Heme Interactions: Comparison
View Latest Version
Please note this is a comparison between Version 2 by Fanny Huang and Version 1 by Stefanos Alexis Tsiftsoglou.

Heme (Fe2+-protoporphyrin IX) is a pigment of life, and as a prosthetic group in several hemoproteins, it contributes to diverse critical cellular processes. Direct interactions of extracellular heme with alternative pathway complement components (APCCs) may be implicated molecularly in diverse conditions at sites of abnormal cell damage and vascular injury. 

  • heme
  • HeBPs
  • HBMs
  • complement
  • genetic

1. Pleiotropic Functions of Heme, Transport and Heme-Associcated Pathologies

Heme (Fe2+-protoporphyrin IX) is a pigment of life in all organisms ranging from bacteria to mammals [1,2,3,4][1][2][3][4]. In terms of structure, heme exhibits a protoporphyrin IX tetrapyrrole ring system that is coordinated by a central iron ion through the four nitrogen atoms of the assembled moiety [5]. Heme also exhibits eight alkyl substituents (four methyl, two propionates and two vinyl groups) attached to its pyrrole rings. As a covalent prosthetic group in several vital hemoproteins, such as hemoglobins, myoglobins, cytochromes and enzymes, it serves as the essential gas carrier of oxygen (O2), nitrogen oxide (NO) and carbon monoxide (CO) [6,7,8,9][6][7][8][9].
In the hemoglobin chains, the iron ion is bound to a histidine residue and to oxygen which binds at the other coordinated position of iron. The iron ion in hemoglobin is in its ferrous state (Fe2+) facilitating the reversible association with molecular oxygen. When the oxidation of hemoglobin occurs, iron transitions to its ferric state (Fe3+), thus converting hemoglobin to methemoglobin, which has limited oxygen-carrying capacity. In the presence of chloride (Cl−) ions, heme is converted to hemin, the oxidized form of iron protoporphyrin IX [5]. Researchers current knowledge about the functions of heme has been derived from experimental work using hemin, the oxidized form of heme (Fe3+-protoporphyrin IX) with a chloride ligand.
Heme is a major activator and regulator of erythropoiesis [5[5][10][11][12],10,11,12], an essential constituent of the red blood cells (RBCs), and a central element in cellular metabolism and mitochondrial bioenergetics. In addition, heme contributes to globin biosynthesis [12[12][13],13], induces cell signaling and sensing pathways [14[14][15],15], and it also facilitates proteolysis via ubiquitination [14,15,16][14][15][16] among its several pleiotropic biological activities and properties summarized in Table 1 as examples.
Heme is synthesized de novo in the mitochondria [3,5[3][5][17],17], while it is catabolized by heme oxygenases (HOs) into bilirubin and CO2 [4,5,18,19,20][4][5][18][19][20]. Unfortunately, despite being essential for erythropoiesis and pivotal for several other molecular processes, heme as a free agent can be hazardous as a potent oxidant in the formation of volatile radical oxygen species (ROS) [14,21,22,23][14][21][22][23].
The diverse effects of heme suggest that under healthy conditions, its intracellular levels and trafficking are constantly monitored, and tightly regulated, by an extensively network of heme-binding proteins (HeBPs) [24,25,26,27,28,29,30][24][25][26][27][28][29][30]. These proteins are of diverse ontologies and contain often multiple heme-binding motifs (HBMs) that bind labile heme (biologically available and non-covalently bound) transiently with various affinities (Kd) [1,5,26,31,32,33,34][1][5][26][31][32][33][34]. These classes of motifs exhibit a primary architecture such as X4(C/H/Y)0X4 and contain an amino acid, histidine (H), tyrosine (Y), or cysteine (C), coordinated to the iron ion of heme and surrounded by positively-charged amino acids or cysteine–proline motifs (CP motifs) or cysteine [35,36][35][36]. The transport of labile heme in and out of the cells is also achieved through its transient binding to several shuttle proteins, receptors and complexes [27,37,38,39][27][37][38][39]. Heme is extracellularly sequestered when damaged or ruptured cells release considerable amounts of hemoproteins and eventually labile heme into tissues, organs and into the circulation [22].
Table 1. Heme in diverse molecular processes and pathologies 1.
