@article{1f44695ec8df4b25b462cc80b89b53a7,
title = "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. 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.",
keywords = "HIF2α upregulation, RPE atrophy, iron deficiency, mitochondrial deficit, α-ketoglutarate",
author = "Yang Kong and Liu, {Pei Kang} and Yao Li and Nolan, {Nicholas D.} and Quinn, {Peter M.J.} and Hsu, {Chun Wei} and Jenny, {Laura A.} and Jin Zhao and Xuan Cui and Chang, {Ya Ju} and Wert, {Katherine J.} and Sparrow, {Janet R.} and Wang, {Nan Kai} and Tsang, {Stephen H.}",
note = "Funding Information: This project was supported by the National Institute of Health U01 EY030580, U01EY034590, U54OD020351, R24EY028758, R24EY027285, 5P30EY019007, R01EY018213, R01EY024698, R01EY026682, R01EY031354, R01EY028131, R01EY033770, R21AG050437, S10OD028637, the Schneeweiss Stem Cell Fund, New York State (SDHDOH01-C32590GG-3450000), the Foundation Fighting Blindness New York Regional Research Center Grant (TA-NMT-0116-0692-COLU), Nancy & Kobi Karp, the Crowley Family Funds, the Rosenbaum Family Foundation, Alcon Research Institute, the Gebroe Family Foundation, the Research to Prevent Blindness (RPB) Physician-Scientist Award, unrestricted funds from RPB, New York, NY, USA. This research was also funded in part through the NIH/NCI Cancer Center Support Grant P30CA013696. We thank the Confocal and Specialized Microscopy Shared Resource of the Herbert Irving Comprehensive Cancer Center at Columbia University for their assistance in imaging acquisition. We thank Dr. Michio Hirano, Dr. Jonathan Shintaku and Saba Tadesse for their generous sharing of the Agilent Seahorse XF Analyzer. We thank Sarah R. Levi and Joseph Ryu for managing the IRB and IACUC animal protocols. Funding Information: Stephen H Tsang receives research support from Abeona Therapeutics, Inc. and Emendo. He is also the founder of Rejuvitas and is on the advisory board for Nanoscope Therapeutics. Peter M J Quinn receives research support from Rejuvitas, Inc. The other authors have declared that no conflict of interest exists. Funding Information: This project was supported by the National Institute of Health U01 EY030580, U01EY034590, U54OD020351, R24EY028758, R24EY027285, 5P30EY019007, R01EY018213, R01EY024698, R01EY026682, R01EY031354, R01EY028131, R01EY033770, R21AG050437, S10OD028637, the Schneeweiss Stem Cell Fund, New York State (SDHDOH01‐C32590GG‐3450000), the Foundation Fighting Blindness New York Regional Research Center Grant (TA‐NMT‐0116‐0692‐COLU), Nancy & Kobi Karp, the Crowley Family Funds, the Rosenbaum Family Foundation, Alcon Research Institute, the Gebroe Family Foundation, the Research to Prevent Blindness (RPB) Physician‐Scientist Award, unrestricted funds from RPB, New York, NY, USA. This research was also funded in part through the NIH/NCI Cancer Center Support Grant P30CA013696. We thank the Confocal and Specialized Microscopy Shared Resource of the Herbert Irving Comprehensive Cancer Center at Columbia University for their assistance in imaging acquisition. We thank Dr. Michio Hirano, Dr. Jonathan Shintaku and Saba Tadesse for their generous sharing of the Agilent Seahorse XF Analyzer. We thank Sarah R. Levi and Joseph Ryu for managing the IRB and IACUC animal protocols. Publisher Copyright: {\textcopyright} 2023 The Authors. Published under the terms of the CC BY 4.0 license.",
year = "2023",
month = feb,
day = "8",
doi = "10.15252/emmm.202216525",
language = "English (US)",
volume = "15",
journal = "EMBO Molecular Medicine",
issn = "1757-4676",
publisher = "Wiley-Blackwell",
number = "2",
}