Platelet mitochondrial function and endogenous coenzyme Q10 levels are reduced in patients after COVID-19.

BACKGROUND: After an acute treatment for coronavirus disease (COVID-19), some symptoms may persist for several weeks, for example: fatigue, headaches, muscle and joint pain, cough, loss of taste and smell, sleep and memory disturbances, depression. Many viruses manipulate mitochondrial function, but the exact mechanisms of SARS-CoV-2 virus effect remain unclear. We tested the hypothesis that SARS-CoV-2 virus may affect mitochondrial energy production and endogenous biosynthesis of coenzyme Q10 (CoQ10). METHODS: Ten patients after COVID-19 and 15 healthy individuals were included in the study. Platelets isolated from peripheral blood were used as an accessible source of mitochondria. High-resolution respirometry for the evaluation of platelets mitochondrial function, and HPLC method for CoQ10 determination were used. Oxidative stress was evaluated by TBARS concentration in plasma. RESULTS: Platelet mitochondrial respiratory chain function, oxidative phosphorylation and endogenous CoQ10 level were reduced in the patients after COVID-19. CONCLUSION: We assume that a reduced concentration of endogenous CoQ10 may partially block electron transfer in the respiratory chain resulting in a reduced adenosine triphosphate (ATP) production in the patients after COVID-19. Targeted mitochondrial therapy with CoQ10 supplementation and spa rehabilitation may improve mitochondrial health and accelerate the recovery of the patients after COVID-19. Platelet mitochondrial function and CoQ10 content may be useful mitochondrial health biomarkers after SARS-CoV-2 infection (Tab. 3, Fig. 3, Ref. 46).

Treatment with coenzyme Q10, omega-3-polyunsaturated fatty acids and their combination improved bioenergetics and levels of coenzyme Q9 and Q10 in skeletal muscle mitochondria in experimental model of arthritis.

Rheumatoid arthritis (RA) and its animal model adjuvant arthritis (AA) are inflammatory diseases characterized by chronic inflammation, systemic oxidative stress and disturbed mitochondrial bioenergetics of skeletal muscle. The present study aimed to evaluate the effects of coenzyme Q10 - CoQ10 (100 mg/kg b.w.), omega-3-polyunsaturated fatty acids - omega-3-PUFA (400 mg/kg b.w.) and their combined treatment in AA on impaired skeletal muscle mitochondrial bioenergetics, inflammation and changes in levels CoQ9 and CoQ10 in plasma. Markers of inflammation (C-reactive protein, monocyte-chemotactic protein-1), antioxidant capacity of plasma, respiratory chain parameters of skeletal muscle mitochondria and concentrations of CoQ9 and CoQ10 in plasma and in muscle tissue were estimated. Treatment of the arthritic rats with CoQ10, omega-3-PUFA alone and in combination partially reduced markers of inflammation and increased antioxidant capacity of plasma, significantly increased concentrations of coenzyme Q in mitochondria and improved mitochondrial function in the skeletal muscle. Combined treatment has similar effect on the mitochondrial function as monotherapies; however, it has affected inflammation and antioxidant status more intensively than monotherapies. Long-term supplementary administration of coenzyme Q10 and omega-3-PUFA and especially their combination is able to restore the impaired mitochondrial bioenergetics and antioxidant status in AA.

Is mitochondrial bioenergetics and coenzyme Q10 the target of a virus causing COVID-19?

COVID-19 ‒ a coronavirus disease, affected almost all countries in the world. It is a new virus disease, nobody has prior immunity to it, human population is prone to infections. In March 11 2020, WHO declared the pandemic status. The main symptoms include: fever, dry cough and fatigue. Virus proteins need mitochondrial energy for their own survival and replication. Upon viral infections, mitochondrial dynamics and metabolism can be modulated, which can influence the energy production in the host cells. Coenzyme Q10 is an integral component of mitochondrial respiratory chain and the key component of mitochondrial ATP production. The exact pathobiochemical mechanism of the disease is unknown. Modulated mitochondrial dynamics and metabolism with lower CoQ10 levels in viral infections leads us to the hypothesis that one of the main pathobiochemical effects of SARS-Cov-2 virus could be mitochondrial bioenergetics dysfunction with CoQ10 deficit leading to the reduction of its endogenous biosynthesis. The mechanism might be virus induced oxidative stress causing a mutation of one or more of the nine COQ genes, resulting in primary CoQ10 deficiency. New perspective for patients with COVID-19 may be supportive targeting therapy with coenzyme Q10 to increase the energy production, immunity and decrease oxidative stress (Fig. 1, Ref. 51). Keywords: COVID-19, virus, mitochondrial bioenergetics, coenzyme Q10, oxidative stress.

