Tag: mitochondria

Possible Pathogenesis and Prevention of Long COVID: SARS-CoV-2-Induced Mitochondrial Disorder

Abstract:

Patients who have recovered from coronavirus disease 2019 (COVID-19) infection may experience chronic fatigue when exercising, despite no obvious heart or lung abnormalities. The present lack of effective treatments makes managing long COVID a major challenge.
One of the underlying mechanisms of long COVID may be mitochondrial dysfunction. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections can alter the mitochondria responsible for energy production in cells. This alteration leads to mitochondrial dysfunction which, in turn, increases oxidative stress. Ultimately, this results in a loss of mitochondrial integrity and cell death. Moreover, viral proteins can bind to mitochondrial complexes, disrupting mitochondrial function and causing the immune cells to over-react. This over-reaction leads to inflammation and potentially long COVID symptoms.
It is important to note that the roles of mitochondrial damage and inflammatory responses caused by SARS-CoV-2 in the development of long COVID are still being elucidated. Targeting mitochondrial function may provide promising new clinical approaches for long-COVID patients; however, further studies are needed to evaluate the safety and efficacy of such approaches.
Source: Chen T-H, Chang C-J, Hung P-H. Possible Pathogenesis and Prevention of Long COVID: SARS-CoV-2-Induced Mitochondrial Disorder. International Journal of Molecular Sciences. 2023; 24(9):8034. https://doi.org/10.3390/ijms24098034 https://www.mdpi.com/1422-0067/24/9/8034 (Full text)

Efficacy and tolerability of an endogenous metabolic modulator (AXA1125) in fatigue-predominant long COVID: a single-centre, double-blind, randomised controlled phase 2a pilot study

Summary:

Background: ‘Long COVID’ describes persistent symptoms, commonly fatigue, lasting beyond 12 weeks following SARS-CoV-2 infection. Potential causes include reduced mitochondrial function and cellular bioenergetics. AXA1125 has previously increased β-oxidation and improved bioenergetics in preclinical models along with certain clinical conditions, and therefore may reduce fatigue associated with Long COVID. We aimed to assess the efficacy, safety and tolerability of AXA1125 in Long COVID.

Methods: Patients with fatigue dominant Long COVID were recruited in this single-centre, double-blind, randomised controlled phase 2a pilot study completed in the UK. Patients were randomly assigned (1:1) using an Interactive Response Technology to receive either AXA1125 or matching placebo in a clinical based setting. Each dose (33.9 g) of AXA1125 or placebo was administered orally in a liquid suspension twice daily for four weeks with a two week follow-up period. The primary endpoint was the mean change from baseline to day 28 in the phosphocreatine (PCr) recovery rate following moderate exercise, assessed by 31P-magnetic resonance spectroscopy (MRS). All patients were included in the intention to treat analysis. This trial was registered at ClinicalTrials.gov, NCT05152849.

Findings: Between December 15th 2021, and May 23th 2022, 60 participants were screened and 41 participants were randomised and included in the final analysis. Changes in skeletal muscle phosphocreatine recovery time constant (τPCr) and 6-min walk test (6MWT) did not significantly differ between treatment (n = 21) and placebo group (n = 20). However, treatment with AXA1125 was associated with significantly reduced day 28 Chalder Fatigue Questionnaire [CFQ-11] fatigue score when compared with placebo (least squares mean difference [LSMD] −4.30, 95% confidence interval (95% CI) −7.14, −1.47; P = 0.0039). Eleven (52.4%, AXA1125) and four (20.0%, placebo) patients reported treatment-emergent adverse events; none were serious, or led to treatment discontinuation.

Interpretation: Although treatment with AXA1125 did not improve the primary endpoint (τPCr-measure of mitochondrial respiration), when compared to placebo, there was a significant improvement in fatigue-based symptoms among patients living with Long COVID following a four week treatment period. Further multicentre studies are needed to validate our findings in a larger cohort of patients with fatigue-dominant Long COVID.

