Mitochondrial antioxidants abate SARS-COV-2 pathology in mice

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(30)

Published: July 15, 2024

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection inhibits mitochondrial oxidative phosphorylation (OXPHOS) and elevates reactive oxygen species (ROS, mROS) which activates hypoxia-inducible factor-1alpha (HIF-1α), shifting metabolism toward glycolysis to drive viral biogenesis but also causing the release of DNA (mtDNA) activation innate immunity. To determine whether mitochondrially targeted antioxidants could mitigate these effects, we challenged mice expressing human angiotensin-converting enzyme (ACE2) with SARS-CoV-2 intervened using transgenic pharmacological catalytic antioxidants. Transgenic expression catalase (mCAT) or systemic treatment EUK8 decreased weight loss, clinical severity, circulating levels mtDNA; as well reduced lung HIF-1α, proteins, inflammatory cytokines. RNA-sequencing infected lungs revealed that mCAT Eukarion 8 (EUK8) up-regulated OXPHOS gene down-regulated HIF-1α its target genes immune expression. These data demonstrate pathology can be mitigated by catalytically reducing mROS, potentially providing a unique host-directed therapy for COVID-19 is not subject mutational resistance.

Language: Английский

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Recent advances in nutritional metabolism studies on SARS-CoV-2 infection

Infectious Medicine, Journal Year: 2025, Volume and Issue: 4(1), P. 100162 - 100162

Published: Jan. 16, 2025

In the context of coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome 2 (SARS-CoV-2), metabolic research has become crucial for in-depth exploration viral infection mechanisms and in searching therapeutic strategies. This paper summarizes interrelationships between carbohydrate, lipid, amino acid metabolism COVID-19 infection, discussing their roles progression. SARS-CoV-2 leads to insulin resistance increased glycolysis, reducing glucose utilization shifting use fat as an energy source. Fat is replication, imbalances may interfere with immune regulation. Consequently, changes such hyperglycemia, hypolipidemia, deficiency certain acids following can contribute progression toward conditions. These pathways not only have potential value prediction diagnosis but also provide new perspectives development By monitoring changes, severity be predicted early, modulating these help reduce inflammatory responses, improve risk thrombosis. Research on relationship provides important scientific basis addressing global challenge posed COVID-19, however, further studies are needed validate findings more effective strategies control.

Language: Английский

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Respiratory long COVID in aged hamsters features impaired lung function post-exercise with bronchiolization and fibrosis

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Feb. 28, 2025

Abstract Long-term consequences of SARS-CoV-2 infection affect millions people and strain public health systems. The underlying pathomechanisms remain unclear, necessitating further research in appropriate animal models. This study aimed to characterize the trajectory lung regeneration over 112 days male hamster model by combining morphological, transcriptomic functional readouts. We demonstrate that acute phase, Delta-infected, male, aged hamsters show a severe impairment function at rest. In chronic similar impairments persisted up 7 weeks post-infection but were only evident after exercise on rodent treadmill. recapitulates pulmonary fibrotic changes observed many patients with respiratory long COVID, lacks extra-pulmonary long-term lesions. sub-pleural interstitial fibrosis as well alveolar bronchiolization persist until dpi. Interestingly, CK8 + differentiation intermediate (ADI) cells are becoming less prominent proliferation areas from 28 dpi on. Instead, CK14 airway basal SCGB1A1 club cells, expressing cell markers, mainly populate later time-points. postulate cell-rich represent potential risk factors for other diseases long-COVID survivors.

Language: Английский

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Melatonin regulation of phase separation in Neuro-PASC: out-maneuvering Janus-faced amyloids

Exploration of neuroscience, Journal Year: 2025, Volume and Issue: 4

Published: March 24, 2025

The SAR-CoV-2 virus has evolved to co-exist with human hosts, albeit at a substantial energetic cost resulting in post-infection neurological manifestations [Neuro-post-acute sequelae of SARS-CoV-2 infection (PASC)] that significantly impact public health and economic productivity on global scale. One the main molecular mechanisms responsible for development Neuro-PASC, individuals all ages, is formation inadequate proteolysis/clearance phase-separated amyloid crystalline aggregates—a hallmark feature aging-related neurodegenerative disorders. Amyloidogenesis during viral persistence natural, inevitable, protective defense response exacerbated by SARS-CoV-2. Acting as chemical catalyst, accelerates hydrophobic collapse heterogeneous nucleation amorphous amyloids into stable β-sheet aggregates. clearance aggregates most effective slow wave sleep, when high levels adenosine triphosphate (ATP)—a biphasic modulator biomolecular condensates—and melatonin are available solubilize removal. dysregulation mitochondrial dynamics SARS-CoV-2, particular fusion fission homeostasis, impairs proper distinct subpopulations can remedy challenges created diversion substrates away from oxidative phosphorylation towards glycolysis support replication maintenance. subsequent reduction ATP inhibition synthesis sleep results incomplete brain aggregates, leading commonly associated age-related Exogenous not only prevents dysfunction but also elevates production, effectively augmenting solubilizing effect moiety ensure timely, optimal disaggregation pathogenic prevention attenuation Neuro-PASC.

