Tag: metabolic dysfunction

ME/CFS and PASC Patient-Derived Immunoglobulin Complexes Disrupt Mitochondrial Function and Alter Inflammatory Marker Secretion

Abstract:

Autoimmunity is a key clinical feature in both post-infectious Myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) and Post-Acute Sequelae of COVID (PASC). Passive transfer of immunoglobulins from patients’ sera into mice induces some clinical features of PASC. IgG-induced transfer of disease phenotypes has long been appreciated, yet the exact mechanism of disease development remains largely elusive.

Here, we demonstrate that IgG isolated from post-infectious ME/CFS patients selectively induces mitochondrial fragmentation in human endothelial cells, thereby altering mitochondrial energetics. This effect is lost upon cleavage of IgG into its Fab and Fc fragments.

The digested Fab fragment from ME/CFS alone was able to alter the mitochondrial energetics, resembling the effect of intact IgG. In contrast, the Fc fragment alone induced a hypometabolic phenotype characterized by a trend towards reduced overall ATP content. IgG from ME/CFS and PASC patients induced distinct but separate cytokine secretion profiles in healthy PBMCs.

Proteomics analysis of IgG-bound immune complexes revealed significant changes within the immune complexes of ME/CFS patients, affecting extracellular matrix organization, while the same from PASC patients pointed towards alterations in hemostasis and blood clot regulation.

We demonstrate that IgGs from ME/CFS patients carry a chronic protective stress response that promotes mitochondrial adaptation via fragmentation, without altering mitochondrial ATP generation capacity in endothelial cells. Together, these results highlight a potential pathogenic role of IgG in post-infectious ME/CFS and point to novel therapeutic strategies targeting antibody-mediated metabolic dysregulation.

Source: Bhupesh Kumar Prusty, Zheng Liu, Claudia Hollmann, Sharada Kalanidhi, Andreas Schlosser, Stephanie Lammer, Georgy Nikolayshvili, E mils Edgars Basens, Liba Sokolovska, Zaiga Nora-Krukle, Robert K Naviaux, Gabriela Riemekasten, Rebekka Rust, Judith Bellmann, Friedemann Paul, Franziska Sotzny, Carmen Scheibenbogen. ME/CFS and PASC Patient-Derived Immunoglobulin Complexes Disrupt Mitochondrial Function and Alter Inflammatory Marker Secretion. medRxiv 2025.08.06.25332978; doi: https://doi.org/10.1101/2025.08.06.25332978 https://www.medrxiv.org/content/10.1101/2025.08.06.25332978v1 (Full text available as PDF file)

Unravelling the Connection Between Energy Metabolism and Immune Senescence/Exhaustion in Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating disease, characterized by a diverse array of symptoms including post-exertional malaise (PEM), severe fatigue, and cognitive impairments, all of which drastically diminish the patients’ quality of life. Despite its impact, no curative treatments exist, largely due to the limited understanding of the disease’s underlying pathophysiology.
Mitochondrial dysfunction, leading to impaired energy production and utilization, is believed to play a key role in the onset of fatigue and PEM, positioning it as a potential key pathophysiological mechanism underlying ME/CFS. Additionally, the disorder shows similarities to chronic viral infections, with frequent reports of immune system alterations, suggesting a critical role for immune (dys)functioning. In particular, the roles of immune senescence and immune exhaustion—two fundamental immune states—remain poorly understood in ME/CFS.
This state-of-the-art review explores how metabolic dysfunction and immune dysfunction may be interconnected in ME/CFS, proposing that energy deficits may directly impair immune function. By examining this metabolic–immune interplay, this review highlights potential pathways for developing innovative therapeutic strategies that target both energy metabolism and immune regulation, offering hope for improving patient outcomes.
Source: Van Campenhout J, Buntinx Y, Xiong H-Y, Wyns A, Polli A, Nijs J, Aerts JL, Laeremans T, Hendrix J. Unravelling the Connection Between Energy Metabolism and Immune Senescence/Exhaustion in Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Biomolecules. 2025; 15(3):357. https://doi.org/10.3390/biom15030357 https://www.mdpi.com/2218-273X/15/3/357 (Full text)

Unravelling shared mechanisms: insights from recent ME/CFS research to illuminate long COVID pathologies

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating chronic illness often triggered by an initiating acute event, mainly viral infections. The transition from acute to chronic disease remains unknown, but interest in this phenomenon has escalated since the COVID-19 pandemic and the post-COVID-19 illness, termed ‘long COVID’ (LC). Both ME/CFS and LC share many clinical similarities.

Here, we present recent findings in ME/CFS research focussing on proposed disease pathologies shared with LC. Understanding these disease pathologies and how they influence each other is key to developing effective therapeutics and diagnostic tests. Given that ME/CFS typically has a longer disease duration compared with LC, with symptoms and pathologies evolving over time, ME/CFS may provide insights into the future progression of LC.

