Mitochondrial Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

ME/CFS is a debilitating multisystem disorder of unclear etiology that affects many individuals worldwide. One of its hallmark symptoms is prolonged fatigue following exertion, a feature also observed in long COVID, suggesting an underlying dysfunction in energy production in both conditions. Here, mitochondrial dysfunction and its potential pathogenetic role in these disorders are reviewed.

Source: Syed AM, Karius AK, Ma J, Wang PY, Hwang PM. Mitochondrial Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Physiology (Bethesda). 2025 Feb 17. doi: 10.1152/physiol.00056.2024. Epub ahead of print. PMID: 39960432. https://journals.physiology.org/doi/abs/10.1152/physiol.00056.2024 (Full text available as PDF file)

The search for a blood-based biomarker for Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS): from biochemistry to electrophysiology

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disease of unknown aetiology characterised by symptoms of post-exertional malaise (PEM) and fatigue leading to substantial impairment in functioning. Other key symptoms include cognitive impairment and unrefreshing sleep, with many experiencing pain. To date there is no complete understanding of the triggering pathomechanisms of disease, and no quantitative biomarker available with sufficient sensitivity, specificity, and adoptability to provide conclusive diagnosis. Clinicians thus eliminate differential diagnoses, and rely on subjective, unspecific, and disputed clinical diagnostic criteria-a process that often takes years with patients being misdiagnosed and receiving inappropriate and sometimes detrimental care. Without a quantitative biomarker, trivialisation, scepticism, marginalisation, and misunderstanding of ME/CFS continues despite the significant disability for many. One in four individuals are bed-bound for long periods of time, others have difficulties maintaining a job/attending school, incurring individual income losses of thousands, while few participate in social activities.

Main body: Recent studies have reported promising quantifiable differences in the biochemical and electrophysiological properties of blood cells, which separate ME/CFS and non-ME/CFS participants with high sensitivities and specificities-demonstrating potential development of an accessible and relatively non-invasive diagnostic biomarker. This includes profiling immune cells using Raman spectroscopy, measuring the electrical impedance of blood samples during hyperosmotic challenge using a nano-electronic assay, use of metabolomic assays, and certain techniques which assess mitochondrial dysfunction. However, for clinical application, the specificity of these biomarkers to ME/CFS needs to be explored in more disease controls, and their practicality/logistics considered. Differences in cytokine profiles in ME/CFS are also well documented, but finding a consistent, stable, and replicable cytokine profile may not be possible. Increasing evidence demonstrates acetylcholine receptor and transient receptor potential ion channel dysfunction in ME/CFS, though how these findings could translate to a diagnostic biomarker are yet to be explored.

Conclusion: Different biochemical and electrophysiological properties which differentiate ME/CFS have been identified across studies, holding promise as potential blood-based quantitative diagnostic biomarkers for ME/CFS. However, further research is required to determine their specificity to ME/CFS and adoptability for clinical use.

Source: Clarke KSP, Kingdon CC, Hughes MP, Lacerda EM, Lewis R, Kruchek EJ, Dorey RA, Labeed FH. The search for a blood-based biomarker for Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS): from biochemistry to electrophysiology. J Transl Med. 2025 Feb 4;23(1):149. doi: 10.1186/s12967-025-06146-6. PMID: 39905423.  https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-025-06146-6 (Full text)

Key Pathophysiological Role of Skeletal Muscle Disturbance in Post COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Accumulated Evidence

Abstract:

Background: Recent studies provide strong evidence for a key role of skeletal muscle pathophysiology in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). In a 2021 review article on the pathophysiology of ME/CFS, we postulated that hypoperfusion and ischemia can result in excessive sodium and calcium overload in skeletal muscles of ME/CFS patients to cause mitochondrial damage. Since then, experimental evidence has been provided that supports this concept.

Methods: We collect, summarize and discuss the current state of knowledge for the key role of skeletal muscle pathophysiology. We try to explain which risk factors and mechanisms are responsible for a subgroup of patients with post COVID syndrome (PCS) to develop ME/CFS (PC-ME/CFS).

