Challenges of CoQ10 Deficiency in Diagnostic, New Models of Disease and Therapy

A special issue of Antioxidants (ISSN 2076-3921). This special issue belongs to the section "Health Outcomes of Antioxidants and Oxidative Stress".

Deadline for manuscript submissions: closed (20 October 2022) | Viewed by 32764

Special Issue Editors


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Guest Editor
Centro de Investigación Biomédica en Red (CIBER) de Enfermedades Raras (CIBERER), 28029 Madrid, Spain
Interests: mitochondrial disorders; inborn errors of metabolism; coenzyme Q10; neurotransmitters; targeted metabolomic analysis

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Guest Editor
Department of Physiology, Anatomy and Cellular Biology, University of Pablo d 'Oravide, Seville, Spain
Interests: antioxidants; coenzyme Q; mitochondrial metabolism; bioenergetics; yeasts

Special Issue Information

Dear Colleagues,

Coenzyme Q10 (CoQ) displays fundamental roles in different biological processes, such as cell respiration, antioxidant defenses or regulation of apoptosis, among others. During the last few decades, suboptimal CoQ status has been associated with a great variety of diseases, from rare genetic conditions leading to severe CoQ deficiency to other secondary alterations related to common diseases, such as cardiovascular damage or neurodegenerative conditions. Extensive laboratory tools have been validated, either for the single determination of CoQ concentrations in biological fluids and cell extracts to detect deficiencies or for more sophisticated technologies that can explore CoQ biosynthesis (a very complex and intricate metabolic pathway) and functional aspects in human cells and animal models. For example, extensive research has been conducted on yeast, it being an essential tool to confirm some of the hypotheses regarding CoQ implication in biological processes and human diseases. This Special Issue aims to collect papers dealing with the different approaches for CoQ clinical and basic investigations. Pure methodological papers describing CoQ quantification techniques and biosynthesis and functional studies are welcome. Additionally, the application of such methodologies to elucidate the pathophysiology of CoQ deficiency in patient and cell models will be considered. Finally, reports on available therapeutic approaches will be considered.

Dr. Rafael Artuch
Prof. Dr. Carlos Santos-Ocana
Guest Editors

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Keywords

  • Coenzyme Q10 deficiency
  • Mitochondrial dysfunction
  • CoQ determination in human samples
  • CoQ biosynthesis technologies
  • Cellular and animal models

Published Papers (11 papers)

