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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\u2010related retinopathy and identified retinal pigment epithelium (RPE) as the target tissue in DFO\u2010related retinopathy. Our modeling demonstrated the susceptibility of RPE to DFO compared with the neuroretina. Intriguingly, we established upregulation of hypoxia inducible factor (HIF) 2\u03b1 and mitochondrial deficit as the most prominent pathogenesis underlying the RPE atrophy. Moreover, suppressing hyperactivity of HIF2\u03b1 and preserving mitochondrial dysfunction by \u03b1\u2010ketoglutarate (AKG) protects the RPE against lesions both\n                    <jats:italic>in\u00a0vitro<\/jats:italic>\n                    and\n                    <jats:italic>in\u00a0vivo<\/jats:italic>\n                    . This supported our observation that AKG supplementation alleviates visual impairment in a patient undergoing DFO\u2010chelation therapy. Overall, our study established a significant role of iron deficiency in initiating DFO\u2010related RPE atrophy. Inhibiting HIF2\u03b1 and rescuing mitochondrial function by AKG protect RPE cells and can potentially ameliorate patients' visual function.\n                  <\/jats:p>","DOI":"10.15252\/emmm.202216525","type":"journal-article","created":{"date-parts":[[2023,1,16]],"date-time":"2023-01-16T06:00:34Z","timestamp":1673848834000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["HIF2\u03b1 activation and mitochondrial deficit due to iron chelation cause retinal atrophy"],"prefix":"10.1038","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3925-5572","authenticated-orcid":false,"given":"Yang","family":"Kong","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6417-4363","authenticated-orcid":false,"given":"Pei\u2010Kang","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yao","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9236-8309","authenticated-orcid":false,"given":"Nicholas D","family":"Nolan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9940-4264","authenticated-orcid":false,"given":"Peter M J","family":"Quinn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chun\u2010Wei","family":"Hsu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8959-7074","authenticated-orcid":false,"given":"Laura A","family":"Jenny","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1934-6445","authenticated-orcid":false,"given":"Jin","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuan","family":"Cui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ya\u2010Ju","family":"Chang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8430-2916","authenticated-orcid":false,"given":"Katherine J","family":"Wert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janet R","family":"Sparrow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6277-9879","authenticated-orcid":false,"given":"Nan\u2010Kai","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9082-2427","authenticated-orcid":false,"given":"Stephen H","family":"Tsang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,1,16]]},"reference":[{"key":"BFEMMM202216525_CR1","doi-asserted-by":"crossref","first-page":"2171","DOI":"10.1053\/euhj.2001.2822","volume":"22","author":"LJ Anderson","year":"2001","unstructured":"Anderson LJ, Holden S, Davis B, Prescott E, Charrier CC, Bunce NH, Firmin DN, Wonke B, Porter J, Walker JM et\u00a0al (2001) Cardiovascular T2\u2010star (T2*) magnetic resonance for the early diagnosis of myocardial iron overload. 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