Source: Lucy E.M. Finnigan, Mark Philip Cassar, Margaret James Koziel, Joel Pradines, Hanan Lamlum, Karim Azer, et al. Efficacy and tolerability of an endogenous metabolic modulator (AXA1125) in fatigue-predominant long COVID: a single-centre, double-blind, randomised controlled phase 2a pilot study. The Lancet, Published: April 14, 2023 DOI: https://doi.org/10.1016/j.eclinm.2023.101946 (Full text)

The Behavior of Muscle Oxygen Saturation, Oxy and Deoxy Hemoglobin during a Fatigue Test in Fibromyalgia

Abstract:

Previous studies have reported that people with fibromyalgia (FM) could suffer from mitochondrial dysfunction. However, the consumption of muscle oxygen during physical exercise has been poorly studied. Therefore, this study aimed to explore the response of muscle oxygen during a fatigue protocol in people with FM and healthy controls (HC). In addition, the peak torque and the total work were assessed.

A total of 31 participants (eighteen were people with fibromyalgia and thirteen were healthy controls) were enrolled in this cross-sectional study. All the participants underwent a fatigue protocol consisting of 20 repetitions at 180°·s−1 of quadriceps flexions and extensions using a Biodex System 3. The muscle oxygen saturation (SmO2), total hemoglobin (THb), deoxygenated hemoglobin (HHb) and oxygenated hemoglobin (O2Hb) values were measured using a portable near-infrared spectroscopy (NIRS) device. Significant differences between people with FM and healthy controls were found at baseline: SmO2 (FM: 56.03 ± 21.36; HC: 77.41 ± 10.82; p = 0.036), O2Hb (FM: 6.69 ± 2.59; HC: 9.37 ± 1.31; p = 0.030) and HHb (FM: 5.20 ± 2.51; HC: 2.73 ± 1.32; p = 0.039); during the fatigue protocol: SmO2 (FM: 48.54 ± 19.96; HC: 58.87 ± 19.72; p = 0.038), O2Hb (FM: 5.70 ± 2.34; HC: 7.06 ± 2.09; p = 0.027) and HHb (FM: 5.69 ± 2.65; HC: 4.81 ± 2.39; p = 0.048); and in the recovery at three min and six min for SmO2, O2Hb and HHb (p < 0.005).

Furthermore, healthy control values of SmO2, O2Hb and HHb have been significantly altered by the fatigue protocol (p < 0.005). In contrast, people with FM did not show any significant alteration in these values. Moreover, significant differences were found in the peak torque at extension (FM: 62.48 ± 24.45; HC: 88.31 ± 23.51; p = 0.033) and flexion (FM: 24.16 ± 11.58; HC: 42.05 ± 9.85; p = 0.010), and the total work performed at leg extension (FM: 1039.78 ± 434.51; HC: 1535.61 ± 474.22; p = 0.007) and flexion (FM: 423.79 ± 239.89; HC: 797.16 ± 194.37; p = 0.005).

Source: Villafaina S, Tomas-Carus P, Silva V, Costa AR, Fernandes O, Parraca JA. The Behavior of Muscle Oxygen Saturation, Oxy and Deoxy Hemoglobin during a Fatigue Test in Fibromyalgia. Biomedicines. 2023 Jan 4;11(1):132. doi: 10.3390/biomedicines11010132. PMID: 36672640; PMCID: PMC9856161. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9856161/ (Full text)

Exogenous Players in Mitochondria-Related CNS Disorders: Viral Pathogens and Unbalanced Microbiota in the Gut-Brain Axis

Abstract:

Billions of years of co-evolution has made mitochondria central to the eukaryotic cell and organism life playing the role of cellular power plants, as indeed they are involved in most, if not all, important regulatory pathways. Neurological disorders depending on impaired mitochondrial function or homeostasis can be caused by the misregulation of “endogenous players”, such as nuclear or cytoplasmic regulators, which have been treated elsewhere. In this review, we focus on how exogenous agents, i.e., viral pathogens, or unbalanced microbiota in the gut-brain axis can also endanger mitochondrial dynamics in the central nervous system (CNS).