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Research

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57 pages, 20162 KiB  
Article
Predicting and Understanding the Pathology of Single Nucleotide Variants in Human COQ Genes
by Sining Wang, Akash Jain, Noelle Alexa Novales, Audrey N. Nashner, Fiona Tran and Catherine F. Clarke
Antioxidants 2022, 11(12), 2308; https://doi.org/10.3390/antiox11122308 - 22 Nov 2022
Cited by 3 | Viewed by 2313
Abstract
Coenzyme Q (CoQ) is a vital lipid that functions as an electron carrier in the mitochondrial electron transport chain and as a membrane-soluble antioxidant. Deficiencies in CoQ lead to metabolic diseases with a wide range of clinical manifestations. There are currently few treatments [...] Read more.
Coenzyme Q (CoQ) is a vital lipid that functions as an electron carrier in the mitochondrial electron transport chain and as a membrane-soluble antioxidant. Deficiencies in CoQ lead to metabolic diseases with a wide range of clinical manifestations. There are currently few treatments that can slow or stop disease progression. Primary CoQ10 deficiency can arise from mutations in any of the COQ genes responsible for CoQ biosynthesis. While many mutations in these genes have been identified, the clinical significance of most of them remains unclear. Here we analyzed the structural and functional impact of 429 human missense single nucleotide variants (SNVs) that give rise to amino acid substitutions in the conserved and functional regions of human genes encoding a high molecular weight complex known as the CoQ synthome (or Complex Q), consisting of the COQ3COQ7 and COQ9 gene products. Using structures of COQ polypeptides, close homologs, and AlphaFold models, we identified 115 SNVs that are potentially pathogenic. Further biochemical characterizations in model organisms such as Saccharomyces cerevisiae are required to validate the pathogenicity of the identified SNVs. Collectively, our results will provide a resource for clinicians during patient diagnosis and guide therapeutic efforts toward combating primary CoQ10 deficiency. Full article
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12 pages, 1271 KiB  
Article
Coenzyme Q10 Supplementation in Statin Treated Patients: A Double-Blinded Randomized Placebo-Controlled Trial
by Tine L. Dohlmann, Anja B. Kuhlman, Thomas Morville, Maria Dahl, Magnus Asping, Patrick Orlando, Sonia Silvestri, Luca Tiano, Jørn W. Helge, Flemming Dela and Steen Larsen
Antioxidants 2022, 11(9), 1698; https://doi.org/10.3390/antiox11091698 - 29 Aug 2022
Cited by 2 | Viewed by 4303
Abstract
Myalgia and new-onset of type 2 diabetes have been associated with statin treatment, which both could be linked to reduced coenzyme Q10 (CoQ10) in skeletal muscle and impaired mitochondrial function. Supplementation with CoQ10 focusing on levels of CoQ10 in skeletal muscle and mitochondrial [...] Read more.
Myalgia and new-onset of type 2 diabetes have been associated with statin treatment, which both could be linked to reduced coenzyme Q10 (CoQ10) in skeletal muscle and impaired mitochondrial function. Supplementation with CoQ10 focusing on levels of CoQ10 in skeletal muscle and mitochondrial function has not been investigated in patients treated with statins. To investigate whether concomitant administration of CoQ10 with statins increases the muscle CoQ10 levels and improves the mitochondrial function, and if changes in muscle CoQ10 levels correlate with changes in the intensity of myalgia. 37 men and women in simvastatin therapy with and without myalgia were randomized to receive 400 mg CoQ10 daily or matched placebo tablets for eight weeks. Muscle CoQ10 levels, mitochondrial respiratory capacity, mitochondrial content (using citrate synthase activity as a biomarker), and production of reactive oxygen species were measured before and after CoQ10 supplementation, and intensity of myalgia was determined using the 10 cm visual analogue scale. Muscle CoQ10 content and mitochondrial function were unaltered by CoQ10 supplementation. Individual changes in muscle CoQ10 levels were not correlated with changes in intensity of myalgia. CoQ10 supplementation had no effect on muscle CoQ10 levels or mitochondrial function and did not affect symptoms of myalgia. Full article
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10 pages, 1326 KiB  
Article
Plasma CoQ10 Status in Patients with Propionic Acidaemia and Possible Benefit of Treatment with Ubiquinol
