HIF2α activation and mitochondrial deficit due to iron chelation cause retinal atrophy

• Published in: EMBO molecular medicine Vol. 15; no. 2; pp. e16525 - n/a
• Main Authors: Kong, Yang, Liu, Pei‐Kang, Li, Yao, Nolan, Nicholas D, Quinn, Peter M J, Hsu, Chun‐Wei, Jenny, Laura A, Zhao, Jin, Cui, Xuan, Chang, Ya‐Ju, Wert, Katherine J, Sparrow, Janet R, Wang, Nan‐Kai, Tsang, Stephen H
• Format: Journal Article
• Language: English
• Published: Germany EMBO Press 08.02.2023; John Wiley and Sons Inc; Springer Nature
• Subjects: Apoptosis; Atrophy; Atrophy - chemically induced; Blood diseases; Cell Death; Chelation; Chelation therapy; Deferoxamine; Epithelium; HIF2α upregulation; Homeostasis; Humans; Hyperactivity; Hypoxia; Iron; Iron Chelating Agents - adverse effects; Iron deficiency; Ketoglutaric acid; Metabolism; Mitochondria; mitochondrial deficit; Nutrient deficiency; Pathology; Respiration; Retina; Retinal degeneration; Retinal Diseases; Retinal pigment epithelium; Retinopathy; RPE atrophy; Toxicity; Visual perception; α‐ketoglutarate; HIF2α upregulation; iron deficiency; mitochondrial deficit; RPE atrophy; α-ketoglutarate
• ISSN: 1757-4676; 1757-4684
• DOI: 10.15252/emmm.202216525

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. Synopsis Deferoxamine (DFO) stabilizes HIF2α and disrupts mitochondrial oxidative phosphorylation, leading to RPE atrophy. Inhibiting HIF2α and preserving mitochondrial oxidative phosphorylation by α‐ketoglutarate (AKG) mitigate RPE cell death and ameliorate visual impairment in the clinic. DFO primarily acts on RPE and disrupts its iron homeostasis, causing atrophic lesions. DFO upregulates HIF2α and undermines mitochondrial oxidative phosphorylation in the RPE, accounting for its susceptibility to iron depletion. RPE intolerance to HIF2α‐induced anaerobic glycolysis contributes to susceptibility to DFO toxicity. RPE survival is sustained by mitochondrial oxidative phosphorylation. The glycolytic photoreceptor is initially spared from the DFO‐enhanced HIF levels. AKG, an intermediary metabolite of the Krebs cycle, destabilizes HIF2α and preserves mitochondrial respiration capacity, which protect RPE from damage and mitigates visual impairment in the clinic. Deferoxamine (DFO) stabilizes HIF2α and disrupts mitochondrial oxidative phosphorylation, leading to RPE atrophy. Inhibiting HIF2α and preserving mitochondrial oxidative phosphorylation by α‐ketoglutarate (AKG) mitigate RPE cell death, and ameliorate visual impairment in the clinic.