Neurotropic viruses such as Herpes, Rabies, West-Nile, and Polioviruses seem to hijack neuronal transport networks, commandeering the proteins that mitochondria typically use to move along neurites. However, several neurological complications are also associated to infections by pandemic viruses, such as Influenza A virus and SARS-CoV-2 coronavirus, representing a relevant risk associated to seasonal flu, coronavirus disease-19 (COVID-19) and “Long-COVID”.

Emerging evidence is depicting the gut microbiota as a source of signals, transmitted via sensory neurons innervating the gut, able to influence brain structure and function, including cognitive functions. Therefore, the direct connection between intestinal microbiota and mitochondrial functions might concur with the onset, progression, and severity of CNS diseases.

Source: Righetto I, Gasparotto M, Casalino L, Vacca M, Filippini F. Exogenous Players in Mitochondria-Related CNS Disorders: Viral Pathogens and Unbalanced Microbiota in the Gut-Brain Axis. Biomolecules. 2023 Jan 13;13(1):169. doi: 10.3390/biom13010169. PMID: 36671555; PMCID: PMC9855674. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9855674/ (Full text)

Phenotypic characteristics of peripheral immune cells of Myalgic encephalomyelitis/chronic fatigue syndrome via transmission electron microscopy: A pilot study

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex chronic multi-systemic disease characterized by extreme fatigue that is not improved by rest, and worsens after exertion, whether physical or mental. Previous studies have shown ME/CFS-associated alterations in the immune system and mitochondria.

We used transmission electron microscopy (TEM) to investigate the morphology and ultrastructure of unstimulated and stimulated ME/CFS immune cells and their intracellular organelles, including mitochondria. PBMCs from four participants were studied: a pair of identical twins discordant for moderate ME/CFS, as well as two age- and gender- matched unrelated subjects-one with an extremely severe form of ME/CFS and the other healthy.

TEM analysis of CD3/CD28-stimulated T cells suggested a significant increase in the levels of apoptotic and necrotic cell death in T cells from ME/CFS patients (over 2-fold). Stimulated Tcells of ME/CFS patients also had higher numbers of swollen mitochondria. We also found a large increase in intracellular giant lipid droplet-like organelles in the stimulated PBMCs from the extremely severe ME/CFS patient potentially indicative of a lipid storage disorder. Lastly, we observed a slight increase in platelet aggregation in stimulated cells, suggestive of a possible role of platelet activity in ME/CFS pathophysiology and disease severity.

These results indicate extensive morphological alterations in the cellular and mitochondrial phenotypes of ME/CFS patients’ immune cells and suggest new insights into ME/CFS biology.

Source: Jahanbani F, Maynard RD, Sing JC, Jahanbani S, Perrino JJ, Spacek DV, Davis RW, Snyder MP. Phenotypic characteristics of peripheral immune cells of Myalgic encephalomyelitis/chronic fatigue syndrome via transmission electron microscopy: A pilot study. PLoS One. 2022 Aug 9;17(8):e0272703. doi: 10.1371/journal.pone.0272703. PMID: 35943990. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0272703 (Full text)

Intracellular Nutritional Biomarker Differences in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Subjects and Healthy Controls

Abstract:

Objectives

A comparison of the nutritional biomarkers between ME/CFS subjects and healthy controls (HC) was undertaken on secondary data collected from an IRB approved cross-sectional study in ME/CFS patients.

Methods

ME/CFS participants were recruited per the 2018 revised Canadian Clinical Case Definition for ME/CFS along with age matched HCs. Self-reported information on demographics and supplement use was collected, and body mass index calculated. HEI was calculated from Willet FFQ and multiple day 24-hour recall data, and severity of fatigue measured by Multidimensional Fatigue Inventory (MFI). Lymphocyte transformation assay by SpectraCell Lab (Houston, TX) was employed for intracellular micronutrient status. A series of two-tailed Mann-Whitney U tests (ɑ = 0.05) were performed for the non-parametric data expressed as mean ± standard error of the mean. All statistical analyses were conducted in IBM SPSS Statistics version 25 (Armonk, NY).