Beneficial Effects (+)
  • Serves as prosthetic group in hemoproteins such as hemoglobin, myoglobin, cytochromes and enzymes [1,2,3,4,5,10][1][2][3][4][5][10]
  • Acts as a gas carrier for O2, CO and NO [6,7,8,9][6][7][8][9]
  • Enhances globin mRNA translation [12,13][12][13]
  • Activates cell signaling and regulates sensing [14,15][14][15]
  • Regulates mitochondrial respiratory bioenergetics [17,44,45][17][44][45]
  • Binds to DNA G4 structural domains [46]
  • Regulates the transcriptional dynamics of several genes [5,10][5][10]
  • Activates chaperones such as the heat shock proteins HSP70 and HSP90 [47]
  • Forms conjugation adducts with N-acetyl cysteine (NAC) and other thiols [21]
Harmful Effects (−)
  • Stimulates toll-like receptors (TLRs) affecting the immune response [48,49][48][49]
  • Promotes ubiquitination and proteolysis [14,16][14][16]
  • Acts as a major oxidant promoting ROS accumulation and cell stress [14,[22,1424]][22][24]
  • Stimulates stroke cell lysis and neuron ferroptosis [56,57,58][56][57][58]
  • Inhibits neuronal functions such as the low conductance K+ channels [59,60][59][60]
Heme-Associated Pathologies
  • Severe hematological disorders such as acute intermittent porphyrias [61] and anemias [5] that include congenital sideroblastic anemia [62] and Diamond–Blackfan anemia [63,64][63][64]
  • Hemolytic syndromes [66]
  • Severe sepsis [65]
  • Neurological disorders [69,70][69][70]
  • Cardiovascular arrythmias [71,72][71][72]
Heme-Associated Complementopathies [73]
  • Hemostasis-driven thromboinflammation [74]
  • Paroxysmal nocturnal hemoglobinuria (PNH) [75,[7576]][76]
  • Hemolytic diseases and cell lysis conditions such as hemolytic uremic syndromes, hemorrhage, sepsis and sickle cell disease [53,77,78][53][77][78]
  • Age-related macular degeneration (AMD) [75,79,80][75][79][80]
  • Ferroptosis in traumatic brain injury [68]
  • Ischemic stroke with cerebral hemorrhage [81]
  • Neurodegeneration [82]
  • Huntington’s disease [83]

2. Interactions of Heme with Complement Components

Extracellularly, in plasma, heme is scavenged by hemopexin (HPX) [84], albumin and several other proteins [85], while it also interacts directly with the complement components C1q [55], C3 [54] and factor I [51]. These direct interactions influence the activation and regulation dynamics of the classical (CP) and alternative (AP) complement pathways. Heme can interact with C1q and inhibit the classical complement pathway that is typically associated with the specific recognition and tagging of surface blebs of apoptotic vascular endothelial cells [55,86,87][55][86][87]. In addition, the association of heme with C3 at sites of endothelial damage was found to downregulate the expression of CD46/MCP and CD55/DAF, thus limiting the decay accelerative capacity of the compromised cells mainly to locally available CFH, and therefore promoting the formation of a hyperactive AP C3 convertase [54]. The interaction of heme with CFI blocks its proteolytic capacity against C3b, therefore also supporting the formation of a hyperactive AP C3 convertase [51].
The AP has recently attracted renewed interest due to its multidimensional involvement in important immune [88,89,90][88][89][90] and hemostatic processes [74]. Interestingly and in terms of the competing biochemical dynamics between the CP and AP, recent data have suggested that the contribution of the AP in complement activation on cell surfaces depends on the strength of CP initiation [91]. In that perspective, a heme-crippled C1q can enhance the AP activation dynamics, if there is lack of effective decay accelerating activity to control the formation of a C3bBb convertase.
Heme can downregulate CD46/MCP and CD55/DAF limiting the local decay accelerator factor potential to CFH, while it can also distort C3 [54] and block the proteolytic capacity of CFI [51]. The exposure of endothelia to heme can also promote the rapid exocytosis of Weibel–Palade bodies, the TLR4-dependent surface membrane expression of P-selectin known to bind C3b/C3(H2O) and trigger the AP, and the release of the prothrombotic von Willebrand factor [54,77][54][77]. The occurrence of local noncanonical AP activation and its association with the induction of thrombosis hemostatic responses has been recently discussed for SARS-CoV-2 infection in COVID-19 [92,93,94,95,96][92][93][94][95][96]. In both of these quite different scenarios, the heme-induced stress and the viral infection, the disruption of the physiological heparan sulphate–CFH coating could be a common and pivotal attribute for the maintenance of a deregulated AP amplification loop [79]. Other parameters in the host background, such as natural genetic variation (e.g., indels, SNPs) and epigenetic modifications (e.g., phosphorylation) of complement AP components, may also synergistically favor the enhanced assembly of a deregulated AP amplification loop.

