Tag: energy metabolism

Systematic Examination of Gene Expression and Proteomic Evidence Across Tissues Supports the Role of Mitochondrial Dysregulation in ME/CFS

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic, multisystem disease characterized by post-exertional malaise and persistent fatigue. The cause of ME/CFS is not well understood, and there are no established biomarkers or FDA-approved pharmacotherapies. The clinical heterogeneity of ME/CFS presents challenges to diagnosis and treatment and necessitates collaborative efforts to generate robust findings. This study leveraged gene and protein expression data from the mapMECFS data repository and the DecodeME Genome-Wide Association Study (GWAS) to assess consistent gene signatures across studies.

The mitochondrial genes MT-RNR1 and MT-RNR2 exhibited lower expression in ME/CFS cases in two studies. Combining this with increased expression of mitochondrial genes in platelets from another study, this supports mitochondrial dysregulation as having a role in ME/CFS.

Furthermore, ME/CFS-associated genes were mapped to compounds in drug databases as possible treatments for further investigation. In muscle gene expression data, 107 approved compounds target 26 genes with functions relevant to mitochondrial support and immunomodulators. From the DecodeME GWAS, 83 approved compounds target 24 genes with functions related to energy metabolism and mitochondrial function.

Though little consistency in specific genes was observed across studies, which highlights the need for larger studies, mitochondrial dysfunction in ME/CFS cases was evident across studies.

Source: Keele GR, Enger M, Barnette Q, Ruiz-Esparza R, Alvarado M, Mathur R, Stratford JK, Giamberardino SN, Brown LM, Webb BT, Carnes MU. Systematic Examination of Gene Expression and Proteomic Evidence Across Tissues Supports the Role of Mitochondrial Dysregulation in ME/CFS. Int J Mol Sci. 2026 Feb 19;27(4):1997. doi: 10.3390/ijms27041997. PMID: 41752134. https://www.mdpi.com/1422-0067/27/4/1997 (Full text)

Uncovering the genetic architecture of ME/CFS: a precision approach reveals impact of rare monogenic variation

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disabling and heterogeneous disorder lacking validated biomarkers or targeted therapies. Clinical variability and elusive pathophysiology hinder progress toward effective diagnostics and treatment. Core symptoms include persistent fatigue, post-exertional malaise, unrefreshing sleep, cognitive dysfunction, and pain. We tested whether an individualized, “n-of-1” genomic and transcriptomic framework combined with comprehensive, participant-informed phenotyping could reveal molecular signatures unique to each patient.

Methods: Clinical-grade whole-genome sequencing was conducted in 31 affected individuals from 25 families, with RNA-seq performed on a subset (16 affected, 7 unaffected) using blood samples. Machine-learning assisted variant triage, transcript-aware damage prediction, and expert review identified pathogenic or likely pathogenic variants in 8 of 25 probands (32%) and 12 of 31 affected individuals (39%).

Results: Findings revealed marked genetic heterogeneity, including large-effect rare and more common variants. Implicated pathways included ATP generation, oxidative phosphorylation, fatty acid oxidation; regulation of glycolysis, amino acid and lipid turnover; ion and solute homeostasis; synaptic signaling, excitability, oxygen transport, and muscle integrity, resilience, and post-exertional recovery; previously implicated processes. Plausible modifiers influencing disease onset, severity, and relapsing–remitting patterns and possibly explaining intrafamilial variability and inconsistent findings across studies, were also identified. Despite gene-level diversity, downstream effects converged on impaired energy production, reduced stress resilience, and vulnerability to post-exertional metabolic failure; disruptions consistent with core ME/CFS symptoms of exertional intolerance, cognitive fog, and fatigue.

