bims-oxygme 2025-07-20 papers

bims-oxygme

Biomed News

on Oxygen metabolism

Issue of 2025–07–20
nine papers selected by
Onurkan Karabulut, Berkeley City College

Purple Potato Extract Suppresses Hypoxia-Induced Metabolic Reprogramming and Inhibits HIF-1α Signaling in Caco-2 Cells.
Effect of Intermittent Hypoxia on the Expression of Glucocorticoid Receptors and Hypoxia-Inducible Factor in Rat Brain.
Pharmacological targeting of the helminth complex II: are there any rhodoquinone-driven adaptations?
The plant-specific protein IQD22 interacts with calcium sensors to activate anaerobic respiration during hypoxia in Arabidopsis.
Measuring mitochondrial oxygenation and respiration during systemic inflammation in humans in vivo.
An Anaerobic Biomimetic Metal-Free AIE Polymersome Nanozyme as NADH Oxidase Mimic for Photocatalytic Tumor Suppression by Impairing Cancer Cell Energy Metabolism under Hypoxia.
Quantitative Proteomics Links Mitochondrial Dysfunction to Metabolic Changes and Epithelial Differentiation Defects in Hyperoxia-Exposed Neonatal Airway Cells.
Respiratory complex III 2 assembles complex I via toxic intermediate in mitochondrial disease.
Hemoglobin β-F41K: a recombinant oxygen carrier prototype engineered for enhanced heme retention, stability, and optimal oxygenation properties.

Nutrients. 2025 Jun 23. pii: 2079. [Epub ahead of print]17(13):

Purple Potato Extract Suppresses Hypoxia-Induced Metabolic Reprogramming and Inhibits HIF-1α Signaling in Caco-2 Cells.

Qiaorong Cui, Qi Sun, Alejandro Bravo Iniguez, Xinrui Li, Min Du, Mei-Jun Zhu.

   BACKGROUND: The hypoxia-inducible factor 1α (HIF-1α) pathway plays a key role in promoting glycolysis and tumor progression under hypoxic conditions in cancer cells. Purple potato (PP) extract, which is a polyphenol-rich natural product, has previously been shown to enhance mitochondrial function and suppress tumor growth in several cancer models. We hypothesized that PP extract could counteract hypoxia-induced glycolysis by targeting the HIF-1α pathway.
METHODS: Human colonic epithelial Caco-2 cells were treated with PP extract under hypoxic conditions, and its effects on glycolysis, oxidative phosphorylation, and HIF-1α signaling were evaluated.
RESULTS: Under hypoxia PP extract suppressed glycolysis, as evidenced by reduced lactate production and lower phosphorylated pyruvate dehydrogenase levels. In parallel, genes associated with oxidative phosphorylation were upregulated by PP extract, suggesting a metabolic shift under hypoxia. Additionally, PP extract reduced the protein accumulation of HIF-1α and its transcriptional activator XBP1 induced by hypoxia. Correspondingly, the expression of several HIF-1α downstream target genes, including Vegfa, Pdk1, Ldha, Hk1, and Glut1, was markedly reduced. Functionally, PP extract inhibited cell proliferation, migration, and drug resistance under hypoxic stress, indicating a broader inhibitory effect on hypoxia-driven malignant phenotypes.
CONCLUSION: These findings suggest that PP extract disrupts cancer cell adaptation to hypoxia and supports its potential as a dietary approach against hypoxia-driven colorectal cancer, through further preclinical studies are warranted.

Keywords:  Caco-2 cell; HIF-1α signaling; glycolytic metabolism; hypoxia; purple potato extract

DOI:  https://doi.org/10.3390/nu17132079
Bull Exp Biol Med. 2025 Jul 18.

Effect of Intermittent Hypoxia on the Expression of Glucocorticoid Receptors and Hypoxia-Inducible Factor in Rat Brain.

E A Rybnikova, K A Baranova, M Y Zenko.

  The effect of intermittent normobaric hypoxia on the expression of hypoxia-inducible factor 1α (HIF-1α) and glucocorticoid receptors in the brain of male Wistar rats was studied in the context of developing neuroprotective methods of hypoxytherapy. Hypoxia in three modes of different effectiveness was modeled by three cycles of 5-min inhalation of a hypoxic mixture (9, 12, or 16% O2) with 15-min intervals of normoxia (21% O2) over 3 days. Immunopositive staining for glucocorticoid receptors and HIF-1α in rat brain increased, which correlated with the protective effectiveness of the regimen. The protective mode (9% O2) increased the expression of these proteins in all regions, the medium mode (12% O2) stimulated expression of glucocorticoid receptors only in layer V of the neocortex and HIF-1α only in the CA1 field. The least effective mode (16% O2) did not affect these parameters. Thus, neuroprotective normobaric hypoxia activates the same adaptive mechanisms as hypobaric hypoxia.

