Guest editorial: hypoxia biology in health and disease

Abstract

In adult tissues, normal partial oxygen pressure is around 2–9 % (14–65 mmHg) [1], substantially lower than inhaled ambient oxygen tensions of 21 % (160 mmHg). Such low oxygen conditions do not compromise the activity of the mitochondrial respiratory chain, which retains its great potential to produce cellular energy ATP, and are, therefore, considered physiologically normoxic in this context. However, certain types of cells, such as kidney medulla, bone marrow, and pericentral hepatocytes, are exposed to even lower oxygen tensions (10–25 mmHg, physiological hypoxia) in physiological conditions, suggesting that appropriate oxygen concentrations varies by cell and tissue type and environment. Disease conditions such as cancer, ischemic heart disease, and obstructive pulmonary disease may, in contrast, impair the balance between oxygen supply and demand, exposing the affected cells and tissues to severely low oxygen conditions (pathological hypoxia) [2]. As such, cells in the body experience a wide range of oxygen tensions in physiological and pathological conditions and are, therefore, equipped to sense and respond to changes in oxygen concentration. Hypoxia-inducible factor (HIF) is a key transcription factor responsible for hypoxic responses, and consists of two distinct subunits: an oxygen-sensitive a subunit, and a constitutively expressed b subunit. HIF-1 is first described by Semenza and colleagues [3] as an inducer of erythropoietin gene expression in response to hypoxia; this discovery accelerated and expanded research into hypoxia biology dramatically. It has been reported that there are three HIFa isoforms in mammalian cells; of these, HIF-1a and HIF-2a have been extensively studied [4]. HIFs have been reported to play central roles in the adaptive response to hypoxic stress through the activation of genes involved in angiogenesis, erythropoiesis, energy metabolism, cell proliferation, and differentiation [5]. Much insight into the roles of HIFs have been gained from cancer research, and these have recently led to a better understanding of unexpected HIF functions in other pathological (e.g., ischemia heart disease, inflammation, diabetes, fatty liver) and physiological conditions, revealing a greater complexity of HIF-mediated regulations in isoform-, cell typeand context-specific manner than had previously been thought. In addition, central molecular mechanisms underlying the oxygen-mediated instability of HIFa have revealed a novel class of 2-oxoglutarate-dependent iron (II)-dioxygenases (e.g., PHD and FIH) as critical regulators of HIFa in the oxygen-sensing system [6]. In conjunction with the discovery of the molecular basis for VHL-dependent HIFa degradation [7], HIF transcriptional activity has been shown to be regulated largely at its protein levels by cellular oxygen concentrations. However, the biochemical properties of these enzyme reactions also suggest that the oxygen-dependent hydroxylation modification transmits clues not only of environmental oxygen concentrations, but also cellular metabolic and redox status of the nucleus, suggesting an intimate crosstalk between oxygen, cellular N. Goda (&) Department of Life Science and Medical BioScience, School of Advanced Science and Engineering, Waseda University, TWIns Room 02C218, 2-2 Wakamatsu-cho, Shinjuku-ku, Tokyo 162-8480, Japan e-mail: goda@waseda.jp