bims-oxygme 2025-09-28 papers

bims-oxygme

Biomed News

on Oxygen metabolism

Issue of 2025–09–28
nine papers selected by
Onurkan Karabulut, Berkeley City College

Hypoxia exposure fine-tunes mitochondrial function in sea turtle cells.
Glucose-Fueled Histone Modifications Drive HIV-1 Latency Reversal at Hypoxia.
Hypoxia reverses the early anti-inflammatory microglial response to the β-amyloid peptide: mitochondrial involvement and beneficial roles of melatonin and naringenin.
Mitochondrial adaptations and regulation of OPA1 and PERK in Tibetan sheep myocardium under high altitude conditions.
Changes in the gut microbiota in mice exposed to chronic intermittent hypoxia.
Exploring the Influence of Metabolic Changes in Fibrotic Lung Diseases.
Utility of Drosophila for studying hypoxia-inducible factor (HIF) in neurodegenerative diseases: Advantages versus limitations.
A new investigation of nonalcoholic fatty liver disease: Effects of hypoxia on mitochondrial function and lipid droplet autophagy.
Unraveling the Mystery of Hemoglobin in Hypoxia-Accelerated Neurodegenerative Diseases.

J Physiol. 2025 Sep 24.

Hypoxia exposure fine-tunes mitochondrial function in sea turtle cells.

B Gabriela Arango, David C Ensminger, Dianna Xing, Céline A Godard-Codding, José Pablo Vázquez-Medina.

  Sea turtles experience extreme fluctuations in oxygen levels derived from extended breath-hold diving, yet the cellular adjustments underlying hypoxia tolerance in these animals remain poorly understood. Here, we employed metabolite profiling, extracellular flux assays and microscopy analyses of the mitochondrial reticulum to investigate how primary cells derived from sea turtles and lizards cope with extended hypoxia exposure. Cells from both species proliferate in primary culture, stain positive for fibroblast markers, are metabolically active and stabilize HIF1-α when exposed to chemical or environmental hypoxia. In contrast to lizard cells, sea turtle cells exhibit a faster and more robust response to 1 h or 24 h of hypoxia exposure (0.1% O2), upregulating antioxidant pathways and optimizing oxygen use rather than relying on glycolytic metabolism. Similarly, mitochondrial reticulum architecture is maintained without apparent fragmentation during hypoxia exposure in sea turtle cells. Consistent with these observations, sea turtle mitochondria maintain better function during reoxygenation following 24 h of hypoxia exposure. These findings show that sea turtle cells undergo intrinsic metabolic adjustments to cope with extreme oxygen fluctuations, aligning with the remarkable hypoxic tolerance exhibited by these animals, which can endure up to 7 h of breath-holding underwater. KEY POINTS: Hypoxic sea turtle cells bypass the Crabtree effect and boost antioxidant defences. Hypoxia exposure fine-tunes mitochondrial function in sea turtle cells. Preserving mitochondrial architecture during hypoxia may help sea turtle cells restart respiration upon reoxygenation after extended hypoxia.

Keywords:  cellular respiration; diving; metabolomics; oxidative stress; reptiles

DOI:  https://doi.org/10.1113/JP288755
bioRxiv. 2025 Sep 16. pii: 2025.09.14.676169. [Epub ahead of print]

Glucose-Fueled Histone Modifications Drive HIV-1 Latency Reversal at Hypoxia.

Yetunde I Kayode, Deanna C Clemmer, Adebola A Owolabi, AbdulKareem A AlShaheeb, Elyse K McMahon, Anna Tangiyan, Lauren Clark, Glenn E Simmons, Alberto Bosque, Melanie R McReynolds, Harry E Taylor.

