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Nature Reviews. Nephrology Sep 2022Cellular hypoxia occurs when the demand for sufficient molecular oxygen needed to produce the levels of ATP required to perform physiological functions exceeds the... (Review)
Review
Cellular hypoxia occurs when the demand for sufficient molecular oxygen needed to produce the levels of ATP required to perform physiological functions exceeds the vascular supply, thereby leading to a state of oxygen depletion with the associated risk of bioenergetic crisis. To protect against the threat of hypoxia, eukaryotic cells have evolved the capacity to elicit oxygen-sensitive adaptive transcriptional responses driven primarily (although not exclusively) by the hypoxia-inducible factor (HIF) pathway. In addition to the canonical regulation of HIF by oxygen-dependent hydroxylases, multiple other input signals, including gasotransmitters, non-coding RNAs, histone modifiers and post-translational modifications, modulate the nature of the HIF response in discreet cell types and contexts. Activation of HIF induces various effector pathways that mitigate the effects of hypoxia, including metabolic reprogramming and the production of erythropoietin. Drugs that target the HIF pathway to induce erythropoietin production are now approved for the treatment of chronic kidney disease-related anaemia. However, HIF-dependent changes in cell metabolism also have profound implications for functional responses in innate and adaptive immune cells, and thereby heavily influence immunity and the inflammatory response. Preclinical studies indicate a potential use of HIF therapeutics to treat inflammatory diseases, such as inflammatory bowel disease. Understanding the links between HIF, cellular metabolism and immunity is key to unlocking the full therapeutic potential of drugs that target the HIF pathway.
Topics: Cell Hypoxia; Erythropoietin; Humans; Hypoxia; Kidney; Oxygen
PubMed: 35726016
DOI: 10.1038/s41581-022-00587-8 -
Nature Reviews. Molecular Cell Biology May 2020Molecular oxygen (O) sustains intracellular bioenergetics and is consumed by numerous biochemical reactions, making it essential for most species on Earth. Accordingly,... (Review)
Review
Molecular oxygen (O) sustains intracellular bioenergetics and is consumed by numerous biochemical reactions, making it essential for most species on Earth. Accordingly, decreased oxygen concentration (hypoxia) is a major stressor that generally subverts life of aerobic species and is a prominent feature of pathological states encountered in bacterial infection, inflammation, wounds, cardiovascular defects and cancer. Therefore, key adaptive mechanisms to cope with hypoxia have evolved in mammals. Systemically, these adaptations include increased ventilation, cardiac output, blood vessel growth and circulating red blood cell numbers. On a cellular level, ATP-consuming reactions are suppressed, and metabolism is altered until oxygen homeostasis is restored. A critical question is how mammalian cells sense oxygen levels to coordinate diverse biological outputs during hypoxia. The best-studied mechanism of response to hypoxia involves hypoxia inducible factors (HIFs), which are stabilized by low oxygen availability and control the expression of a multitude of genes, including those involved in cell survival, angiogenesis, glycolysis and invasion/metastasis. Importantly, changes in oxygen can also be sensed via other stress pathways as well as changes in metabolite levels and the generation of reactive oxygen species by mitochondria. Collectively, this leads to cellular adaptations of protein synthesis, energy metabolism, mitochondrial respiration, lipid and carbon metabolism as well as nutrient acquisition. These mechanisms are integral inputs into fine-tuning the responses to hypoxic stress.
Topics: Adenosine Triphosphate; Cell Hypoxia; Energy Metabolism; Humans; Mitochondria; Oxidative Stress; Oxygen; Reactive Oxygen Species; Signal Transduction
PubMed: 32144406
DOI: 10.1038/s41580-020-0227-y -
Training-Induced Changes in Mitochondrial Content and Respiratory Function in Human Skeletal Muscle.Sports Medicine (Auckland, N.Z.) Aug 2018A sedentary lifestyle has been linked to a number of metabolic disorders that have been associated with sub-optimal mitochondrial characteristics and an increased risk... (Review)
Review
A sedentary lifestyle has been linked to a number of metabolic disorders that have been associated with sub-optimal mitochondrial characteristics and an increased risk of premature death. Endurance training can induce an increase in mitochondrial content and/or mitochondrial functional qualities, which are associated with improved health and well-being and longer life expectancy. It is therefore important to better define how manipulating key parameters of an endurance training intervention can influence the content and functionality of the mitochondrial pool. This review focuses on mitochondrial changes taking place following a series of exercise sessions (training-induced mitochondrial adaptations), providing an in-depth analysis of the effects of exercise intensity and training volume on changes in mitochondrial protein synthesis, mitochondrial content and mitochondrial respiratory function. We provide evidence that manipulation of different exercise training variables promotes specific and diverse mitochondrial adaptations. Specifically, we report that training volume may be a critical factor affecting changes in mitochondrial content, whereas relative exercise intensity is an important determinant of changes in mitochondrial respiratory function. As a consequence, a dissociation between training-induced changes in mitochondrial content and mitochondrial respiratory function is often observed. We also provide evidence that exercise-induced changes are not necessarily predictive of training-induced adaptations, we propose possible explanations for the above discrepancies and suggestions for future research.