3. Heme Interactions with APCCs and Complement Deregulation

Therefore, the direct extracellular interactions of heme with complement components, and in particular with AP complement components (APCCs), are of particular interest towards understanding molecularly, diverse heme-associated pathologies mediated by complement deregulation. Such heme-associated complementopathies [73] (Table 1) are characterized by cell populations or sites of abnormal cellular damage and vascular injury. This potential involvement of the AP activation as a mediator of disease pathologies, triggered by heme-induced stress, formed the conceptual basis for investigating the heme binding interactions with APCCs. Given the recent progress in the advanced computational prediction of HBMs in HeBPs, the questions of whether the APCCs carry putative HBMs and whether these HBMs overlay with sites or residues that may genetically (encoded SNPs) and/or epigenetically (PTMs: post-translational modifications) vary among individuals were assessed. Such natural variability could be interesting in explaining, mechanistically, a tendency towards the deregulation of the AP, identifying potential personalized biomarkers of susceptibility for advanced diagnostics and revealing common targets for personalized pharmacological intervention in a diverse range of diseases induced by poorly controlled heme-driven cell stress. 

References

  1. Gallio, A.E.; Fung, S.S.-P.; Cammack-Najera, A.; Hudson, A.J.; Raven, E.L. Understanding the Logistics for the Distribution of Heme in Cells. JACS Au 2021, 1, 1541–1555.
  2. Furuyama, K.; Kaneko, K.; Vargas, V. Heme as a Magnificent Molecule with Multiple Missions: Heme Determines Its Own Fate and Governs Cellular Homeostasis. Tohoku J. Exp. Med. 2007, 213, 1–16.
  3. Ajioka, R.S.; Phillips, J.D.; Kushner, J.P. Biosynthesis of heme in mammals. Biochim. Biophys. Acta-Mol. Cell Res. 2006, 1763, 723–736.
  4. Ponka, P. Cell biology of heme. Am. J. Med. Sci. 1999, 318, 241–256.
  5. Tsiftsoglou, A.S.; Tsamadou, A.I.; Papadopoulou, L.C. Heme as key regulator of major mammalian cellular functions: Molecular, cellular, and pharmacological aspects. Pharmacol. Ther. 2006, 111, 327–345.
  6. Martínková, M.; Kitanishi, K.; Shimizu, T. Heme-based globin-coupled oxygen sensors: Linking oxygen binding to functional regulation of diguanylate cyclase, histidine kinase, and methyl-accepting chemotaxis. J. Biol. Chem. 2013, 288, 27702–27711.
  7. Shimizu, T.; Lengalova, A.; Martínek, V.; Martínková, M. Heme: Emergent roles of heme in signal transduction, functional regulation and as catalytic centres. Chem. Soc. Rev. 2019, 48, 5624–5657.
  8. Martínková, M.; Vávra, J.; Sergunin, A.; Jeřábek, P.; Shimizu, T. Signal transduction mechanisms in heme-based globin-coupled oxygen sensors with a focus on a histidine kinase (AfGcHK) and a diguanylate cyclase (YddV or EcDosC). Biol. Chem. 2022, 403, 1031–1042.
  9. Shimizu, T.; Huang, D.; Yan, F.; Stranava, M.; Bartosova, M.; Fojtíková, V.; Martínková, M. Gaseous O2, NO, and CO in Signal Transduction: Structure and Function Relationships of Heme-Based Gas Sensors and Heme-Redox Sensors. Chem. Rev. 2015, 115, 6491–6533.
  10. Tsiftsoglou, A.S.; Vizirianakis, I.S.; Strouboulis, J. Erythropoiesis: Model systems, molecular regulators, and developmental programs. IUBMB Life 2009, 61, 800–830.
  11. Tsiftsoglou, A.S.; Wong, W.; Robinson, S.H.; Hensold, J. Hemin increases production of β-like globin RNA transcripts in human erythroleukemia K-562 cells. Dev. Genet. 1989, 10, 311–317.
  12. Bruns, G.P.; London, I.M. The effect of hemin on the synthesis of globin. Biochem. Biophys. Res. Commun. 1965, 18, 236–242.
  13. Hunt, T.; Vanderhoff, G.; London, I.M. Control of globin synthesis: The role of heme. J. Mol. Biol. 1972, 66, 471–481.
