Intestinal ferritinophagy is regulated by HIF-2α and is essential for systemic iron homeostasis

Abstract

Iron is critical for many processes including oxygen transport and erythropoiesis. Transcriptomic analysis demonstrates that HIF-2a induced following iron deficiency in the intestine. However, beyond divalent metal transporter 1 (DMT1), ferroportin 1 (Fpn1) and duodenal cytochrome b (Dcytb), no other genes/pathways have been critically assessed with respects to their importance in intestinal iron absorption. Ferritinophagy is associated with cargo specific autophagic breakdown of ferritin and subsequent release of iron. We show here that nuclear receptor co-activator 4 (NCOA4)-mediated intestinal ferritinophagy is integrated to systemic iron demand via HIF-2a. Duodenal NCOA4 expression is regulated by HIF-2a during high systemic iron demands. Moreover, overexpression of intestinal HIF-2a is sufficient to activate NCOA4 and promote lysosomal degradation of ferritin. Promoter analysis revealed NCOA4 as a direct HIF-2a target. To demonstrate the importance of intestinal HIF-2a/ferritinophagy axis in systemic iron homeostasis, whole body and intestine-specific NCOA4-null mouse lines were assessed. These analyses demonstrate an iron sequestration in the enterocytes, and significantly high tissue ferritin levels in the dietary iron deficiency and acute hemolytic anemia models. Together, our data suggests efficient ferritinophagy is critical for intestinal iron absorption and systemic iron homeostasis.

Ferritinophagy and ferroptosis in the management of metabolic diseases

“…Endothelial PAS domain protein 1 (EPAS1/HIF2A) regulates intestinal ferritinophagy through inducing NCOA4 upregulation during high iron demands. Thus, EPAS1-NCOA4-mediated ferritinophagy is cardinal for systemic intestinal iron homeostasis and absorption [124].…”

Identification of Novel Direct Small-Molecule Inhibitors against HIF-2A using Structure-based Virtual Screening and Molecular Dynamics Simulation

“…Indole analogs, Thiophene and Tricyclic derivatives are other class of small-molecule inhibitors that directly target HIF2A subunit and have been shown to successfully prevent HIF2A activity in 786-Ocells (62)(63)(64). Inhibition of the HIF2A subunit was a treatment option not only for specific types of cancers, but also other diseases, such as muscle injury, and disorders related to iron overload as well (43,(65)(66)(67)(68)(69). Therefore, the need for design of direct and specific HIF2A inhibitors has real potential to target aberrant expression of HIF-2A and warrants further investigations to evaluate the effectiveness of HIF2A small-molecule inhibitors beyond cancer therapy.…”

IRE-dependent Regulation of Intestinal Dmt1 Prevails During Chronic Dietary Iron Deficiency but is Dispensable in Conditions of Acute Erythropoietic Stress

“…The intestinal iron absorption machinery is also controlled locally by mechanisms acting within duodenal enterocytes. This includes the regulation of Dmt1 and Fpn transcription and possibly ferritin turnover by hypoxia inducible factor 2 (HIF2) 6–8 …”

“…This includes the regulation of Dmt1 and Fpn transcription and possibly ferritin turnover by hypoxia inducible factor 2 (HIF2). 6–8…”

“…This includes the regulation of Dmt1 and Fpn transcription and possibly ferritin turnover by hypoxia inducible factor 2 (HIF2). [6][7][8] Four Dmt1 mRNA isoforms with distinct 5′ and 3′ ends are transcribed from the Dmt1 locus. 3 3′ variants harbor or lack an iron-responsive element (IRE) in their 3′ untranslated region (UTR).…”