Topics: Adaptation, Physiological; Cell Respiration; Exercise; Exercise Test; Humans; Mitochondria, Muscle; Muscle, Skeletal; Oxygen Consumption; Physical Conditioning, Human
PubMed: 29934848
DOI: 10.1007/s40279-018-0936-y -
Cell Metabolism Apr 2020NADH provides electrons for aerobic ATP production. In cells deprived of oxygen or with impaired electron transport chain activity, NADH accumulation can be toxic. To...
NADH provides electrons for aerobic ATP production. In cells deprived of oxygen or with impaired electron transport chain activity, NADH accumulation can be toxic. To minimize such toxicity, elevated NADH inhibits the classical NADH-producing pathways: glucose, glutamine, and fat oxidation. Here, through deuterium-tracing studies in cultured cells and mice, we show that folate-dependent serine catabolism also produces substantial NADH. Strikingly, when respiration is impaired, serine catabolism through methylene tetrahydrofolate dehydrogenase (MTHFD2) becomes a major NADH source. In cells whose respiration is slowed by hypoxia, metformin, or genetic lesions, mitochondrial serine catabolism inhibition partially normalizes NADH levels and facilitates cell growth. In mice with engineered mitochondrial complex I deficiency (NDUSF4-/-), serine's contribution to NADH is elevated, and progression of spasticity is modestly slowed by pharmacological blockade of serine degradation. Thus, when respiration is impaired, serine catabolism contributes to toxic NADH accumulation.
Topics: Animals; Cell Hypoxia; Cell Line; Humans; Mice; Mice, Inbred C57BL; Mice, Nude; Mitochondria; NAD; Oxygen; Serine
PubMed: 32187526
DOI: 10.1016/j.cmet.2020.02.017 -
Biomolecules Jun 2020Effective metabolism is highly dependent on a narrow therapeutic range of oxygen. Accordingly, low levels of oxygen, or hypoxia, are one of the most powerful inducers of... (Review)
Review
Effective metabolism is highly dependent on a narrow therapeutic range of oxygen. Accordingly, low levels of oxygen, or hypoxia, are one of the most powerful inducers of gene expression, metabolic changes, and regenerative processes, including angiogenesis and stimulation of stem cell proliferation, migration, and differentiation. The sensing of decreased oxygen levels (hypoxia) or increased oxygen levels (hyperoxia), occurs through specialized chemoreceptor cells and metabolic changes at the cellular level, which regulate the response. Interestingly, fluctuations in the free oxygen concentration rather than the absolute level of oxygen can be interpreted at the cellular level as a lack of oxygen. Thus, repeated intermittent hyperoxia can induce many of the mediators and cellular mechanisms that are usually induced during hypoxia. This is called the hyperoxic-hypoxic paradox (HHP). This article reviews oxygen physiology, the main cellular processes triggered by hypoxia, and the cascade of events triggered by the HHP.
Topics: Animals; Cell Hypoxia; Humans; Hyperoxia; Oxygen
PubMed: 32630465
DOI: 10.3390/biom10060958 -
Cell Death & Disease Sep 2020Oxygen glucose deprivation/re-oxygenation (OGD/R) induces neuronal injury via mechanisms that are believed to mimic the pathways associated with brain ischemia. In...
Oxygen glucose deprivation/re-oxygenation (OGD/R) induces neuronal injury via mechanisms that are believed to mimic the pathways associated with brain ischemia. In SH-SY5Y cells and primary murine neurons, we report that OGD/R induces the accumulation of the microRNA miR-422a, leading to downregulation of miR-422a targets myocyte enhancer factor-2D (MEF2D) and mitogen-activated protein kinase kinase 6 (MAPKK6). Ectopic miR-422a inhibition attenuated OGD/R-induced cell death and apoptosis, whereas overexpression of miR-422a induced significant neuronal cell apoptosis. In addition, OGD/R decreased the expression of the long non-coding RNA D63785 (Lnc-D63785) to regulate miR-422a accumulation. Lnc-D63785 directly associated with miR-422a and overexpression of Lnc-D63785 reversed OGD/R-induced miR-422a accumulation and neuronal cell death. OGD/R downregulated Lnc-D63785 expression through increased methyltransferase-like protein 3 (METTL3)-dependent Lnc-D63785 m6A methylation. Conversely METTL3 shRNA reversed OGD/R-induced Lnc-D63785 m6A methylation to decrease miR-422a accumulation. Together, Lnc-D63785 m6A methylation by OGD/R causes miR-422a accumulation and neuronal cell apoptosis.