  14. Georgiou-Siafis, S.K.; Tsiftsoglou, A.S. Activation of KEAP1/NRF2 stress signaling involved in the molecular basis of hemin-induced cytotoxicity in human pro-erythroid K562 cells. Biochem. Pharmacol. 2020, 175, 113900.
  15. Hou, S.; Reynolds, M.F.; Horrigan, F.T.; Heinemann, S.H.; Hoshi, T. Reversible binding of heme to proteins in cellular signal transduction. Acc. Chem. Res. 2006, 39, 918–924.
  16. Ishikawa, H.; Kato, M.; Hori, H.; Ishimori, K.; Kirisako, T.; Tokunaga, F.; Iwai, K. Involvement of heme regulatory motif in heme-mediated ubiquitination and degradation of IRP2. Mol. Cell 2005, 19, 171–181.
  17. Yien, Y.Y.; Perfetto, M. Regulation of Heme Synthesis by Mitochondrial Homeostasis Proteins. Front. Cell Dev. Biol. 2022, 10, 895521.
  18. Gozzelino, R.; Jeney, V.; Soares, M.P. Mechanisms of cell protection by heme Oxygenase-1. Annu. Rev. Pharmacol. Toxicol. 2010, 50, 323–354.
  19. Belcher, J.D.; Beckman, J.D.; Balla, G.; Balla, J.; Vercellotti, G. Heme degradation and vascular injury. Antioxid. Redox Signal. 2010, 12, 233–248.
  20. Ryter, S.W.; Tyrrell, R.M. The heme synthesis and degradation pathways: Role in oxidant sensitivity. Free Radic. Biol. Med. 2000, 28, 289–309.
  21. Georgiou-Siafis, S.K.; Samiotaki, M.K.; Demopoulos, V.J.; Panayotou, G.; Tsiftsoglou, A.S. Formation of novel N-acetylcysteine-hemin adducts abrogates hemin-induced cytotoxicity and suppresses the NRF2-driven stress response in human pro-erythroid K562 cells. Eur. J. Pharmacol. 2020, 880, 173077.
  22. Kumar, S.; Bandyopadhyay, U. Free heme toxicity and its detoxification systems in human. Toxicol. Lett. 2005, 157, 175–188.
  23. Jeney, V.; Balla, J.; Yachie, A.; Varga, Z.; Vercellotti, G.M.; Eaton, J.W.; Balla, G. Pro-oxidant and cytotoxic effects of circulating heme. Blood 2002, 100, 879–887.
  24. Chiabrando, D.; Vinchi, F.; Fiorito, V.; Mercurio, S.; Tolosano, E. Heme in pathophysiology: A matter of scavenging, metabolism and trafficking across cell membranes. Front. Pharmacol. 2014, 5, 61.
  25. Leung, G.C.H.; Fung, S.S.P.; Gallio, A.E.; Blore, R.; Alibhai, D.; Raven, E.L.; Hudson, A.J. Unravelling the mechanisms controlling heme supply and demand. Proc. Natl. Acad. Sci. USA 2021, 118, e2104008118.
  26. Donegan, R.K.; Moore, C.M.; Hanna, D.A.; Reddi, A.R. Handling heme: The mechanisms underlying the movement of heme within and between cells. Free Radic. Biol. Med. 2019, 133, 88–100.
  27. Ponka, P.; Sheftel, A.D.; English, A.M.; Scott Bohle, D.; Garcia-Santos, D. Do Mammalian Cells Really Need to Export and Import Heme? Trends Biochem. Sci. 2017, 42, 395–406.
  28. Reddi, A.R.; Hamza, I. Heme Mobilization in Animals: A Metallolipid’s Journey. Acc. Chem. Res. 2016, 49, 1104–1110.
  29. Hamza, I.; Dailey, H.A. One ring to rule them all: Trafficking of heme and heme synthesis intermediates in the metazoans. Biochim. Biophys. Acta-Mol. Cell Res. 2012, 1823, 1617–1632.
  30. Fleming, M.D.; Hamza, I. Mitochondrial heme: An exit strategy at last. J. Clin. Investig. 2012, 122, 4328–4330.
  31. Kim, H.; Moore, C.M.; Mestre-Fos, S.; Hanna, D.A.; Williams, L.D.; Reddi, A.R.; Torres, M.P. Depletion Assisted Hemin Affinity (DAsHA) Proteomics Reveals an Expanded Landscape of Heme Binding Proteins in the Human Proteome. Metallomics 2023, 15, mfad004.