by Sinziana Stanescu, Amaya Belanger-Quintana, Borja Manuel Fernández-Felix, Pedro Ruiz-Sala, Patricia Alcaide, Francisco Arrieta and Mercedes Martínez-Pardo
Antioxidants 2022, 11(8), 1588; https://doi.org/10.3390/antiox11081588 - 16 Aug 2022
Cited by 2 | Viewed by 1263
Abstract
Propionic acidaemia (PA) is an innate error of metabolism involving a deficiency in the enzyme propionyl-CoA carboxylase. Better control of acute decompensation episodes together with better treatment and monitoring have improved the prognosis of patients with this problem. However, long-term complications can arise [...] Read more.
Propionic acidaemia (PA) is an innate error of metabolism involving a deficiency in the enzyme propionyl-CoA carboxylase. Better control of acute decompensation episodes together with better treatment and monitoring have improved the prognosis of patients with this problem. However, long-term complications can arise in those in whom good metabolic control is achieved, the result of mitochondrial dysfunction caused by deficient anaplerosis, increased oxidative stress, and reduced antioxidative capacity. Coenzyme Q10 (CoQ10) is a nutritional supplement that has a notable antioxidative effect and has been shown to improve mitochondrial function. The present prospective, interventional study examines the plasma concentration of CoQ10 in patients with PA, their tolerance of such supplementation with ubiquinol, and its benefits. Seven patients with PA (aged 2.5 to 20 years, 4 males) received supplements of CoQ10 in the form of ubiquinol (10 mg/kg/day for 6 months). A total of 6/7 patients showed reduced plasma CoQ10 concentrations that normalized after supplementation with ubiquinol (p-value < 0.001), which was well tolerated. Urinary citrate levels markedly increased during the study (p-value: 0.001), together with elevation of citrate/methlycitrate ratio (p-value: 0.03). No other significant changes were seen in plasma or urine biomarkers of PA. PA patients showed a deficiency of plasma CoQ10, which supplementation with ubiquinol corrected. The urinary excretion of Krebs cycle intermediate citrate and the citrate/methylcitrate ratio significantly increased compared to the baseline, suggesting improvement in anaplerosis. This treatment was well tolerated and should be further investigated as a means of preventing the chronic complications associated with likely multifactorial mitochondrial dysfunction in PA. Full article
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11 pages, 3088 KiB  
Article
Identification of Coenzyme Q10 and Skeletal Muscle Protein Biomarkers as Potential Factors to Assist in the Diagnosis of Sarcopenia
by Chi-Hua Yen, Po-Sheng Chang, Yu-Hsun Chang and Ping-Ting Lin
Antioxidants 2022, 11(4), 725; https://doi.org/10.3390/antiox11040725 - 06 Apr 2022
Cited by 4 | Viewed by 2095
Abstract
The aim of this study was to explore the use of coenzyme Q10 and skeletal muscle protein biomarkers in the diagnosis of sarcopenia. Subjects with or without sarcopenia were recruited. The anthropometric, muscle strength and endurance measurements were assessed. Muscle proteins (albumin and [...] Read more.
The aim of this study was to explore the use of coenzyme Q10 and skeletal muscle protein biomarkers in the diagnosis of sarcopenia. Subjects with or without sarcopenia were recruited. The anthropometric, muscle strength and endurance measurements were assessed. Muscle proteins (albumin and creatine kinase), myokines (irisin and myostatin), and the coenzyme Q10 level were measured. Approximately half of the subjects suffered from a low coenzyme Q10 concentration (<0.5 μM). The levels of creatinine kinase and irisin were significantly lower in subjects with sarcopenia (p ≤ 0.05). In receiver operating characteristic analyses, irisin and creatine kinase showed a better prediction capability for sarcopenia (area under the curve, irisin: 0.64 vs. creatinine kinase: 0.61) than other biomarkers. Additionally, a low level of irisin (<118.0 ng/mL, odds ratio, 6.46, p < 0.01), creatine kinase (<69.5 U/L, odds ratio, 3.31, p = 0.04), or coenzyme Q10 (<0.67 μM, odds ratio, 9.79, p < 0.01) may increase the risk for sarcopenia even after adjusting for confounders. Since the levels of coenzyme Q10 and muscle biomarkers, such as irisin and creatine kinase, are associated with sarcopenia, we suggest they could be used as candidate markers to assist in the diagnosis of sarcopenia. Full article
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16 pages, 1922 KiB  
Article
