Tag: mitochondria

Mitochondrial dysfunction in long COVID: mechanisms, consequences, and potential therapeutic approaches

Abstract:

The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has introduced the medical community to the phenomenon of long COVID, a condition characterized by persistent symptoms following the resolution of the acute phase of infection. Among the myriad of symptoms reported by long COVID sufferers, chronic fatigue, cognitive disturbances, and exercise intolerance are predominant, suggesting systemic alterations beyond the initial viral pathology. Emerging evidence has pointed to mitochondrial dysfunction as a potential underpinning mechanism contributing to the persistence and diversity of long COVID symptoms.

This review aims to synthesize current findings related to mitochondrial dysfunction in long COVID, exploring its implications for cellular energy deficits, oxidative stress, immune dysregulation, metabolic disturbances, and endothelial dysfunction. Through a comprehensive analysis of the literature, we highlight the significance of mitochondrial health in the pathophysiology of long COVID, drawing parallels with similar clinical syndromes linked to post-infectious states in other diseases where mitochondrial impairment has been implicated.

We discuss potential therapeutic strategies targeting mitochondrial function, including pharmacological interventions, lifestyle modifications, exercise, and dietary approaches, and emphasize the need for further research and collaborative efforts to advance our understanding and management of long COVID. This review underscores the critical role of mitochondrial dysfunction in long COVID and calls for a multidisciplinary approach to address the gaps in our knowledge and treatment options for those affected by this condition.

Source: Molnar T, Lehoczki A, Fekete M, Varnai R, Zavori L, Erdo-Bonyar S, Simon D, Berki T, Csecsei P, Ezer E. Mitochondrial dysfunction in long COVID: mechanisms, consequences, and potential therapeutic approaches. Geroscience. 2024 Apr 26. doi: 10.1007/s11357-024-01165-5. Epub ahead of print. PMID: 38668888. https://link.springer.com/article/10.1007/s11357-024-01165-5 (Full text)

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)

Reinforcing the Evidence of Mitochondrial Dysfunction in Long COVID Patients Using a Multiplatform Mass Spectrometry-Based Metabolomics Approach

Abstract:

Despite the recent and increasing knowledge surrounding COVID-19 infection, the underlying mechanisms of the persistence of symptoms for a long time after the acute infection are still not completely understood. Here, a multiplatform mass spectrometry-based approach was used for metabolomic and lipidomic profiling of human plasma samples from Long COVID patients (n = 40) to reveal mitochondrial dysfunction when compared with individuals fully recovered from acute mild COVID-19 (n = 40).

Untargeted metabolomic analysis using CE-ESI(+/-)-TOF-MS and GC-Q-MS was performed. Additionally, a lipidomic analysis using LC-ESI(+/-)-QTOF-MS based on an in-house library revealed 447 lipid species identified with a high confidence annotation level. The integration of complementary analytical platforms has allowed a comprehensive metabolic and lipidomic characterization of plasma alterations in Long COVID disease that found 46 relevant metabolites which allowed to discriminate between Long COVID and fully recovered patients.

We report specific metabolites altered in Long COVID, mainly related to a decrease in the amino acid metabolism and ceramide plasma levels and an increase in the tricarboxylic acid (TCA) cycle, reinforcing the evidence of an impaired mitochondrial function. The most relevant alterations shown in this study will help to better understand the insights of Long COVID syndrome by providing a deeper knowledge of the metabolomic basis of the pathology.

Source: Martínez S, Albóniga OE, López-Huertas MR, Gradillas A, Barbas C. Reinforcing the Evidence of Mitochondrial Dysfunction in Long COVID Patients Using a Multiplatform Mass Spectrometry-Based Metabolomics Approach. J Proteome Res. 2024 Apr 2. doi: 10.1021/acs.jproteome.3c00706. Epub ahead of print. PMID: 38566450. https://pubmed.ncbi.nlm.nih.gov/38566450/

Conceptual foundations of acetylcarnitine supplementation in neuropsychiatric long COVID syndrome: a narrative review

Abstract:

Post-acute sequelae of COVID-19 can present as multi-organ pathology, with neuropsychiatric symptoms being the most common symptom complex, characterizing long COVID as a syndrome with a significant disease burden for affected individuals. Several typical symptoms of long COVID, such as fatigue, depressive symptoms and cognitive impairment, are also key features of other psychiatric disorders such as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and major depressive disorder (MDD). However, clinically successful treatment strategies are still lacking and are often inspired by treatment options for diseases with similar clinical presentations, such as ME/CFS.