Conclusions: Our findings support the hypothesis that at least a subset of ME/CFS cases represent distinct molecular disorders that converge on shared physiological pathways. Validation in larger, more diverse cohorts will be essential to test this hypothesis and establish generalizability, but increase size alone is unlikely to resolve causation in a disorder defined by rarity, heterogeneity, and molecular complexity. We suggest that progress will require experimental designs that integrate individual-level genomic data with deep, participant-informed deep phenotyping, capturing the combined effects of rare and common variants and environmental modifiers on disease expression and progression. We believe that an individualized precision medicine framework will uncover molecular drivers and modifiers of ME/CFS previously obscured by heterogeneity, enabling biologically informed stratification, improved trial design, biomarker discovery, and targeted interventions in this historically neglected condition.

Source: Birch CL, Wilk BM, Gajapathy M, Hutchins SD, Kaur G, Brown DM, Mamidi TKK, Hodgin KS, Turgut A, Younger JW, Worthey EA. Uncovering the genetic architecture of ME/CFS: a precision approach reveals impact of rare monogenic variation. J Transl Med. 2025 Dec 24. doi: 10.1186/s12967-025-07586-w. Epub ahead of print. PMID: 41444612. https://link.springer.com/article/10.1186/s12967-025-07586-w (Full text available as PDF file)

Inefficient energy consumption is related to post exertional malaise during cardiopulmonary exercise testing in long COVID

Abstract:

Background: Dyspnea, fatigue and post-exertional malaise (PEM) are hallmark features of long Covid and emerging evidence suggests that abnormal energy metabolism may contribute to these symptoms. A cardiopulmonary exercise test (CPET) provides a detailed physiologic assessment of ventilatory and cardiovascular function and can offer insights into metabolic substrate utilization energy at rest and during exertion. Our aim was to evaluate patterns of energy metabolism at rest and during exercise during a CPET in patients with long Covid.

Methods: We conducted a cross-sectional study of consecutive non-selected patients that had been referred for a CPET. We included two groups: a long COVID and a control group. The CPET was performed on a cycle ergometer and we measured standard variables including oxygen uptake (V̇O₂), respiratory exchange ratio (RER), breathing reserve, heart rate, O2 pulse, and anaerobic threshold. We used RER to calculate indirect calorimetry estimating the use of carbohydrates and fat at rest and exertion. We analyzed the association between long COVID symptom severity symptoms including fatigue and post-exertional malaise (PEM) with patterns of energy consumption. We used logistic regression and area under the receiver operating characteristic curve to determine which CPET variables were most associated with long COVID.

Results: CPET results were analyzed for 50 patients who met the definition of long COVID and 45 patients controls. Long COVID patients and controls had similar peak V̇O₂, heart rate on exertion and V̇O₂ at anaerobic threshold. Seventy-three percent of patients with long COVID had predominant energy use of carbohydrates rather than fat at rest compared to 20% of controls. In multivariable models the odds ratio of using fat as energy source at rest was 0.99; 95% CI 0.99–0.99; p = 0.04. Patients with long COVID and severe fatigue as well as severe PEM had higher usage of carbohydrates (p < 0.01) and similar use of fat.

Conclusion: Patients with long COVID use energy inefficiently and this pattern could serve as a diagnostic feature in certain presentations of long COVID.

Source: Leonardo Tamariz, Brian Garnet, Santiago Avecillas et al. Inefficient energy consumption is related to post exertional malaise during cardiopulmonary exercise testing in long COVID, 15 December 2025, PREPRINT (Version 1) available at Research Square [https://doi.org/10.21203/rs.3.rs-8072121/v1] https://www.researchsquare.com/article/rs-8072121/v1 (Full text)

Mapping the complexity of ME/CFS: Evidence for abnormal energy metabolism, altered immune profile, and vascular dysfunction

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex disorder with undefined mechanisms, no diagnostic tools and treatments. To investigate concurrent system dysfunctions, we recruited age- and sex-matched ME/CFS patients and healthy controls for a multimodal analysis of energy metabolism, immune profiles, and plasma proteomics.