Sex-Dependent Protective Effect of Combined Application of Solubilized Ubiquinol and Selenium on Monocrotaline-Induced Pulmonary Hypertension in Wistar Rats
by Tatyana Kuropatkina, Olga Pavlova, Mikhail Gulyaev, Yury Pirogov, Anastasiya Khutorova, Sergey Stvolinsky, Natalia Medvedeva and Oleg Medvedev
Antioxidants 2022, 11(3), 549; https://doi.org/10.3390/antiox11030549 - 14 Mar 2022
Cited by 5 | Viewed by 2132
Abstract
Ubiquinol exhibits anti-inflammatory and antioxidant properties. Selenium is a part of a number of antioxidant enzymes. The monocrotaline inducible model of pulmonary hypertension used in this study includes pathological links that may act as an application for the use of ubiquinol with high [...] Read more.
Ubiquinol exhibits anti-inflammatory and antioxidant properties. Selenium is a part of a number of antioxidant enzymes. The monocrotaline inducible model of pulmonary hypertension used in this study includes pathological links that may act as an application for the use of ubiquinol with high bioavailability and selenium metabolic products. On day 1, male and female rats were subcutaneously injected with a water-alcohol solution of monocrotaline or only water-alcohol solution. On days 7 and 14, some animals were intravenously injected with either ubiquinol’s vehicle or solubilized ubiquinol, or orally with selenium powder daily, starting from day 7, or received both ubiquinol + selenium. Magnetic resonance imaging of the lungs was performed on day 20. Hemodynamic parameters and morphometry were measured on day 22. An increased right ventricle systolic pressure in relation to control was demonstrated in all groups of animals of both sexes, except the group of males receiving the combination of ubiquinol + selenium. The relative mass of the right ventricle did not differ from the control in all groups of males and females receiving either ubiquinol alone or the combination. Magnetic resonance imaging revealed impaired perfusion in almost all animals examined, but pulmonary fibrosis developed in only half of the animals in the ubiquinol group. Intravenous administration of ubiquinol has a protective effect on monocrotaline-induced pulmonary hypertension development resulting in reduced right ventricle hypertrophy, and lung mass. Ubiquinol + selenium administration resulted in a less severe increase in the right ventricle systolic pressure in male rats but not in females 3 weeks after the start of the experiment. This sex-dependent effect was not observed in the influence of ubiquinol alone. Full article
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13 pages, 1093 KiB  
Article
Technical Aspects of Coenzyme Q10 Analysis: Validation of a New HPLC-ED Method
by Abraham J. Paredes-Fuentes, Clara Oliva, Raquel Montero, Patricia Alcaide, George J. G. Ruijter, Judit García-Villoria, Pedro Ruiz-Sala and Rafael Artuch
Antioxidants 2022, 11(3), 528; https://doi.org/10.3390/antiox11030528 - 10 Mar 2022
Cited by 2 | Viewed by 2092
Abstract
The biochemical measurement of the CoQ status in different tissues can be performed using HPLC with electrochemical detection (ED). Because the production of the electrochemical cells used with the Coulochem series detectors was discontinued, we aimed to standardize a new HPLC-ED method with [...] Read more.
The biochemical measurement of the CoQ status in different tissues can be performed using HPLC with electrochemical detection (ED). Because the production of the electrochemical cells used with the Coulochem series detectors was discontinued, we aimed to standardize a new HPLC-ED method with new equipment. We report all technical aspects, troubleshooting and its performance in different biological samples, including plasma, skeletal muscle homogenates, urine and cultured skin fibroblasts. Analytical variables (intra- and inter-assay precision, linearity, analytical measurement range, limit of quantification, limit of detection and accuracy) were validated in calibrators and plasma samples and displayed adequate results. The comparison of the results of a new ERNDIM external quality control (EQC) scheme for the plasma CoQ determination between HPLC-ED (Lab 1) and LC-MS/MS (Lab 2) methods shows that the results of the latter were slightly higher in most cases, although a good consistency was generally observed. In conclusion, the new method reported here showed a good analytical performance. The global quality of the EQC scheme results among different participants can be improved with the contribution of more laboratories. Full article
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Review

