bims-oxygme 2025-02-16 papers

bims-oxygme

Biomed News

on Oxygen metabolism

Issue of 2025–02–16
eleven papers selected by
Onurkan Karabulut, Berkeley City College

Time and Tissue-Specific Responses of Mitochondrial Metabolism to Hypoxia in Fish.
Effects of Non-linear Interaction Between Oxygen and Lactate on Solid Tumor Growth Under Cyclic Hypoxia.
HIF1α controls steroidogenesis under acute hypoxic stress.
Modulatory and protective effects of prolyl hydroxylase domain inhibitors in the central nervous system.
Proteomic analysis of chick embryonic heart in experimental hypoxia.
Transcriptomic signatures of severe acute mountain sickness during rapid ascent to 4,300 m.
Roles of Post-Translational Modifications of Transcription Factors Involved in Breast Cancer Hypoxia.
HIF2α: the interface between oxygen-sensing systems in physiology and pathology.
Transcriptomic analysis of iPSC-derived endothelium reveals adaptations to high altitude hypoxia in energy metabolism and inflammation.
Intracellular signalling in arterial chemoreceptors during acute hypoxia and glucose deprivation: role of ATP.
A Review on Drug-Metabolizing Enzymes, Transporters, and Gut Microbiota on Pharmacokinetics in High-Altitude Environment.

Ecol Evol Physiol. 2024 Nov-Dec;97(6):97(6): 371-381

Time and Tissue-Specific Responses of Mitochondrial Metabolism to Hypoxia in Fish.

Léna Jégo, Jean-Baptiste Quéméneur, Antoine Stier, Sophie Collet, Damien Roussel, Anthony Hickey, Karine Salin.

  AbstractPeriods of hypoxia are extremely common in aquatic systems and are predicted to have enduring impacts on aquatic life. Mitochondrial metabolic responses are important for animal performance during hypoxia, but tissue-specific responses and time needed for mitochondria to adjust remain unclear. Here, we investigate how mitochondrial metabolism responds to hypoxia (50% air saturation) over a prolonged period (15-21 wk) in sea bass (Dicentrarchus labrax). We used a longitudinal assessment of mitochondria from three repeated, but nonlethal, samplings of red blood cells (RBCs) at 3-wk intervals (15, 18, and 21 wk of hypoxia) alongside a terminal sampling of two other tissues (liver and heart). We found that hypoxic fish increased their RBC oxidative phosphorylation between weeks 15 and 18 but did not change it between weeks 18 and 21. We also show that mitochondrial respiratory capacities were depressed in the heart but not in the liver or RBCs of sea bass held for 21 wk in hypoxia compared with those of sea bass maintained in normoxia. The time and tissue-specific responses to hypoxia likely have consequences for how organisms adjust their different organ functions under the constraints of oxygen availability. As the occurrence of hypoxia is expected to increase in marine ecosystems, our data also indicate that understanding temporal changes in mitochondrial metabolism is crucial to predict organismal responses in the face of ongoing environmental change.

Keywords:  global change; heart; marine biology; oxidative phosphorylation; red blood cell; sea bass

DOI:  https://doi.org/10.1086/734065
Bull Math Biol. 2025 Feb 11. 87(3): 41

Effects of Non-linear Interaction Between Oxygen and Lactate on Solid Tumor Growth Under Cyclic Hypoxia.

Gopinath Sadhu, D C Dalal.

  Oxygen is a crucial element for cellular respiration. Based on oxygen concentration, tumor regions can be categorized as normoxic, hypoxic, and necrotic. Hypoxic tumor cells switch their metabolism from aerobic glycolysis to anaerobic glycolysis. As a result, lactate is produced in hypoxic regions and is used as an alternative metabolic fuel by normoxic tumor cells. The consumption of lactate and oxygen by tumor cells does not follow a linear pattern. Scientific studies suggest that oxygen consumption and lactate production are non-linear phenomena. In this study, we propose a two-dimensional mathematical model to investigate lactate dynamics in avascular tumors with various initial shapes, such as circular, elliptical, and petal, and to explore its growth patterns in the context of non-linear interactions between oxygen and lactate. In certain human tumors, particularly in kidney, skin, and liver, multiple tumors may emerge within a tissue domain simultaneously. We also examine how the growth patterns of multiple tumors evolve within a shared domain. Cyclic hypoxia, commonly observed in solid tumors, results from oxygen fluctuations over time at the tumor site. Additionally, we analyze lactate dynamics and tumor growth patterns in environments with cyclic hypoxia. In order to simulate the proposed model, we use finite element based COMSOL Multiphysics 6.0 interface. The simulated results show excellent agreement with experimental data. Our findings reveal that the initial tumor shape significantly influences the lactate distribution and the tumor's internal structure. Furthermore, the simulations indicate that multiple tumors eventually merge into a single tumor. We also observe that cyclic hypoxia with short periodicity increases tumor volume.