  32. Homan, R.A.; Jadhav, A.M.; Conway, L.P.; Parker, C.G. A Chemical Proteomic Map of Heme-Protein Interactions. J. Am. Chem. Soc. 2022, 144, 15013–15019.
  33. Tsolaki, V.-D.C.; Georgiou-Siafis, S.K.; Tsamadou, A.I.; Tsiftsoglou, S.A.; Samiotaki, M.; Panayotou, G.; Tsiftsoglou, A.S. Hemin accumulation and identification of a heme-binding protein clan in K562 cells by proteomic and computational analysis. J. Cell. Physiol. 2022, 237, 1315–1340.
  34. Chambers, I.G.; Willoughby, M.M.; Hamza, I.; Reddi, A.R. One ring to bring them all and in the darkness bind them: The trafficking of heme without deliverers. Biochim. Biophys. Acta-Mol. Cell Res. 2021, 1868, 118881.
  35. Paul George, A.A.; Lacerda, M.; Syllwasschy, B.F.; Hopp, M.T.; Wißbrock, A.; Imhof, D. HeMoQuest: A webserver for qualitative prediction of transient heme binding to protein motifs. BMC Bioinform. 2020, 21, 124.
  36. Wißbrock, A.; George, A.A.P.; Brewitz, H.H.; Kühl, T.; Imhof, D. The molecular basis of transient heme-protein interactions: Analysis, concept and implementation. Biosci. Rep. 2019, 39, BSR20181940.
  37. Severance, S.; Hamza, I. Trafficking of Heme and Porphyrins in Metazoa. Chem. Rev. 2009, 109, 4596–4616.
  38. Krishnamurthy, P.; Xie, T.; Schuetz, J.D. The role of transporters in cellular heme and porphyrin homeostasis. Pharmacol. Ther. 2007, 114, 345–358.
  39. Latunde-Dada, G.O.; Simpson, R.J.; McKie, A.T. Recent advances in mammalian haem transport. Trends Biochem. Sci. 2006, 31, 182–188.
  40. Rutherford, T.; Clegg, J.B.; Higgs, D.R.; Jones, R.W.; Thompson, J.; Weatherall, D.J. Embryonic erythroid differentiation in the human leukemic cell line K562. Proc. Natl. Acad. Sci. USA 1981, 78, 348–352.
  41. Dean, A.; Erard, F.; Schneider, A.B.; Schechter, A.N. Induction of hemoglobin accumulation in human K562 cells by hemin is reversible. Science 1981, 212, 459–461.
  42. Gusella, J.; Weil, S.; Tsiftsoglou, A.; Volloch, V.; Neumann, J.; Keys, C.; Housman, D. Hemin does not cause commitment of murine erythroleukemia (MEL) cells to terminal differentiation. Blood 1980, 56, 481–487.
  43. Rutherford, T.R.; Clegg, J.B.; Weatherall, D.J. K562 human leukaemic cells synthesise embryonic haemoglobin in response to haemin. Nature 1979, 280, 164–165.
  44. Piel, R.B.; Dailey, H.A.; Medlock, A.E. The mitochondrial heme metabolon: Insights into the complex(ity) of heme synthesis and distribution. Mol. Genet. Metab. 2019, 128, 198–203.
  45. Medlock, A.E.; Shiferaw, M.T.; Marcero, J.R.; Vashisht, A.A.; Wohlschlegel, J.A.; Phillips, J.D.; Dailey, H.A. Identification of the mitochondrial heme metabolism complex. PLoS ONE 2015, 10, e0135896.
  46. Gray, L.T.; Puig Lombardi, E.; Verga, D.; Nicolas, A.; Teulade-Fichou, M.P.; Londoño-Vallejo, A.; Maizels, N. G-quadruplexes Sequester Free Heme in Living Cells. Cell Chem. Biol. 2019, 26, 1681–1691.e5.
  47. Ghosh, A.; Garee, G.; Sweeny, E.A.; Nakamura, Y.; Stuehr, D.J. Hsp90 chaperones hemoglobin maturation in erythroid and nonerythroid cells. Proc. Natl. Acad. Sci. USA 2018, 115, E1117–E1126.
  48. Canesin, G.; Hejazi, S.M.; Swanson, K.D.; Wegiel, B. Heme-Derived Metabolic Signals Dictate Immune Responses. Front. Immunol. 2020, 11, 66.