Acetylcarnitine, the shortest metabolite of a class of fatty acid metabolites called acylcarnitines and one of the most abundant blood metabolites in humans can be used as a dietary/nutritional supplement with proven clinical efficacy in the treatment of MDD, ME/CFS and other neuropsychiatric disorders. Basic research in recent decades has established acylcarnitines in general, and acetylcarnitine in particular, as important regulators and indicators of mitochondrial function and other physiological processes such as neuroinflammation and energy production pathways.

In this review, we will compare the clinical basis of neuropsychiatric long COVID with other fatigue-associated diseases. We will also review common molecular disease mechanisms associated with altered acetylcarnitine metabolism and the potential of acetylcarnitine to interfere with these as a therapeutic agent. Finally, we will review the current evidence for acetylcarnitine as a supplement in the treatment of fatigue-associated diseases and propose future research strategies to investigate the potential of acetylcarnitine as a treatment option for long COVID.

Source: Helbing DL, Dommaschk EM, Danyeli LV, Liepinsh E, Refisch A, Sen ZD, Zvejniece L, Rocktäschel T, Stabenow LK, Schiöth HB, Walter M, Dambrova M, Besteher B. Conceptual foundations of acetylcarnitine supplementation in neuropsychiatric long COVID syndrome: a narrative review. Eur Arch Psychiatry Clin Neurosci. 2024 Jan 3. doi: 10.1007/s00406-023-01734-3. Epub ahead of print. PMID: 38172332. https://link.springer.com/article/10.1007/s00406-023-01734-3 (Full text)

In vitro B cell experiments explore the role of CD24, CD38 and energy metabolism in ME/CFS

Abstract:

Disturbances of energy metabolism contribute to clinical manifestations of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Previously we found that B cells from ME/CFS patients have increased expression of CD24, a modulator of many cellular functions including those of cell stress.

The relative ability of B cells from ME/CFS patients and healthy controls (HC) to respond to rapid changes in energy demand were compared. CD24, the ectonucleotidases CD39, CD73, the NAD-degrading enzyme CD38 and mitochondrial mass (MM) were measured following cross-linking of the B cell receptor (BCR) and co-stimulation with either T cell dependent or Toll-like receptor-9 dependent agonists. Levels of metabolites consumed/produced were measured using 1H-NMR spectroscopy and analysed in relation to cell growth and immunophenotype.

Proliferating B cells from patients with ME/CFS showed lower mitochondrial mass and a significantly increased usage of essential amino acids compared those from HC, with a significantly delayed loss of CD24 and increased expression of CD38 following stimulation. Immunophenotype results suggested the triggering of a stress response in ME/CFS B cells associated with increased usage of additional substrates to maintain necessary ATP levels. Disturbances in energy metabolism in ME/CFS B cells were thus confirmed in a dynamic in vitro model, providing the basis for further mechanistic investigations.

Source: Christopher Armstrong, Fane F. Mensah, Maria Leandro, Venkat Reddy, Paul R. Gooley, Saul Berkovitz, Geraldine Cambridge. In vitro B cell experiments explore the role of CD24, CD38 and energy metabolism in ME/CFS. Front. Immunol. Sec. B Cell Biology, Volume 14 – 2023 | doi: 10.3389/fimmu.2023.1178882 https://www.frontiersin.org/articles/10.3389/fimmu.2023.1178882/abstract

Mitochondrial Dysfunction and Coenzyme Q10 Supplementation in Post-Viral Fatigue Syndrome: An Overview

Abstract:

Post-viral fatigue syndrome (PVFS) encompasses a wide range of complex neuroimmune disorders of unknown cause characterized by disabling post-exertional fatigue, myalgia and joint pain, cognitive impairments, unrefreshing sleep, autonomic dysfunction, and neuropsychiatric symptoms. It includes myalgic encephalomyelitis, also known as chronic fatigue syndrome (ME/CFS), fibromyalgia (FM), and more recently post-COVID-19 condition (Long COVID).

To date, there are no definitive clinical case criteria and no FDA-approved pharmacological therapies for PVFS. Given the current lack of effective treatments, there is a need to develop novel therapeutic strategies for these disorders.

Mitochondria, the cellular organelles responsible for tissue energy production, have recently garnered attention in research into PVFS due to their crucial role in cellular bioenergetic metabolism in these conditions. Accumulating literature has identified a link between mitochondrial dysfunction and low-grade systemic inflammation in ME/CFS, FM, and Long COVID.

To address this issue, this article aimed to critically review the evidence relating to mitochondrial dysfunction in the pathogenesis of these disorders; in particular, to evaluate the effectiveness of coenzyme Q10 supplementation on chronic fatigue and pain symptoms as a novel therapeutic strategy for the treatment of PVFS.

