Stimulation of Hepatic Ferritinophagy Mitigates Irp2 Depletion-Induced Anemia

Abstract

Background: Iron regulatory proteins (IRPs) maintain cellular iron homeostasis. Due to aberrant tissue-iron distribution, Irp2-deficient mice suffer microcytic anemia and neurodegeneration, while iron overload occurs in the liver and intestine. We previously found that Irp2 deficiency-induced Hif2 plays an important role in neurodegeneration. Methods: To test the role of Hif2 in Irp2 deficiency-induced anemia, we used Irp2 global knockout mice. Following Hif2 inhibition, routine blood tests, iron availability in bone marrow, histological assays, and biochemical analysis were performed to assess anemia improvement and tissue iron distribution. Results: We found that Hif2 inhibition improved anemia. The increased iron bioavailability for erythropoiesis was mainly derived from hepatic iron release, and secondly from enhanced intestinal absorption. We further demonstrate that nuclear receptor coactivator 4 (Ncoa4) was upregulated for iron release via the process of ferritinophagy. The released iron was utilized not only for intracellular Fe-S biogenesis but also for erythropoiesis after being exported from the liver to circulation. The hepatic iron export reduced hepcidin expression to further support iron absorption through the hepcidin-ferroportin axis to alleviate intestinal iron overload. Conclusion: Irp2 not only regulates cellular iron homeostasis but also tissue iron distribution by managing the involvement of Hif2-Ncoa4.

NCOA4 requires a [3Fe-4S] to sense and maintain the iron homeostasis

“…However, hypoxia rescues frataxin loss by restoring Fe-S cluster biogenesis ( 33 ), which would promote HERC2-dependent degradation of NCOA4 due to Fe-S cluster acquisition. Our previous study revealed that HIF2α was significantly upregulated in Irp2 -deficient mice ( 34 , 35 ), accompanied by decreased NCOA4 protein levels and weakened ferritinophagy in the gut and liver ( 36 ). Stimulating ferritinophagy by HIF2 inhibition facilitates iron release from ferritin to improve anemia ( 36 ).…”

“…Our previous study revealed that HIF2α was significantly upregulated in Irp2 -deficient mice ( 34 , 35 ), accompanied by decreased NCOA4 protein levels and weakened ferritinophagy in the gut and liver ( 36 ). Stimulating ferritinophagy by HIF2 inhibition facilitates iron release from ferritin to improve anemia ( 36 ). These studies all indicate that the participation of NCOA4 in ferritinophagy may also be regulated by oxygen at transcriptional and/or posttranslational levels in a context dependence of physiological conditions, which has recently been revealed ( 12 ).…”

“…The information for primary antibodies is as follows: anti-NCOA4 (cat#ab86707) from Abcam, anti-HA (cat#14832901) from Covance, anti-His (cat#A00186), and anti-myc (cat#A00704) from Genscript, anti-FXN, ferritin light chain, ISCU, FTH, and IRP2 (polyclonal, self-made, and raised from rabbits). All self-made antibodies were validated in previous studies ( 35 , 36 , 38 ).…”

Critical re‐evaluation of the identification of iron deficiency states and effective iron repletion strategies in patients with chronic heart failure

“…32,47 In healthy cells, when cytosolic Fe 2+ levels are low, iron is liberated when ferritin is degraded through an autophagy-dependent mechanism known as ferritinophagy 17 (Figure 1). Cytosolic iron increases when ferritinophagy is stimulated, 48 whereas genetic suppression of ferritinophagy causes sequestration of iron and depletion of cytosolic iron levels, leading to impaired erythropoiesis and mitochondrial function. 49,50 Conversely, accelerated degradation of ferritin causes excessive levels of cytosolic Fe 2+ , thereby promoting ferroptosis, heart failure and chronic kidney disease.…”

Iron Metabolism, Redox Balance and Neurological Diseases

“…Liu et al demonstrated that IRP2 not only regulated cellular iron homeostasis, but also medicated tissue iron distribution by managing the involvement of hypoxia-inducible factor 2 (HIF2) and nuclear receptor coactivator 4 (Ncoa4) [ 19 ]. This study highlights that HIF2-NCOA4 is a complex axis that contributes to iron metabolic disorders, including anemia, iron-overload disorder, and neurodegeneration, and provides new target molecules for the treatment of diseases with iron dysregulation.…”