NCOA4 maintains murine erythropoiesis via cell autonomous and non-autonomous mechanisms

Santana-Codina, Naiara; Gableske, Sebastian; Rey, Maria Quiles del; Małachowska, Beata; Jedrychowski, Mark P.; Biancur, Douglas E.; Schmidt, Paul; Fleming, Mark D.; Fendler, Wojciech; Harper, J. Wade; Kimmelman, Alec C.; Mancias, Joseph D.

doi:10.3324/haematol.2018.204123

Cited by 47 publications

(53 citation statements)

References 44 publications

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“…An erythropoietic role for NCOA4 was suggested also in vivo in zebrafish embryos treated with morpholinos to Ncoa4 (4). A moderate-severe anemia was observed in Ncoa4-ko mice at birth, mostly rescued in adult animals (9,10). Despite all these findings suggest a role for NCOA4 in erythropoiesis, a formal proof that anemia of adult Ncoa4-ko mice is due to loss of protein activity in erythroid cells is still lacking.…”

Section: Introductionmentioning

confidence: 99%

“…Despite all these findings suggest a role for NCOA4 in erythropoiesis, a formal proof that anemia of adult Ncoa4-ko mice is due to loss of protein activity in erythroid cells is still lacking. Recent data (10) point toward both an autonomous and nonautonomous effect of NCOA4 in erythropoiesis. The Authors generated a conditional tamoxifen-induced total Ncoa4-ko model and a tissue specific one [through the expression of CRE-recombinase under the control of Erythropoietin Receptor (EPOR) promoter in Ncoa4-floxed transgenic animals].…”

Section: Introductionmentioning

confidence: 99%

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NCOA4-mediated ferritinophagy in macrophages is crucial to sustain erythropoiesis in mice

et al. 2020

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The Nuclear Receptor Coactivator 4 (NCOA4) promotes ferritin degradation and Ncoa4-ko mice in C57BL/6 background show microcytosis and mild anemia, aggravated by iron deficiency. To understand tissue specific contribution of NCOA4-mediated ferritinophagy we explored the effect of Ncoa4 genetic ablation in the iron-rich strain Sv129/J. Increased body iron content protects mice from anemia and, in basal conditions, Sv129/J Ncoa4-ko mice show only microcytosis; nevertheless, when fed a low-iron diet they develop a more severe anemia compared to wild-type animals. Reciprocal bone marrow (BM) transplantation from wild-type donors into Ncoa4-ko and from Ncoa4-ko into wild-type mice revealed that microcytosis and susceptibility to iron deficiency anemia depend on BM-derived cells. Erythropoiesis reconstitution with RBC count and hemoglobin normalization occurred at the same rate in transplanted animals independently of the genotype. Importantly, NCOA4 loss did not affect terminal erythropoiesis in iron deficiency, both in total and specific BM Ncoa4-ko animals compared to controls. On the contrary, upon a low iron diet, spleen from wild-type animals with Ncoa4-ko BM displayed marked iron retention compared to (wild-type BM) controls, indicating defective macrophage iron release in the former. Thus, EPO administration failed to mobilize iron from stores in Ncoa4-ko animals. Furthermore, Ncoa4 inactivation in thalassemic mice did not worsen the hematological phenotype. Overall our data reveal a major role for NCOA4-mediated ferritinophagy in macrophages to favor iron release for erythropoiesis, especially in iron deficiency.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

NCOA4-mediated ferritinophagy in macrophages is crucial to sustain erythropoiesis in mice

et al. 2020

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“…To date, little is known about the expression of NCOA4 in the human brain, however, it’s expression in murine and rat brains has been identified ( Siriett et al, 2006 ; Kollara and Brown, 2010 ). Acute systemic consumption of NCOA4 shows accumulation of FTH1 within a week, which suggest a potential role of NCOA4 for FTH1 turnover in the brain ( Santana-Codina et al, 2019 ). Interestingly, excessive iron measured as serum ferritin was also associated with poor prognosis following ischemic stroke ( García-Yébenes et al, 2012 ), indicating the important role of ferritin as an iron carrier to mediate iron storage and release under ischemic conditions.…”

Section: Crosstalk Between Autophagy and Ferroptosismentioning

confidence: 99%

Crosstalk Between Autophagy and Ferroptosis and Its Putative Role in Ischemic Stroke

Liu

Guo

Yan

et al. 2020

Front. Cell. Neurosci.

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Autophagy is a conserved process to maintains homeostasis via the degradation of toxic cell contents, which can either promote cell survival or accelerate cellular demise. Ferroptosis is a recently discovered iron-dependent cell death pathway associated with the accumulation of lethal reactive lipid species. In the past few years, an increasing number of studies have suggested the crosstalk between autophagy and ferroptosis. Ischemic stroke is a complex brain disease regulated by several cell death pathways, including autophagy and ferroptosis. However, the potential links between autophagy and ferroptosis in ischemic stroke have not yet been explored. In this review, we briefly overview the mechanisms of ferroptosis and autophagy, as well as their possible connections in ischemic stroke. The elucidation of crosstalk between different cell death pathways may provide insight into new future ischemic stroke therapies.

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“…Previous reports have shown that whole body NCOA4 deficiency has variable effects on systemic iron parameters (6,8). To characterize and confirm the role of NCOA4 in systemic iron homeostasis, we have generated a NCOA4 knockout (KO) mouse line by using CRISPRmediated guide RNA ( Figure 3A-C).…”

Section: Systemic Ncoa4 Deficiency Causes Tissue Iron Sequestration Amentioning

confidence: 99%

“…Ferritinophagy occupies a critical place in systemic iron homeostasis and is itself regulated by cellular iron levels (6). More recent discoveries about the role of NCOA4 in erythropoiesis highlights its connection with mammalian oxygen carrying function (7)(8)(9).…”

Section: Introductionmentioning

confidence: 99%

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

Das

Sankar

et al. 2020

Preprint

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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.

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NCOA4 maintains murine erythropoiesis via cell autonomous and non-autonomous mechanisms

Cited by 47 publications

References 44 publications

NCOA4-mediated ferritinophagy in macrophages is crucial to sustain erythropoiesis in mice

NCOA4-mediated ferritinophagy in macrophages is crucial to sustain erythropoiesis in mice

Crosstalk Between Autophagy and Ferroptosis and Its Putative Role in Ischemic Stroke

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

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