  49. Dutra, F.F.; Bozza, M.T. Heme on innate immunity and inflammation. Front. Pharmacol. 2014, 5, 115.
  50. Hopp, M.-T.; Imhof, D. Hemolysis-derived heme interacts with components of the blood coagulation system. Hamostaseologie 2023, 43, T-02-03.
  51. Gerogianni, A.; Dimitrov, J.D.; Zarantonello, A.; Poillerat, V.; Chonat, S.; Sandholm, K.; McAdam, K.E.; Ekdahl, K.N.; Mollnes, T.E.; Mohlin, C.; et al. Heme Interferes With Complement Factor I-Dependent Regulation by Enhancing Alternative Pathway Activation. Front. Immunol. 2022, 13, 901876.
  52. Poillerat, V.; Gentinetta, T.; Leon, J.; Wassmer, A.; Edler, M.; Torset, C.; Luo, D.; Tuffin, G.; Roumenina, L.T. Hemopexin as an Inhibitor of Hemolysis-Induced Complement Activation. Front. Immunol. 2020, 11, 1684.
  53. Roumenina, L.T.; Rayes, J.; Lacroix-Desmazes, S.; Dimitrov, J.D. Heme: Modulator of Plasma Systems in Hemolytic Diseases. Trends Mol. Med. 2016, 22, 200–213.
  54. Frimat, M.; Tabarin, F.; Dimitrov, J.D.; Poitou, C.; Halbwachs-Mecarelli, L.; Fremeaux-Bacchi, V.; Roumenina, L.T. Complement activation by heme as a secondary hit for atypical hemolytic uremic syndrome. Blood 2013, 122, 282–292.
  55. Roumenina, L.T.; Radanova, M.; Atanasov, B.P.; Popov, K.T.; Kaveri, S.V.; Lacroix-Desmazes, S.; Frémeaux-Bacchi, V.; Dimitrov, J.D. Heme interacts with C1q and inhibits the classical complement pathway. J. Biol. Chem. 2011, 286, 16459–16469.
  56. Zille, M.; Oses-Prieto, J.A.; Savage, S.R.; Karuppagounder, S.S.; Chen, Y.; Kumar, A.; Morris, J.H.; Scheidt, K.A.; Burlingame, A.L.; Ratan, R.R. Hemin-Induced Death Models Hemorrhagic Stroke and Is a Variant of Classical Neuronal Ferroptosis. J. Neurosci. 2022, 42, 2065–2079.
  57. Zille, M.; Karuppagounder, S.S.; Chen, Y.; Gough, P.J.; Bertin, J.; Finger, J.; Milner, T.A.; Jonas, E.A.; Ratan, R.R. Neuronal Death after Hemorrhagic Stroke in Vitro and in Vivo Shares Features of Ferroptosis and Necroptosis. Stroke 2017, 48, 1033–1043.
  58. Gatidis, S.; Föller, M.; Lang, F. Hemin-induced suicidal erythrocyte death. Ann. Hematol. 2009, 88, 721–726.
  59. Sahoo, N.; Yang, K.; Coburger, I.; Bernert, A.; Swain, S.M.; Gessner, G.; Kappl, R.; Kühl, T.; Imhof, D.; Hoshi, T.; et al. Intracellular hemin is a potent inhibitor of the voltage-gated potassium channel Kv10.1. Sci. Rep. 2022, 12, 14645.
  60. Burton, M.J.; Kapetanaki, S.M.; Chernova, T.; Jamieson, A.G.; Dorlet, P.; Santolini, J.; Moody, P.C.E.; Mitcheson, J.S.; Davies, N.W.; Schmid, R.; et al. A heme-binding domain controls regulation of ATP-dependent potassium channels. Proc. Natl. Acad. Sci. USA 2016, 113, 3785–3790.
  61. Balwani, M.; Desnick, R.J. The porphyrias: Advances in diagnosis and treatment. Blood 2012, 120, 4496–4504.
  62. Bergmann, A.K.; Campagna, D.R.; McLoughlin, E.M.; Agarwal, S.; Fleming, M.D.; Bottomley, S.S.; Neufeld, E.J. Systematic molecular genetic analysis of congenital sideroblastic anemia: Evidence for genetic heterogeneity and identification of novel mutations. Pediatr. Blood Cancer 2010, 54, 273–278.
  63. Tolosano, E.; Chiabrando, D. Diamond Blackfan anemia at the crossroad between ribosome biogenesis and heme metabolism. Adv. Hematol. 2010, 2010, 790632.
