In Vivo and Ex Vivo Mitochondrial Function in COVID-19 Patients on the Intensive Care Unit

Abstract

Mitochondrial dysfunction has been linked to disease progression in COVID-19 patients. This observational pilot study aimed to assess mitochondrial function in COVID-19 patients at intensive care unit (ICU) admission (T1), seven days thereafter (T2), and in healthy controls and a general anesthesia group. Measurements consisted of in vivo mitochondrial oxygenation and oxygen consumption, in vitro assessment of mitochondrial respiration in platelet-rich plasma (PRP) and peripheral blood mononuclear cells (PBMCs), and the ex vivo quantity of circulating cell-free mitochondrial DNA (mtDNA). The median mitoVO2 of COVID-19 patients on T1 and T2 was similar and tended to be lower than the mitoVO2 in the healthy controls, whilst the mitoVO2 in the general anesthesia group was significantly lower than that of all other groups. Basal platelet (PLT) respiration did not differ substantially between the measurements. PBMC basal respiration was increased by approximately 80% in the T1 group when contrasted to T2 and the healthy controls. Cell-free mtDNA was eight times higher in the COVID-T1 samples when compared to the healthy controls samples. In the COVID-T2 samples, mtDNA was twofold lower when compared to the COVID-T1 samples. mtDNA levels were increased in COVID-19 patients but were not associated with decreased mitochondrial O2 consumption in vivo in the skin, and ex vivo in PLT or PBMC. This suggests the presence of increased metabolism and mitochondrial damage.

Opposite Effect of Thyroid Hormones on Oxidative Stress and on Mitochondrial Respiration in COVID-19 Patients

“…Since severe COVID-19 progression can be divided into phases, including early infection, host immune response, hyperinflammatory phase, and multiorgan dysfunction [ 70 ], we cannot exclude that the discrepancies between our results and those reported by Streng et al [ 69 ] could be due to a different timing of patient inclusion, or alternatively, to the different methods used to analyze mitochondrial respiration. Our results regarding the stimulatory effects of LT3 on mitochondrial respiration are in accordance with those previously reported in other conditions and in different types of cells, including murine brown adipocytes [ 71 ] and murine, as well as human alveolar epithelial cells [ 72 ].…”

“…In another study, the Seahorse XFe24 analyzer was used to demonstrate the effect on neutrophils metabolism of COVID-19 patients, measured as ECAR, of the combined treatment with lipopolysaccharide and colchicine [ 68 ]. In disagreement with the previous study, a very recent observation, based on the analysis by high-resolution respirometry using the Oxygraph O 2 k (OROBOROS Instruments, Innsbruck, Austria) and by the Cellular Oxygen METabolism (COMET) monitor, found an increase in mitochondrial oxygen tension (mitoPO 2 ) and mitochondrial oxygen consumption (mitoVO 2 ) between the isolated PBMCs from the SARS-CoV-2 patient groups, as compared to those from healthy controls and those patients without COVID-19 undergoing general anesthesia because of cardiothoracic surgery [ 69 ]. According to these results, mitochondrial respiration is increased in cases of severe COVID-19 compared to other critically ill patients, suggesting the occurrence of a relative hypermetabolic state in such patients.…”

Self-DNA driven inflammation in COVID-19 and after mRNA-based vaccination: lessons for non-COVID-19 pathologies

“…The DAMP most frequently reported for COVID-19 is lactate dehydrogenase, a central enzyme of anaerobic glycolysis that is present in virtually all cells and that, therefore, reliably indicates cell death when occurring at high concentrations in the extracellular space ( 200 – 202 ). Other DAMPs which have been observed at elevated levels in the blood or plasma of patients with severe COVID-19 comprise high-mobility group box protein (HMGB)1 ( 51 , 110 , 111 , 202 – 206 ), S100 proteins ( 108 , 110 , 202 , 207 – 209 ), plasma hyaluronan ( 210 ), extracellular (e)ATP ( 211 , 212 ), the antimicrobial peptide LL-37 ( 213 , 214 ), histones (e.g ( 215 – 217 ), reviewed in ( 218 , 219 ) and circulating self-DNA, including nDNA ( 13 , 20 , 21 , 42 , 46 , 47 ), mtDNA ( 13 , 18 , 21 , 42 , 43 , 48 , 49 ), NET-associated cfDNA ( 201 , 215 , 220 – 222 ), histone-DNA complexes ( 219 ), and cfDNA of non-specified subcellular origin ( 45 , 48 , 50 – 54 ). As recently reviewed for sepsis ( 72 ), most of these studies reported a positive correlation of the plasma levels of at least some of the beforementioned DAMPs with the degree of disease severity (e.g., mild versus severe cases, COVID-19 patients at ICU admission versus healthy controls, ICU-admitted cases with fatal outcomes versus surviving patients, poor oxygenation status, patients with acute respiratory distress syndrome or with multisystem inflammatory syndrome in children, etc.).…”

“…It turns out that fragments of the host’s ‘self-DNA’ activate the before mentioned dsDNA sensors to trigger - eventually detrimental - inflammation and cell death ( Figure 2 ). Several groups reported that SARS-CoV-2 infection generates oxidative stress, damages the mitochondrial genome, destabilizes the mitochondrial membrane and subsequently, triggers a release of mitochondrial (mt)DNA to the cytosol ( 9 , 13 , 18 , 41 , 42 ). Thereby, mtDNA becomes accessible to cGAS, AIM2 or NLRP3 ( 9 , 18 , 22 ).…”

“…Elevated levels of cf nDNA or mtDNA have been detected in plasma of HIV-1-infected patients ( 87 – 91 ) and of SARS-CoV-2-infected patients ( 19 , 20 , 42 – 44 , 47 , 49 , 52 – 56 , 119 ), as well as in the supernatant of SARS-CoV—infected human airway epithelial cells ( 13 , 18 ).…”