Platelet mitochondrial bioenergetic analysis in patients with nephropathies and non-communicable diseases: a new method.

OBJECTIVES: To test the hypothesis if mitochondrial bioenergetic function analyzed in circulating platelets may represent peripheral signature of mitochondrial dysfunction in nephropathy associated to non-communicable human diseases such as cardiovascular diseases, diabetes and with statins treatment. METHODS: High-resolution respirometry was used for analysis of mitochondrial bioenergetics in human platelets isolated from peripheral blood. This method is less-invasively compared to skeletal muscle biopsy. Patients with nephropathies and in combination with non-communicable diseases were included in the study. RESULTS: This pilot study showed platelet mitochondrial bioenergy dysfunction in patients with nephropathies and non-communicable diseases. Positive effect of treatment with 10 mg atorvastatin on platelet mitochondrial respiratory chain Complex I-linked respiration and ATP production in patients with nephropathies, diabetes and 80 mg atorvastatin in patient with nephropathy and dialysis was found. Positive effect of 80 mg fluvastatin treatment, and negative effect of thrombocytopenia and renal transplantation on platelet mitochondrial bioenergy was determined. CONCLUSION: High-resolution respirometry allowed detection of small changes in platelet mitochondrial function. This method could be used as a sensitive bioenergetic test of mitochondrial function for diagnosis and monitoring the therapy in patients with nephropathy (Tab. 1, Fig. 3, Ref. 39).

Effects of atorvastatin on heart mitochondrial function and coenzyme Q content in the experiment.

We focused on determination of whether atorvastatin: 1) reduces CoQ content, 2) impairs mitochondrial function and 3) induces dose-dependent changes. Although the high dose of atorvastatin exerted a beneficial effect on the lipid peroxidation in plasma, coenzyme Q content was reduced and heart mitochondrial function was impaired. Physicians should be aware when prescribing statins mainly in higher doses to the patients with co-existing proved or supposed CoQ10 deficiency resulting from age-related decline, and metabolic or mitochondrial diseases (Ref. 3).

Complementary therapy in diabetic patients with chronic complications: a pilot study.

BACKGROUND: Oxidative stress and dysregulation of antioxidant function play a pivotal role in the diabetic complications. METHODS: Fifty-nine patients with diabetes were randomly assigned into three groups. 1) PL group (n = 19): Polarized light (PL) was applied to neuropathic ulcers of diabetic foot twice daily for ten minutes in pulse regimen during three months. 2) QALA group (n = 20): Antioxidants (60 mg hydrosoluble CoQ10, 100 mg alpha-lipoic acid (ALA) and 200 mg vitamin E) were used in two daily doses for three months. 3) QALAPL group (n = 20): Patients used antioxidants along with PL applications. To test for differences in means, paired Student's t-test (before and after three months) was used. RESULTS: Three months application of PL significantly increased plasma concentrations of coenzyme Q10, alpha-tocopherol, tau-tocopherol and beta-carotene, and decreased lactate dehydrogenase (LDH) activity. Supplementation with antioxidants decreased plasma lipid peroxides, increased concentration of CoQ10 and improved echocardiographic parameters. Simultaneous application of PL and antioxidants significantly stimulated plasma CoQ10 and alpha-tocopherol concentrations, decreased LDH activity and contributed to improvement in heart left ventricular function in diabetics. CONCLUSION: Thus the data show that supportive therapy with PL along with the antioxidants hydrosoluble CoQ10, alpha-lipoic acid and vitamin E is an effective way of controlling the complications of type 2 diabetes (Tab. 7, Fig. 2, Ref. 44).

Regeneration of coenzyme Q9 redox state and inhibition of oxidative stress by Rooibos tea (Aspalathus linearis) administration in carbon tetrachloride liver damage.

