Special issue on hypoxia

Yeo Experimental & Molecular Medicine (2019) 51:69 https://doi.org/10.1038/s12276-019-0257-8 EDITORIAL Experimental & Molecular Medicine Open Access Special issue on hypoxia 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; Eui-Ju Yeo1 The critical roles of oxygen (O2) in aerobic respiration and metabolism are indisputable. Oxygen acts as the final electron acceptor in the mitochondrial electron transport chain to generate ATP within eukaryotic cells1. Therefore, an adequate concentration of oxygen is required by eukaryotic cells to maintain a variety of biological activities and ensure survival. When oxygen levels in the whole body or local tissues are severely reduced, hypoxia occurs, leading to a metabolic crisis and threatening physiological functions and viability. Because of the importance of oxygen, eukaryotes have developed an efficient and rapid oxygen-sensing system: hypoxia-inducible factors (HIFs)2. Hypoxic responses are controlled by HIF stabilization, which induces the expression of more than 100 downstream target genes to increase the oxygen supply and support anaerobic ATP generation in eukaryotic cells. Over the past two decades, HIF isotypes and their functions, and binding factors/coactivators, and the regulatory mechanisms by which cells sense hypoxia and transduce a signal to the HIF pathway have been intensively studied by many researchers and expanded our knowledge of hypoxia to the cellular and molecular levels. The HIF pathway is summarized in the introduction section of the review by Holger K. Eltzschig’s group (The University of Texas Health Science Center) and in the first section (“Hypoxia and the HIF pathway”) of the review by Eui-Ju Yeo (Gachon University). In humans, oxygen is exchanged in the alveoli of the lungs. Over 95% of the oxygen delivered into the capillary vessels binds to hemoglobin. The heart pumps blood containing oxygenated hemoglobin, which is crucial for the biological function of organs and cells, to the periphery. Any failure during this process can cause hypoxia in organs and cells. Interestingly, hypoxia and tissue inflammation are closely related to each other in various organ injuries3,4. Hypoxia can activate the nuclear factor κB (NF-κB) pathway, an HIF-independent signaling Correspondence: Eui-Ju Yeo () 1 Department of Biochemistry, College of Medicine, Gachon University, Incheon 21999, South Korea pathway. IκBα is phosphorylated during hypoxia, resulting in the degradation of IκBα and the activation of NF-κB5. In fact, many studies demonstrate that while hypoxia causes tissue inflammation, HIF stabilization can reduce tissue inflammation and promote its repair6–8. HIF may elicit the upregulation of transcriptional cascades important for tissue protection and adaptation. The HIF-driven adenosine signaling pathway is well-known to serve as a protective mechanism and provide ischemic tolerance in tissues exposed to acute hypoxia6,9. Upon hypoxic cellular and tissue injury, stabilized HIF1A binds to the promoter region of ecto-5′-nucleotidase (CD73) and increases the CD73 enzyme levels, resulting in increases in the levels of extracellular adenosine and ATP/ADP10. Extracellular adenosine can act directly as a signaling molecule working through adenosine receptors. Adenosine receptors 2B and 2A are direct targets of HIF1A and HIF2A, respectively11. Indeed, increasing extracellular adenosine levels by the inhibition of equilibrative nucleoside transporters results in protection from inflammation12. Due to the undisputed biological importance and protective function of HIF and its downstream targets, hypoxia and the HIF signaling pathways are emerging as novel therapeutic options to treat various organ injuries. The review by Holger K. Eltzschig’s group highlights the current understanding of hypoxia signaling in different human diseases related to four different organ systems: the heart, lung, liver, and kidney. This review also discusses the divergent roles of HIFs in acute and chronic disease conditions in these four organ systems. In general, HIF stabilization by preconditioning/postconditioning or pharmacologic intervention confers a protective phenotype across all organs during acute conditions, as shown in various in vivo studies and human clinical trials. However, modulating the HIF pathway in chronic disease conditions seems to be more complex than in acute conditions, because the effects of HIF stabilization are controversial in different studies. Nonetheless, targeting the HIF signaling pathway in chronic disease conditions still holds promise in effectively managing or delaying the © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Official journal of the Korean Society for Biochemistry and Molecular Biology Yeo Experimental & Molecular Medicine (2019) 51:69 progression of disease. Finally, the review introduces some efforts to translate current knowledge about hypoxia signaling to clinical medicine. As our understanding of the pathophysiology of diseases and its relation to hypoxia signaling deepens, it will be possible to discover additional therapeutic targets and niches for intervention. Hypoxia also contributes to functional decline during the aging process. The putative molecular mechanisms underlying the effects of hypoxia and HIF-1α on aging are discussed in the section “HIF-1α and aging” of the review by Eui-Ju Yeo. This section includes a discussion of crosstalk between HIF pathways and aging-associated signaling proteins, such as sirtuins, AMP-activated protein kinase, mechanistic target of rapamycin complex 1, UNC-51-like kinase 1, and NF-κB, in aging and aging-related diseases13–16. In recent years, the effects of prenatal hypoxia and obstructive sleep apnea (OSA) have garnered interest due to their effect on accelerating the progression and increasing the severity of many diseases. Prenatal hypoxia leads to insufficient oxygen supply to the fetus during critical periods of brain development, which is one of the most important factors manifesting in early aging, mental retardation, and cognitive deficits at various postnatal stages17. An OSA, characterized by repeated epis (...truncated)