Language: Английский

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Environmental exposures and familial background alter the induction of neuropathology and inflammation after SARS-CoV-2 infection

npj Parkinson s Disease, Journal Year: 2025, Volume and Issue: 11(1)

Published: April 23, 2025

Language: Английский

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Long‐term persistence of mitochondrial dysfunctions after viral infections and antiviral therapies: A review of mechanisms involved

Journal of Medical Virology, Journal Year: 2024, Volume and Issue: 96(9)

Published: Sept. 1, 2024

Mitochondria are vital for most cells' functions. Viruses hijack mitochondria machinery misappropriation of energy supply or to bypass defense mechanisms. Many these mitochondrial dysfunctions persist after recovery from treated untreated viral infections, particularly when DNA is permanently damaged. Quantitative defects and structural rearrangements accumulate in post-mitotic tissues as recently reported long SARS-CoV-2 HIV infection, following antiviral therapy. These observations consistent with the "hit-and-run" concept proposed decades ago explain viro-induced cell transformation it could apply delayed post-viral onsets symptoms advocate complementary supportive care. Thus, according this concept, exposure viruses agents, damage evolve into an autonomous clinical condition. It also establishes a pathogenic link between communicable non-communicable chronic diseases.

Language: Английский

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Guardians of the Mitochondria: Space Mitochondria 2.0 Systemic Analysis Reveals Bioenergetic Dysregulation Across Species

Published: Jan. 1, 2025

Spaceflight imposes unique stressors that disrupt mitochondrial function, vital for energy production and immune regulation. Our multi-omics analysis (proteomics, bisulfite sequencing, RNA-seq, single-nuclei RNA/ATAC-seq) on astronauts, rodents, model organisms (flies, worms, plants) revealed progressive impairment of oxidative phosphorylation (OXPHOS) during spaceflight, with delayed recovery post-return across species. In radiation ≥10.34 mGy activated persistent stress pathways multiple organs except in the spleen, older male C57BL/6 mice most affected. Astronaut data from NASA Twins Study, JAXA, Inspiration4 missions showed prolonged dysfunction, OXPHOS suppression TCA cycle inhibition lasting up to 82 days. Bisulfite sequencing confirmed epigenetic changes genes. Lastly, Kaempferol, an antioxidant activator, mitigated radiation-induced liver atrophy preserved function human organoids. This cross-species study underscores need targeted therapies protect biogenesis long-duration space missions.

Language: Английский

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Cytosolic nucleic acid sensing as driver of critical illness: mechanisms and advances in therapy

Signal Transduction and Targeted Therapy, Journal Year: 2025, Volume and Issue: 10(1)

Published: March 19, 2025

Abstract Nucleic acids from both self- and non-self-sources act as vital danger signals that trigger immune responses. Critical illnesses such acute respiratory distress syndrome, sepsis, trauma ischemia lead to the aberrant cytosolic accumulation massive release of nucleic are detected by antiviral innate receptors in endosome or cytosol. Activation for deoxyribonucleic ribonucleic triggers inflammation, a major contributor morbidity mortality critically ill patients. In past decade, there has been growing recognition therapeutic potential targeting acid sensing critical care. This review summarizes current knowledge ischemia. Given extensive research on common pathological conditions like cancer, autoimmune disorders, metabolic disorders aging, we provide comprehensive summary beyond illness offer insights may inform its role conditions. Additionally, discuss strategies specifically target sensing. By examining sources, sensor activation function, well impact regulating these pathways across various diseases, highlight driving illness.

Language: Английский

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Stable expression of SARS-CoV-2 envelope viroporin promotes intracellular calcium depletion in human cells: relevance for endoplasmic reticulum stress, cell proliferation, pluripotency and lineage differentiation

Cell Calcium, Journal Year: 2025, Volume and Issue: 128, P. 103032 - 103032

Published: April 18, 2025

Language: Английский

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Sex-specific associations between exposure to metal mixtures and mitochondrial DNA copy number: A repeated-measures study

Journal of Environmental Sciences, Journal Year: 2025, Volume and Issue: unknown

Published: May 1, 2025

Language: Английский

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