Heme in pathophysiology: a matter of scavenging, metabolism and trafficking across cell membranes

Heme (iron-protoporphyrin IX) is an essential co-factor involved in multiple biological processes: oxygen transport and storage, electron transfer, drug and steroid metabolism, signal transduction, and micro RNA processing. However, excess free-heme is highly toxic due to its ability to promote oxidative stress and lipid peroxidation, thus leading to membrane injury and, ultimately, apoptosis. Thus, heme metabolism needs to be finely regulated. Intracellular heme amount is controlled at multiple levels: synthesis, utilization by hemoproteins, degradation and both intracellular and intercellular trafficking.This review focuses on recent findings highlighting the importance of controlling intracellular heme levels to counteract heme-induced oxidative stress. The contributions of heme scavenging from the extracellular environment, heme synthesis and incorporation into hemoproteins, heme catabolism and heme transport in maintaining adequate intracellular heme content are discussed. Particular attention is put on the recently described mechanisms of heme trafficking through the plasma membrane mediated by specific heme importers and exporters. Finally, the involvement of genes orchestrating heme metabolism in several pathological conditions is illustrated and new therapeutic approaches aimed at controlling heme metabolism are discussed. <br/

Il limes della Calabria bizantina: tracce, percorsi e vie

The case-study focusses on Byzantine fortifications along the limes that cross the region of Calabria. The theme is related to Goal 11: "Making cities and human settlements inclusive, secure, lasting and sustainable" and specifically to Goal 11.4: "Strengthen commitments to protect and safeguard the world’s cultural and natural heritage", set out in the 2030 Strategy Agenda. The methodological process is defined, therefore, upon improving protection measures with the use of special equipment with archaeological and architectural purposes for the relief of walled cities and fortresses in hazardous areas.The historical heritage helps to return the identity of peoples. The application of research areas extend both into the fields of archeology and that of architecture. The overall goal is to provide a picture of the state of study and research into the Byzantine system in Calabria. A fundamental role in defining the Byzantine architectural character in Calabria has since 1970 through "Byzantine studies Meetings", with the formulation of the first archaeological map. Il limes della Calabria bizantina: tracce, percorsi e vieIl contributo si occuperà come caso studio delle vie bizantine in Calabria, rintracciabili e ancora riconoscibili lungo il limes che attraversa la Regione Calabria.Il tema è riconducibile al Goal 11: "Rendere le città e gli insediamenti umani inclusivi, sicuri, duraturi e sostenibili" e nello specifico al Goal 11.4: "Rafforzare gli impegni per proteggere e salvaguardare il patrimonio culturale e naturale del mondo", presenti nella Strategia Agenda 2030.Il contributo mostra il risultato delle campagne effettuate sui siti e sulle architetture bizantine nell’area di studio. Il processo metodologico definito è volto a migliorare gli interventi di salvaguardia, di osservazione e di analisi con finalità archeologica ed architettonica per il rilievo di città murate, architetture (sacre e civili), fortezze.Il patrimonio storico contribuisce a restituire le identità dei popoli. Gli ambiti di applicazione della ricerca si estendono al campo dell’architettura e dell’archeologia. Il fine che ci proponiamo è quello di fornire un quadro dello stato degli studi e della ricerca sul sistema bizantino in Calabria.Un ruolo fondamentale nella definizione dei caratteri architettonici bizantini nell’area Calabrese si ha dal 1970 con gli “Incontri di studi bizantini” e la formulazione della prima carta archeologica della Calabria.Il contributo si occuperà come caso studio delle vie bizantine in Calabria, rintracciabili e ancora riconoscibili lungo il limes che attraversa la Regione Calabria.Il tema è riconducibile al Goal 11: "Rendere le città e gli insediamenti umani inclusivi, sicuri, duraturi e sostenibili" e nello specifico al Goal 11.4: "Rafforzare gli impegni per proteggere e salvaguardare il patrimonio culturale e naturale del mondo", presenti nella Strategia Agenda 2030.Il contributo mostra il risultato delle campagne effettuate sui siti e sulle architetture bizantine nell’area di studio. Il processo metodologico definito è volto a migliorare gli interventi di salvaguardia, di osservazione e di analisi con finalità archeologica ed architettonica per il rilievo di città murate, architetture (sacre e civili), fortezze.Il patrimonio storico contribuisce a restituire le identità dei popoli. Gli ambiti di applicazione della ricerca si estendono al campo dell’architettura e dell’archeologia. Il fine che ci proponiamo è quello di fornire un quadro dello stato degli studi e della ricerca sul sistema bizantino in Calabria.Un ruolo fondamentale nella definizione dei caratteri architettonici bizantini nell’area Calabrese si ha dal 1970 con gli “Incontri di studi bizantini” e la formulazione della prima carta archeologica della Calabria. The Limes of Byzantine Calabria: Evidences, Routes, WaysThe case-study focusses on Byzantine fortifications along the limes that cross the region of Calabria. The theme is related to Goal 11: "Making cities and human settlements inclusive, secure, lasting and sustainable" and specifically to Goal 11.4: "Strengthen commitments to protect and safeguard the world’s cultural and natural heritage", set out in the 2030 Strategy Agenda. The methodological process is defined, therefore, upon improving protection measures with the use of special equipment with archaeological and architectural purposes for the relief of walled cities and fortresses in hazardous areas.The historical heritage helps to return the identity of peoples. The application of research areas extend both into the fields of archeology and that of architecture. The overall goal is to provide a picture of the state of study and research into the Byzantine system in Calabria. A fundamental role in defining the Byzantine architectural character in Calabria has since 1970 through "Byzantine studies Meetings", with the formulation of the first archaeological map