The major barrier to curing HIV-1 infection is the persistence of a latent reservoir in CD4 T cells within tissues which readily fuel viral rebound upon antiretroviral therapy (ART) interruption. Clinical trials aimed at purging these viral reservoirs with latency reversal agents (LRAs) have been unsuccessful owing to our incomplete understanding of the molecular and physiological determinants that underlie latency reversal in these virus-harboring tissues. Here, using a combination of complementary pharmacological and metabolomic approaches, we uncover glucose as a conditionally essential nutrient for HIV-1 latency reversal at hypoxic conditions. By modelling physiological variations in both glucose and oxygen availability as found in vivo within tissues that may harbor the HIV reservoir, we show that hyperglycemic conditions potentiate HIV-1 latency reversal. Importantly, we found major classes of clinically relevant LRAs, PKC agonists (PKCags) and histone deacetylase inhibitors (HDACis) have disparate efficacies under glucose-limiting conditions. Mechanistically, we show that this differential glycolytic dependency is due to distinct capacities of LRAs to induce glycolytic flux during adaptation to hypoxia, a condition that increases glycolytic dependence. Furthermore, we show that PKCag-induced glycolysis drives histone lactylation, a post-translational modification (PTM) we found to be associated with HIV-1 latency reversal and promotes increased chromatin accessibility at the HIV promoter. Importantly, we identify KAT2A as a lactyl-transferase critical for histone lactylation induced upon latency reversal. Taken together, our findings uncover glucose and oxygen availability as critical metabolic determinants of HIV-1 latency reversal and underscore the importance of modeling physiologically relevant experimental conditions in vitro aimed at identifying therapeutic agents that effectively target the latent reservoir in vivo .

DOI: https://doi.org/10.1101/2025.09.14.676169
J Transl Med. 2025 Sep 24. 23(1): 1012

Hypoxia reverses the early anti-inflammatory microglial response to the β-amyloid peptide: mitochondrial involvement and beneficial roles of melatonin and naringenin.

Cristiana Lucia Rita Lipari, Aurora Patti, Stefano Conti-Nibali, Angela Anna Messina, Andrea Magrì, Maria Angela Sortino, Sara Merlo.

   BACKGROUND: Early Alzheimer's disease (AD) is characterized by anti-inflammatory microglial responses to the beta amyloid peptide (Aβ), which later switch to pro-inflammatory. Such transition is relevant to disease progression and can be affected by concurrent insults, such as hypoxia (HY). This study explored whether a mild hypoxic stimulus could anticipate the microglial phenotypic switch, focusing in particular on involvement of SIRT1 and mitochondrial function.
METHODS: HMC3 human microglia were polarized to an anti-inflammatory phenotype by 3 h of exposure to 0.2 μM of Aβ42 to mimic early AD and transferred to a hypoxic chamber with 3% of O2 for 1 h. Effects on microglial activation were investigated by analysis of the SIRT1-BDNF axis activation and enzymatic and ELISA assays of inflammatory markers. Mitochondrial function and morphology were analyzed by high resolution respirometry and laser scanning confocal microscopy.
RESULTS: Hypoxia (HY) prevented the Aβ42-induced early induction of SIRT1 translocation and BDNF release and significantly increased caspase 1 and NF-kB activity. Moreover, mitochondrial oxygen flows evaluated by high resolution respirometry were significantly reduced, while mitochondrial area, perimeter and branching were increased by Aβ42 + HY, compared to Aβ alone. These changes were contrasted by both melatonin (1 μM) and naringenin (10 μM), natural substances able to induce SIRT1. However, use of the selective SIRT1 inhibitor EX-527 (5 μM) suggested only a partial involvement for SIRT1 in the observed effects, prevalent for naringenin.
CONCLUSIONS: Our results suggest that mild hypoxic insults during early asymptomatic stages of AD can pose as a risk factor for an accelerated progression of the disease and show the benefits of SIRT1 induction strategies, including use of natural substances like melatonin and naringenin.

Keywords:  Alzheimer’s disease; High resolution respirometry; Hypoxia; Microglial HMC3 cells; Mitochondrial dynamics; Natural substances; Neuroinflammation; SIRT1

DOI:  https://doi.org/10.1186/s12967-025-07044-7
J Anim Sci. 2025 Sep 25. pii: skaf321. [Epub ahead of print]

Mitochondrial adaptations and regulation of OPA1 and PERK in Tibetan sheep myocardium under high altitude conditions.