Results

Out of the 21 participants (11 ME/CFS and 10 HC), 82% of ME/CFS and 50% of HC were female. Higher fatigue scores were observed in ME/CFS (16.64 ± 1.36) than HC (10.78 ± 2.14). ME/CFS had better HEI scores (63.36 ± 13.44) than the HC (38.55 ± 12.29). However, despite better diet quality and supplementation, ME/CFS group showed lower intracellular Vitamin B3 and manganese (Mn) (86.3 ± 2.42 and 53.6 ± 2.81 respectively) but higher calcium (Ca) (57.5 ± 3.55) as compared to HC (97.2 ± 2.31, 64.5 ± 1.87 and 46.5 ± 0.96 respectively).

Conclusions

The results align with the current literature on indications of mitochondrial dysfunction in ME/CFS. Reduced intracellular vit B3 provides suboptimal production of the NAD(P)(H)-cofactor family, thus affecting mitochondrial function and consequently energy production. The aberration in energy metabolism is compounded by other factors, such as reduced Mn but higher Ca intracellular levels seen in this study indicating disruptions in oxidative stress pathways, resulting in debilitating fatigue experienced by individuals with ME/CFS.

Source: Priya Krishnakumar, Camila Jaramillo, Shawn Kurian, Wendy Levy, Cara Milman, Nadine Mikati, Fatma Huffman, Maria Abreu, Amanpreet Cheema, Intracellular Nutritional Biomarker Differences in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Subjects and Healthy Controls, Current Developments in Nutrition, Volume 6, Issue Supplement_1, June 2022, Page 745, https://doi.org/10.1093/cdn/nzac062.014

Carnitine Palmitoyl Transferase Deficiency in a University Immunology Practice

Abstract:

Purpose: This report describes the clinical manifestations of 35 patients sent to a University Immunology clinic with a diagnosis of fatigue and exercise intolerance who were identified to have low carnitine palmitoyl transferase activity on muscle biopsies.

Recent findings: All of the patients presented with fatigue and exercise intolerance and many had been diagnosed with fibromyalgia. Their symptoms responded to treatment of the metabolic disease. Associated symptoms included bloating, diarrhea, constipation, gastrointestinal reflux symptoms, recurrent infections, arthritis, dyspnea, dry eye, visual loss, and hearing loss. Associated medical conditions included Hashimoto thyroiditis, Sjogren’s syndrome, seronegative arthritis, food hypersensitivities, asthma, sleep apnea, and vasculitis. This study identifies clinical features that should alert physicians to the possibility of an underlying metabolic disease. Treatment of the metabolic disease leads to symptomatic improvement.

Source: Bax K, Isackson PJ, Moore M, Ambrus JL Jr. Carnitine Palmitoyl Transferase Deficiency in a University Immunology Practice. Curr Rheumatol Rep. 2020 Feb 14;22(3):8. doi: 10.1007/s11926-020-0879-9. PMID: 32067119. https://pubmed.ncbi.nlm.nih.gov/32067119/

Pharmacological significance of MitoQ in ameliorating mitochondria-related diseases

Abstract:

The Mitochondria is a critical sub-cellular organelle that plays an integral part in a normal cellular process. Besides ATP production, the mitochondria participate in various key cellular processes such as cell signaling, epigenetic regulation leading to cell proliferation, migration, apoptosis, differentiation, and autophagy – highlighting their importance to cellular health. However, mitochondrial dysfunction has serious organismal consequences, playing critical roles in the pathophysiology of many diseases, including neurodegenerative disorders, cardiovascular diseases, cancer, pulmonary and liver diseases. In recent years, mitochondrial dysfunction has spurred a surge of interest in developing mitochondria-targeted therapies.

MitoQ is a selective antioxidant that concentrates in the mitochondria and prevents oxidative damage to the mitochondria. The therapeutic relevance of MitoQ has been studied in various diseased conditions to determine its efficacy in either slowing disease progression or alleviating symptoms. In this review, we discussed mitochondrial dysfunction in selected diseases and the therapeutic benefit of MitoQ in numerous studies.

