Oxygen‐sensing mechanisms in cells

Abstract

The importance of oxygen for the survival of multicellular and aerobic organisms is well established and documented. Over the years, increased knowledge of its use for bioenergetics has placed oxygen at the centre of research on mitochondria and ATP‐generating processes. Understanding the molecular mechanisms governing cellular oxygen sensing and response has allowed for the discovery of novel pathways oxygen is involved in, culminating with the award of the Nobel Prize for Medicine and Physiology in 2019 to the pioneers of this field, Greg Semenza, Peter Ratcliffe and William Kaelin. However, it is now beginning to be appreciated that oxygen can be a signalling molecule involved in a vast array of molecular processes, most of which impinge on gene expression control. This review will focus on the knowns and unknowns of oxygen as a signalling molecule, highlighting the role of 2‐oxoglutarate‐dependent dioxygenases as central players in the cellular response to deviations in oxygen tension.

The Role of Sumoylation in the Response to Hypoxia: An Overview

“…Multicellular organisms have evolved homeostatic mechanisms in order to maintain cellular and tissue function upon changes of oxygen tension. Exposure of human tissues or cells to reduced oxygen concentration (a condition known as hypoxia) is encountered both during physiological (e.g., high altitude, intense exercise and embryogenesis) and pathological processes (e.g., ischemia and cancer) [71][72][73]. Hypoxia promotes dramatic reprogramming of gene expression followed by a cascade of events including switching to anaerobic production of energy, modulation of lipid metabolism, increased transport and delivery of oxygen, invasion and metastasis (in the case of cancer cells), which, overall, facilitate adaptation and survival of cells in the hypoxic environment [74][75][76].…”

Roles Of HIF and 2-Oxoglutarate Dependent Enzymes in Controlling Gene Expression In Hypoxia

“…Some mRNAs contain an RNA HRE (rHRE), a sequence which can recruit an alternative initiation complex for selective cap-dependent translation [44]. This complex involves HIF-2α, one of [11][12][13]). However, this is still a vastly unexplored aspect of the hypoxia response.…”

“…In recent years, non-HIF targets have been identified to be hydroxylated on prolines by PHDs (reviewed in [13]), resulting in their degradation and/or changes to downstream activity including Centrosomal Protein 192 (CEP192) [90] and Forkhead Box O3 (FOXO3) [91] by PHD1, Actin Beta (ACTB) by PHD3 [92], and AKT Serine/Threonine Kinase 1 (AKT1) by PHD2 [93]. Interestingly, a new study indicated that prolyl-hydroxylation could be crucial for GMGC kinase activation [94].…”

“…There are now thousands of identified hypoxia responsive genes and over 100 validated HIF target genes, with over a thousand putative targets, and all classes of RNAs can be induced by low oxygen (reviewed in [11]). The discovery of hypoxia responsive genes and HIF targets has been driven greatly by transcript profiling and genome occupancy technologies, including microarrays, RNA-seq and ChIPseq (reviewed in [12][13][14]). These and analyses of publicly available transcriptional datasets [15,16] [12][13][14]17]).…”

Roles of HIF and 2-Oxoglutarate-Dependent Dioxygenases in Controlling Gene Expression in Hypoxia

“…Genetic models in several model organisms have helped identify the key roles of HIFs as well as 2-OGDs in development and disease ( Table 2 ; Supplementary Table S2 ). Furthermore, genome wide mapping techniques such as chromatin immunoprecipitation followed by sequencing (ChIP-seq), RNA sequencing (RNA-seq), and Chromatin capture have more recently been used to better understand how cells responds to changes in oxygen, but also in response to 2-OGD inhibition ([ 13 , 14 ] and reviewed in [ 15 , 16 ]).…”