Archives

  • 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-07
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • br Heme and the HO

    2021-09-13


    Heme and the HO system Heme, a complex of iron and protoporphyrin IX, has versatile functions, which are critical for the survival of all aerobic organisms including mammalians and bacteria [9]. The central iron in heme facilitates six ligand binding sites [10], four of which are occupied by nitrogen atoms of the tetrapyrrole ring. The remaining two binding sites can be occupied by specific 5 03 of proteins [11] or by gases such as oxygen, nitric oxide and carbon monoxide (CO) [12]. Heme as the prosthetic group of hemoglobin (Hb) and myoglobin is crucially involved in transport and storage of oxygen, respectively. Moreover, heme serves critical functions in numerous other hemoproteins to mediate fundamental cellular processes such as electron transfer of the respiratory chain, drug metabolism, oxidase and peroxidase enzyme reactions [13], [14]. It has been proposed that most mammalian cells may contain a ‘committed’ heme pool, where heme is covalently or non-covalently bound to hemoproteins, and a labile ‘regulatory’ heme pool, which is available for trafficking within the cell [15]. Thus, specific heme transporters and chaperones are necessary to harness the oxidative properties, while distributing heme to the various cellular apo-hemoproteins [16], [17]. Intracellular heme can be acquired via de novo synthesis from glycine and succinyl CoA by multi-enzymatic conversion [18]. Because of its redox capability heme is crucial as a prosthetic group in mitochondrial respiratory chain complexes. Alternatively, heme can be exported via the mitochondrial heme exporter feline leukemia virus subgroup C receptor (Flvcr) 1b [19], which allows trafficking within the cell to virtually all other subcellular compartments and organelles via distinct cellular routes [15], [17]. Moreover, heme can also be exported from the cell via breast cancer resistance protein and Flvcr1a [16], [20]. Heme up-take from the extracellular compartment is mediated by heme importers, such as heme carrier protein 1 (HCP1) and Flvcr2. Extracellular heme can be derived from the diet, which is taken up by enterocytes in the intestine via specific transporter molecules, including the heme importer HCP1 [21]. A small portion of this heme will be exported from the cell [17]. Hemopexin and, to a lesser extent, albumin binds heme and transfers it to other cells and tissues. There are many different heme importers and exporters underscoring the importance of intra- and extra-cellular heme trafficking [16], [17]. In human, approximately 80% of heme is present in erythrocytes, 15% in liver and 5% in non-erythroid cells of other tissues [22]. Heme of erythrocytes is ultimately recycled in the reticuloendothelial system of the spleen and liver [23], [24]. Notably, HO, which enzymatically degrades heme into equimolar amounts of CO, iron and biliverdin, plays a critical role in this process [25]. Biliverdin, in turn is enzymatically converted to bilirubin via biliverdin reductase [26]. In physiological conditions the highest HO-activity is detected in cells and tissues, which are involved in the removal of senescent erythrocytes [27], [28], [29]. Two different isoforms of HO are known: an inducible isoform, HO-1, and a constitutive isoform, HO-2 [30], [31]. Interestingly, heme synthesis is intimately intertwined with heme degradation. To meet the high demand of iron for Hb synthesis, erythrocytes are able to utilize iron from HO-degraded heme [32].
    The heme-HO system in macrophages
    Regulation of HO-1 gene expression HO-1 is transcriptionally up-regulated by a plethora of stimuli, which activate numerous signaling cascades and transcriptional factors (TFs). TFs such as AP-1 and NF-kB, which are critical for stress- and inflammation-dependent gene induction, along with a number of other nuclear factors have been shown to activate HO-1 gene expression [95], [96], [97], [98], [99], [100]. The complex mechanisms how these TFs act in concert to up-regulate HO-1 for a given stimulus have been reviewed elsewhere [29], [101], [102], [103]. Second messengers such as nitric oxide (NO) [104] and the prostaglandin 15-deoxy-Δ12,14-prostaglandin J2 (15dPGJ2) can also induce HO-1 gene expression in macrophages [105]. In the following, a brief summary on the basic principles of HO-1 gene regulation via its substrate heme, and the specific role of the mutual interplay of the nuclear factor NF-E2-related factor 2 (NRF2) and BTB and CNC homology 1 (BACH1) will be given. However, it should be pointed out that heme-mediated induction of HO-1 in macrophages is not restricted to the NRF2/BACH1 system, but activating transcriptional factor 1 (ATF1) has also been implicated in this regulation [91].