Keywords:  Cyclic hypoxia; Growth pattern; Lactate; Mathematical model; Oxygen; Solid tumor

DOI:  https://doi.org/10.1007/s11538-025-01420-6
Cell Commun Signal. 2025 Feb 13. 23(1): 86

HIF1α controls steroidogenesis under acute hypoxic stress.

Stephen Ariyeloye, Deepika Watts, Mangesh T Jaykar, Cagdas Ermis, Anja Krüger, Denise Kaden, Barbara K Stepien, Vasileia Ismini Alexaki, Mirko Peitzsch, Nicole Bechmann, Peter Mirtschink, Ali El-Armouche, Ben Wielockx.

   BACKGROUND: Hypoxia is a critical physiological and pathological condition known to influence various cellular processes, including steroidogenesis. While previous studies, including our own, have highlighted the regulatory effects of Hypoxia-Inducible Factor 1α (HIF1α) on steroid production, the specific molecular mechanisms remain poorly understood. This study investigates the role of hypoxia and HIF1α in steroid biosynthesis across multiple experimental models during acute exposure to low oxygen levels.
METHODS: To assess the extent to which acute hypoxia modulates steroidogenesis, we employed several approaches, including the Y1 adrenocortical cell line, and a conditional HIF1α-deficient mouse line in the adrenal cortex. We focused on various regulatory patterns that may critically suppress steroidogenesis.
RESULTS: In Y1 cells, hypoxia upregulated specific microRNAs in a HIF1α-dependent manner, resulting in the suppression of mRNA levels of critical steroidogenic enzymes and a subsequent reduction in steroid hormone production. The hypoxia/HIF1α-dependent induction of these microRNAs and the consequent modulation of steroid production were confirmed in vivo. Notably, using our adrenocortical-specific HIF1α-deficient mouse line, we demonstrated that the increase in miRNA expression in vivo is also directly HIF1α-dependent, while the regulation of steroidogenic enzymes (e.g., StAR and Cyp11a1) and steroid production occurs at the level of protein translation, revealing an unexpected layer of control under hypoxic/HIF1 α conditions in vivo.
CONCLUSIONS: These findings elucidate the molecular mechanisms underlying acute hypoxia/HIF1α-induced changes in steroid biosynthesis and may also be useful in developing new strategies for various steroid hormone pathologies.

Keywords:  Adrenal gland; Hypoxia-inducible factors; MicroRNA; Oxygen sensors; Steroidogenesis

DOI:  https://doi.org/10.1186/s12964-025-02080-8
Adv Pharmacol. 2025 ;pii: S1054-3589(24)00035-8. [Epub ahead of print]102 211-235

Modulatory and protective effects of prolyl hydroxylase domain inhibitors in the central nervous system.

Konstantinos Matheoudakis, John J O'Connor.

  Oxygen is essential for all mammalian species, with complex organs such as the brain requiring a large and steady supply to function. During times of low or inadequate oxygen supply (hypoxia), adaptation is required in order to continue to function. Hypoxia inducible factors (HIF) are transcription factors which are activated during hypoxia and upregulate protective genes. Normally, when oxygen levels are sufficient (normoxia) HIFs are degraded by oxygen sensing prolyl hydroxylase domain proteins (PHD), but during hypoxia PHDs no longer exert influence on HIFs allowing their activation. Given that PHDs regulate the activity of HIFs, their pharmacological inhibition through PHD inhibitors (PHDIs) is believed to be the basis of their neuroprotective benefits. This review discusses some of the potential therapeutic benefits of PHDIs in a number of neurological disorders which see hypoxia as a major pathophysiological mechanism. These include stroke, Parkinson's disease, and amyotrophic lateral sclerosis. We also explore the potential neuroprotective benefits and limitations of PHDIs in a variety of disorders in the central nervous system (CNS). Additionally, the activation of HIFs by PHDIs can have modulatory effects on CNS functions such as neurotransmission and synaptic plasticity, mechanisms critical to cognitive processes such as learning and memory.

