Cell‐type‐specific insights into iron regulatory processes

Mleczko-Sanecka, Katarzyna; Silvestri, Laura

doi:10.1002/ajh.26001

Cited by 35 publications

(23 citation statements)

References 193 publications

(242 reference statements)

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“…Ferritin is an iron-storing heteropolymer composed of H and L subunits. Due to its ferroxidase activity, H ferritin is a key endogenous protective protein that converts redox-active ferrous iron to inert ferric iron retained inside the ferritin shells (Mleczko-Sanecka and Silvestri, 2021). Using intracellular staining and flow cytometric analyses, we uncovered that RPMs [gated as CD11b-dim, F4/80-high, TREML4-high (Haldar et al, 2014); Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Our data assign physiological context to this previous knowledge, as RPMs constitutive rely on lysosomal activity to exert their functions. The underlying mechanisms for the presence of excessive iron in aged RPMs likely include reduced FPN protein levels and deficient functional H ferritin that detoxifies redox-active ferrous iron (Mleczko-Sanecka and Silvestri, 2021). It is also plausible that, like neurons, aged RPMs may also show low capacity for heme synthesis (Atamna et al, 2002), which may lead to defective iron utilization in the mitochondria and increased cytoplasmic iron burden.…”

Section: Discussionmentioning

confidence: 99%

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Impaired iron recycling from erythrocytes is an early hallmark of aging

Mandal

Slusarczyk

Zurawska

et al. 2022

Preprint

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Aging affects iron homeostasis and erythropoiesis, as evidenced by tissue iron loading in rodents and common anemia in the elderly. Since red pulp macrophages (RPMs) continuously process iron, their cellular functions might be susceptible to age-dependent decline, affecting organismal iron metabolism and red blood cells (RBCs) parameters. However, little is known about the effects of aging on the functioning of RPMs. To study aging RPMs, we employed 10-11-months-old female mice that show serum iron deficiency and iron overload primarily in spleens compared to young controls. We observed that this is associated with iron loading, oxidative stress, diminished mitochondrial and lysosomal activities, and most relevantly, decreased erythrophagocytosis rate in RPMs. We uncovered that these impairments of RPMs lead to the retention of senescent RBCs in the spleen, their excessive local hemolysis, and the formation of iron- and heme-rich large extracellular protein aggregates, likely derived from damaged RBCs and RPMs. We further found that feeding mice an iron-reduced diet alleviates iron accumulation and reactive oxygen species build-up in RPMs, restores mitochondrial and lysosomal functions, and improves their ability to clear erythrocytes. Consequently, this diet improves splenic RBCs fitness, limits hemolysis and formation of iron-rich aggregates, normalizes splenic iron levels, and tends to increase serum iron availability in aging mice. Mechanistically, using readouts from aged RPMs and in vitro cultures of RPM-like cells, we show that diminished erythrophagocytic activity of RPMs can be attributed to a combination of increased iron levels, reduced expression of heme-catabolizing enzyme heme oxygenase 1 (HO-1), and endoplasmic reticulum stress. Taken together, we identified RPM dysfunction as an early hallmark of physiological aging and demonstrated that dietary iron reduction improves iron turnover efficacy.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Impaired iron recycling from erythrocytes is an early hallmark of aging

Mandal

Slusarczyk

Zurawska

et al. 2022

Preprint

Self Cite

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“…Several mRNAs coding for proteins involved in iron metabolism include an iron responsive element (IRE) [9]. When iron availability is low, iron regulatory proteins (IRPs) 1 and 2 are able to bind to IRE [9,32]. If the IRE is in the 5′ UTR (ALAS2, ferroportin, L and H-ferritin) or in the 3′ UTR (RTf1, DMT1), of mRNA, IRP binding will lead to a translation inhibition or to an enhanced mRNA stability, respectively.…”

Section: Ire/irp Systemmentioning

confidence: 99%

Iron, Heme Synthesis and Erythropoietic Porphyrias: A Complex Interplay

et al. 2021

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Erythropoietic porphyrias are caused by enzymatic dysfunctions in the heme biosynthetic pathway, resulting in porphyrins accumulation in red blood cells. The porphyrins deposition in tissues, including the skin, leads to photosensitivity that is present in all erythropoietic porphyrias. In the bone marrow, heme synthesis is mainly controlled by intracellular labile iron by post-transcriptional regulation: translation of ALAS2 mRNA, the first and rate-limiting enzyme of the pathway, is inhibited when iron availability is low. Moreover, it has been shown that the expression of ferrochelatase (FECH, an iron-sulfur cluster enzyme that inserts iron into protoporphyrin IX to form heme), is regulated by intracellular iron level. Accordingly, there is accumulating evidence that iron status can mitigate disease expression in patients with erythropoietic porphyrias. This article will review the available clinical data on how iron status can modify the symptoms of erythropoietic porphyrias. We will then review the modulation of heme biosynthesis pathway by iron availability in the erythron and its role in erythropoietic porphyrias physiopathology. Finally, we will summarize what is known of FECH interactions with other proteins involved in iron metabolism in the mitochondria.

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“…Due to its unique function in iron metabolism, Fpn expression remains under tight and complex control at the transcriptional, post-transcriptional, and posttranslational level [ 1 ]. Moreover, local and cell-type-specific Fpn regulation seems to be critical for maintaining iron homeostasis [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

The Role of Copper in the Regulation of Ferroportin Expression in Macrophages

Jończy

Mazgaj

Smuda

et al. 2021

Cells

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The critical function of ferroportin (Fpn) in maintaining iron homeostasis requires complex and multilevel control of its expression. Besides iron-dependent cellular and systemic control of Fpn expression, other metals also seem to be involved in regulating the Fpn gene. Here, we found that copper loading significantly enhanced Fpn transcription in an Nrf2-dependent manner in primary bone-marrow-derived macrophages (BMDMs). However, prolonged copper loading resulted in decreased Fpn protein abundance. Moreover, CuCl2 treatment induced Fpn expression in RAW 264.7 macrophages at both the mRNA and protein level. These data suggest that cell-type-specific regulations have an impact on Fpn protein stability after copper loading. Transcriptional suppression of Fpn after lipopolysaccharide (LPS) treatment contributes to increased iron storage inside macrophages and may result in anemia of inflammation. Here, we observed that in both primary BMDMs and RAW 264.7 macrophages, LPS treatment significantly decreased Fpn mRNA levels, but concomitant CuCl2 stimulation counteracted the transcriptional suppression of Fpn and restored its expression to the control level. Overall, we show that copper loading significantly enhances Fpn transcription in macrophages, while Fpn protein abundance in response to CuCl2 treatment, depending on macrophage type and factors specific to the macrophage population, can influence Fpn regulation in response to copper loading.

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Cell‐type‐specific insights into iron regulatory processes

Cited by 35 publications

References 193 publications

Impaired iron recycling from erythrocytes is an early hallmark of aging

Impaired iron recycling from erythrocytes is an early hallmark of aging

Iron, Heme Synthesis and Erythropoietic Porphyrias: A Complex Interplay

The Role of Copper in the Regulation of Ferroportin Expression in Macrophages

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