Heme Exporter FLVCR1a Regulates Heme Synthesis and Degradation and Controls Activity of Cytochromes P450

Background & AimsThe liver has one of the highest rates of heme synthesis of any organ. More than 50% of the heme synthesized in the liver is used for synthesis of P450 enzymes, which metabolize exogenous and endogenous compounds that include natural products, hormones, drugs, and carcinogens. Feline leukemia virus subgroup C cellular receptor 1a (FLVCR1a) is plasma membrane heme exporter that is ubiquitously expressed and controls intracellular heme content in hematopoietic lineages. We investigated the role of Flvcr1a in liver function in mice.MethodsWe created mice with conditional disruption of Mfsd7b, which encodes Flvcr1a, in hepatocytes (Flvcr1a fl/fl;alb-cre mice). Mice were analyzed under basal conditions, after phenylhydrazine-induced hemolysis, and after induction of cytochromes P450 synthesis. Livers were collected and analyzed by histologic, quantitative real-time polymerase chain reaction, and immunoblot analyses. Hepatic P450 enzymatic activities were measured.ResultsFlvcr1afl/fl;alb-cre mice accumulated heme and iron in liver despite up-regulation of heme oxygenase 1, ferroportin, and ferritins. Hepatic heme export activity of Flvcr1a was closely associated with heme biosynthesis, which is required to sustain cytochrome induction. Upon cytochromes P450 stimulation, Flvcr1afl/fl;alb-cre mice had reduced cytochrome activity, associated with accumulation of heme in hepatocytes. The expansion of the cytosolic heme pool in these mice was likely responsible for the early inhibition of heme synthesis and increased degradation of heme, which reduced expression and activity of cytochromes P450.ConclusionsIn livers of mice, Flvcr1a maintains a free heme pool that regulates heme synthesis and degradation as well as cytochromes P450 expression and activity. These findings have important implications for drug metabolism

The mitochondrial heme exporter FLVCR1b mediates erythroid differentiation

Feline leukemia virus subgroup C receptor 1 (FLVCR1) is a cell membrane heme exporter that maintains the balance between heme levels and globin synthesis in erythroid precursors. It was previously shown that Flvcr1-null mice died in utero due to a failure of erythropoiesis. Here, we identify Flvcr1b, a mitochondrial Flvcr1 isoform that promotes heme efflux into the cytoplasm. Flvcr1b overexpression promoted heme synthesis and in vitro erythroid differentiation, whereas silencing of Flvcr1b caused mitochondrial heme accumulation and termination of erythroid differentiation. Furthermore, mice lacking the plasma membrane isoform (Flvcr1a) but expressing Flvcr1b had normal erythropoiesis, but exhibited hemorrhages, edema, and skeletal abnormalities. Thus, FLVCR1b regulates erythropoiesis by controlling mitochondrial heme efflux, whereas FLVCR1a expression is required to prevent hemorrhages and edema. The aberrant expression of Flvcr1 isoforms may play a role in the pathogenesis of disorders characterized by an imbalance between heme and globin synthesis

Heme and erythropoieis: more than a structural role

Erythropoiesis is the biological process that consumes the highest amount of body iron for heme synthesis. Heme synthesis in erythroid cells is finely coordinated with that of alpha (α) and beta (β)-globin, resulting in the production of hemoglobin, a tetramer of 2α- and 2β-globin chains, and heme as the prosthetic group. Heme is not only the structural component of hemoglobin, but it plays multiple regulatory roles during the differentiation of erythroid precursors since it controls its own synthesis and regulates the expression of several erythroid-specific genes. Heme is synthesized in developing erythroid progenitors by the stage of proerythroblast, through a series of eight enzymatic reactions divided between mitochondria and cytosol. Defects of heme synthesis in the erythroid lineage result in sideroblastic anemias, characterized by microcytic anemia associated to mitochondrial iron overload, or in erythropoietic porphyrias, characterized by porphyrin deposition in erythroid cells. Here, we focus on the heme biosynthetic pathway and on human erythroid disorders due to defective heme synthesis. The regulatory role of heme during erythroid differentiation is discussed as well as the heme-mediated regulatory mechanisms that allow the orchestration of the adaptive cell response to heme deficiency

Alteration of heme metabolism in a cellular model of Diamond-Blackfan anemia

Diamond-Blackfan anemia (DBA) is a congenital pure red cell aplasia often associated with skeletal malformations. Mutations in ribosomal protein coding genes, mainly in RPS19, account for the majority of DBA cases. The molecular mechanisms underlying DBA pathogenesis are still not completely understood. Alternative spliced isoforms of FLVCR1 (feline leukemia virus subgroup C receptor 1) transcript coding for non-functional proteins have been reported in some DBA patients. Consistently, a phenotype very close to DBA has been described in animal models of FLVCR1 deficiency. FLVCR1 gene codes for two proteins: the plasma membrane heme exporter FLVCR1a and the mitochondrial heme exporter FLVCR1b. The coordinated expression of both FLVCR1 isoforms regulates an intracellular heme pool, necessary for proper expansion and differentiation of erythroid precursors. Here, we investigate the role of FLVCR1 isoforms in a cellular model of DBA. RPS19-downregulated TF1 cells show reduced FLVCR1a and FLVCR1b mRNA levels associated with heme overload. The downregulation of FLVCR1 isoforms affects cell cycle progression and apoptosis in differentiating K562 cells, a phenotype similar to DBA. Taken together, these data suggest that alteration of heme metabolism could play a role in the pathogenesis of DBA