Tag: reactive oxygen species

SARS-CoV-2 Mitochondrial Metabolic and Epigenomic Reprogramming in COVID-19

Abstract:

To determine the effects of SARS-CoV-2 infection on cellular metabolism, we conducted an exhaustive survey of the cellular metabolic pathways modulated by SARS-CoV-2 infection and confirmed their importance for SARS-CoV-2 propagation by cataloging the effects of specific pathway inhibitors. This revealed that SARS-CoV-2 strongly inhibits mitochondrial oxidative phosphorylation (OXPHOS) resulting in increased mitochondrial reactive oxygen species (mROS) production.

The elevated mROS stabilizes HIF-1α which redirects carbon molecules from mitochondrial oxidation through glycolysis and the pentose phosphate pathway (PPP) to provide substrates for viral biogenesis. mROS also induces the release of mitochondrial DNA (mtDNA) which activates innate immunity. The restructuring of cellular energy metabolism is mediated in part by SARS-CoV-2 Orf8 and Orf10 whose expression restructures nuclear DNA (nDNA) and mtDNA OXPHOS gene expression.

These viral proteins likely alter the epigenome, either by directly altering histone modifications or by modulating mitochondrial metabolite substrates of epigenome modification enzymes, potentially silencing OXPHOS gene expression and contributing to long-COVID.

Source: Guarnieri JW, Haltom JA, Albrecht YES, Lie T, Olali AZ, Widjaja GA, Ranshing SS, Angelin A, Murdock D, Wallace DC. SARS-CoV-2 Mitochondrial Metabolic and Epigenomic Reprogramming in COVID-19. Pharmacol Res. 2024 Apr 11:107170. doi: 10.1016/j.phrs.2024.107170. Epub ahead of print. PMID: 38614374. https://www.sciencedirect.com/science/article/pii/S1043661824001142 (Full text)

The molecular fingerprint of neuroinflammation in COVID-19: A comprehensive discussion on molecular mechanisms of neuroinflammation due to SARS-COV2 antigens

Abstract:

Background and objective: Severe acute respiratory syndrome coronavirus 2 attacks the neural system directly and indirectly via various systems, such as the nasal cavity, olfactory system, and facial nerves. Considering the high energy requirement, lack of antioxidant defenses, and high amounts of metal ions in the brain, oxidative damage is very harmful to the brain. Various neuropathic pain conditions, neurological disorders, and neuropsychiatric complications were reported in Coronavirus disease 2019, prolonged Coronavirus disease 2019, and after Coronavirus disease 2019 immunization. This manuscript offers a distinctive outlook on the interconnectedness between neurology and neuropsychiatry through its meticulous analysis of complications.

Discussion: After recovering from Coronavirus disease 2019, approximately half of the patients reported developing Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Long Coronavirus disease 2019 imaging reports illustrated the hypometabolism in various parts of the brain, such as olfactory bulbs, limbic/paralimbic domains, the brainstem, and the cerebellum. Ninety imaging and neuropathological studies of Coronavirus disease 2019 have shown evidence of white matter, brainstem, frontotemporal, and oculofrontal lesions. Emotional functions, such as pleasant, long/short-term memory, movement, cognition and cognition in decision-making are controlled by these regions. The neuroinflammation and the mechanisms of defense are well presented in the discussion. The role of microglia activation, Inducible NO synthase, Cyclooxygenases ½, Reactive oxygen species, neurotoxic toxins and pro-inflammatory cytokines, such as Interleukin-1 beta, Interleukin-6 and Tumor Necrosis Factor-alpha are highlighted in neuronal dysfunction and death. Nuclear factor kappa-light-chain-enhancer of activated B cells, Mitogen-activated protein kinase, Activator Protein 1, and Interferon regulatory factors are the main pathways involved in microglia activation in Coronavirus disease 2019 neuroinflammation.

Conclusion: The neurological aspect of Coronavirus disease 2019 should be highlighted. Neurological, psychological, and behavioral aspects of Coronavirus disease 2019, prolonged Coronavirus disease 2019, and Coronavirus disease 2019 vaccines can be the upcoming issues. We need a global awareness where this aspect of the disease should be more considered in health research.