  64. Flygare, J.; Karlsson, S. Diamond-Blackfan anemia: Erythropoiesis lost in translation. Blood 2007, 109, 3152–3160.
  65. Larsen, R.; Gozzelino, R.; Jeney, V.; Tokaji, L.; Bozza, F.A.; Japiassú, A.M.; Bonaparte, D.; Cavalcante, M.M.; Chora, Â.; Ferreira, A.; et al. A central role for free heme in the pathogenesis of severe sepsis. Sci. Transl. Med. 2010, 2, 51ra71.
  66. Larsen, R.; Gouveia, Z.; Soares, M.P.; Gozzelino, R. Heme cytotoxicity and the pathogenesis of immune-mediated inflammatory diseases. Front. Pharmacol. 2012, 3, 77.
  67. Chiabrando, D.; Fiorito, V.; Petrillo, S.; Tolosano, E. Unraveling the Role of Heme in Neurodegeneration. Front. Neurosci. 2018, 12, 712.
  68. Wagner, K.R.; Sharp, F.R.; Ardizzone, T.D.; Lu, A.; Clark, J.F. Heme and Iron Metabolism: Role in Cerebral Hemorrhage. J. Cereb. Blood Flow Metab. 2003, 23, 629–652.
  69. Koudo, R.; Kurokawa, H.; Sato, E.; Igarashi, J.; Uchida, T.; Sagami, I.; Kitagawa, T.; Shimizu, T. Spectroscopic characterization of the isolated heme-bound PAS-B domain of neuronal PAS domain protein 2 associated with circadian rhythms. FEBS J. 2005, 272, 4153–4162.
  70. Doré, S.; Takahashi, M.; Ferris, C.D.; Zakhary, R.; Hester, L.D.; Guastella, D.; Snyder, S.H. Bilirubin, formed by activation of heme oxygenase-2, protects neurons against oxidative stress injury. Proc. Natl. Acad. Sci. USA 1999, 96, 2445–2450.
  71. Guo, Y.; Zhao, H.; Lin, Z.; Ye, T.; Xu, D.; Zeng, Q. Heme in Cardiovascular Diseases: A Ubiquitous Dangerous Molecule Worthy of Vigilance. Front. Cell Dev. Biol. 2022, 9, 781839.
  72. Sawicki, K.T.; Chang, H.C.; Ardehali, H. Role of heme in cardiovascular physiology and disease. J. Am. Heart Assoc. 2015, 4, e001138.
  73. Gavriilaki, E.; Brodsky, R.A. Complementopathies and precision medicine. J. Clin. Investig. 2020, 130, 2152–2163.
  74. Noris, M.; Galbusera, M. The complement alternative pathway and hemostasis. Immunol. Rev. 2023, 313, 139–161.
  75. Dreismann, A.K.; Hallam, T.M.; Tam, L.C.S.; Nguyen, C.V.; Hughes, J.P.; Ellis, S.; Harris, C.L. Gene targeting as a therapeutic avenue in diseases mediated by the complement alternative pathway. Immunol. Rev. 2023, 313, 402–419.
  76. Risitano, A.M.; Frieri, C.; Urciuoli, E.; Marano, L. The complement alternative pathway in paroxysmal nocturnal hemoglobinuria: From a pathogenic mechanism to a therapeutic target. Immunol. Rev. 2023, 313, 262–278.
  77. Merle, N.S.; Paule, R.; Leon, J.; Daugan, M.; Robe-Rybkine, T.; Poillerat, V.; Torset, C.; Frémeaux-Bacchi, V.; Dimitrov, J.D.; Roumenina, L.T. P-selectin drives complement attack on endothelium during intravascular hemolysis in TLR-4/heme-dependent manner. Proc. Natl. Acad. Sci. USA 2019, 116, 6280–6285.
  78. Hopp, M.T.; Imhof, D. Linking labile heme with thrombosis. J. Clin. Med. 2021, 10, 427.
  79. Armento, A.; Ueffing, M.; Clark, S.J. The complement system in age-related macular degeneration. Cell. Mol. Life Sci. 2021, 78, 4487–4505.
  80. Geerlings, M.J.; de Jong, E.K.; den Hollander, A.I. The complement system in age-related macular degeneration: A review of rare genetic variants and implications for personalized treatment. Mol. Immunol. 2017, 84, 65–76.
  81. Sato, Y.; Falcone-Juengert, J.; Tominaga, T.; Su, H.; Liu, J. Remodeling of the Neurovascular Unit Following Cerebral Ischemia and Hemorrhage. Cells 2022, 11, 2823.