Immune cells from ME/CFS patients show elevated adenosine monophosphate (AMP) and adenosine diphosphate (ADP) with a reduced ATP/ADP ratio, indicating decreased ATP generation and cellular energy stress. Immune profiling reveals skewing toward less mature effector subsets of CD4+, CD8+, and γδ T cells, with reduced CD1c+CD141– conventional DC type 2 and CD56lowCD16+ terminal natural killer cells.

Elevated levels of plasma proteins associated with thrombus formation and vascular reactivity may contribute to the endothelial dysfunction observed in ME/CFS patients. Classification and regression tree modeling identifies variables with strong predictive potential for ME/CFS. Together, this study provides insights into the somatic symptoms and underlying biology of ME/CFS.

Source: Heng B, Gunasegaran B, Krishnamurthy S, Bustamante S, Pires AS, Chow S, Ahn SB, Paul-Heng M, Maciver Y, Smith K, Tran DP, Howley PP, Bilgin AA, Sharland A, Schloeffel R, Guillemin GJ. Mapping the complexity of ME/CFS: Evidence for abnormal energy metabolism, altered immune profile, and vascular dysfunction. Cell Rep Med. 2025 Dec 16;6(12):102514. doi: 10.1016/j.xcrm.2025.102514. PMID: 41406947. https://www.sciencedirect.com/science/article/pii/S2666379125005877 (Full text)

Leveraging Explainable Automated Machine Learning (AutoML) and Metabolomics for Robust Diagnosis and Pathophysiological Insights in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

Abstract:

Background/Objectives: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating complex disease with an elusive etiology, lacking objective diagnostic biomarkers. This study leverages advanced Automated Machine Learning (AutoML) to analyze plasma metabolomic and lipidomic profiles for the purpose of ME/CFS detection.

Methods: We utilized a publicly available dataset comprising 888 metabolic features from 106 ME/CFS patients and 91 matched controls. Three AutoML frameworks-TPOT, Auto-Sklearn, and H2O AutoML-were benchmarked under identical time constraints. Univariate ROC and PLS-DA analyses with cross-validation, permutation testing, and VIP-based feature selection were applied to standardized, log-transformed omics data to identify significant discriminatory metabolites/lipids and assess their intercorrelations.

Results: TPOT significantly outperformed its counterparts, achieving an area under the curve (AUC) of 92.1%, accuracy of 87.3%, sensitivity of 85.8%, and specificity of 89.0%. The PLS-DA model revealed a moderate but statistically significant discrimination between ME/CFS and controls. Explainable artificial intelligence (XAI) via SHAP analysis of the optimal TPOT model identified key metabolites implicating dysregulated pathways in mitochondrial energy metabolism (succinic acid, pyruvic acid, leucine), chronic inflammation (prostaglandin D2, 11,12-EET), gut-brain axis communication (glycocholic acid), and cell membrane integrity (pc(35:2)a).

Conclusions: Our results demonstrate that TPOT-derived models not only provide a highly accurate and robust diagnostic tool but also yield biologically interpretable insights into the pathophysiology of ME/CFS, highlighting its potential for clinical decision support and elucidating novel therapeutic targets.

Source: Yagin FH, Colak C, Al-Hashem F, Alzakari SA, Alhussan AA, Aghaei M. Leveraging Explainable Automated Machine Learning (AutoML) and Metabolomics for Robust Diagnosis and Pathophysiological Insights in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Diagnostics (Basel). 2025 Oct 30;15(21):2755. doi: 10.3390/diagnostics15212755. PMID: 41226047. https://www.mdpi.com/2075-4418/15/21/2755 (Full text)

A Perspective on the Role of Metformin in Treating Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Long COVID

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Long COVID (LC) are increasingly recognized as debilitating postinfectious conditions that impact both individuals and society. Recent research highlights the potential of metformin, an antidiabetic agent, as a treatment for these syndromes by targeting their underlying mechanisms. This review assesses the effectiveness of metformin in ME/CFS and LC, which involve complex dysfunctions related to cytokines, glycolysis, ATP generation, oxidative stress, gastrointestinal microbiomes, and vascular endothelial function.

