Reduced platelet mitochondrial respiration and oxidative phosphorylation in patients with post COVID-19 syndrome are regenerated after spa rehabilitation and targeted ubiquinol therapy

Abstract

European Association of Spa Rehabilitation recommend spa rehabilitation for patients with post COVID-19 syndrome (post C-19). We studied effects of special mountain spa rehabilitation program and its combination with ubiquinol (reduced form of coenzyme Q10-CoQ10) supplementation on pulmonary function, clinical symptoms, endogenous CoQ10 levels, and platelet mitochondrial bioenergetics of patients with post C-19. 36 patients with post C-19 enrolled for rehabilitation in mountain spa resort and 15 healthy volunteers representing the control group were included in this study. 14 patients with post C-19 (MR group) were on mountain spa rehabilitation lasting 16-18 days, 22 patients (MRQ group) were supplemented with ubiquinol (2 × 100 mg/day) during the rehabilitation and additional 12-14 days at home. Clinical symptoms and functional capacity of the lungs were determined in the patients before and after the spa rehabilitation program. Platelet bioenergetics by high-resolution respirometry, plasma TBARS concentration, and CoQ10 concentration in blood, plasma and platelets were evaluated before and after the spa rehabilitation program, and in 8 patients of MRQ group also after additional 12-14 days of CoQ10 supplementation. Pulmonary function and clinical symptoms improved after the rehabilitation program in both groups, 51.8% of symptoms disappeared in the MR group and 62.8% in the MRQ group. Platelet mitochondrial Complex I (CI)-linked oxidative phosphorylation (OXPHOS) and electron transfer (ET) capacity were markedly reduced in both groups of patients. After the rehabilitation program the improvement of these parameters was significant in the MRQ group and moderate in the MR group. CI-linked OXPHOS and ET capacity increased further after additional 12-14 days of CoQ10 supplementation. CoQ10 concentration in platelets, blood and plasma markedly raised after the spa rehabilitation with ubiquinol supplementation, not in non-supplemented group. In the MRQ group all parameters of platelet mitochondrial respiration correlated with CoQ10 concentration in platelets, and the increase in CI-linked OXPHOS and ET capacity correlated with the increase of CoQ10 concentration in platelets. Our data show a significant role of supplemented ubiquinol in accelerating the recovery of mitochondrial health in patients with post C-19. Mountain spa rehabilitation with coenzyme Q10 supplementation could be recommended to patients with post C-19. This study was registered as a clinical trial: ClinicalTrials.gov ID: NCT05178225.

Keywords: mitochondrial oxidative phosphorylation; platelets; post COVID-19 syndrome; pulmonary function; spa rehablitation; ubiquinol.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2022 Sumbalová, Kucharská, Rausová, Palacka, Kovalčíková, Takácsová, Mojto, Navas, Lopéz-Lluch and Gvozdjáková.

Figures

FIGURE 1

The trace from the measurement of platelet mitochondrial respiration following SUIT reference protocol 1 (Doerrier et al., 2018). The blue line represents oxygen concentration (µM), and the red trace oxygen consumption as flow per cells (pmol O2/s/106 cells). The protocol includes following titration steps: ce—cells; Dig—Digitonin; PM—pyruvate + malate; ADP; cyt c—cytochrome c; U—the uncoupler FCCP; G—glutamate; S—succinate. All substrates were titrated in kinetically saturating concentrations, uncoupler FCCP was titrated in optimum concentration for evaluation of maximum O2 flow at given titration step. The evaluated respiratory capacities are marked according to the titration steps in the reference protocol 1 and correspond to following respiratory states: ce—routine respiration of intact cells; Dig—residual oxygen consumption (ROX) after permeabilization with digitonin; 1PM—LEAK respiration with CI-linked substrates pyruvate + malate; 2D—CI-linked OXPHOS capacity; 2D;c—CI-linked OXPHOS capacity after addition of cytochrome c; 3U—CI-linked electron transfer (ET) capacity with pyruvate + malate; 4G—CI-linked ET capacity with pyruvate + malate + glutamate; 5S—CI&II-linked ET capacity. (Author ZS, published in Gvozdjáková et al., 2022).

FIGURE 2

The effect of rehabilitation program on 6MWT and exercise dyspnea of patients with post C-19. Reference—the reference values for healthy subjects of age 50–59 years (Casanova et al., 2011). MR1, MRQ1—the group of patients with post C-19 at the beginning of the study; MR2, MRQ2—the groups of patients with post C-19 after 16–18 days of rehabilitation program without/with CoQ10 supplementation. +p < 0.05, ++p < 0.01 vs. the same group at the beginninng of the study.

FIGURE 3

Platelet mitochondrial respiration in control subjects and patients with post C-19. The respiration was measured in freshly isolated platelets following substrate-uncoupler-inhibitor titration (SUIT) reference protocol 1 (Doerrier et al., 2018) and valuated as O2 flux per mitochondrial marker citrate synthase activity, JO2/CS (pmol/s/IU). A) The graph show mean ± sem of the respiratory capacities after titration step indicated on the x-axis: ce—intact cells; Dig—digitonin; 1p.m.—pyruvate plus malate; 2D—ADP—adenosine diphosphate; 2D; c—cytochrome c; 3U—uncoupler FCCP; 4G—glutamate; 5S—succinate. For linking the respiratory rates to respiratory states refer to Figure 1. Control—the control group; MR1, MRQ1 the groups of patients at the beginning of the study; MR2, MRQ2—the MR and MRQ group after 16–18 days of rehabilitation program without/with CoQ10 supplementation; MRQ3—the MRQ group after 12–14 days of completion of the rehabilitation program and continuation of CoQ10 supplementation at home. *p < 0.05, **p < 0.01, ***p < 0.01 vs. Control. +p < 0.05, ++p < 0.01 vs. the same group at the biginning of the study.

FIGURE 4

OXPHOS efficiency of platelet mitochondrial respiration of patients with post C-19. P-L control efficiency was calculated from parameters of mitochondrial respiration as (2D-1PM)/2D (for parameters and groups refer to Figure 3). *p < 0.05 vs. Control. +p < 0.05 vs. the same group at the beginning of the study.

FIGURE 5

The effect of mountain spa rehabilitation program on CoQ10 concentration and lipid peroxidation in patients with post C-19. The concentration of coenzyme Q10-TOTAL in blood (A), plasma (B), platelets (C), and the concentration of TBARS in plasma (D) of control subjects and patients with post C-19. The groups names as for Figure 3. +p < 0.05, +++p < 0.001 vs. the same group at the biginning of the study.

FIGURE 6

The correlations between CoQ10-TOTAL concentration in platelets (CoQ10-PLT) and platelet mitochondrial respiration rates (A) 1PM, (B) 2D, (C) 2D; c, (D) 3U, (E) 4G, (F) 5S of patients with post C-19. The groups names and respiration rates labeling as for Figure 3. r—Pearson correlation coefficient; p-values show statistical significance of the correlations.

FIGURE 7

The correlations between an increase of CoQ10 concentration in platelets (ΔCoQ10-PLT) and an increase in parameters of platelet mitochondrial respiration of patients of MRQ group (A) Δ2D, (B) Δ2D; c, (C) Δ3U, (D) Δ4G. The markers show the difference values between MRQ2 and MRQ1, and between MRQ3 and MRQ1 time points for each patient from MRQ group. The groups names and respiration rates labeling as for Figure 3. r—Pearson correlation coefficient; p-values show statistical significance of the correlations.