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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 -
Nature Reviews. Nephrology May 2021Kidney damage varies according to the primary insult. Different aetiologies of acute kidney injury (AKI), including kidney ischaemia, exposure to nephrotoxins,... (Review)
Review
Kidney damage varies according to the primary insult. Different aetiologies of acute kidney injury (AKI), including kidney ischaemia, exposure to nephrotoxins, dehydration or sepsis, are associated with characteristic patterns of damage and changes in gene expression, which can provide insight into the mechanisms that lead to persistent structural and functional damage. Early morphological alterations are driven by a delicate balance between energy demand and oxygen supply, which varies considerably in different regions of the kidney. The functional heterogeneity of the various nephron segments is reflected in their use of different metabolic pathways. AKI is often linked to defects in kidney oxygen supply, and some nephron segments might not be able to shift to anaerobic metabolism under low oxygen conditions or might have remarkably low basal oxygen levels, which enhances their vulnerability to damage. Here, we discuss why specific kidney regions are at particular risk of injury and how this information might help to delineate novel routes for mitigating injury and avoiding permanent damage. We suggest that the physiological heterogeneity of the kidney should be taken into account when exploring novel renoprotective strategies, such as improvement of kidney tissue oxygenation, stimulation of hypoxia signalling pathways and modulation of cellular energy metabolism.
Topics: Acute Kidney Injury; Animals; Cell Hypoxia; Disease Susceptibility; Energy Metabolism; Gene Expression; Humans; Kidney; Mitochondria; Oxygen; PPAR gamma; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
PubMed: 33547418
DOI: 10.1038/s41581-021-00394-7 -
Nature Medicine Oct 2020Insights into the role of the tumor suppressor pVHL in oxygen sensing motivated the testing of drugs that target the transcription factor HIF or HIF-responsive growth... (Review)
Review
Insights into the role of the tumor suppressor pVHL in oxygen sensing motivated the testing of drugs that target the transcription factor HIF or HIF-responsive growth factors, such as VEGF, for the treatment of cancers caused by VHL inactivation, such as clear-cell renal cell carcinoma (ccRCC). Multiple VEGF inhibitors are now approved for the treatment of ccRCC, and a HIF2α inhibitor has advanced to phase 3 development for this disease. These inhibitors are now also increasingly combined with immune-checkpoint blockers. In this Perspective, we describe the understanding of the mechanisms of oxygen sensing and hypoxia signaling that resulted in the development of HIF2α-targeted therapies for patients with VHL-associated tumors. We also present future directions for extending the use of these therapies to other cancers.
Topics: Antineoplastic Agents; Basic Helix-Loop-Helix Transcription Factors; Carcinoma, Renal Cell; Cell Respiration; Gene Expression Regulation, Neoplastic; Humans; Kidney Neoplasms; Molecular Targeted Therapy; Oxygen; Signal Transduction; Tumor Hypoxia; Vascular Endothelial Growth Factor A
PubMed: 33020645
DOI: 10.1038/s41591-020-1093-z -
La Revue de Medecine Interne Oct 2019Oxygen therapy is used to reverse hypoxemia since more than a century. Current usage is broader and includes routine oxygen administration despite normoxemia which may... (Review)
Review
Oxygen therapy is used to reverse hypoxemia since more than a century. Current usage is broader and includes routine oxygen administration despite normoxemia which may result in prolonged periods of hyperoxemia. While systematic oxygen therapy was expected to be of benefit in some ischemic diseases such as stroke or acute myocardial infarction, recent randomised controlled trials (RCTs) have challenged this hypothesis by showing the absence of clinical improvement. Although oxygen is known to be toxic at high inspired oxygen fractions, a recent meta-analysis of RCTs revealed the life-threatening effect of hyperoxemia, with a dose-dependent relationship. Several recommendations have therefore been updated: (i) to monitor peripheral oxygen saturation (SpO) as a surrogate for arterial oxygen saturation (SaO); (ii) to initiate oxygen only when the lower SpO threshold is crossed; (iii) to titrate the delivered oxygen fraction to maintain SpO within a target range; and (iv) to stop supplying oxygen when the upper limit of SpO is surpassed, in order to prevent hyperoxemia. The lower and upper limits of SpO depend on the presence of risk factors for oxygen-induced hypercapnia (Chronic obstructive pulmonary disease, asthma, and obesity-associated hypoventilation). For patients at risk, oxygen therapy should be started when SpO is≤88% and stopped when it is>92%. For patients without risk factors, oxygen therapy should be started when SpO is≤92% and stopped when it is >96%. High-flow oxygen should only be used in a few diseases such as carbon monoxide poisoning, cluster headaches, sickle cell crisis and pneumothorax.
Topics: Acute Disease; Cell Hypoxia; Heart Arrest; Humans; Hypercapnia; Hyperoxia; Hypoxia; Myocardial Infarction; Oxygen; Oxygen Inhalation Therapy; Partial Pressure; Practice Guidelines as Topic; Pulmonary Disease, Chronic Obstructive; Reference Values; Respiratory Insufficiency; Risk Factors; Sepsis; Stroke
PubMed: 31054779
DOI: 10.1016/j.revmed.2019.04.003 -
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 -
Plant Physiology Apr 2023
Topics: Respiration; Ecosystem; Cell Respiration
PubMed: 36703191
DOI: 10.1093/plphys/kiad041 -
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 -
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