Biology subjects

Mleczko-Sanecka, K.

Publications and source records attributed to Mleczko-Sanecka, K..

4 recordsLinked to original sources

bioRxiv2025

Nutritional iron deficiency elicits profound rewiring of red pulp macrophage functions via high FPN and SYK-mediated signaling

Iron deficiency is the most common nutritional disorder worldwide, yet how individual cell types adjust to iron scarcity remains unclear. Splenic red pulp macrophages (RPMs) are essential for systemic iron homeostasis. They manage exceptionally high iron flux by recycling aged red blood cells through erythrophagocytosis, a specialized form of efferocytosis. However, how RPMs adapt their clearance and metabolic programs to iron deficiency remains unexplored. Here, we show that RPMs from mildly anemic, iron-deficient mice exhibit enhanced erythrophagocytic capacity. Proteomic profiling and flow cytometry revealed expansion and activation of lysosomal and mitochondrial networks, accompanied by elevated mitochondrial respiration. This metabolic rewiring and the increase in erythrophagocytosis depended on branched-chain amino acid (BCAA) catabolism. These responses were distinct from alternative macrophage activation states and absent in liver and peritoneal macrophages. Mechanistically, the low hepcidin-high ferroportin axis and SYK kinase activity emerged as drivers of this functional rewiring. Pharmacological inhibition of SYK or BCAA catabolism blunted iron-deficiency-induced erythrophagocytic and mitochondrial adaptations of RPMs. Together, these findings reveal a non-canonical metabolic reprogramming of RPMs that enhances their specialized clearance functions during systemic iron scarcity, raising possiblity that similar signaling circuits may operate in other efferocytic macrophage subsets under altered ferroportin-SYK axis activity.

cell biology↗

bioRxiv2024

Efficient globin production during terminal erythropoiesis depends on the synergistic action of TENT5C poly(A) polymerase and LARP4/5

Red blood cell development is a unique process where reduced transcriptome and proteome complexity facilitates vast hemoglobin production. Here, we describe the cooperative role of cytoplasmic poly(A) polymerase TENT5C and the poly(A) tail-protecting LARP4/5 RNA-binding proteins in ensuring proper hemoglobin production. TENT5C catalytic mutant knock-in mice display microcytic hypochromic anemia resembling constitutive knockout. TENT5C counteracts gradual globin mRNA deadenylation during erythropoiesis. In the late stages, TENT5C dysfunction leads to globin poly(A) tail shortening and a drastic reduction of mRNA levels in reticulocytes. Proteomic experiments revealed transient but specific association of TENT5C with LARP4/5. Indeed, LARP4/5 depletion leads to downregulation and poly(A) tail shortening of globin mRNAs. Furthermore, lack of TENT5C catalytic activity is accompanied by compensatory upregulation of LARP4/5. Finally, the importance of precise regulation of globin poly(A) tails by deadenylation and re-adenylation is highlighted by the destabilization of TENT5C by CCR4-NOT deadenylase complex-associated E3 ubiquitin ligase CNOT4. O_FIG O_LINKSMALLFIG WIDTH=198 HEIGHT=200 SRC="FIGDIR/small/623596v1_ufig1.gif" ALT="Figure 1"> View larger version (59K): org.highwire.dtl.DTLVardef@82c736org.highwire.dtl.DTLVardef@1e4ea16org.highwire.dtl.DTLVardef@1c482b7org.highwire.dtl.DTLVardef@61e54a_HPS_FORMAT_FIGEXP M_FIG C_FIG

developmental biology↗

bioRxiv2023

Liver sinusoidal endothelial cells constitute a major route for hemoglobin clearance

Mild rupture of aged erythrocytes occurs physiologically in the spleen, leading to the release of hemoglobin (Hb), while pathological hemolysis characterizes several diseases. The detoxification of Hb has traditionally been attributed to the sequestration of Hb-haptoglobin complexes by macrophages. However, this process remains incompletely studied in animal models or primary cells, leaving the precise mechanisms of Hb clearance elusive. Using mice and primary liver cell cultures (murine and human), we uncovered that Hb uptake is chiefly performed by liver sinusoidal endothelial cells (LSECs) and involves macropinocytosis. Consistently, mouse LSECs displayed proteomic signatures indicative of active heme catabolism, ferritin iron storage, antioxidant defense, and macropinocytic capacity. LSECs also exhibited high iron content and the expression of hepcidin-regulated iron exporter ferroportin. Using erythrocyte/Hb transfusion assays in mice, we demonstrated that while splenic macrophages excel in phagocytosis of erythrocytes, LSECs primarily scavenge Hb and Kupffer cells clear erythrocyte membranes, the spleen-borne hemolysis products delivered to the liver via the portal circulation. High-dose Hb injections resulted in transient hepatic iron retention, early LSEC-specific induction of heme-catabolizing Hmox1 and iron-sensing Bmp6, culminating in hepcidin-mediated temporary hypoferremia. Transcriptional induction of Bmp6 in mice was phenocopied by erythrocyte lysis upon phenylhydrazine or iron citrate injection, although the latter elicited a distinct LSEC transcriptional signature compared to Hb. In conclusion, we identify LSECs as key Hb scavengers, a function that establishes the spleen-to-liver axis for iron recycling and contributes to heme detoxification during hemolysis, coupled with the induction of the BMP6-hepcidin axis to restore iron homeostasis.

cell biology↗

bioRxiv2022

Impaired iron recycling from erythrocytes is an early iron-dependent hallmark of aging

Aging affects iron homeostasis, as evidenced by tissue iron loading and toxicity and common anemia in the elderly. Iron needs in mammals are met primarily by iron-recycling from senescent red blood cells (RBCs), a task chiefly accomplished by splenic red pulp macrophages (RPMs) via erythrophagocytosis. Given that RPMs continuously process iron, their cellular functions might be susceptible to age-dependent decline, a condition that has been largely unexplored to date. Here, we found that 10-11-months-old female mice exhibit iron loading, diminished lysosomal activity, and decreased erythrophagocytosis rate in RPMs. These impairments lead to the retention of senescent hemolytic RBCs in the spleen, and the formation of undegradable iron- and heme-rich extracellular protein aggregates, likely derived from ferroptotic RPMs. We further found that feeding mice an iron-reduced diet alleviates iron accumulation in RPMs, enhances their ability to clear erythrocytes, and limits ferroptosis. Consequently, this diet ameliorates hemolysis of splenic RBCs and the formation of iron-rich aggregates, increasing serum iron availability in aging mice. Using RPM-like cells, we show that the diminished iron-recycling capacity of RPMs is underlain by iron accumulation and reduced expression of heme-catabolizing enzyme heme oxygenase 1 (HO-1). Taken together, we identified RPM collapse as an early hallmark of aging and demonstrated that dietary iron reduction improves iron turnover efficacy.

physiology↗