Keywords:  Hippocampus; Hypoxia; Hypoxia-inducible factor; Ischemia; Neuroprotection; Prolyl hydroxylase inhibitors; Stroke; Synaptic plasticity

DOI:  https://doi.org/10.1016/bs.apha.2024.10.006
Dev Biol. 2025 Feb 09. pii: S0012-1606(25)00036-3. [Epub ahead of print]521 28-36

Proteomic analysis of chick embryonic heart in experimental hypoxia.

David Sedmera, Eliska Drobna Krejci, Ondrej Nanka, Adam Eckhardt.

  Investigating prenatal hypoxia is difficult in mammals, as there are confounding factors stemming from maternal adaptations and compensatory mechanisms. We have thus established an avian model of hypoxic incubation (starting after 2 days of normoxia, 15% O2, normobaric, until the time of sampling at embryonic day 8) to study embryonic reactions to low oxygen concentration. Our previous studies have shown increased vascularization, oedema, and ventricular wall thinning preceding the lethality at mid-gestation. Analysis of the cardiac proteome after 6 days of hypoxic incubation showed strong upregulation of enzymes involved in anaerobic glycolysis as well as an increase in apoptosis-related proteins, cell adhesion proteins, and secretory activity.

Keywords:  Chick embryo; Glycolysis; Heart; Hypoxia; Metabolism; Proteomics

DOI:  https://doi.org/10.1016/j.ydbio.2025.02.006
Front Physiol. 2024 ;15 1477070

Transcriptomic signatures of severe acute mountain sickness during rapid ascent to 4,300 m.

Ruoting Yang, Aarti Gautam, Rasha Hammamieh, Robert C Roach, Beth A Beidleman.

   Introduction: Acute mountain sickness (AMS) is a common altitude illness that occurs when individuals rapidly ascend to altitudes ≥2,500 m without proper acclimatization. Genetic and genomic factors can contribute to the development of AMS or predispose individuals to susceptibility. This study aimed to investigate differential gene regulation and biological pathways to diagnose AMS from high-altitude (HA; 4,300 m) blood samples and predict AMS-susceptible (AMS+) and AMS-resistant (AMS─) individuals from sea-level (SL; 50 m) blood samples.
Methods: Two independent cohorts were used to ensure the robustness of the findings. Blood samples were collected from participants at SL and HA. RNA sequencing was employed to profile gene expression. Differential expression analysis and pathway enrichment were performed to uncover transcriptomic signatures associated with AMS. Biomarker panels were developed for diagnostic and predictive purposes.
Results: At HA, hemoglobin-related genes (HBA1, HBA2, and HBB) and phosphodiesterase 5A (PDE5A) emerged as key differentiators between AMS+ and AMS- individuals. The cAMP response element-binding protein (CREB) pathway exhibited contrasting regulatory patterns at SL and HA, reflecting potential adaptation mechanisms to hypoxic conditions. Diagnostic and predictive biomarker panels were proposed based on the identified transcriptomic signatures, demonstrating strong potential for distinguishing AMS+ from AMS- individuals.
Discussion: The findings highlight the importance of hemoglobin-related genes and the CREB pathway in AMS susceptibility and adaptation to hypoxia. The differential regulation of these pathways provides novel insights into the biological mechanisms underlying AMS. The proposed biomarker panels offer promising avenues for the early diagnosis and prediction of AMS risk, which could enhance preventive and therapeutic strategies.

Keywords:  NGS - next generation sequencing; acute mountain sickness; biomarker; high altitude; machine learning

DOI:  https://doi.org/10.3389/fphys.2024.1477070
Molecules. 2025 Feb 01. pii: 645. [Epub ahead of print]30(3):

Roles of Post-Translational Modifications of Transcription Factors Involved in Breast Cancer Hypoxia.

Logan Seymour, Niyogushima Nuru, Kaya R Johnson, Jennifer Michel Villalpando Gutierrez, Victor Tochukwu Njoku, Costel C Darie, Anca-Narcisa Neagu.