Source: Mantle, D.; Hargreaves, I.P.; Domingo, J.C.; Castro-Marrero, J. Mitochondrial Dysfunction and Coenzyme Q10 Supplementation in Post-Viral Fatigue Syndrome: An Overview. Preprints 2023, 2023111554. https://doi.org/10.20944/preprints202311.1554.v1 https://www.preprints.org/manuscript/202311.1554/v1 (Full text available as PDF file)

Successful treatment of myalgic encephalomyelitis/chronic fatigue syndrome using hydrogen gas: four case reports

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by unexplained fatigue and malaise that persist for more than 6 months with neuropsychiatric symptoms, including slight fever, headache, weakness, impaired thinking, and depression.[1,2] The onset and severity of these symptoms vary and reduce the quality of life as well as social, occupational, and personal activities of those affected, with some becoming bedridden.[1,2] The number of ME/CFS patients in the United States is estimated to be between 836,000 and 2.5 million.[3]

Although it currently remains unclear whether there are objective and biological abnormalities in ME/CFS, recent neuroimaging, blood marker analyses, and energy metabolism and mitochondrial studies detected these abnormalities in ME/CFS patients.[4] ME/CFS may be caused by the activation of the immune system, both within and outside the brain, which induces the release of inflammatory cytokines. ME/CFS is presumed to cause abnormalities in the central and autonomic nervous systems, systemic energy metabolism, and immune system and also involve oxidative and nitrosative stress.[4,5,6] Dysfunctions in systemic energy metabolism may be related to abnormalities in the structure and function of mitochondria.[7,8,9,10]

Molecular hydrogen (H2) is a gaseous molecule that selectively scavenges reactive oxygen and nitrogen species with strong oxidizing power, namely, hydroxyl radicals (·OH) and peroxynitrite, respectively.[11,12] H2 easily crosses the blood-brain barrier and biological membranes, reaches mitochondria, and protects cells from ·OH-induced cell damage.[11,12] A recent literature review revealed that H2 attenuated acute or chronic fatigue in animals and healthy subjects.[13] We also reported that the anti-fatigue effects of H2 involved the protection of mitochondria, which may also ameliorate the pathogenesis of ME/CFS.[13] Therefore, we conducted this case study to test this hypothesis by examining the efficacy of H2 gas inhalation in four patients with ME/CFS.

Source: Hirano, Shin-ichi*; Ichikawa, Yusuke; Sato, Bunpei; Takefuji, Yoshiyasu; Satoh, Fumitake. Successful treatment of myalgic encephalomyelitis/chronic fatigue syndrome using hydrogen gas: four case reports. Medical Gas Research 14(2):p 84-86, June 2024. | DOI: 10.4103/2045-9912.385441 https://journals.lww.com/mgar/fulltext/2024/14020/successful_treatment_of_myalgic.7.aspx (Full text)

Maximal Oxidative Capacity During Exercise is Associated with Muscle Power Output in Patients with Long coronavirus disease 2019 (COVID-19) Syndrome. A Moderation Analysis

Abstract:

Background & Aims: Long COVID syndrome (LCS) involves persistent symptoms experienced by many patients after recovering from coronavirus disease 2019 (COVID-19). We aimed to assess skeletal muscle energy metabolism, which is closely related to peak fat oxidation rates during exercise, in patients with LCS compared with healthy controls. We also examined whether muscle power output mediates the relationship between COVID-19 and skeletal muscle energy metabolism.

Methods: In this cross-sectional study, we enrolled 71 patients with LCS and 63 healthy controls. We assessed clinical characteristics such as body composition, physical activity, and muscle strength. We used cardiopulmonary exercise testing to evaluate substrate oxidation rates during graded exercise. We performed statistical analyses to compare group characteristics and peak fat oxidation differences based on power output.

Results: The two-way analysis of covariance (ANCOVA) results, adjusted for covariates, showed that the patients with LCS had lower absolute maximal fatty acid oxidation (MFO), relative MFO/fat-free mass (FFM), absolute carbohydrates oxidation (CHox), relative CHox/FFM, and oxygen uptake (VO2) at maximum fat oxidation (mL∙min−1) than the healthy controls (P < 0.05). Moderation analysis indicated that muscle power output significantly influenced the relationship between LCS and reduced peak fat oxidation (interaction β = −0.105 [95% confidence interval −0.174; −0.036]; P = 0.026). Therefore, when muscle power output was below 388 W, the effect of the LCS on MFO was significant (62% in our study sample P = 0.010). These findings suggest compromised mitochondrial bioenergetics and muscle function, represented by lower peak fat oxidation rates, in the patients with LCS compared with the healthy controls.