  82. Dalakas, M.C.; Alexopoulos, H.; Spaeth, P.J. Complement in neurological disorders and emerging complement-targeted therapeutics. Nat. Rev. Neurol. 2020, 16, 601–617.
  83. Singhrao, S.; Neal, J.; Morgan, B.; Gasque, P. Increased Complement Biosynthesis By Microglia and Complement Activation on Neurons in Huntington’s Disease. Exp. Neurol. 1999, 159, 362–376.
  84. Hvidberg, V.; Maniecki, M.B.; Jacobsen, C.; Højrup, P.; Møller, H.J.; Moestrup, S.K. Identification of the receptor scavenging hemopexin-heme complexes. Blood 2005, 106, 2572–2579.
  85. Ascenzi, P.; Bocedi, A.; Visca, P.; Altruda, F.; Tolosano, E.; Beringhelli, T.; Fasano, M. Hemoglobin and heme scavenging. IUBMB Life 2005, 57, 749–759.
  86. Nauta, A.J.; Trouw, L.A.; Daha, M.R.; Tijsma, O.; Nieuwland, R.; Schwaeble, W.J.; Gingras, A.R.; Mantovani, A.; Hack, E.C.; Roos, A. Direct binding of C1q to apoptotic cells and cell blebs induces complement activation. Eur. J. Immunol. 2002, 32, 1726–1736.
  87. Navratil, J.S.; Watkins, S.C.; Wisnieski, J.J.; Ahearn, J.M. The Globular Heads of C1q Specifically Recognize Surface Blebs of Apoptotic Vascular Endothelial Cells. J. Immunol. 2001, 166, 3231–3239.
  88. Liszewski, M.K.; Atkinson, J.P. Alternative pathway activation: Ever ancient and ever new. Immunol. Rev. 2022, 313, 60–63.
  89. Harrison, R.A.; Harris, C.L.; Thurman, J.M. The complement alternative pathway in health and disease—Activation or amplification? Immunol. Rev. 2022, 313, 6–14.
  90. Shaughnessy, J.; Chabeda, A.; Lewis, L.A.; Ram, S. Alternative pathway amplification and infections. Immunol. Rev. 2023, 313, 162–180.
  91. de Boer, E.C.; Thielen, A.J.; Langereis, J.D.; Kamp, A.; Brouwer, M.C.; Oskam, N.; Jongsma, M.L.; Baral, A.J.; Spaapen, R.M.; Zeerleder, S.; et al. The contribution of the alternative pathway in complement activation on cell surfaces depends on the strength of classical pathway initiation. Clin. Transl. Immunol. 2023, 12, e1436.
  92. Lo, M.W.; Amarilla, A.A.; Lee, J.D.; Albornoz, E.A.; Modhiran, N.; Clark, R.J.; Ferro, V.; Chhabra, M.; Khromykh, A.A.; Watterson, D.; et al. SARS-CoV-2 triggers complement activation through interactions with heparan sulfate. Clin. Transl. Immunol. 2022, 11, e1413.
  93. Boussier, J.; Yatim, N.; Marchal, A.; Hadjadj, J.; Charbit, B.; El Sissy, C.; Carlier, N.; Pène, F.; Mouthon, L.; Tharaux, P.L.; et al. Severe COVID-19 is associated with hyperactivation of the alternative complement pathway. J. Allergy Clin. Immunol. 2022, 149, 550–556.e2.
  94. Clausen, T.M.; Sandoval, D.R.; Spliid, C.B.; Pihl, J.; Perrett, H.R.; Painter, C.D.; Narayanan, A.; Majowicz, S.A.; Kwong, E.M.; McVicar, R.N.; et al. SARS-CoV-2 Infection Depends on Cellular Heparan Sulfate and ACE2. Cell 2020, 183, 1043–1057.e15.
  95. Zheng, Y.; Zhao, J.; Li, J.; Guo, Z.; Sheng, J.; Ye, X.; Jin, G.; Wang, C.; Chai, W.; Yan, J.; et al. SARS-CoV-2 spike protein causes blood coagulation and thrombosis by competitive binding to heparan sulfate. Int. J. Biol. Macromol. 2021, 193, 1124–1129.
  96. Loeven, M.A.; Rops, A.L.; Berden, J.H.; Daha, M.R.; Rabelink, T.J.; van der Vlag, J. The role of heparan sulfate as determining pathogenic factor in complement factor H-associated diseases. Mol. Immunol. 2015, 63, 203–208.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/)
ScholarVision Creations
Feedback