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Systems biology of oxygen homeostasis

Advanced Review

Gregg L. Semenza, Nanduri R. Prabhakar, Debangshu Samanta

Published Online: Feb 21 2017

DOI: 10.1002/wsbm.1382

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Metazoan species maintain oxygen homeostasis through the activity of hypoxia‐inducible factors, which are transcriptional activators that regulate the expression of hundreds of genes to match O2 supply and demand. Here, we review the involvement of hypoxia‐inducible factors in the molecular physiology and pathophysiology of cellular O2 sensing, O2 delivery, O2 utilization, and systemic O2 sensing. WIREs Syst Biol Med 2017, 9:e1382. doi: 10.1002/wsbm.1382 This article is categorized under: Biological Mechanisms > Metabolism Physiology > Mammalian Physiology in Health and Disease Physiology > Organismal Responses to Environment

O₂ sensing and signaling by gas messengers in the carotid body. O₂ stimulates CO production, which inhibits H₂S production, thereby inhibiting glomus cell depolarization. ROS generated by CIH inhibit HO2 activity, probably by oxidation of Cys‐265, thereby increasing H₂S production and CSN activity. cGMP, cyclic GMP; CIH, chronic intermittent hypoxia; CSE, cystathionine–γ‐lyase; CSN, carotid sinus nerve; Cys‐265, cysteine residue 265; HO2, heme oxygenase 2; Homocys, homocysteine; PKG, cGMP‐dependent protein kinase; ROS, reactive oxygen species; sGC, soluble guanylate cyclase.

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Neural transmission of reflex arcs that result in changes in heart rate (HR), respiratory rate (RR), and blood pressure (BP) in response to depolarization of glomus cells in the carotid body (CB). AM, adrenal medulla; ASN, adrenal sympathetic nerve; CSN, carotid sinus nerve; CST, corticospinal tract; Epi, epinephrine; NE, norepinephrine; nTS, nucleus tractus solitarius; RVLM, rostral ventro‐lateral medulla; SG, sympathetic ganglion.

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Oxygen‐dependent regulation of antioxidant production by HIF‐1 in human breast cancer cells. Under hypoxic conditions, HIFs activate the transcription of PHGDH, PSAT1, and PSPH (red) to increase conversion of glucose to serine (serine synthesis pathway); and SHMT2, MTHFD2, and MTHFD1L (blue) to increase generation of mitochondrial NADPH (mitochondrial one‐carbon metabolism), which is required to convert glutathione from oxidized (GSSG) to reduced (GSH) form to protect against increased ROS generated by the electron transport chain (ETC). Genes encoding proteins that generate cytosolic NADPH are either not consistently induced [SHMT1, MTHFD1 (purple)] or actively repressed [G6PD (green)] under hypoxic conditions. G6PD, glucose‐6‐phosphate dehydrogenase; MTHFD, methylene tetrahydrofolate dehydrogenase; MTHFD1L, MTHFD1‐like; PHGDH, phosphoglycerate dehydrogenase; PSAT, phosphoserine aminotransferase; PSPH, phosphoserine phosphatase; SHMT, serine hydroxymethyltransferase.

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Oxygen‐dependent regulation of oxidant production by hypoxia‐inducible factor (HIF)‐1. In hypoxic cells, HIF‐1 suppresses glucose oxidation, by activating the transcription of LDHA and PDK1 (blue), and fatty acid oxidation, by repressing the expression of MCAD and LCAD (green). In addition, under hypoxic conditions, HIF‐1 activates the transcription of BNIP3 (blue) to induce mitochondrial‐selective autophagy and thereby suppress both glucose and fatty acid oxidation. BNIP3, BCL2/adenovirus E1B 19‐kDa protein‐interacting protein 3; LCAD, long‐chain acyl‐CoA dehydrogenase; LDHA, lactate dehydrogenase A; MCAD, medium‐chain acyl‐CoA dehydrogenase; and PDK1, pyruvate dehydrogenase kinase 1.

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The hypoxia‐inducible factor (HIF) target genes VEGFA and ANGPTL4 encode secreted proteins that mediate angiogenesis and vascular permeability that leads to proliferative retinopathy and macular edema, respectively. Vascular endothelial growth factor A (VEGFA) binds to VEGFR2 on retinal vascular endothelial cells (VECs); the receptor for ANGPTL4 on retinal VECs has not been identified. Drugs inhibiting VEGFA binding to VEGFR2 on VECs are used to treat ocular diseases; inhibition of HIF activity or ANGPTL4 binding to its receptor on retinal VECs may also have therapeutic utility.

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Hypoxia‐inducible factor (HIF)‐1 and HIF‐2 are master regulators of tissue vascularization. Eight genes activated by HIF‐1 and HIF‐2 encode secreted proteins (blue ovals) that bind to cognate receptors (red ovals) on vascular cells to stimulate angiogenesis and vascular remodeling in response to hypoxia/ischemia.

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Hypoxia‐inducible factor (HIF)‐2 is a master regulator of erythropoiesis. Eight genes activated by HIF‐2 encode protein products that are required for iron absorption, transport, and incorporation into hemoglobin for red blood cell production. CYBRD1, SLC11A2, and SLC40A1 are expressed in duodenal enterocytes; TF is expressed in hepatocytes; EPO is expressed in renal interstitial cells; EPOR, FECH, and TFRC are expressed in erythroid progenitors.

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O₂‐dependent hydroxylation of hypoxia‐inducible factor (HIF)‐α subunits. Hydroxylation of specific proline (Pro) and asparagine (Asn) residues promote von Hippel‐Lindau (VHL) binding and block P300/CBP binding, respectively. VHL recruits an E3‐ubiquitin protein ligase (BCCRE2) consisting of Elongin B, Elongin C, Cullin 2, RBX1, and an E2 ubiquitin ligase that ubiquitinates HIF‐α, thereby targeting the protein for proteasomal degradation.

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Chronic intermittent hypoxia disrupts redox and HIF balance, leading to sympathetic activation and hypertension. HIF, hypoxia‐inducible factor; mTOR, mammalian target of rapamycin; NOX, NADPH oxidase; PKC, Ca²⁺‐dependent protein kinase; SOD, superoxide dismutase.

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Oxygen homeostasis
Gregg L. Semenza
Published Online: April 09 2010
DOI: 10.1002/wsbm.69

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