Source: Annesley SJ, Missailidis D, Heng B, Josev EK, Armstrong CW. Unravelling shared mechanisms: insights from recent ME/CFS research to illuminate long COVID pathologies. Trends Mol Med. 2024 Mar 4:S1471-4914(24)00028-5. doi: 10.1016/j.molmed.2024.02.003. Epub ahead of print. PMID: 38443223. https://www.sciencedirect.com/science/article/pii/S1471491424000285 (Full text)

Neutrophil degranulation, endothelial and metabolic dysfunction in unvaccinated long COVID patients

Abstract:

Background: Long COVID symptoms are widely diffused and have a poorly understood pathophysiology, with possible involvement of inflammatory cytokines.

Materials and methods: A prospective follow-up study involved 385 unvaccinated patients, started 1 month after SARS-CoV-2 infection and continued for up to 12 months. We compared circulating biomarkers of neutrophil degranulation, endothelial and metabolic dysfunction in subjects with long COVID symptoms and in asymptomatic post-COVID controls.

Results: The highest occurrence of symptoms (71%) was after 3 months from the infection, decreasing to 62.3% and 29.4% at 6 and 12 months, respectively. Compared to controls, long COVID patients had increased levels of the neutrophilic degranulation indices MMP-8 and MPO, of endothelial dysfunction indices L-selectin and P-selectin. Among indices of metabolic dysfunction, leptin levels were higher in long COVID patients than in controls.

Conclusion: In unvaccinated patients, symptoms may persist up to 1 year after acute COVID infection, with increased indices of neutrophil degranulation, endothelial and metabolic dysfunction. The clinical implications of specific inflammatory biomarkers require further attention, especially in individuals with fatigue and long COVID-linked cognitive dysfunctions.

Source: Di Ciaula A, Liberale L, Portincasa P, Khalil M, Galerati I, Farella I, Noto A, JohnBritto S, Moriero M, Michelauz C, Frè F, Olivero C, Bertolotto M, Montecucco F, Carbone F, Bonfrate L. Neutrophil degranulation, endothelial and metabolic dysfunction in unvaccinated long COVID patients. Eur J Clin Invest. 2024 Jan 16:e14155. doi: 10.1111/eci.14155. Epub ahead of print. PMID: 38226472. https://pubmed.ncbi.nlm.nih.gov/38226472/

Metabolic and endocrine complications of long COVID-19: A review

Abstract:

Over the past two years, the COVID-19 outbreak caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), centralized the interest of the health care systems and the scientific world. Majority of the COVID-19 infected individuals fully recover. However, about 12%-50% of patients experience a variety of mid- and long-term effects after recovering from the initial illness. These mid- and long-term effects are collectively known as post-COVID-19 condition or ‘long-COVID’. In the coming months, the long-term consequences of COVID-19 on the metabolic and endocrine systems may expect to rise and pose a global health care challenge. This review article aims to discuss the possible metabolic and endocrine complications of long-COVID and the relevant research findings.

Source: Bandara T, Deshmukh HA, Abdalla M, Sathyapalan T. Metabolic and endocrine complications of long COVID-19: A review. Exp Clin Endocrinol Diabetes. 2023 Mar 28. doi: 10.1055/a-2063-8697. Epub ahead of print. PMID: 36977491. https://pubmed.ncbi.nlm.nih.gov/36977491/

Altered Fatty Acid Oxidation in Lymphocyte Populations of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disabling multisystem illness in which individuals are plagued with fatigue, inflammatory symptoms, cognitive dysfunction, and the hallmark symptom, post-exertional malaise. While the cause of this disease remains unknown, there is evidence of a potential infectious component that, along with patient symptoms and common onsets of the disease, implicates immune system dysfunction. To further our understanding of the state of ME/CFS lymphocytes, we characterized the role of fatty acids in isolated Natural Killer cells, CD4+ T cells, and CD8+ T cells in circulation and after overnight stimulation, through implicit perturbations to fatty acid oxidation.

We examined samples obtained from at least 8 and as many as 20 subjects for immune cell fatty acid characterization in a variety of experiments and found that all three isolated cell types increased their utilization of lipids and levels of pertinent proteins involved in this metabolic pathway in ME/CFS samples, particularly during higher energy demands and activation. In T cells, we characterized the cell populations contributing to these metabolic shifts, which included CD4+ memory cells, CD4+ effector cells, CD8+ naïve cells, and CD8+ memory cells.

We also discovered that patients with ME/CFS and healthy control samples had significant correlations between measurements of CD4+ T cell fatty acid metabolism and demographic data. These findings provide support for metabolic dysfunction in ME/CFS immune cells. We further hypothesize about the consequences that these altered fuel dependencies may have on T and NK cell effector function, which may shed light on the illness’s mechanism of action.