Keywords:  OXYTERRA apparatus; glucocorticoid receptors; hypoxia-inducible factor HIF; interval normobaric hypoxia; neuroprotection

DOI:  https://doi.org/10.1007/s10517-025-06436-5
Trends Parasitol. 2025 Jul 16. pii: S1471-4922(25)00189-8. [Epub ahead of print]

Pharmacological targeting of the helminth complex II: are there any rhodoquinone-driven adaptations?

Franco Vairoletti, Cecilia Saiz, Gustavo Salinas.

  Based on a particular biochemical model, the use of rhodoquinone (RQ) under hypoxic conditions has been linked to an alternative complex II in the electron transport chain in helminths. This model was derived from detailed studies on Ascaris suum and generalized for helminths. However, accumulated evidence warrants a critical model re-examination. RQ facilitates complex II to operate in reverse as a fumarate reductase when oxygen is unavailable, but this biochemical adaptation typically does not involve a dedicated alternative complex II. Based on recent genomic, biochemical, and pharmacological data, we argue that the Ascaris scenario cannot be extrapolated to other helminths. Complex II is a promising pharmacological target for helminths; thus, the revision of the model also has practical consequences.

Keywords:  benzamide; electron transport chain; fumarate reductase; hypoxia; rhodoquinone; succinate dehydrogenase

DOI:  https://doi.org/10.1016/j.pt.2025.06.016
Mol Plant. 2025 Jul 12. pii: S1674-2052(25)00234-5. [Epub ahead of print]

The plant-specific protein IQD22 interacts with calcium sensors to activate anaerobic respiration during hypoxia in Arabidopsis.

Shanshan Zhao, Qin-Fang Chen, Li Chen, Ying Zhou, Ke Liao, Fengzhu Wang, Xue Zhang, Moxian Chen, Ruo-Han Xie, Shi Xiao.

  Louis Pasteur first reported that living cells switch from aerobic to anaerobic metabolism under low-oxygen conditions, but the underlying regulatory mechanism remains to be fully elucidated. ALCOHOL DEHYDROGENASE 1 (ADH1) encodes a key enzyme in ethanolic fermentation and is upregulated under hypoxia. Here, we searched for Arabidopsis thaliana mutants with defects in hypoxia-induced ADH1 expression. This screen identified a mutant in IQ DOMAIN containing protein 22 (IQD22). The iqd22 mutants were hypersensitive to submergence and hypoxic stress, whereas IQD22 overexpressors were more tolerant of both compared to wild type. Under hypoxia, IQD22 modulated the interaction of the calcium-dependent protein kinase CPK12 with the ERF-VII-type transcription factor RELATED TO AP2.12 (RAP2.12) to upregulate hypoxia-responsive genes, including ADH1. Moreover, IQD22 interacted with calmodulins (CaMs) in vivo and facilitated their association with ADH1, stimulating its abundance, in response to hypoxia. Metabolic profiling of the iqd22-2 mutant revealed that hypoxia caused significant increases of glycolytic metabolites, but significantly lower ethanol accumulation compared to the wild type. Furthermore, deleting ADH1 suppressed the improved hypoxia-tolerance phenotype of IQD22 overexpressors. Our findings thus demonstrate that IQD22 functions in the CaM-ADH1 and CPK12-RAP2.12 regulatory modules, which coordinately mediate calcium-dependent activation of anaerobic respiration to control metabolic flux during hypoxia.

Keywords:  ADH1; IQD22; anaerobic respiration; calcium sensors; hypoxia tolerance; metabolic reprogramming

DOI:  https://doi.org/10.1016/j.molp.2025.07.005
Sci Rep. 2025 Jul 16. 15(1): 25815

Measuring mitochondrial oxygenation and respiration during systemic inflammation in humans in vivo.

Mark A Wefers Bettink, Jelle Zwaag, Bernard Schockaert, Peter Pickkers, Matthijs Kox, Egbert G Mik.