Guan Wang, Yanyan Cui, Hongjian Hou, Junfang Hao, Jincheng Han, Guangli Yang.

  To elucidate the physiological mechanisms by which Tibetan sheep myocardium adapts to chronic hypoxia in high-altitude environments, this study investigated the effects of altitude on Optic Atrophy 1 (OPA1) and Protein Kinase RNA-like Endoplasmic Reticulum Kinase (PERK) expression, mitochondrial morphology, and functional integrity. Utilizing transmission electron microscopy (TEM), enzyme-linked immunosorbent assay (ELISA), immunohistochemistry, and reverse transcription quantitative PCR (RT-qPCR), we analyzed the protein localization and gene/protein expression levels of PERK and OPA1, the activities of malate dehydrogenase (MDH), citrate synthase (CS), and oxidative phosphorylation (OXPHOS) complexes I, II, and IV, as well as mitochondrial ultrastructure in the myocardium of Tibetan sheep inhabiting high-altitude and very-high-altitude environments. Results demonstrated significantly elevated expression levels of OPA1 and PERK proteins and their corresponding genes in very-high-altitude myocardium compared to high-altitude counterparts (P < 0.05), with a strong positive correlation between their protein expressions. Mitochondrial density in very-high-altitude cardiac muscle was markedly reduced (P < 0.05), yet these mitochondria exhibited enhanced fusion-fission dynamics, increased number and density of cristae, and a more compact arrangement (P < 0.05). Concurrently, the activity of MDH and OXPHOS complex IV was significantly higher in very-high-altitude myocardium (P < 0.05), indicative of augmented tricarboxylic acid cycle flux. Furthermore, mitochondria-associated endoplasmic reticulum (ER) membranes were more abundant in very-high-altitude samples. Collectively, these findings suggest that chronic hypoxia drives coordinated upregulation of OPA1 and PERK, remodeling mitochondrial architecture and enhancing metabolic activity. This adaptive response likely underpins the superior energy production capacity of high-altitude Tibetan sheep myocardium, ensuring functional integrity under sustained hypoxic stress.

Keywords:  Altitude; Myocardial mitochondria; OPA1; PERK; Tibetan Sheep

DOI:  https://doi.org/10.1093/jas/skaf321
J Med Microbiol. 2025 Sep;74(9):

Changes in the gut microbiota in mice exposed to chronic intermittent hypoxia.

Man-Lu Lu, Jing-Lin Wu, Ji-Wei Zhu, Lu Liu, Ming-Zhen Li, Yan Yu, Lei Pan.

  Introduction. Obstructive sleep apnoea syndrome (OSAS) is characterized by chronic intermittent hypoxia (CIH), which contributes to systemic complications, including metabolic and gastrointestinal disorders. Emerging evidence suggests a critical role of the gut microbiota in mediating these effects; however, the impact of CIH on the gut microbiota remains poorly understood.Gap Statement. While CIH is associated with systemic metabolic dysfunction, the specific alterations in gut microbiota composition and function induced by CIH remain understudied. Filling this knowledge gap could elucidate microbiota-mediated mechanisms of OSAS pathogenesis and identify therapeutic targets.Aim. To investigate the effects of CIH on the gut microbiota structure and functional pathways in a mouse model of OSAS.Methodology. Male C57BL/6 mice were exposed to normoxia (NM) or CIH conditions for 6 weeks. Faecal samples were collected via stress defecation before intervention (NM0 and CIH0 groups) and after 6 weeks (NM6 and CIH6 groups). Gut microbiota composition was assessed using 16S rRNA gene sequencing, and functional potential was predicted via Phylogenetic Investigation of Communities by Reconstruction of Unobserved States 2.Results. A total of 40 faecal samples (10 mice/group) were analysed. No significant differences in microbiota composition, alpha diversity or beta diversity were observed between groups before intervention. CIH significantly altered gut microbiota composition and abundance. At the genus level, Bacteroides abundance increased (rank-biserial=0.558, P=0.014) in CIH6 mice, while Bifidobacterium (Cohen's d=1.779, P=0.002), Helicobacter (rank-biserial=0.609, P=0.007) and Prevotella (rank-biserial=0.541, P=0.0173) decreased. Linear discriminant analysis effect size (LEfSe) and random forest model analyses identified these genera as key discriminators of microbiota composition. Kyoto Encyclopedia of Genes and Genomes functional prediction revealed 28 significantly altered tertiary metabolic pathways in CIH6 mice, including biotin, lipoic acid, beta-alanine and cyanoamino acid metabolism.Conclusion. CIH induces gut microbiota dysbiosis, disrupts short-chain fatty acid-producing bacteria and impacts multiple metabolic pathways. This study provides evidence linking gut microbiota alterations to OSAS pathogenesis and offers a theoretical foundation for targeting the microbiome as a potential therapeutic strategy for CIH-related disorders.