Source: Maya J, Leddy SM, Gottschalk CG, Peterson DL, Hanson MR. Altered Fatty Acid Oxidation in Lymphocyte Populations of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Int J Mol Sci. 2023 Jan 19;24(3):2010. doi: 10.3390/ijms24032010. PMID: 36768336; PMCID: PMC9916395. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9916395/ (Full text)

Investigating Fatigue and Exercise Intolerance in a University Immunology Clinic

Abstract:

Purpose: This manuscript reviews the experience of a University Immunology clinic with the evaluation of patients with idiopathic fatigue and exercise intolerance for the presence of metabolic disorders. Laboratory, biochemical and genetic studies were utilized in the evaluation.

Recent Findings: Of the 372 patients evaluated, 95% were found to have a treatable metabolic disorder. A defect in the glycogen storage pathway was found in 78 patients. Mitochondrial disorders were found in 258 patients. Myoadenylate deaminase deficiency was found in 7 patients. Various congenital myopathies were identified in 11 patients. Inflammatory myopathies were identified in 25 patients, 6 of whom had normal muscle enzymes on the initial evaluation.

Summary: The majority of patients (95%) referred with idiopathic fatigue and exercise intolerance after extensive evaluations were found to have underlying metabolic dysfunction. Frequently associated problems included gastrointestinal dysmotility disorders, recurrent infections, Raynaud’s, migraine headaches and various autoimmune diseases. Most patients showed symptomatic improvement with treatment of their metabolic dysfunction.

Source: Julian L A, Paul I, Molly M, John B, Lucia B. Investigating Fatigue and Exercise Intolerance in a University Immunology Clinic. Arch Rheum & Arthritis Res. 1(1): 2020. ARAR.MS.ID.000505. https://irispublishers.com/arar/fulltext/Investigating-Fatigue-and-Exercise-Intolerance-in-a-University.ID.000505.php (Full study)

Investigating Fatigue and Exercise Intolerance in a University Immunology Clinic

Abstract:

Purpose: This manuscript reviews the experience of a University Immunology clinic with the evaluation of patients with idiopathic fatigue and exercise intolerance for the presence of metabolic disorders. Laboratory, biochemical and genetic studies were utilized in the evaluation.

Recent Findings: Of the 372 patients evaluated, 95% were found to have a treatable metabolic disorder. A defect in the glycogen storage pathway was found in 78 patients. Mitochondrial disorders were found in 258 patients. Myoadenylate deaminase deficiency was found in 7 patients. Various congenital myopathies were identified in 11 patients. Inflammatory myopathies were identified in 25 patients, 6 of whom had normal muscle enzymes on the initial evaluation.

Summary: The majority of patients (95%) referred with idiopathic fatigue and exercise intolerance after extensive evaluations were found to have underlying metabolic dysfunction. Frequently associated problems included gastrointestinal dysmotility disorders, recurrent infections, Raynaud’s, migraine headaches and various autoimmune diseases. Most patients showed symptomatic improvement with treatment of their metabolic dysfunction.

Source: Julian L A, Paul I, Molly M, John B, Lucia B. Investigating Fatigue and Exercise Intolerance in a University Immunology Clinic. Arch Rheum & Arthritis Res. 1(1): 2020. ARAR.MS.ID.000505. https://irispublishers.com/arar/fulltext/Investigating-Fatigue-and-Exercise-Intolerance-in-a-University.ID.000505.php (Full text)

A map of metabolic phenotypes in patients with myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease usually presenting after infection. Emerging evidence supports that energy metabolism is affected in ME/CFS, but a unifying metabolic phenotype has not been firmly established. We performed global metabolomics, lipidomics, and hormone measurements, and we used exploratory data analyses to compare serum from 83 patients with ME/CFS and 35 healthy controls.

Some changes were common in the patient group, and these were compatible with effects of elevated energy strain and altered utilization of fatty acids and amino acids as catabolic fuels. In addition, a set of heterogeneous effects reflected specific changes in 3 subsets of patients, and 2 of these expressed characteristic contexts of deregulated energy metabolism. The biological relevance of these metabolic phenotypes (metabotypes) was supported by clinical data and independent blood analyses.

In summary, we report a map of common and context-dependent metabolic changes in ME/CFS, and some of them presented possible associations with clinical patient profiles. We suggest that elevated energy strain may result from exertion-triggered tissue hypoxia and lead to systemic metabolic adaptation and compensation. Through various mechanisms, such metabolic dysfunction represents a likely mediator of key symptoms in ME/CFS and possibly a target for supportive intervention.

Source: Hoel F, Hoel A, Pettersen IK, Rekeland IG, Risa K, Alme K, Sørland K, Fosså A, Lien K, Herder I, Thürmer HL, Gotaas ME, Schäfer C, Berge RK, Sommerfelt K, Marti HP, Dahl O, Mella O, Fluge Ø, Tronstad KJ. A map of metabolic phenotypes in patients with myalgic encephalomyelitis/chronic fatigue syndrome. JCI Insight. 2021 Aug 23;6(16):149217. doi: 10.1172/jci.insight.149217. PMID: 34423789. https://pubmed.ncbi.nlm.nih.gov/34423789/