  Disturbances in mitochondrial function are implicated in several chronic and acute diseases. Systemic inflammation has been described to affect mitochondrial respiration. Yet, in vivo measurement of mitochondrial respiration is notoriously difficult. We measured mitochondrial oxygen tension (mitoPO2) and mitochondrial oxygen consumption (mitoVO2) using the bedside COMET (Cellular Oxygen METabolism) system during systemic inflammation elicited by intravenous administration of 2 ng/kg lipopolysaccharide (LPS) in 42 healthy male volunteers. Four male subjects who did not receive LPS served as uninflamed controls. MitoPO2 and mitoVO2 were measured immediately prior to LPS administration, and at 1.45 h, 4 h, and 7 h, as well as at the corresponding timepoints in the control group. Compared to the control group, MitoPO2 significantly decreased over time in the LPS group (p = 0.002), with the nadir observed at 1.45 h post-LPS administration (45.8 ± 1.8 vs. 75.2 ± 2.6 mmHg); while mitoVO2 did not change. Concluding, the COMET monitor detects changes in mitochondrial parameters in a relatively mild model of systemic inflammation. This study paves the way for bedside monitoring of alterations in mitochondrial oxygenation and respiration, which may represent a vital next step in early diagnosis of mitochondrial dysfunction and stratification of patients in the intensive care unit.Trial registration: ClinicalTrials.gov NCT03240497. (12/04/2016) toetsingonline.nl NL56686.091.16 (11/04/2016) and NL65767.078.18 (01/05/2018).

Keywords:  5-aminolevulinic acid; Endotoxemia; Healthy volunteers; Lipopolysaccharides; Mitochondria

DOI:  https://doi.org/10.1038/s41598-025-10715-6
J Am Chem Soc. 2025 Jul 17.

An Anaerobic Biomimetic Metal-Free AIE Polymersome Nanozyme as NADH Oxidase Mimic for Photocatalytic Tumor Suppression by Impairing Cancer Cell Energy Metabolism under Hypoxia.

Yandong Ma, Yakui Deng, Wei Xue, Xin Ji, Min-Hui Li.

The intracellular balance between nicotinamide adenine dinucleotide and its reduced form (NAD+/NADH) is essential for cell metabolism. The NAD+/NADH redox imbalance strategy using NADH-oxidase-mimic nanozymes has emerged as an attractive antitumor strategy. Here, we develop a photocatalytic metal-free nanozyme that is a polymer vesicle (polymersome) self-assembled from PEG-block-poly(amino acid) functionalized by photocatalytic moieties with aggregation-induced emission (AIE). To enhance biocompatibility and tumor-targetability, the vesicle is coated with a folate-modified red-blood-cell membrane (FA-RBC) to get biomimetic AIE polymersome nanozyme (BV). Unlike conventional photocatalysts, BV can achieve the cyclical photocatalytic process for NADH-NAD+ conversion without O2 or additional electron acceptors. A new mechanism is proposed in which adjacent excited triplet molecules in the AIE assembly play the role of electron acceptors for complete NADH-NAD+ conversion and catalyst turnover. This O2-independent photocatalysis is appealing in anticancer treatment since the tumor has a hypoxic microenvironment. In vitro and in vivo investigations demonstrate BV induces a severe NAD+/NADH imbalance under hypoxia to lead to inhibition of oxidative phosphorylation and glycolysis, which triggers the energy crisis in 4T1 cancer cells and in the 4T1 tumor of a subcutaneous xenograft model. This work presents a novel approach of cancer therapy through the photocatalytic impairment of tumor energy metabolism by metal-free nanozyme.

DOI: https://doi.org/10.1021/jacs.5c06533
bioRxiv. 2025 Jun 15. pii: 2025.06.15.659571. [Epub ahead of print]

Quantitative Proteomics Links Mitochondrial Dysfunction to Metabolic Changes and Epithelial Differentiation Defects in Hyperoxia-Exposed Neonatal Airway Cells.

Abhrajit Ganguly, Cynthia M Carter, Aristides Rivera Negron, Hua Zhong, Alvaro Moreira, Matthew S Walters, Lynette K Rogers, Y S Prakash, Trent E Tipple, Arlan Richardson.