Metformin, traditionally known for its antihyperglycemic properties may offer broader therapeutic benefits by influencing these pathological pathways. It works by inhibiting complexes I and IV of the electron transport chain, which reduces the strain on malfunctioning complex V and decreases the production of harmful free radicals. Additionally, metformin’s impact on mTOR signaling could improve energy metabolism in ME/CFS and LC by downregulating an overactive but underperforming protein, thereby alleviating symptoms. Beyond the impact on cellular metabolism, metformin has shown to have anti-inflammatory, vascular, gastrointestinal, neuroprotective and epigenetic effects.

We explore this impact of metformin and the potential role it could play to help people with ME/CFS. While metformin shows promise, it is unlikely to be a stand-alone solution. Instead, it may be part of a broader treatment strategy that includes other therapies targeting neurocognitive and autonomic impairments.

Source: David Fineberg, Alain Moreau, Elena K. Schneider-Futschik, and Christopher W. Armstrong. A Perspective on the Role of Metformin in Treating Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Long COVID. ACS Pharmacology & Translational Science Article ASAP. DOI: 10.1021/acsptsci.5c00229 https://pubs.acs.org/doi/full/10.1021/acsptsci.5c00229 (Full text)

Real-Time Measurement of Mitochondrial Function and Glycolysis in Lymphoblastoid Cell Lines

Abstract:

Cells require energy in the form of ATP to function. The two main ways in which cells generate energy in mammalian cells is through glycolysis and oxidative phosphorylation (OXPHOS). Glycolysis takes place in the cytosol and involves the breakdown of glucose molecules, generating ATP and pyruvate, while OXPHOS takes place in the mitochondria and is responsible for producing the majority of ATP for the cell. A dysregulation of these cellular processes has been reported in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). In order to understand the mechanisms of the disease, it is imperative to understand how the bioenergetic pathways are altered in ME/CFS.

Here we describe a method for measuring mitochondrial function and glycolytic function using the Agilent Seahorse Extracellular Flux Analyzer. We have optimized these assays for use in actively proliferating lymphoblastoid cell lines that are generated from blood cells. This assay measures oxygen consumption rate and extracellular acidification rates providing an overview of mitochondrial function and efficiency and glycolytic rate and capacity, respectively. These assays are performed on live, intact cells, and enable us to view different components and measurements of energy metabolism through the injection of different compounds that stimulate or inhibit various sections of these pathways. The below method details an optimized glycolysis and mitochondrial assay for 96-well plates with modifications noted for use in 24-well plates.

Source: Katsaros T, Missailidis D, Annesley SJ. Real-Time Measurement of Mitochondrial Function and Glycolysis in Lymphoblastoid Cell Lines. Methods Mol Biol. 2025;2920:173-202. doi: 10.1007/978-1-0716-4498-0_11. PMID: 40372684. https://link.springer.com/protocol/10.1007/978-1-0716-4498-0_11

Dysregulation of lipid metabolism, energy production, and oxidative stress in myalgic encephalomyelitis/chronic fatigue syndrome, Gulf War Syndrome and fibromyalgia

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), Gulf War Syndrome (GWS), and Fibromyalgia (FM) are complex, chronic illnesses with overlapping clinical features. Symptoms that are reported across these conditions include post-exertional malaise (PEM), fatigue, and pain, yet the etiology of these illnesses remains largely unknown. Diagnosis is challenging in patients with these conditions as definitive biomarkers are lacking; patients are required to meet clinical criteria and often undergo lengthy testing to exclude other conditions, a process that is often prolonged, costly, and burdensome for patients.

The identification of reliable validated biomarkers could facilitate earlier and more accurate diagnosis and drive the development of targeted pharmacological therapies that might address the underlying pathophysiology of these diseases. Major driving forces for biomarker identification are the advancing fields of metabolomics and proteomics that allow for comprehensive characterization of metabolites and proteins in biological specimens. Recent technological developments in these areas enable high-throughput analysis of thousands of metabolites and proteins from a variety of biological samples and model systems, that provides a powerful approach to unraveling the metabolic phenotypes associated with these complex diseases.