Keywords:  gut microbiota; intermittent hypoxia; normoxia; obstructive sleep apnoea

DOI:  https://doi.org/10.1099/jmm.0.002069
Pulm Circ. 2025 Jul;15(3): e70163

Exploring the Influence of Metabolic Changes in Fibrotic Lung Diseases.

Swati Kumari, Kanika Singh, Mohit Khadia, Rohit Kumar, Vishal Bansal, Aastha Mishra.

  Fibrotic lung diseases are often characterized by chronic inflammation and the progressive destruction of the vasculature, parenchyma, and airways, leading to cellular metabolic changes. As a result, these changes activate several pathological pathways, contributing to the disease's progression and worsening. However, the precise impact of metabolic changes and their contributions to the progression of fibrotic lung diseases need deeper exploration. The current review highlights the interplay between immunometabolites and hypoxia in bringing out cellular and epigenetic changes that progress and further exacerbate pulmonary fibrosis. Notably, the mitochondrial-linked immunometabolites such as lactate, succinate, 2-hydroxyglutarate (2-HG), fumarate, and itaconate have the potential to determine cellular fate in health and disease. For instance, lactate accumulation is one of the vital factors associated with pulmonary fibrosis (PF). The metabolite succinate promotes hypoxia response, inflammatory markers accumulation, fibroblast activation, and PF, whereas L-2-HG impairs the TCA cycle, reduces glycolysis, and disrupts the nicotinamide adenine dinucleotide (NADH/NAD+) ratio, ultimately leading to dysfunctional mitochondrial respiration and contributing to lung fibrosis. Due to the progressive and degenerative nature of fibrotic lung diseases, individuals affected by them need ongoing clinical support and monitoring. The currently available pharmacological treatments are limited and come with multiple side effects. Therefore, the search for newer therapeutics in the form of small molecules targeting these metabolites is increasingly being formulated to treat chronic fibrotic pulmonary conditions through their exhaustive mechanistic investigations backed by robust preclinical and clinical trials.

Keywords:  chronic hypoxia; hypoxia inducible factor‐1α; mitochondrial metabolites; phospholipids; pulmonary fibrosis

DOI:  https://doi.org/10.1002/pul2.70163
Brain Res. 2025 Sep 19. pii: S0006-8993(25)00516-5. [Epub ahead of print] 149953

Utility of Drosophila for studying hypoxia-inducible factor (HIF) in neurodegenerative diseases: Advantages versus limitations.

Zoya Serebrovska, Lei Xi, Michael Khetsuriani, Oleksandra Protsenko, Nadiia Morozova, Denis A Tolstun, Oksana Maksymchuk.

  Hypoxia-inducible factor 1α (HIF-1α) plays a critical role in cellular responses to oxygen deprivation and is increasingly recognized as a key regulator in neurodegenerative diseases. Drosophila melanogaster serves as a powerful genetic model for investigating HIF-1α signaling, particularly through its homolog Sima. This review examines the advantages and limitations of using Drosophila to study HIF-1α in the context of neurodegeneration, with a focus on oxidative stress, autophagy, and mitochondrial dysfunction. We discuss the role of HIF-1α/Sima in modulating neuroprotective pathways, including its interactions with DJ-1 (also known as PARK7 Parkinson disease protein 7), SNCA (Alpha-synuclein), and the mTOR-autophagy axis. Moreover, we highlight the potential of Drosophila in elucidating hypoxia-mediated epigenetic modifications, non-coding RNA regulation, and metabolic adaptations relevant to neurodegenerative diseases. Understanding these mechanisms may provide insights into novel therapeutic approaches for the major neurodegenerative conditions in humans, such as Parkinson's disease and Alzheimer's disease.