Results: Mitochondrial dysfunction is a long-held assumption to explain cardinal symptoms of ME/CFS. However, mitochondrial dysfunction could not be convincingly shown in leukocytes. By contrast, recent studies provide strong evidence for mitochondrial dysfunction in skeletal muscle tissue in ME/CFS. An electron microscopy study could directly show damage of mitochondria in skeletal muscle of ME/CFS patients with a preferential subsarcolemmal localization but not in PCS. Another study shows signs of skeletal muscle damage and regeneration in biopsies taken one day after exercise in PC-ME/CFS. The simultaneous presence of necroses and signs of regeneration supports the concept of repeated damage. Other studies correlated diminished hand grip strength (HGS) with symptom severity and prognosis. A MRI study showed that intracellular sodium in muscles of ME/CFS patients is elevated and that levels correlate inversely with HGS. This finding corroborates our concept of sodium and consecutive calcium overload as cause of muscular and mitochondrial damage caused by enhanced proton-sodium exchange due to anaerobic metabolism and diminished activity of the sodium-potassium-ATPase. The histological investigations in ME/CFS exclude ischemia by microvascular obstruction, viral presence or immune myositis. The only known exercise-induced mechanism of damage left is sodium induced calcium overload. If ionic disturbance and mitochondrial dysfunction is severe enough the patient may be captured in a vicious circle. This energy deficit is the most likely cause of exertional intolerance and post exertional malaise and is further aggravated by exertion.

Conclusion: Based on this pathomechanism, future treatment approaches should focus on normalizing the cause of ionic disbalance. Current treatment strategies targeting hypoperfusion have the potential to improve the dysfunction of ion transporters.

Source: Scheibenbogen C, Wirth KJ. Key Pathophysiological Role of Skeletal Muscle Disturbance in Post COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Accumulated Evidence. J Cachexia Sarcopenia Muscle. 2025 Feb;16(1):e13669. doi: 10.1002/jcsm.13669. PMID: 39727052; PMCID: PMC11671797. https://pmc.ncbi.nlm.nih.gov/articles/PMC11671797/ (Full text)

Mitochondrial structural alterations in fibromyalgia: a pilot electron microscopy study

Abstract:

Objectives: The pathogenesis of fibromyalgia (FM), characterised by chronic widespread pain and fatigue, remains notoriously elusive, hampering attempts to develop disease modifying treatments. Mitochondria are the headquarters of cellular energy metabolism, and their malfunction has been proposed to contribute to both FM and chronic fatigue. Thus, the aim of the current pilot study, was to detect structural changes in mitochondria of peripheral blood mononuclear cells (PBMCs) of FM patients, using transmission electron microscopy (TEM).

Methods: To detect structural mitochondrial alterations in FM, we analysed PBMCs from seven patients and seven healthy controls, using TEM. Patients were recruited from a specialised Fibromyalgia Clinic at a tertiary medical centre. After providing informed consent, participants completed questionnaires including the widespread pain index (WPI), symptoms severity score (SSS), fibromyalgia impact questionnaire (FIQ), beck depression inventory (BDI), and visual analogue scale (VAS), to verify a diagnosis of FM according to ACR criteria. Subsequently, blood samples were drawn and PBMCs were collected for EM analysis.

Results: TEM analysis of PBMCs showed several distinct mitochondrial cristae patterns, including total loss of cristae in FM patients. The number of mitochondria with intact cristae morphology was reduced in FM patients and the percentage of mitochondria that completely lacked cristae was increased. These results correlated with the WPI severity. Moreover, in the FM patient samples we observed a high percentage of cells containing electron dense aggregates, which are possibly ribosome aggregates. Cristae loss and possible ribosome aggregation were intercorrelated, and thus may represent reactions to a shared cellular stress condition. The changes in mitochondrial morphology suggest that mitochondrial dysfunction, resulting in inefficient oxidative phosphorylation and ATP production, metabolic and redox disorders, and increased reactive oxygen species (ROS) levels, may play a pathogenetic role in FM.

Conclusions: We describe novel morphological changes in mitochondria of FM patients, including loss of mitochondrial cristae. While these observations cannot determine whether the changes are pathogenetic or represent an epiphenomenon, they highlight the possibility that mitochondrial malfunction may play a causative role in the cascade of events leading to chronic pain and fatigue in FM. Moreover, the results offer the possibility of utilising changes in mitochondrial morphology as an objective biomarker in FM. Further understanding the connection between FM and dysfunction of mitochondria physiology, may assist in developing both novel diagnostic tools as well as specific treatments for FM, such as approaches to improve/strengthen mitochondria function.