The effect of rooibos tea (Aspalathus linearis) on liver antioxidant status and oxidative stress was investigated in rat model of carbon tetrachloride-induced liver damage. Synthetic antioxidant N-acetyl-L-cysteine (NAC) was used for comparison. Administration of carbon tetrachloride (CCl4) for 10 weeks decreased liver concentrations of reduced and oxidized forms of coenzyme Q9 (CoQ9H2 and CoQ9), reduced -tocopherol content and simultaneously increased the formation of malondialdehyde (MDA) as indicator of lipid peroxidation. Rooibos tea and NAC administered to CCl4-damaged rats restored liver concentrations of CoQ9H2 and alpha-tocopherol and inhibited the formation of MDA, all to the values comparable with healthy animals. Rooibos tea did not counteract the decrease in CoQ9, whereas NAC was able to do it. Improved regeneration of coenzyme Q9 redox state and inhibition of oxidative stress in CCl4-damaged livers may explain the beneficial effect of antioxidant therapy. Therefore, the consumption of rooibos tea as a rich source of natural antioxidants could be recommended as a market available, safe and effective hepatoprotector in patients with liver diseases.

Decreased levels of coenzyme Q(10) in patients with bronchial asthma.

BACKGROUND: The contribution of free oxygen radicals in the pathogenesis of bronchial asthma is generally accepted. The modulation of antioxidative defence by supplementation with antioxidants represents additive therapy in complex management of disease. The aim of the study was to assess the levels of coenzyme Q10, alpha-tocopherol, and beta-carotene both in plasma and whole blood, and malondialdehyde (MDA) and eosinophil cationic protein (ECP) in plasma of asthmatics (As). METHODS: Fifty-six As (15 males and 41 females) aged from 19 to 72 years (mean age 46 years) suffering from allergic asthma were enrolled into the study. The control group comprised 25 healthy volunteers (16 males, 9 females) aged 25-50 years. RESULTS: The concentrations of CoQ10 decreased significantly both in plasma and whole blood, compared with healthy volunteers (0.34 +/- 0.15 micromol/l vs. 0.52 +/- 0.15 micromol/l, 0.33 +/- 0.14 micromol/l vs. 0.50 +/- 0.13 micromol/l, P < 0.001, P< 0.001, respectively). The levels of alpha-tocopherol were decreased both in plasma and whole blood in comparison with controls [24.10 micromol/l (19.8; 30.5), vs. 33.20 micromol/l (28.25; 38.05), 17.22 +/- 6.45 micromol/l vs. 21.58 +/- 7.92 micromol/l, P= 0.006, P = 0.01, respectively]. The levels of MDA were elevated over the reference range in both groups (reference range < 4.5 micromol/l). No changes were seen in beta-carotene concentrations. Positive correlation was found between whole blood CoQ10 and alpha-tocopherol concentrations. CONCLUSION: Results of the study suggest a possible contribution of suboptimal concentrations of CoQ10 on antioxidative dysbalance in As and provide a rationale for its supplementation.

Levels of coenzyme Q10 in asthmatics.

BACKGROUND: The contribution of free oxygen radicals in the pathogenesis of bronchial asthma is generally accepted. The modulation of antioxidative defence by supplementation with antioxidants represents additive approach in complex management of the disease. The aim of the study was to assess the levels of coenzyme Q10, alpha-tocopherol, beta-carotene and malondialdehyde (end-stage parameter of lipid peroxidation) in asthmatics (As). METHODS: Fifty six As (15 males and 41 females) aged from 19 to 72 yrs (mean age 46 yrs) were enrolled into the study. The control group comprised of 25 healthy volunteers (16 males, 9 females) aged 25-50 years. RESULTS: Concentrations of CoQ10 and alpha-tocopherol, decresed significantly both in plasma and whole blood, compared with healthy volunteers (p < 0.009, p < 0.004; p < 0.035, p < 0.001, respectively). The level of MDA was elevated, but not statisticaly significantly. No changes were seen in beta-carotene levels. Positive correlation was found between concentrations of CoQ10 and alpha-tocopherol. CONCLUSION: Our results suggest possible contribution of suboptimal concentrations of CoQ10 on antioxidative dysbalance in As and provide rationale for its supplementation with clinical evaluation. (Tab. 2, Fig. 1, Ref. 39.).

[Effect of coenzyme Q10 in patients with kidney diseases]. / Ucinok koenzýmu Q10 u pacientov s ochoreniami obliciek.

