‐ketoglutarate |
| title | HIF2α activation and mitochondrial deficit due to iron chelation cause retinal atrophy |
| title_full | HIF2α activation and mitochondrial deficit due to iron chelation cause retinal atrophy |
| title_fullStr | HIF2α activation and mitochondrial deficit due to iron chelation cause retinal atrophy |
| title_full_unstemmed | HIF2α activation and mitochondrial deficit due to iron chelation cause retinal atrophy |
| title_short | HIF2α activation and mitochondrial deficit due to iron chelation cause retinal atrophy |
| title_sort | hif2α activation and mitochondrial deficit due to iron chelation cause retinal atrophy |
| topic | HIF2α upregulation iron deficiency mitochondrial deficit RPE atrophy α‐ketoglutarate |
| url | https://doi.org/10.15252/emmm.202216525 |
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