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15 pages, 3179 KiB  
Review
Neuroimaging in Primary Coenzyme-Q10-Deficiency Disorders
by Juliane Münch, Jannik Prasuhn, Lucia Laugwitz, Cheuk-Wing Fung, Brian H.-Y. Chung, Marcello Bellusci, Ertan Mayatepek, Dirk Klee and Felix Distelmaier
Antioxidants 2023, 12(3), 718; https://doi.org/10.3390/antiox12030718 - 14 Mar 2023
Cited by 2 | Viewed by 2876
Abstract
Coenzyme Q10 (CoQ10) is an endogenously synthesized lipid molecule. It is best known for its role as a cofactor within the mitochondrial respiratory chain where it functions in electron transfer and ATP synthesis. However, there are many other cellular pathways [...] Read more.
Coenzyme Q10 (CoQ10) is an endogenously synthesized lipid molecule. It is best known for its role as a cofactor within the mitochondrial respiratory chain where it functions in electron transfer and ATP synthesis. However, there are many other cellular pathways that also depend on the CoQ10 supply (redox homeostasis, ferroptosis and sulfide oxidation). The CoQ10 biosynthesis pathway consists of several enzymes, which are encoded by the nuclear DNA. The majority of these enzymes are responsible for modifications of the CoQ-head group (benzoquinone ring). Only three enzymes (PDSS1, PDSS2 and COQ2) are required for assembly and attachment of the polyisoprenoid side chain. The head-modifying enzymes may assemble into resolvable domains, representing COQ complexes. During the last two decades, numerous inborn errors in CoQ10 biosynthesis enzymes have been identified. Thus far, 11 disease genes are known (PDSS1, PDSS2, COQ2, COQ4, COQ5, COQ6, COQ7, COQ8A, COQ8B, COQ9 and HPDL). Disease onset is highly variable and ranges from the neonatal period to late adulthood. CoQ10 deficiency exerts detrimental effects on the nervous system. Potential consequences are neuronal death, neuroinflammation and cerebral gliosis. Clinical features include encephalopathy, regression, movement disorders, epilepsy and intellectual disability. Brain magnetic resonance imaging (MRI) is the most important tool for diagnostic evaluation of neurological damage in individuals with CoQ10 deficiency. However, due to the rarity of the different gene defects, information on disease manifestations within the central nervous system is scarce. This review aims to provide an overview of brain MRI patterns observed in primary CoQ10 biosynthesis disorders and to highlight disease-specific findings. Full article
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15 pages, 874 KiB  
Review
The Use of the Coenzyme Q10 as a Food Supplement in the Management of Fibromyalgia: A Critical Review
by Luca Campisi and Concettina La Motta
Antioxidants 2022, 11(10), 1969; https://doi.org/10.3390/antiox11101969 - 30 Sep 2022
Cited by 4 | Viewed by 2303
Abstract
The coenzyme Q10 is a naturally occurring benzoquinone derivative widely prescribed as a food supplement for different physical conditions and pathologies. This review aims to sum up the key structural and functional characteristics of Q10, taking stock of its use [...] Read more.
The coenzyme Q10 is a naturally occurring benzoquinone derivative widely prescribed as a food supplement for different physical conditions and pathologies. This review aims to sum up the key structural and functional characteristics of Q10, taking stock of its use in people affected by fibromyalgia. A thorough survey has been conducted, using Pubmed, Scifinder, and ClinicalTrials.gov as the reference research applications and registry database, respectively. Original articles, reviews, and editorials published within the last 15 years, as well as open clinical investigations in the field, if any, were analyzed to point out the lights and shadows of this kind of supplementation as they emerge from the literature. Full article
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12 pages, 1411 KiB  
Review
Mechanisms and Therapeutic Effects of Benzoquinone Ring Analogs in Primary CoQ Deficiencies
by Alba Pesini, Agustin Hidalgo-Gutierrez and Catarina M. Quinzii
Antioxidants 2022, 11(4), 665; https://doi.org/10.3390/antiox11040665 - 30 Mar 2022
Cited by 3 | Viewed by 2224
Abstract
Coenzyme Q (CoQ) is a conserved polyprenylated lipid composed of a redox-active benzoquinone ring and a long polyisoprenyl tail that serves as a membrane anchor. CoQ biosynthesis involves multiple steps, including multiple modifications of the precursor ring 4-hydroxybenzoic acid. Mutations in the enzymes [...] Read more.
Coenzyme Q (CoQ) is a conserved polyprenylated lipid composed of a redox-active benzoquinone ring and a long polyisoprenyl tail that serves as a membrane anchor. CoQ biosynthesis involves multiple steps, including multiple modifications of the precursor ring 4-hydroxybenzoic acid. Mutations in the enzymes involved in CoQ biosynthesis pathway result in primary coenzyme Q deficiencies, mitochondrial disorders whose clinical heterogenicity reflects the multiple biological function of CoQ. Patients with these disorders do not always respond to CoQ supplementation, and CoQ analogs have not been successful as alternative approaches. Progress made in understanding the CoQ biosynthesis pathway and studies of supplementation with 4-hydroxybenzoic acid ring analogs have opened a new area in the field of primary CoQ deficiencies treatment. Here, we will review these studies, focusing on efficacy of the different 4-hydroxybenzoic acid ring analogs, models in which they have been tested, and their mechanisms of action. Understanding how these compounds ameliorate biochemical, molecular, and/or clinical phenotypes of CoQ deficiencies is important to develop the most rational treatment for CoQ deficient patients, depending on their molecular defects. Full article
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27 pages, 1286 KiB  
Review
Animal Models of Coenzyme Q Deficiency: Mechanistic and Translational Learnings
by Pilar González-García, Eliana Barriocanal-Casado, María Elena Díaz-Casado, Sergio López-Herrador, Agustín Hidalgo-Gutiérrez and Luis C. López
Antioxidants 2021, 10(11), 1687; https://doi.org/10.3390/antiox10111687 - 26 Oct 2021
Cited by 4 | Viewed by 2640
Abstract
Coenzyme Q (CoQ) is a vital lipophilic molecule that is endogenously synthesized in the mitochondria of each cell. The CoQ biosynthetic pathway is complex and not completely characterized, and it involves at least thirteen catalytic and regulatory proteins. Once it is synthesized, CoQ [...] Read more.
Coenzyme Q (CoQ) is a vital lipophilic molecule that is endogenously synthesized in the mitochondria of each cell. The CoQ biosynthetic pathway is complex and not completely characterized, and it involves at least thirteen catalytic and regulatory proteins. Once it is synthesized, CoQ exerts a wide variety of mitochondrial and extramitochondrial functions thank to its redox capacity and its lipophilicity. Thus, low levels of CoQ cause diseases with heterogeneous clinical symptoms, which are not always understood. The decreased levels of CoQ may be primary caused by defects in the CoQ biosynthetic pathway or secondarily associated with other diseases. In both cases, the pathomechanisms are related to the CoQ functions, although further experimental evidence is required to establish this association. The conventional treatment for CoQ deficiencies is the high doses of oral CoQ10 supplementation, but this therapy is not effective for some specific clinical presentations, especially in those involving the nervous system. To better understand the CoQ biosynthetic pathway, the biological functions linked to CoQ and the pathomechanisms of CoQ deficiencies, and to improve the therapeutic outcomes of this syndrome, a variety of animal models have been generated and characterized in the last decade. In this review, we show all the animal models available, remarking on the most important outcomes that each model has provided. Finally, we also comment some gaps and future research directions related to CoQ metabolism and how the current and novel animal models may help in the development of future research studies. Full article
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Other