Premature infants often require supplemental oxygen therapy, however, exposure to supraphysiological oxygen (hyperoxia) can disrupt normal lung development and contribute to bronchopulmonary dysplasia (BPD). Mitochondrial dysfunction is increasingly recognized as a contributor to hyperoxia-induced BPD. However, the effects of hyperoxia on mitochondrial function and mucociliary differentiation in the developing upper airway epithelium remain poorly understood. This study tested the hypothesis that hyperoxia impairs neonatal airway mucociliary differentiation by disrupting mitochondrial bioenergetic function. Neonatal tracheal airway epithelial cells (nTAECs) from term infants (n=5) were cultured in a 3D air-liquid interface (ALI) model and exposed to 60% O₂ during the mid-phase of differentiation (ALI day 7-14). Cellular phenotype was assessed using immunofluorescence staining and gene expression analyses. Mitochondrial function was evaluated through Seahorse metabolic flux analysis, and global protein changes were characterized by quantitative proteomics. Hyperoxia exposure significantly impaired terminal epithelial differentiation, characterized by reductions in ciliated and goblet cells. Seahorse assay revealed a decrease in baseline oxygen consumption and mitochondrial ATP production, accompanied by a compensatory increase in glycolytic ATP production. Quantitative proteomics identified disruption of mitochondrial Complex I as a central feature of the hyperoxic response. Downstream proteomic pathway analyses further confirmed the metabolic shift from mitochondrial to glycolytic ATP production and demonstrated altered epithelial differentiation pathways, including NOTCH and TGF-β signaling. These findings reveal that moderate hyperoxia impairs mitochondrial bioenergetics and alters metabolic programming, leading to disrupted mucociliary differentiation. Future in vivo studies should evaluate mitochondrial oxidative fitness as a therapeutic target in neonatal lung disease.
NEW & NOTEWORTHY: We report that moderate hyperoxia during a critical window of mucociliary differentiation disrupts terminal maturation in neonatal airway epithelial cells cultured in a 3D model. Hyperoxia induced mitochondrial bioenergetic dysfunction and metabolic reprogramming, with proteomic analysis identifying Complex I disruption as a key driver of impaired differentiation. Overall, these findings reveal a previously underrecognized link between mitochondrial bioenergetics and airway epithelial development, positioning metabolic dysfunction as an early trigger of hyperoxia-induced neonatal airway injury.

DOI: https://doi.org/10.1101/2025.06.15.659571
bioRxiv. 2025 Jun 18. pii: 2025.06.17.660237. [Epub ahead of print]

Respiratory complex III 2 assembles complex I via toxic intermediate in mitochondrial disease.

Maria G Ayala-Hernandez, Anetzy Bermudez Torales, Hannah Camille Tan, Claire B Montgomery, Abhilash Padavannil, Gino Cortopassi, James A Letts.

Mutations in mitochondrial complex I can cause severe metabolic disease. Although no treatments are available for complex I deficiencies, chronic hypoxia improves lifespan and function in a mouse model of the severe mitochondrial disease Leigh syndrome caused by mutation of complex I subunit NDUFS4. To understand the molecular mechanism of NDUFS4 mutant pathophysiology and hypoxia rescue, we investigated the structure of complex I in respiratory supercomplexes isolated from NDUFS4 mutant mice. We identified complex I assembly intermediates bound to complex III 2 , proving the cooperative assembly model. Further, an accumulated complex I intermediate is structurally consistent with pathological oxygen-dependent reverse electron transfer, revealing unanticipated pathophysiology and hypoxia rescue mechanisms. Thus, the build-up of toxic intermediates and not simply decreases in complex I levels underlie mitochondrial disease.

DOI: https://doi.org/10.1101/2025.06.17.660237
J Biol Chem. 2025 Jul 11. pii: S0021-9258(25)02327-0. [Epub ahead of print] 110477

Hemoglobin β-F41K: a recombinant oxygen carrier prototype engineered for enhanced heme retention, stability, and optimal oxygenation properties.

Mohd Asim Khan, Kajal Yadav, Anthony V Signore, Nidhi Mittal, Sheetal Uppal, Amit K Tyagi, Gaurav Mittal, Jay F Storz, Suman Kundu.

  Recombinant hemoglobin-based oxygen carriers (rHBOCs) have several potential advantages as blood substitutes in transfusion medicine, especially in emergency situations. However, the wide use of rHBOCs in humans has been limited by challenges including hypertension due to nitric oxide scavenging, autoregulatory responses, and rapid heme dissociation. Among these, heme dissociation remains a critical unresolved issue, as it leads to toxicity and compromises oxygen delivery efficiency. Heme retention in the globin moiety is a key problem that needs to be solved to develop recombinant HBOCs as safe transfusion agents. Here, we report the results of protein engineering experiments to enhance heme retention and thermal stability with the aim of designing stable HBOCs. We successfully introduced a mutation into recombinant human Hb0.1 (rHb0.1), named β-F41K, that significantly reduced the rate of heme dissociation with increased thermal stability, while simultaneously maintaining oxygen affinities and reducing the rates of auto-oxidation at levels well suited to respiratory gas transport in vivo. The higher rate of heme retention in recombinant Hb0.1 β-F41K makes this protein an especially promising HBOC prototype.

Keywords:  Hb0.1 β-F41K; Hemoglobin based oxygen carrier; autooxidation; cooperativity; heme retention; heme stability; oxygen affinity; thermal stability

DOI:  https://doi.org/10.1016/j.jbc.2025.110477