Source: Zayeri ZD, Torabizadeh M, Kargar M, Kazemi H. The molecular fingerprint of neuroinflammation in COVID-19: A comprehensive discussion on molecular mechanisms of neuroinflammation due to SARS-COV2 antigens. Behav Brain Res. 2024 Jan 20;462:114868. doi: 10.1016/j.bbr.2024.114868. Epub ahead of print. PMID: 38246395. https://www.sciencedirect.com/science/article/abs/pii/S016643282400024X

Innate Immune Activation and Mitochondrial ROS Invoke Persistent Cardiac Conduction System Dysfunction after COVID-19

Abstract:

Background Cardiac risk rises during acute SARS-CoV-2 infection and in long COVID syndrome in humans, but the mechanisms behind COVID-19-linked arrhythmias are unknown. This study explores the acute and long term effects of SARS-CoV-2 on the cardiac conduction system (CCS) in a hamster model of COVID-19.

Methods Radiotelemetry in conscious animals was used to non-invasively record electrocardiograms and subpleural pressures after intranasal SARS-CoV-2 infection. Cardiac cytokines, interferon-stimulated gene expression, and macrophage infiltration of the CCS, were assessed at 4 days and 4 weeks post-infection. A double-stranded RNA mimetic, polyinosinic:polycytidylic acid (PIC), was used in vivo and in vitro to activate viral pattern recognition receptors in the absence of SARS-CoV-2 infection.

Results COVID-19 induced pronounced tachypnea and severe cardiac conduction system (CCS) dysfunction, spanning from bradycardia to persistent atrioventricular block, although no viral protein expression was detected in the heart. Arrhythmias developed rapidly, partially reversed, and then redeveloped after the pulmonary infection was resolved, indicating persistent CCS injury. Increased cardiac cytokines, interferon-stimulated gene expression, and macrophage remodeling in the CCS accompanied the electrophysiological abnormalities. Interestingly, the arrhythmia phenotype was reproduced by cardiac injection of PIC in the absence of virus, indicating that innate immune activation was sufficient to drive the response. PIC also strongly induced cytokine secretion and robust interferon signaling in hearts, human iPSC-derived cardiomyocytes (hiPSC-CMs), and engineered heart tissues, accompanied by alterations in electrical and Ca2+ handling properties. Importantly, the pulmonary and cardiac effects of COVID-19 were blunted by in vivo inhibition of JAK/STAT signaling or by a mitochondrially-targeted antioxidant.

Conclusions The findings indicate that long term dysfunction and immune cell remodeling of the CCS is induced by COVID-19, arising indirectly from oxidative stress and excessive activation of cardiac innate immune responses during infection, with implications for long COVID Syndrome.

Source: Deepthi Ashok, Ting Liu, Joseph Criscione, Meghana Prakash, Byunggik Kim, Julian Chow, Morgan Craney, Kyriakos N. Papanicolaou, Agnieszka Sidor, D. Brian Foster, Andrew Pekosz, Jason Villano, Deok-Ho Kim, Brian O’Rourke. Innate Immune Activation and Mitochondrial ROS Invoke Persistent Cardiac Conduction System Dysfunction after COVID-19. bioRxiv 2024.01.05.574280; doi: https://doi.org/10.1101/2024.01.05.574280 https://www.biorxiv.org/content/10.1101/2024.01.05.574280v1.full (Full text)

Microvascular Capillary and Precapillary Cardiovascular Disturbances Strongly Interact to Severely Affect Tissue Perfusion and Mitochondrial Function in ME/CFS Evolving from the Post COVID-19 Syndrome