Source: Israel L, Furer V, Levin-Zaidman S, Dezorella N, Brontvein O, Ablin JN, Gross A. Mitochondrial structural alterations in fibromyalgia: a pilot electron microscopy study. Clin Exp Rheumatol. 2024 Jun;42(6):1215-1223. doi: 10.55563/clinexprheumatol/3l0ihz. Epub 2024 Jun 28. PMID: 38966946. https://www.clinexprheumatol.org/abstract.asp?a=21119 (Full text available as PDF file)

Mitochondrial function in patients affected with fibromyalgia syndrome is impaired and correlates with disease severity

Abstract:

Fibromyalgia is a musculoskeletal syndrome characterized by chronic widespread pain that is often associated with systemic manifestations. Since mitochondria are the main source of cellular energy, we hypothesized that fibromyalgia syndrome (FMS) could be linked to mitochondrial impairment. Aim was to study mitochondrial dysfunction in peripheral blood mononuclear cells isolated from 50 patients with primary FMS and 20 apparently healthy controls.

Although no differences in mitochondrial basal respiration were observed between patients with primary FMS and healthy controls, a lower median bioenergetic health index (BHI; – 22.1%, p = 0.03), a proxy of mitochondrial function, was found in patients. According to fibromyalgia severity score (FSS), a composite of widespread pain index and symptom severity scale, a lower median BHI (- 18.7%) was found in patients with a FSS ≥ 20 compared to those with a FSS < 20. Negative moderate correlations were found only between BHI and FSS (r = – 0.36) and widespread pain index (r = – 0.38).

We demonstrated that patients with FMS had an impaired mitochondrial function. Additionally, we found a mild correlation between the widespread pain index and the BHI, possibly indicating that the altered mitochondrial function, in these patients, narrows musculoskeletal rather than central nervous system involvement.

Source: Macchi C, Giachi A, Fichtner I, Pedretti S, Puttini PS, Mitro N, Corsini A, Ruscica M, Gualtierotti R. Mitochondrial function in patients affected with fibromyalgia syndrome is impaired and correlates with disease severity. Sci Rep. 2024 Dec 4;14(1):30247. doi: 10.1038/s41598-024-81298-x. PMID: 39632893; PMCID: PMC11618515. https://pmc.ncbi.nlm.nih.gov/articles/PMC11618515/ (Full text)

Upregulation of olfactory receptors and neuronal-associated genes highlights complex immune and neuronal dysregulation in Long COVID patients

Abstract:

A substantial portion of patients infected with SARS-CoV-2 experience prolonged complications, known as Long COVID (LC). A subset of these patients exhibits the most debilitating symptoms, similar to those defined in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). We performed bulk RNA sequencing (RNAseq) on the whole blood of LC with ME/CFS, at least 12 months post-onset of the acute disease, and compared them with controls.

We found that LC patients had a distinct transcriptional profile compared to controls. Key findings include the upregulation of genes involved in immune dysregulation and neuronal development, such as Fezf2, BRINP2, HOXC12, MEIS2, ZFHX3, and RELN. These genes are linked to neuroinflammatory responses, cognitive impairments, and hematopoietic disturbances, suggesting ongoing neurological and immune disturbances in LC patients. RELN, encoding the Reelin protein, was notably elevated in LC patients, potentially serving as a biomarker for LC pathogenesis due to its role in inflammation and neuronal function.

Immune cell analysis showed altered profiles in LC patients, with increased activated memory CD4 + T cells and neutrophils, and decreased regulatory T cells and NK cells, reflecting immune dysregulation. Changes in cytokine and chemokine expression further underscore the chronic inflammatory state in LC patients. Notably, a unique upregulation of olfactory receptors (ORs) suggest alternative roles for ORs in non-olfactory tissues. Pathway analysis revealed upregulation in ribosomal RNA processing, amino acid metabolism, protein synthesis, cell proliferation, DNA repair, and mitochondrial pathways, indicating heightened metabolic and immune demands. Conversely, downregulated pathways, such as VEGF signaling and TP53 activity, point to impaired tissue repair and cellular stress responses.

Overall, our study underscores the complex interplay between immune and neuronal dysfunction in LC patients, providing insights into potential diagnostic biomarkers and therapeutic targets. Future research is needed to fully understand the roles and interactions of these genes in LC pathophysiology.