  BC is the most commonly diagnosed cancer and the second leading cause of cancer death among women worldwide. Cellular stress is a condition that leads to disrupted homeostasis by extrinsic and intrinsic factors. Among other stressors, hypoxia is a driving force for breast cancer (BC) progression and a general hallmark of solid tumors. Thus, intratumoral hypoxia is an important determinant of invasion, metastasis, treatment failure, prognosis, and patient mortality. Acquisition of the epithelial-mesenchymal transition (EMT) phenotype is also a consequence of tumor hypoxia. The cellular response to hypoxia is mainly regulated by the hypoxia signaling pathway, governed by hypoxia-inducible factors (HIFs), mainly HIF1α. HIFs are a family of transcription factors (TFs), which induce the expression of target genes involved in cell survival and proliferation, metabolic reprogramming, angiogenesis, resisting apoptosis, invasion, and metastasis. HIF1α cooperates with a large number of other TFs. In this review, we focused on the crosstalk and cooperation between HIF1α and other TFs involved in the cellular response to hypoxia in BC. We identified a cluster of TFs, proposed as the HIF1α-TF interactome, that orchestrates the transcription of target genes involved in hypoxia, due to their post-translational modifications (PTMs), including phosphorylation/dephosphorylation, ubiquitination/deubiquitination, SUMOylation, hydroxylation, acetylation, S-nitrosylation, and palmitoylation. PTMs of these HIF1α-related TFs drive their stability and activity, degradation and turnover, and the bidirectional translocation between the cytoplasm or plasma membrane and nucleus of BC cells, as well as the transcription/activation of proteins encoded by oncogenes or inactivation of tumor suppressor target genes. Consequently, PTMs of TFs in the HIF1α interactome are crucial regulatory mechanisms that drive the cellular response to oxygen deprivation in BC cells.

Keywords:  breast cancer (BC); hypoxia; post-translational modifications (PTMs); transcription factors (TFs)

DOI:  https://doi.org/10.3390/molecules30030645
Physiology (Bethesda). 2025 Feb 13.

HIF2α: the interface between oxygen-sensing systems in physiology and pathology.

Tammie Bishop, Peter J Ratcliffe.

  More than 100 years after the original descriptions of altitude adaptation, it is now clear that many of these responses are mediated by a specific isoform of the transcription factor hypoxia-inducible factor (HIF-2α). Here, we review this work, including connectivity with the oxygen chemosensitive response itself, and with paraganglioma, a tumour often affecting chemosensitive tissues.

Keywords:  HIF; carotid body; hypoxia; oxygen chemosensitivity; ventilation

DOI:  https://doi.org/10.1152/physiol.00043.2024
PLoS Genet. 2025 Feb;21(2): e1011570

Transcriptomic analysis of iPSC-derived endothelium reveals adaptations to high altitude hypoxia in energy metabolism and inflammation.

Olivia A Gray, David B Witonsky, Jordan Jousma, Débora R Sobreira, Alexander Van Alstyne, Ru-Ting Huang, Yun Fang, Anna Di Rienzo.

Tibetan adaptation to high-altitude hypoxia remains a classic example of Darwinian selection in humans. Amongst Tibetan populations, alleles in the EPAS1 gene - whose protein product, HIF-2α, is a central regulator of the hypoxia response - have repeatedly been shown to carry some of the strongest signals of positive selection in humans. However, selective sweep signals alone may only account for some of the phenotypes that differentiate high-altitude adapted populations from closely related lowlanders. Therefore, there is a pressing need to functionally probe adaptive alleles and their impact at both the locus-specific and genome-wide levels and across cell types to uncover the full range of beneficial traits. To this end, we established a library of induced pluripotent stem cells (iPSCs) derived from Tibetan and Han Chinese individuals, a robust model system allowing precise exploration of allelic effects on transcriptional responses, and we differentiated them into vascular endothelium. Using this system, we focus first on a hypoxia-dependent enhancer (ENH5) that contributes to the regulation of EPAS1 to investigate its locus-specific effects in endothelium. Then, to cast a wider net, we harness the same experimental system to compare the transcriptome of Tibetan and Han Chinese cells in hypoxia and find evidence that angiogenesis, energy metabolism and immune pathways differ between these two populations with different histories of long-term residence at high altitude. Coupled with evidence of polygenic adaptations targeting the same pathways, these results suggests that the observed transcriptional differences between the two populations were shaped by natural selection.

DOI: https://doi.org/10.1371/journal.pgen.1011570
J Physiol. 2025 Feb 12.

Intracellular signalling in arterial chemoreceptors during acute hypoxia and glucose deprivation: role of ATP.