BACKGROUND: Coenzyme Q10 belongs to important antioxidants and it has a key role in the synthesis of adenosinetriphosphate. Its beneficial effect was proved in several diseases, e.g. in mitochondrial encephalopathy, mitochondrial myopathy, mitochondrial cardiomyopathy. MATERIAL AND METHODS: All 15 patients of the studied group (5 with tubulopathy and 10 with chronic tubulointersticial nephritis) received antioxidative therapy for three months (E vitamin, C vitamin, riboflavin) and for the last two months coenzyme Q10 was added. Renal functions, spectrum of lipids, parameters of lipid peroxidation (malondialdehyde), levels of alpha-tocopherol, beta-carotene, coenzyme Q10. RESULTS: Before the substitutive antioxidative treatment, coenzyme Q10 levels reached in blood 0.11 +/- 0.03 mumol/l and 0.15 +/- 0.04 mumol/l in plasma. These values were well below the reference range (rr) is 0.4 +/- 1.0 mumol/l). After the substitution coenzyme Q10 levels significantly increased (p < 0.001) to the values of 1.66 +/- 0.16 mumol/l in blood and to 1.78 +/- 0.27 mumol/l in plasma. Plasma levels of beta-carotene increased from the markedly subnormal values 0.25 +/- 0.07 mumol/l (rr > 0.8 mumol/l) to 0.56 +/- 0.02 mumol/l (no statistical difference). Plasma levels of alpha-tocopherol remained within the reference range 32.15 +/- 4.73 mumol/l (rr 15-30 mumol/l) and they increased up to the plasma level of 44.83 +/- 5.82 mumol/l during the period of testing. Malondialdehyde levels did not significantly change within the testing period. No changes in renal functions and parameters of lipid metabolism were described. Patients well tolerated the treatment and no adverse effects were seen during the period of observation. CONCLUSIONS: Our results ascertained that levels of antioxidant CoQ10 were lower in patients with nephropathy who underwent conservative treatment with peroral substation. Such deficit can be amended by CoQ10 administration, which could be therefore taken as complementary treatment of nephrology.

Metabolic changes in rat brain after prolonged ethanol consumption measured by 1H and 31P MRS experiments.

1. In vivo 1H and 31P magnetic resonance spectroscopy techniques were applied to reveal biochemical changes in the rat brain caused by prolonged ethanol consumption. 2. Three models of ethanol intoxication were used. 3. 1H MRS showed a significant decrease in the concentration of myo-inositol in the brain of rats fed with 20% ethanol for 8 weeks. This change is consistent with perturbances in astrocytes. On the other hand, N-acetyl aspartate and choline content did not differ from controls. 4. 31P MRS did not reveal any significant changes in the high-energy phosphates or intracellular free Mg2+ content in the brain of rats after 14 weeks of 20% ethanol drinking. The intracellular pH was diminished. 5. By means of a 31P saturation transfer technique, a significant decrease was observed for the pseudo first-order rate constant k(for) of the creatine kinase reaction in the brain of rats administered 30% ethanol for 3 weeks using a gastric tube. 6. The 1H MRS results may indicate that myo-inositol loss, reflecting a disorder in astrocytes, might be one of the first changes associated with alcoholism, which could be detected in the brain by means of in vivo 1H MRS. 7. The results from 31p MRS experiments suggest that alcoholism is associated with decreased brain energy metabolism. 8. 31P saturation transfer, which provides insight into the turnover of high-energy phosphates, could be a more suitable technique for studying the brain energetics in chronic pathological states than conventional 31P MRS.

Effect of dietary supplementation with the pyridoindole antioxidant stobadine on antioxidant state and ultrastructure of diabetic rat myocardium.

Consistent with the postulated role of oxidative stress in the etiology of late diabetic complications, pharmacological interventions based on biological antioxidants have been suggested. The aim of the present study was to investigate the effect of dietary supplementation with the pyridoindole antioxidant stobadine on the myocardial antioxidant status and ultrastructure of streptozotocin-diabetic rats. Diabetic male Wistar rats were fed for 32 weeks a standard diet or a diet supplemented with stobadine (0.05% w/w). Control rats received a standard diet or stobadine-supplemented diet (0.16% w/w). Plasma levels of glucose, cholesterol and triglycerides were increased significantly by diabetes. Activities of superoxide dismutase and catalase were markedly elevated in the diabetic myocardium. Myocardial levels of conjugated dienes increased after eight months of diabetes, in spite of significantly increased myocardial alpha-tocopherol and coenzyme Q9 content. The long-term treatment of diabetic animals with stobadine (i) reduced plasma cholesterol and triglyceride levels yet left the severe hyperglycemia unaffected, (ii) reduced oxidative damage of myocardial tissue as measured by conjugated dienes, (iii) reversed myocardial levels of alpha-tocopherol and coenzyme Q9 to near control values, (iv) reduced elevated activity of superoxide dismutase in the diabetic myocardium, and (v) attenuated angiopathic and atherogenic processes in the myocardium as assessed by electron microscopy examination. These results are in accordance with the postulated prooxidant role of chronic hyperglycemia and provide further evidence that development of pathological changes in diabetic myocardium is amenable to pharmacological intervention by biological antioxidants.