Topics: Animals; Cell Death; Cell Hypoxia; Cell Line, Tumor; DNA Methylation; Glucose; Humans; Mice; MicroRNAs; Neurons; Oxygen; RNA, Long Noncoding; Transfection
PubMed: 32999283
DOI: 10.1038/s41419-020-03021-8 -
Experimental & Molecular Medicine Jun 2019
Topics: Animals; Cell Hypoxia; Humans; Hypoxia; Hypoxia-Inducible Factor 1; Oxygen; Signal Transduction
PubMed: 31221954
DOI: 10.1038/s12276-019-0257-8 -
Clinical Oncology (Royal College of... Nov 2021Regions of reduced oxygenation (hypoxia) are a characteristic feature of virtually all animal and human solid tumours. Numerous preclinical studies, both in vitro and... (Review)
Review
Regions of reduced oxygenation (hypoxia) are a characteristic feature of virtually all animal and human solid tumours. Numerous preclinical studies, both in vitro and in vivo, have shown that decreasing oxygen concentration induces resistance to radiation. Importantly, hypoxia in human tumours is a negative indicator of radiotherapy outcome. Hypoxia also contributes to resistance to other cancer therapeutics, including immunotherapy, and increases malignant progression as well as cancer cell dissemination. Consequently, substantial effort has been made to detect hypoxia in human tumours and identify realistic approaches to overcome hypoxia and improve cancer therapy outcomes. Hypoxia-targeting strategies include improving oxygen availability, sensitising hypoxic cells to radiation, preferentially killing these cells, locating the hypoxic regions in tumours and increasing the radiation dose to those areas, or applying high energy transfer radiation, which is less affected by hypoxia. Despite numerous clinical studies with each of these hypoxia-modifying approaches, many of which improved both local tumour control and overall survival, hypoxic modification has not been established in routine clinical practice. Here we review the background and significance of hypoxia, how it can be imaged clinically and focus on the various hypoxia-modifying techniques that have undergone, or are currently in, clinical evaluation.
Topics: Animals; Cell Hypoxia; Humans; Hypoxia; Neoplasms; Oxygen
PubMed: 34535359
DOI: 10.1016/j.clon.2021.08.014 -
The New Phytologist Jan 2021The major consequence of hypoxia is a dramatic reduction in energy production. At the onset of hypoxia, both oxygen and ATP availability decrease. Oxygen and energy... (Review)
Review
The major consequence of hypoxia is a dramatic reduction in energy production. At the onset of hypoxia, both oxygen and ATP availability decrease. Oxygen and energy sensing therefore converge to induce an adaptive response at both the transcriptional and translational levels. Oxygen sensing results in stabilization of the transcription factors that activate hypoxia-response genes, including enzymes required for efficient sugar metabolism, allowing plants to produce enough energy to ensure survival. The translation of the resulting mRNAs is mediated by SnRK1, acting as an energy sensor. However, as soon as the sugar availability decreases, a homeostatic mechanism, detecting sugar starvation, dampens the hypoxia-dependent transcription to reduce energy consumption and preserves carbon reserves for regrowth when oxygen availability is restored.
Topics: Cell Hypoxia; Hypoxia; Oxygen; Signal Transduction; Sugars; Transcription Factors
PubMed: 31733144
DOI: 10.1111/nph.16326 -
Virology Journal Jul 2020The oxygen levels organ and tissue microenvironments vary depending on the distance of their vasculature from the left ventricle of the heart. For instance, the oxygen... (Review)
Review
The oxygen levels organ and tissue microenvironments vary depending on the distance of their vasculature from the left ventricle of the heart. For instance, the oxygen levels of lymph nodes and the spleen are significantly lower than that in atmospheric air. Cellular detection of oxygen and their response to low oxygen levels can exert a significant impact on virus infection. Generally, viruses that naturally infect well-oxygenated organs are less able to infect cells under hypoxic conditions. Conversely, viruses that infect organs under lower oxygen tensions thrive under hypoxic conditions. This suggests that in vitro experiments performed exclusively under atmospheric conditions ignores oxygen-induced modifications in both host and viral responses. Here, we review the mechanisms of how cells adapt to low oxygen tensions and its impact on viral infections. With growing evidence supporting the role of oxygen microenvironments in viral infections, this review highlights the importance of factoring oxygen concentrations into in vitro assay conditions. Bridging the gap between in vitro and in vivo oxygen tensions would allow for more physiologically representative insights into viral pathogenesis.
Topics: Cell Hypoxia; Humans; Oxygen; Virus Diseases; Viruses
PubMed: 32718318
DOI: 10.1186/s12985-020-01374-2