Emerging evidence suggests that ME/CFS, GWS, and FM are all characterized by disturbances in metabolic pathways, particularly those related to energy production, lipid metabolism, and oxidative stress. Altered levels of key metabolites in these pathways have been reported in studies highlighting potential common biochemical abnormalities. The precise mechanisms driving altered metabolic pathways in ME/CFS, GWS, and FM remain to be elucidated; however, the elevated oxidative stress observed across these illnesses may contribute to symptoms and offer a potential target for therapeutic intervention.

Investigating the mechanisms, and their role in the disease process, could provide insights into disease pathogenesis and reveal novel treatment targets. As such, comprehensive metabolomic and proteomic analyses are crucial for advancing the understanding of these conditions in-order to identify both common, and unique, metabolic alterations that could serve as diagnostic markers or therapeutic targets.

Source: Davis L, Higgs M, Snaith A, Lodge TA, Strong J, Espejo-Oltra JA, Kujawski S, Zalewski P, Pretorius E, Hoerger M, Morten KJ. Dysregulation of lipid metabolism, energy production, and oxidative stress in myalgic encephalomyelitis/chronic fatigue syndrome, Gulf War Syndrome and fibromyalgia. Front Neurosci. 2025 Mar 10;19:1498981. doi: 10.3389/fnins.2025.1498981. PMID: 40129725; PMCID: PMC11931034. https://pmc.ncbi.nlm.nih.gov/articles/PMC11931034/ (Full text)

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)

Mapping the Complexity of ME/CFS: Evidence for Abnormal Energy Metabolism, Altered Immune Profile and Vascular Dysfunction

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex disorder with no known underlying mechanisms, diagnostic tools, or treatments.  Multiple areas of dysfunction have been extensively studied, but rarely examined together. We recruited age- and sex-matched ME/CFS patients and healthy controls for a multi-modal study examining energy metabolism, immune profiles and plasma protein levels.

Elevated levels of adenosine monophosphate (AMP) were detected in both plasma and immune cells. Additionally, immune cells showed higher levels of adenosine diphosphate (ADP) and a reduced adenosine triphosphate/adenosine diphosphate (ATP/ADP) ratio.

These findings imply decreased ATP generation and the presence of energy stress within the immune cell population. Adaptive immune cell populations were skewed towards less mature effector subsets of CD4+, CD8+ and gd T cells, and proportions of CD1c+CD141-conventional DC type 2 (cDC2) and CD56lowCD16+ terminal natural killer (NK) cells were also reduced. Elevated levels of plasma proteins associated with thrombus formation and vascular reactivity may contribute to the endothelial dysfunction observed in ME/CFS patients. Using Classification and Regression Tree (CART) modelling, we identified variables from each mode of investigation with strong predictive potential for ME/CFS. Together, this study provides new insights into the somatic symptoms and underlying biology of ME/CFS.

Source: Heng, Ruiwen Benjamin and Gunasegaran, Bavani and Krishnamurthy, Shivani and Bustamante, Sonia and Staats, Ananda and Chow, Sharron and Ahn, Seong Beom and Paul-Heng, Moumita and Maciver, Yolande and Smith, Kirsten and Tran, Denise Phuong and Howley, Peter P. and Bilgin, Ayse Aysin and Sharland, Alexandra and Schloeffel, Richard and Guillemin, Gilles J. and Administrator, Sneak Peek, Mapping the Complexity of ME/CFS: Evidence for Abnormal Energy Metabolism, Altered Immune Profile and Vascular Dysfunction. Available at SSRN: https://ssrn.com/abstract=5131664 or http://dx.doi.org/10.2139/ssrn.5131664  https://papers.ssrn.com/sol3/papers.cfm?abstract_id=5131664 (Full text available as PDF file)