Conclusion: The patients with LCS had lower peak fat oxidation during exercise compared with the healthy controls, potentially indicating impairment in skeletal muscle function. The relationship between peak fat oxidation and LCS appears to be mediated predominantly by muscle power output. Additional research should continue investigating LCS pathogenesis and the functional role of mitochondria.

Source: Robinson Ramírez-Vélez, Sergio Oscoz-Ochandorena, Yesenia García-Alonso, Nora García-Alonso, Gaizka Legarra-Gorgoñon, Julio Oteiza, Ander Ernaga Lorea, Mikel Izquierdo, María Correa-Rodríguez. Maximal Oxidative Capacity During Exercise is Associated with Muscle Power Output in Patients with Long coronavirus disease 2019 (COVID-19) Syndrome. A Moderation Analysis. Clinical Nutrition ESPEN, 2023, ISSN 2405-4577, https://doi.org/10.1016/j.clnesp.2023.10.009. https://www.sciencedirect.com/science/article/pii/S2405457723021666 (Full text)

A Systematic Analysis of the Effectiveness of Mitochondrial-Based Therapies for the Management of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

Abstract:

Background: This study aimed to compile and analyze an assortment of research findings concerning potential therapeutic strategies for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). The understanding of the multifaceted nature of ME/CFS and the need for varied and personalized therapeutic approaches were central to this investigation.

Methods: A comprehensive review and analysis of various studies conducted on ME/CFS was undertaken. These studies covered a wide array of interventions, including pharmacological treatments, nutritional supplements, dietary changes, physical therapies, and lifestyle modifications. The analysis pertained to the effectiveness of these interventions, potential physiological and biochemical markers, and the response of ME/CFS patients to different treatment strategies.

Results: The 22 selected papers investigated demonstrated varied responses to the multitude of interventions. While some interventions showed significant improvement in fatigue and biochemical parameters, others found no significant differences between the treated and control groups. Potential physiological and biochemical markers for ME/CFS, such as impaired T cell metabolism, reduced flow-mediated dilation, and decreased work rate at the ventilatory threshold, were highlighted.

Conclusion: The findings underscored the complexity of ME/CFS and the need for personalized treatment strategies. Despite mixed results and several limitations, these studies collectively contributed to understanding ME/CFS’s complex pathophysiology and treatment, laying the groundwork for future research towards more effective therapeutic strategies for this debilitating disease.

Source: Keferstein, L.G. A Systematic Analysis of the Effectiveness of Mitochondrial-Based Therapies for the Management of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Preprints 2023, 2023100637. https://doi.org/10.20944/preprints202310.0637.v1 https://www.preprints.org/manuscript/202310.0637/v1 (Full text available as PDF)

Immune cell proteomes of Long COVID patients have functional changes similar to those in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Of those infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), ~ 10% develop the chronic post-viral debilitating condition, Long COVID (LC). Although LC is a heterogeneous condition, about half of cases have a typical post-viral fatigue condition with onset and symptoms that are very similar to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). A key question is whether these conditions are closely related.

ME/CFS is a post-stressor fatigue condition that arises from multiple triggers. To investigate the pathophysiology of LC, a pilot study of patients and healthy controls has used quantitative proteomics to discover changes in peripheral blood mononuclear cell (PBMC) proteins. A principal component analysis separated all Long COVID patients from healthy controls.

Analysis of 3131 proteins identified 162 proteins differentially regulated, of which 37 were related to immune functions, and 21 to mitochondrial functions. Markov cluster analysis identified clusters involved in immune system processes, and two aspects of gene expression-spliceosome and transcription. These results were compared with an earlier dataset of 346 differentially regulated proteins in PBMC’s from ME/CFS patients analysed by the same methodology.

There were overlapping protein clusters and enriched molecular pathways particularly in immune functions, suggesting the two conditions have similar immune pathophysiology as a prominent feature, and mitochondrial functions involved in energy production were affected in both conditions.

Source: Katie Peppercorn, Christina D. Edgar, Torsten Kleffmann, Warren. P Tate. Immune cell proteomes of Long COVID patients have functional changes similar to those in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Research Square preprint https://doi.org/10.21203/rs.3.rs-3335919/v1 https://www.researchsquare.com/article/rs-3335919/v1 (Full text) https://www.nature.com/articles/s41598-023-49402-9 (Final full text)