Source: Shahbaz S, Rezaeifar M, Syed H, Redmond D, Terveart JWC, Osman M, Elahi S. Upregulation of olfactory receptors and neuronal-associated genes highlights complex immune and neuronal dysregulation in Long COVID patients. Brain Behav Immun. 2024 Nov 28:S0889-1591(24)00721-9. doi: 10.1016/j.bbi.2024.11.032. Epub ahead of print. PMID: 39615603. https://www.sciencedirect.com/science/article/pii/S0889159124007219 (Full text)

Replicating human characteristics: A promising animal model of central fatigue

Highlights:

  • A new method: Modified Multiple Platform Method combined with alternate-day fasting.
  • Modeling method has successfully constructed animal model of central fatigue.
  • Our rat model mimics human emotional, cognitive, and physical fatigue.
  • Hippocampus and muscle tissues show damage and mitochondrial changes.
  • Mitochondrial dysfunction and oxidative stress in hippocampus and muscle tissues.

Abstract:

Central fatigue is a common pathological state characterized by psychological loss of drive, lack of appetite, drowsiness, and decreased psychic alertness. The mechanism underlying central fatigue is still unclear, and there is no widely accepted successful animal model that fully represents human characteristics. We aimed to construct a more clinically relevant and comprehensive animal model of central fatigue.

In this study, we utilized the Modified Multiple Platform Method (MMPM) combined with alternate-day fasting (ADF) to create the animal model. The model group rats are placed on a stationary water environment platform for sleep deprivation at a fixed time each day, and they were subjected to ADF treatment. On non-fasting days, the rats were allowed unrestricted access to food. This process was sustained over a period of 21 days.

We evaluated the model using behavioral assessments such as open field test, elevated plus maze testtail suspension testMorris water maze testgrip strength test, and forced swimming test, as well as serum biochemical laboratory indices. Additionally, we conducted pathological observations of the hippocampus and quadriceps muscle tissues, transmission electron microscope observation of mitochondrial ultrastructure, and assessment of mitochondrial energy metabolism and oxidative stress-related markers.

The results revealed that the model rats displayed emotional anomalies resembling symptoms of depression and anxiety, decreased exploratory behavior, decline in learning and memory function, and signs of skeletal muscle fatigue, successfully replicating human features of negative emotions, cognitive decline, and physical fatigue. Pathological damage and mitochondrial ultrastructural alterations were observed in the hippocampus and quadriceps muscle tissues, accompanied by abnormal mitochondrial energy metabolism and oxidative stress in the form of decreased ATP and increased ROS levels.

In conclusion, our ADF+MMPM model comprehensively replicated the features of human central fatigue and is a promising platform for preclinical research. Furthermore, the pivotal role of mitochondrial energy metabolism and oxidative stress damage in the occurrence of central fatigue in the hippocampus and skeletal muscle tissues was corroborated.

Source: Zhang Y, Zhang Z, Yu Q, Lan B, Shi Q, Li R, Jiao Z, Zhang W, Li F. Replicating human characteristics: A promising animal model of central fatigue. Brain Res Bull. 2024 Jun 15;212:110951. doi: 10.1016/j.brainresbull.2024.110951. Epub 2024 Apr 19. PMID: 38642899. https://www.sciencedirect.com/science/article/pii/S0361923024000844 (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 substrate 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 (V˙˙O2) at maximum fat oxidation (g 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: Ramírez-Vélez R, Oscoz-Ochandorena S, García-Alonso Y, García-Alonso N, Legarra-Gorgoñon G, Oteiza J, Lorea AE, Izquierdo M, Correa-Rodríguez M. Maximal oxidative capacity during exercise is associated with muscle power output in patients with long coronavirus disease 2019 (COVID-19) syndrome. A moderation analysis. Clin Nutr ESPEN. 2023 Dec;58:253-262. doi: 10.1016/j.clnesp.2023.10.009. Epub 2023 Oct 14. PMID: 38057014. https://clinicalnutritionespen.com/article/S2405-4577(23)02166-6/fulltext (Full text)

Persistent Fatigue, Weakness, and Aberrant Muscle Mitochondria in Survivors of Critical COVID-19

Abstract:

Objectives: Persistent skeletal muscle dysfunction in survivors of critical illness due to acute respiratory failure is common, but biological data elucidating underlying mechanisms are limited. The objective of this study was to elucidate the prevalence of skeletal muscle weakness and fatigue in survivors of critical illness due to COVID-19 and determine if cellular changes associate with persistent skeletal muscle dysfunction.