Keywords:  Drosophila; Hypoxia; Mobile genetic elements; Neurodegenerative disease; Non-coding RNA

DOI:  https://doi.org/10.1016/j.brainres.2025.149953
PLoS One. 2025 ;20(9): e0331305

A new investigation of nonalcoholic fatty liver disease: Effects of hypoxia on mitochondrial function and lipid droplet autophagy.

Meiyuan Tian, Yaogang Zhang, Zhe Liu, Na Zhao, Dengliang Huang, Jing Hou, Li Sun, Yuan Jiang, Guangcun Zhang, Yanyan Ma.

An expanding body of research has highlighted the intimate connection between nonalcoholic fatty liver disease (NAFLD) and the dysregulation of hepatic lipid droplet autophagy as well as mitochondrial function. Nevertheless, the intricate interplay between lipid droplet autophagy and mitochondrial function under hypoxic conditions remains largely uncharted territory. Constructing NAFLD mouse models at altitudes of 2200 meters and 4500 meters and simultaneously culturing hepatocytes under oxygen concentrations of 21% and 1%, with the addition of oleic acid to induce lipid accumulation. A comprehensive evaluation of the NAFLD mice at different altitudes was conducted, including a combination of NMR, PAS, and Oil Red O staining, immunofluorescence, qPCR, flow cytometry, ELISA, electron microscopy, and cellular energy metabolism experiments. The high-altitude, high-fat diet group exhibited a reduction in lipid deposition and glycogen content, an increase in lipid droplet autophagy, and a decrease in mitochondrial damage and inflammatory injury when compared to the moderate-altitude, high-fat diet group. The 1% O2 + oleic acid group exhibited enhanced lipid droplet autophagy and increased cellular adaptation in comparison to the 21% O2 + oleic acid group. This study revealed that hypoxic conditions enhanced lipid droplet autophagy, reduced glycolipid accumulation, and alleviated mitochondrial damage in NAFLD mice.

DOI: https://doi.org/10.1371/journal.pone.0331305
Biomolecules. 2025 Aug 25. pii: 1221. [Epub ahead of print]15(9):

Unraveling the Mystery of Hemoglobin in Hypoxia-Accelerated Neurodegenerative Diseases.

Zhengming Tian, Feiyang Jin, Zhuowen Geng, Zirui Xu, Qianqian Shao, Guiyou Liu, Xunming Ji, Jia Liu.

  Hypoxic stress is increasingly recognized as a convergent pathological factor in various age-related neurodegenerative diseases (NDDs), encompassing both acute events such as stroke and traumatic brain injury (TBI), and chronic disorders including Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS). Recent studies have revealed that hemoglobin (Hb), beyond its classical oxygen-transport function, exhibits unexpected expression and functional relevance within the central nervous system. Notably, both cerebral and circulating Hb appear to be dysregulated under hypoxic and aging conditions, potentially influencing disease onset and progression of these diseases. However, Hb's impact on neurodegeneration appears to be context-dependent: in acute NDDs, it may exert neuroprotective effects by stabilizing mitochondrial and iron homeostasis, whereas in chronic NDDs, aberrant Hb accumulation may contribute to toxic protein aggregation and neuronal dysfunction. This review provides an integrative overview of the emerging roles of Hb in hypoxia-related NDDs, highlighting both shared and distinct mechanisms across acute and chronic conditions. We further discuss potential therapeutic implications of targeting Hb-related pathways in NDDs and identify key gaps for future investigation.

Keywords:  acute/chronic neurodegenerative diseases; aging; cerebral hemoglobin; circulating hemoglobin; hypoxia; non-oxygen-binding functionality

DOI:  https://doi.org/10.3390/biom15091221