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7 pages, 593 KiB  
Perspective
Lyme Disease: A Role for Coenzyme Q10 Supplementation?
by David Mantle, Nadia Turton and Iain P. Hargreaves
Antioxidants 2022, 11(4), 667; https://doi.org/10.3390/antiox11040667 - 30 Mar 2022
Cited by 2 | Viewed by 7167
Abstract
Lyme disease results from a bacterial infection following a bite from an infected tick. Patients are initially treated with antibiotics; however, in cases where antibiotic treatment is delayed, or when patients do not respond to antibiotic treatment, fatigue may develop alongside problems affecting [...] Read more.
Lyme disease results from a bacterial infection following a bite from an infected tick. Patients are initially treated with antibiotics; however, in cases where antibiotic treatment is delayed, or when patients do not respond to antibiotic treatment, fatigue may develop alongside problems affecting the nervous system, cardiovascular system, and joints. It is thought that most of the damage to these tissues results from the excessive inflammatory response of the host, involving a self-reinforcing cycle of mitochondrial dysfunction, oxidative stress and inflammation. In this article, we review the potential role of supplementary coenzyme Q10 (CoQ10) in mediating the pathogenic mechanism underlying Lyme disease, on the basis of its role in mitochondrial function, as well as its anti-inflammatory and antioxidant actions. Full article
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