María Torres-López, Patricia González-Rodríguez, Olalla Colinas, Hee-Sool Rho, Hortensia Torres-Torrelo, Antonio Castellano, Lin Gao, Patricia Ortega-Sáenz, José López-Barneo.

  The carotid body (CB) is the main oxygen (O2) sensing organ that mediates reflex hyperventilation and increased cardiac output in response to hypoxaemia. Acute O2 sensing is an intrinsic property of CB glomus cells, which contain special mitochondria to generate signalling molecules (NADH and H2O2) that modulate membrane K+ channels in response to lowered O2 tension (hypoxia). In parallel with these membrane-associated events, glomus cells are highly sensitive to mitochondrial electron transport chain (ETC) inhibitors. It was suggested that a decrease in oxidative production of ATP is a critical event mediating hypoxia-induced cell depolarization. Here, we show that rotenone [an inhibitor of mitochondrial complex (MC) I] activates rat and mouse glomus cells but abolishes their responsiveness to hypoxia. Rotenone does not prevent further activation of the cells by cyanide (a blocker of MCIV) or glucose deprivation. Responsiveness to glucose deprivation is enhanced in O2-insenstive glomus cells with genetic disruption of MCI. These findings suggest that acute O2 sensing requires a functional MCI but that a decrease in intracellular ATP, presumably produced by the simultaneous inhibition of MCI and MCIV, is not involved in hypoxia signalling. In support of this concept, ATP levels in single glomus cells were unaltered by hypoxia, but rapidly declined following exposure of the cells to low glucose or to inhibitors of oxidative phosphorylation. These observations indicate that a reduction in intracellular ATP does not participate in physiological acute O2 sensing. However, local decreases in ATP of glycolytic origin may contribute to low glucose signalling in glomus cells. KEY POINTS: The carotid body contains oxygen-sensitive glomus cells with specialized mitochondria that generate signalling molecules (NADH and H2O2) to inhibit membrane K+ channels in response to hypoxia. Glomus cells are highly sensitive to electron transport chain (ETC) blockers. It was suggested that a decrease in intracellular ATP is the main signal inducing K+ channel inhibition and depolarization in response to hypoxia or ETC blockade. Rotenone, an inhibitor of mitochondrial complex (MC) I, activates glomus cells but abolishes their responsiveness to hypoxia. However, rotenone does not prevent further activation of glomus cells by cyanide (an MCIV blocker) or glucose deprivation. Single-cell ATP levels were unaltered by hypoxia, but decreased rapidly following exposure of glomus cells to 0 mM glucose or inhibitors of oxidative phosphorylation. A reduction in intracellular ATP does not participate in signalling acute hypoxia. However, it may contribute to hypoglycaemia signalling in glomus cells.

Keywords:  H2O2; NADH; TASK3 channels; acute oxygen sensing; carotid body glomus cells; cytosolic ATP; electron transport chain inhibitors; glucose sensing; hypoxia; mitochondria‐to‐membrane signalling

DOI:  https://doi.org/10.1113/JP287130
Curr Drug Metab. 2025 Feb 11.

A Review on Drug-Metabolizing Enzymes, Transporters, and Gut Microbiota on Pharmacokinetics in High-Altitude Environment.

Fangfang Qiu, Yuemei Sun, Wenbin Li, Rong Wang.

  The most significant feature of the high-altitude environment is hypoxia, which affects the activity and expression of drug-metabolizing enzymes and transporters, leading to changes in pharmacokinetic parameters. Notably, gut microbiota is a hidden organ in the body. High-altitude hypoxia will change the composition and quantity of gut microbiota, affect drug metabolism, and change the bioavailability of drugs. This will provide a new perspective on changes in pharmacokinetics at high-altitude. Most studies have revealed that for drugs with low bioavailability and high clearance, the dosage may be increased accordingly. Conversely, the dosage may be reduced to achieve individualized medication. Therefore, this article reviews the changes and mechanisms of drug-metabolizing enzymes, transporters, and gut microbiota in a high-altitude environment and explains the impact of their changes on pharmacokinetics, aiming to provide theories and bases for the adjustment of drug dosage and the rational use of drugs in the clinic under high-altitude environment.

Keywords:  High-altitude hypoxia; and enhance or weaken the efficacy of transporters; drug-metabolizing enzymes; gut microbiota; into active metabolites; pharmacokinetics.

DOI:  https://doi.org/10.2174/0113892002356402250130075811