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a frequent, debilitating and still enigmatic disease. There is a broad overlap in the symptomatology of ME/CFS and the Post-COVID Syndrome (PCS). A fraction of the PCS patients develops the full clinical picture of ME/CFS.
New observations in microvessels and blood from patients suffering from PCS have appeared and include microclots and malformed pathological blood cells. Capillary blood flow is impaired not only by pathological blood components but also by prothrombotic changes in the vascular wall, endothelial dysfunction, and expression of adhesion molecules in the capillaries. These disturbances can finally cause a low capillary flow and even capillary stasis. A low cardiac stroke volume due to hypovolemia and the inability of the capacitance vessels to adequately constrict to deliver the necessary cardiac preload generate an unfavorable low precapillary perfusion pressure.
Furthermore, a predominance of vasoconstrictor over vasodilator influences exists, in which sympathetic hyperactivity and endothelial dysfunction play a strong role, causing constriction of resistance vessels and of precapillary sphincters which leads to a fall in capillary pressure behind the sphincters. The interaction of these two precapillary cardiovascular mechanisms causing a low capillary perfusion pressure is hemodynamically highly unfavorable in the presence of a primary capillary stasis already caused by the pathological blood components and their interaction with the capillary wall, to severely impair organ perfusion.
The detrimental coincidence of the microcirculatory with the precapillary cardiovascular disturbances may constitute the key disturbance of the Post-COVID-19 syndrome and finally lead to ME/CFS in pre-disposed patients because the interaction causes a particular kind of perfusion disturbance – capillary ischemia-reperfusion – which has a high potential of causing mitochondrial dysfunction by inducing sodium- and calcium-overload in skeletal muscles. The latter in turns worsens the vascular situation by the generation of reactive oxygen species to close a vicious cycle from which the patient can hardly escape.
Source: Wirth, K.J.; Löhn, M. Microvascular Capillary and Precapillary Cardiovascular Disturbances Strongly Interact to Severely Affect Tissue Perfusion and Mitochondrial Function in ME/CFS Evolving from the Post COVID-19 Syndrome. Preprints 2023, 2023120791. https://doi.org/10.20944/preprints202312.0791.v1  https://www.preprints.org/manuscript/202312.0791/v1 (Full text available as PDF file)

Hyperbaric Oxygen Therapy Counters Oxidative Stress/Inflammation-Driven Symptoms in Long COVID-19 Patients: Preliminary Outcomes

Abstract:

Long COVID-19 patients show systemic inflammation and persistent symptoms such as fatigue and malaise, profoundly affecting their quality of life. Since improving oxygenation can oppose inflammation at multiple tissue levels, we hypothesized that hyperbaric oxygen therapy (HBOT) could arrest inflammation progression and thus relieve symptoms of COVID-19.
We evaluated oxy-inflammation biomarkers in long COVID-19 subjects treated with HBOT and monitored with non-invasive methods. Five subjects (two athletes and three patients with other comorbidities) were assigned to receive HBOT: 100% inspired O2 at 2.4 ATA in a multiplace hyperbaric chamber for 90 min (three athletes: 15 HBOT × 5 days/wk for 3 weeks; two patients affected by Idiopathic Sudden Sensorineural Hearing Loss: 30 HBOT × 5 days/wk for 6 weeks; and one patient with osteomyelitis: 30 HBOT × 5 days/wk for week for 6 weeks and, after a 30-day break, followed by a second cycle of 20 HBOT).
Using saliva and/or urine samples, reactive oxygen species (ROS), antioxidant capacity, cytokines, lipids peroxidation, DNA damage, and renal status were assessed at T1_pre (basal level) and at T2_pre (basal level after treatment), and the results showed attenuated ROS production, lipid peroxidation, DNA damage, NO metabolites, and inflammation biomarker levels, especially in the athletes post-treatment. Thus, HBOT may represent an alternative non-invasive method for treating long COVID-19-induced long-lasting manifestations of oxy-inflammation.
Source: Mrakic-Sposta S, Vezzoli A, Garetto G, Paganini M, Camporesi E, Giacon TA, Dellanoce C, Agrimi J, Bosco G. Hyperbaric Oxygen Therapy Counters Oxidative Stress/Inflammation-Driven Symptoms in Long COVID-19 Patients: Preliminary Outcomes. Metabolites. 2023; 13(10):1032. https://doi.org/10.3390/metabo13101032 https://www.mdpi.com/2218-1989/13/10/1032 (Full text)

Potential Prion Involvement in Long COVID-19 Neuropathology, Including Behavior

Abstract:

Prion is a term used to describe a protein infectious particle responsible for several neurodegenerative diseases in mammals, e.g., Creutzfeldt-Jakob disease. The novelty is that it is protein based infectious agent not involving a nucleic acid genome as found in viruses and bacteria.