Source: Lateef Adegboyega Sulaimon, Lukman Olalekan Afolabi, Rahmat Adetutu Adisa, Akinrinade George Ayankojo, Mariam Olanrewaju Afolabi, Abiodun Mohammed Adewolu, Xiaochun Wan. Pharmacological significance of MitoQ in ameliorating mitochondria-related diseases. Advances in Redox Research, 2022 [In Press, Journal pre-proof]  https://www.sciencedirect.com/science/article/pii/S2667137922000091 (Full text)

Clinically proven mtDNA mutations are not common in those with chronic fatigue syndrome

Abstract:

Background: Chronic Fatigue Syndrome (CFS) is a prevalent debilitating condition that affects approximately 250,000 people in the UK. There is growing interest in the role of mitochondrial function and mitochondrial DNA (mtDNA) variation in CFS. It is now known that fatigue is common and often severe in patients with mitochondrial disease irrespective of their age, gender or mtDNA genotype. More recently, it has been suggested that some CFS patients harbour clinically proven mtDNA mutations.

Methods: MtDNA sequencing of 93 CFS patients from the United Kingdom (UK) and South Africa (RSA) was performed using an Ion Torrent Personal Genome Machine. The sequence data was examined for any evidence of clinically proven mutations, currently; more than 200 clinically proven mtDNA mutations point mutations have been identified.

Results: We report the complete mtDNA sequence of 93 CFS patients from the UK and RSA, without finding evidence of clinically proven mtDNA mutations. This finding demonstrates that clinically proven mtDNA mutations are not a common element in the aetiology of disease in CFS patients. That is patients having a clinically proven mtDNA mutation and subsequently being misdiagnosed with CFS are likely to be rare.

Conclusion: The work supports the assertion that CFS should not be considered to fall within the spectrum of mtDNA disease. However, the current study cannot exclude a role for nuclear genes with a mitochondrial function, nor a role of mtDNA population variants in susceptibility to disease. This study highlights the need for more to be done to understand the pathophysiology of CFS.

Source: Schoeman EM, Van Der Westhuizen FH, Erasmus E, van Dyk E, Knowles CV, Al-Ali S, Ng WF, Taylor RW, Newton JL, Elson JL. Clinically proven mtDNA mutations are not common in those with chronic fatigue syndrome. BMC Med Genet. 2017 Mar 16;18(1):29. doi: 10.1186/s12881-017-0387-6. PMID: 28302057; PMCID: PMC5356238. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5356238/ (Full text)

The role of mitochondria in ME/CFS: a perspective

Abstract:

Chronic fatigue syndrome (CFS) also known as Myalgic encephalomyelitis (ME) is a debilitating disease, characterized by the symptom of severe fatigue. ME/CFS is a heterogeneous condition in both clinical presentation and disease duration. A diagnosis of ME/CFS is based on the exclusion of other diseases due to a current lack of known biomarkers for the disease. Patients may be split into categories based on the severity of their illness – mild, moderate and severe. Here we consider some of the recent advances in the understanding of mitochondrial dysfunction and mitochondrial DNA (mtDNA) variation that may have relevance to ME/CFS.

Thus far, we have shown that ME/CFS patients do not harbor proven mtDNA mutations, another exclusion, albeit an important one. As such this group of patients do not fall within the category of patients with mitochondrial disorder. If ME/CFS patients have some form of mitochondrial dysfunction, the form and cause of this dysfunction is a matter of debate. The current data underlines the need to move from small studies to larger endeavors applying multiple methods to well-defined cohorts with samples taken longitudinally.

Source: Cara Tomas & Joanna L Elson (2019) The role of mitochondria in ME/CFS: a perspective, Fatigue: Biomedicine, Health & Behavior, 7:1, 52-58, DOI: 10.1080/21641846.2019.1580855 https://www.tandfonline.com/doi/abs/10.1080/21641846.2019.1580855  (Full text)