Design: A prospective observational study in two phases: 1) survivors of critical COVID-19 participating in physical outcome measures while attending an ICU Recovery Clinic at short-term follow-up and 2) a nested cohort of patients performed comprehensive muscle and physical function assessments with a muscle biopsy; data were compared with non-COVID controls.

Setting: ICU Recovery Clinic and clinical laboratory.

Patients/subjects: Survivors of critical COVID-19 and non-COVID controls.

Interventions: None.

Measurements and main results: One hundred twenty patients with a median of 56 years old (interquartile range [IQR], 42-65 yr old), 43% female, and 33% individuals of underrepresented race attended follow-up 44 ± 17 days after discharge. Patients had a median Acute Physiology and Chronic Health Evaluation-II score of 24.0 (IQR, 16-29) and 98 patients (82%) required mechanical ventilation with a median duration of 14 days (IQR, 9-21 d). At short-term follow-up significant physical dysfunction was observed with 93% of patients reporting generalized fatigue and performing mean 218 ± 151 meters on 6-minute walk test (45% ± 30% of predicted). Eleven patients from this group agreed to participate in long-term assessment and muscle biopsy occurring a mean 267 ± 98 days after discharge. Muscle tissue from COVID exhibited a greater abundance of M2-like macrophages and satellite cells and lower activity of mitochondrial complex II and complex IV compared with controls.

Conclusions: Our findings suggest that aberrant repair and altered mitochondrial activity in skeletal muscle associates with long-term impairments in patients surviving an ICU admission for COVID-19.

Source: Mayer KP, Ismaeel A, Kalema AG, Montgomery-Yates AA, Soper MK, Kern PA, Starck JD, Slone SA, Morris PE, Dupont-Versteegden EE, Kosmac K. Persistent Fatigue, Weakness, and Aberrant Muscle Mitochondria in Survivors of Critical COVID-19. Crit Care Explor. 2024 Oct 16;6(10):e1164. doi: 10.1097/CCE.0000000000001164. PMID: 39412208; PMCID: PMC11487221. https://pmc.ncbi.nlm.nih.gov/articles/PMC11487221/ (Full text)

Assessment of the therapeutic potential of salubrinal for ME/CFS and long-COVID

Highlights:

  • Long-COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are enigmatic diseases sharing many characteristics.
  • The most debilitating aspects of these diseases are cognitive dysfunction, ‘brain fog’, and exercise intolerance, ‘post-exertional malaise’.
  • There is no cure for these diseases; treatment is palliative only.
  • Mitochondrial dysfunction with endoplasmic reticulum (ER) stress occurs in both diseases.
  • Salubrinal inhibits the phosphatase that dephosphorylates phospho-eukaryotic initiation factor-2α (peIF2α), a protective protein for cells undergoing ER stress when phosphorylated.
  • Salubrinal reduces the formation of Wiskott–Aldrich syndrome protein family member 3 (WASF3), a protein that causes mitochondrial dysfunction that is overexpressed in a cohort of ME/CFS patients.
  • Salubrinal reduces WASF3 expression, restoring mitochondrial function in fibroblasts of a patient with ME/CFS.

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic debilitating condition with no cure that shares commonality with long-COVID.

This review examines current understanding of long-COVID symptoms, characteristics of the affected population, the connection with ME/CFS, and the potential for salubrinal, an agent known for its influence on cellular stress pathways, to mitigate these disorders.

It also describes the historical development and mechanism of action of salubrinal, to mitigate endoplasmic reticulum (ER)/cellular stress responses, that could potentially contribute to symptom improvement in both ME/CFS and long-COVID patients.

Further research and clinical trials are warranted to advance our understanding of the potential role of salubrinal in improving the quality of life for individuals with long-COVID-related ME/CFS symptoms as well as ME/CFS patients.

Source: Aseel Warrayat, Ayah Ali, Joulin Waked, Darcy Tocci, Robert C. Speth. Assessment of the therapeutic potential of salubrinal for ME/CFS and long-COVID. Trends in Molecular Medicine, 2024. ISSN 1471-4914, https://doi.org/10.1016/j.molmed.2024.10.001. https://www.sciencedirect.com/science/article/abs/pii/S1471491424002685