Prion disorders exhibit, in part, incubation periods, neuronal loss, and induce abnormal folding of specific normal cellular proteins due to enhancing reactive oxygen species associated with mitochondria energy metabolism. These agents may also induce memory, personality and movement abnormalities as well as depression, confusion and disorientation.

Interestingly, some of these behavioral changes also occur in COVID-19 and mechanistically include mitochondrial damage caused by SARS-CoV-2 and subsequent production of reactive oxygen species. Taken together, we surmise, in part, long COVID may involve the induction of spontaneous prion emergence, especially in individuals susceptible to its origin may thus explain some of its manisfestions post-acute viral infection.

Source: Stefano GB, Büttiker P, Weissenberger S, Anders M, Raboch J, Ptacek R, Kream RM. Potential Prion Involvement in Long COVID-19 Neuropathology, Including Behavior. Cell Mol Neurobiol. 2023 Mar 28:1–6. doi: 10.1007/s10571-023-01342-8. Epub ahead of print. PMID: 36977809; PMCID: PMC10047479. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10047479/ (Full text)

A Proposed New Model to Explain the Role of Low Dose Non-DNA Targeted Radiation Exposure in Chronic Fatigue and Immune Dysfunction Syndrome

Abstract:

Chronic Fatigue and Immune Dysfunction Syndrome (CFIDS) is considered to be a multidimensional illness whose etiology is unknown. However, reports from Chernobyl, as well as those from the United States, have revealed an association between radiation exposure and the development of CFIDS. As such, we present an expanded model using a systems biology approach to explain the etiology of CFIDS as it relates to this cohort of patients. This paper proposes an integrated model with ionizing radiation as a suggested trigger for CFIDS mediated through UVA induction and biophoton generation inside the body resulting from radiation-induced bystander effects (RIBE).
Evidence in support of this approach has been organized into a systems view linking CFIDS illness markers with the initiating events, in this case, low-dose radiation exposure. This results in the formation of reactive oxygen species (ROS) as well as important immunologic and other downstream effects. Furthermore, the model implicates melanoma and subsequent hematopoietic dysregulation in this underlying process. Through the identification of this association with melanoma, clinical medicine, including dermatology, hematology, and oncology, can now begin to apply its expansive knowledge base to provide new treatment options for an illness that has had few effective treatments.
Source: Cocchetto A, Seymour C, Mothersill C. A Proposed New Model to Explain the Role of Low Dose Non-DNA Targeted Radiation Exposure in Chronic Fatigue and Immune Dysfunction Syndrome. International Journal of Molecular Sciences. 2023; 24(7):6022. https://doi.org/10.3390/ijms24076022 https://www.mdpi.com/1422-0067/24/7/6022 (Full text)

Understanding Long COVID; Mitochondrial Health and Adaptation—Old Pathways, New Problems

Abstract:

Many people infected with the SARS-CoV-2 suffer long-term symptoms, such as “brain fog”, fatigue and clotting problems. Explanations for “long COVID” include immune imbalance, incomplete viral clearance and potentially, mitochondrial dysfunction. As conditions with sub-optimal mitochondrial function are associated with initial severity of the disease, their prior health could be key in resistance to long COVID and recovery.
The SARs virus redirects host metabolism towards replication; in response, the host can metabolically react to control the virus. Resolution is normally achieved after viral clearance as the initial stress activates a hormetic negative feedback mechanism. It is therefore possible that, in some individuals with prior sub-optimal mitochondrial function, the virus can “tip” the host into a chronic inflammatory cycle. This might explain the main symptoms, including platelet dysfunction.
Long COVID could thus be described as a virally induced chronic and self-perpetuating metabolically imbalanced non-resolving state characterised by mitochondrial dysfunction, where reactive oxygen species continually drive inflammation and a shift towards glycolysis. This would suggest that a sufferer’s metabolism needs to be “tipped” back using a stimulus, such as physical activity, calorie restriction, or chemical compounds that mimic these by enhancing mitochondrial function, perhaps in combination with inhibitors that quell the inflammatory response.
Source: Nunn AVW, Guy GW, Brysch W, Bell JD. Understanding Long COVID; Mitochondrial Health and Adaptation—Old Pathways, New Problems. Biomedicines. 2022; 10(12):3113. https://doi.org/10.3390/biomedicines10123113 https://www.mdpi.com/2227-9059/10/12/3113 (Full text)

Altered Erythrocyte biophysical properties in Chronic Fatigue Syndrome

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a multi-systemic illness of unknown etiology affecting millions of individuals worldwide. In this work, we tested the hypothesis that erythrocyte biophysical properties are adversely affected in ME/CFS.