[Mitochondrial bioenergetics in patients before and after heart transplantation]. / Bioenergetika mitochondrií u pacientov pred transplantáciou a po transplantácii srdca.

BACKGROUND: The results of the study of biochemical and genetic characteristics of mitochondria in human medicine become widely used in practice. This is confirmed also by the Nobel Symposium which took place in 1994, and was dedicated to the problem of mitochondrial diseases and the effect of their therapy. Relatively rare is the information on the pathobiochemistry of heart muscle mitochondria in patients with cardiomyopathies. No information, so far, is available on oxidative phosphorylation in cases of myocardium transplantation in patients. MAIN PURPOSE AND OBJECTIVES: To bring early metabolic changes in mitochondria within EMB (endomyocardial biopsy) under control in patients after transplantation of the heart (Htx). These detected metabolic changes can contribute to the clarification of the mechanisms participating in the rejection of the transplanted myocardium. PATIENTS AND METHODS: The investigated group of patients included: a) patients with cardiopathies of unclear origin (NYHA II, NYHAIII) b) patients after transplantation of the heart (NYHAI-II) The authors assessed the properties of the respiratory chain and ATP production in mitochondria of EMB. CONCLUSIONS: The new methodical approach to the study of bioenergy of mitochondria of the myocardium in patients allows an early recognition of pathobiochemical changes in myocardium. Supplementing studies are going to reveal wether the presented methodical approach bear diagnostic value. (Fig. 3, Ref. 25.).

[Metabolic study of mitochondria in myocardial biopsies in patients with cardiopathy of unknown origin]. / Metabolické stúdie mitochondrií v biopsiách myokardu u pacientov s kardiopatiami nejasného pôvodu.

BACKGROUND: Mitochondrial cardiomyopathies are being studied as metabolic diseases of the cardiac muscle which represents a new approach in metabolic studies. The development of mitochondrial diseases is concomited by an impairment in complexes of mitochondrial respiratory chain, which so far could have been possibly studied exclusively on experimental animals. The method of skinned? fibers enables to measure the pathobiochemical processes in mitochondria in a small amount of bioptic myocardial tissue of patients. AIM: The study is aimed at: applying the method of skinned fibers in biopsy of myocardium in patients, trying to localize the impaired loci of the mitochondrial respiratory chains, prospective early and fast assessment of the diagnosis of mitochondrial cardiomyopathy in patients. CONCLUSIONS: The study brings the first information on the possibility of performing more value measurements of mitochondrial respiratory chains per one bioptic sample from the myocardium in patients. The preliminary results indicate to the prospective possibility of early and fast assessment of the diagnosis of mitochondrial cardio(myo)pathies. The presented results require complementary studies involving the development of "mitochondrial medicine".

[The effect of an alpha-tocopherol analog, MDL 73404, on myocardial bioenergetics]. / Vplyv analógu alfatokoferolu MDL 73,404 na bioenergetiku myokardu.

The authors investigated the effect of the synthetic analogue of MDL 73,404 alpha-tocopherol on bioenergetic processes of the cardiac muscle in a control group of rats. After a 10-day application of the presented preparation they analyzed the following parameters of energetic metabolism: ATP, ADP, AMP and inorganic phosphorus. Beside these, the authors investigate the levels of main indicators of the purine metabolism (xanthine, hypoxanthine, inosine and uric acid) in the myocardium. Under the influence of the given analogue of alpha-tocopherol a significant increase in ATP, ADP and hypoxanthine took place in the myocardium. Also the total concentration of adenine nucleotide and relative ATP/ADP ratio increased in the cardiac muscle. On the basis of the gained results the authors came to a conclusion that the synthetic analogue of alpha-tocopherol MDL 73,404 has a favourable effect on the bioenergetic conditions in the myocardium. MDL 73,404 has a favourable cardioprotective effect on the cardiac muscle assumedly by means of stabilization of mitochondrial membranes on the myocardium with a subsequent impact on cellular ATP concentration.