We tested erythrocyte deformability using a high-throughput microfluidic device which mimics microcapillaries. We perfused erythrocytes from ME/CFS patients and from age and sex matched healthy controls (n=14 pairs of donors) through a high-throughput microfluidic platform (5μmx5μm). We recorded cell movement at high speed (4000 fps), followed by image analysis to assess the following parameters: entry time (time required by cells to completely enter the test channels), average transit velocity (velocity of cells inside the test channels) and elongation index (ratio of the major diameter before and after deformation in the test channel). We observed that erythrocytes from ME/CFS patients had higher entry time, lower average transit velocity and lower elongation index as compared to healthy controls.

Taken together, this data shows that erythrocytes from ME/CFS patients have reduced deformability. To corroborate our findings, we measured the erythrocyte sedimentation rate for these donors which show that the erythrocytes from ME/CFS patients had lower sedimentation rates. To understand the basis for differences in deformability, we investigated changes in the fluidity of the membrane using pyrenedecanoic acid and observed that erythrocytes from ME/CFS patients have lower membrane fluidity. Zeta potential measurements showed that ME/CFS patients had lower net negative surface charge on the erythrocyte plasma membrane. Higher levels of reactive oxygen species in erythrocytes from ME/CFS patients were also observed. Using scanning electron microscopy, we also observed changes in erythrocyte morphology between ME/CFS patients and healthy controls.

Finally, preliminary studies show that erythrocytes from “recovering” ME/CFS patients do not show such differences, suggesting a connection between erythrocyte deformability and disease severity.

Source: Amit K. Saha, Brendan R. Schmidt, Julie Wilhelmy, Vy Nguyen, Justin K. Do, Vineeth C. Suja, Mohsen Nemat-Gorgani, Anand K. Ramasubramanian, Ronald W. Davis. Altered Erythrocyte Biophysical Properties in Chronic Fatigue Syndrome. Biophys. Journal. VOLUME 116, ISSUE 3, SUPPLEMENT 1, 122A, FEBRUARY 15, 2019. https://www.cell.com/biophysj/fulltext/S0006-3495(18)31946-5

The many roads to mitochondrial dysfunction in neuroimmune and neuropsychiatric disorders

Abstract:

BACKGROUND: Mitochondrial dysfunction and defects in oxidative metabolism are a characteristic feature of many chronic illnesses not currently classified as mitochondrial diseases. Examples of such illnesses include bipolar disorder, multiple sclerosis, Parkinson’s disease, schizophrenia, depression, autism, and chronic fatigue syndrome.

DISCUSSION: While the majority of patients with multiple sclerosis appear to have widespread mitochondrial dysfunction and impaired ATP production, the findings in patients diagnosed with Parkinson’s disease, autism, depression, bipolar disorder schizophrenia and chronic fatigue syndrome are less consistent, likely reflecting the fact that these diagnoses do not represent a disease with a unitary pathogenesis and pathophysiology. However, investigations have revealed the presence of chronic oxidative stress to be an almost invariant finding in study cohorts of patients afforded each diagnosis. This state is characterized by elevated reactive oxygen and nitrogen species and/or reduced levels of glutathione, and goes hand in hand with chronic systemic inflammation with elevated levels of pro-inflammatory cytokines.

SUMMARY: This paper details mechanisms by which elevated levels of reactive oxygen and nitrogen species together with elevated pro-inflammatory cytokines could conspire to pave a major road to the development of mitochondrial dysfunction and impaired oxidative metabolism seen in many patients diagnosed with these disorders.

 

Source: Morris G, Berk M. The many roads to mitochondrial dysfunction in neuroimmune and neuropsychiatric disorders. BMC Med. 2015 Apr 1;13:68. doi: 10.1186/s12916-015-0310-y. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4382850/ (Full article)