Signatures of Mitochondrial Dysfunction and Impaired Fatty Acid Metabolism in Plasma of Patients with Post-Acute Sequelae of COVID-19 (PASC)

Abstract

Exercise intolerance is a major manifestation of post-acute sequelae of severe acute respiratory syndrome coronavirus infection (PASC, or “long-COVID”). Exercise intolerance in PASC is associated with higher arterial blood lactate accumulation and lower fatty acid oxidation rates during graded exercise tests to volitional exertion, suggesting altered metabolism and mitochondrial dysfunction. It remains unclear whether the profound disturbances in metabolism that have been identified in plasma from patients suffering from acute coronavirus disease 2019 (COVID-19) are also present in PASC. To bridge this gap, individuals with a history of previous acute COVID-19 infection that did not require hospitalization were enrolled at National Jewish Health (Denver, CO, USA) and were grouped into those that developed PASC (n = 29) and those that fully recovered (n = 16). Plasma samples from the two groups were analyzed via mass spectrometry-based untargeted metabolomics and compared against plasma metabolic profiles of healthy control individuals (n = 30). Observational demographic and clinical data were retrospectively abstracted from the medical record. Compared to plasma of healthy controls or individuals who recovered from COVID-19, PASC plasma exhibited significantly higher free- and carnitine-conjugated mono-, poly-, and highly unsaturated fatty acids, accompanied by markedly lower levels of mono-, di- and tricarboxylates (pyruvate, lactate, citrate, succinate, and malate), polyamines (spermine) and taurine. Plasma from individuals who fully recovered from COVID-19 exhibited an intermediary metabolic phenotype, with milder disturbances in fatty acid metabolism and higher levels of spermine and taurine. Of note, depletion of tryptophan—a hallmark of disease severity in COVID-19—is not normalized in PASC patients, despite normalization of kynurenine levels—a tryptophan metabolite that predicts mortality in hospitalized COVID-19 patients. In conclusion, PASC plasma metabolites are indicative of altered fatty acid metabolism and dysfunctional mitochondria-dependent lipid catabolism. These metabolic profiles obtained at rest are consistent with previously reported mitochondrial dysfunction during exercise, and may pave the way for therapeutic intervention focused on restoring mitochondrial fat-burning capacity.

Long COVID: major findings, mechanisms and recommendations

“…Many of these findings have been observed in long COVID studies in both adults and children (Box 1). Long COVID research has found mitochondrial dysfunction including loss of mitochondrial membrane potential 105 and possible dysfunctional mitochondrial metabolism 106 , altered fatty acid metabolism and dysfunctional mitochondriondependent lipid catabolism consistent with mitochondrial dysfunction in exercise intolerance 107 , redox imbalance 108 , and exercise intolerance and impaired oxygen extraction 100,109,110 . Studies have also found endothelial dysfunction 29 , cerebral blood flow abnormalities and metabolic changes 81,[111][112][113] (even in individuals with long COVID whose POTS symptoms abate 114 ), extensive neuroinflammation 42,80 , reactivated herpesviruses 18,21,27 , deformed red blood cells 64 Dysautonomia, particularly POTS, is commonly comorbid with ME/CFS 116 and also often has a viral onset 117 .…”

SARS-CoV-2 causes periodontal fibrosis by deregulating mitochondrial β-oxidation

“…Impeding the pathway can cause different disorders (Merritt et al 2018). Very recent studies have observed mitochondrial dysregulation in COVID-19 patient blood cells (Ajaz et al 2021;Guntur et al 2022). Interestingly, the dysfunction of the fatty acid oxidation has been previously connected with fibrosis particularly in the lung and kidney (Geng et al 2021;Jang et al 2020){Merritt, 2018 For the first time, our findings further confirmed that in the fibroblasts, SARS-CoV-2 could induce fibrotic degeneration directly, through down-regulating fatty acid b-oxidation, particularly by the virus' envelope and membrane proteins.…”

“…Impeding the pathway can cause different disorders (Merritt et al 2018). Very recent studies have observed mitochondrial dysregulation in COVID-19 patient blood cells (Ajaz et al 2021; Guntur et al 2022). Interestingly, the dysfunction of the fatty acid oxidation has been previously connected with fibrosis particularly in the lung and kidney (Geng et al 2021; Jang et al 2020){Merritt, 2018 #12}.…”

Role of different types of RNA molecules in the severity prediction of SARS-CoV-2 patients

“…Next set of features are related to the prediction of treatment stage of the COVID-19 patients. Same analysis on those genes shows that they are closely related to the biological processes such as neutral amino acid transport [95] , regulation of cellular protein metabolic process [84] , negative regulation of cellular macromolecule biosynthetic process [93] , endosome to lysosome transport [50] , chondrocyte morphogenesis involved in endochondral bone morphogenesis, growth plate cartilage chondrocyte morphogenesis, ferrochelatase activity, chondrocyte morphogenesis, phosphatase activator activity [116] , regulation of protein kinase activity [52] , [79] , negative regulation of cellular metabolic process [11] , [8] , response to inorganic substance [111] , [22] , toll-like receptor 9 signaling pathway [1] , [25] , [49] , [70] , [90] , positive regulation of NIK/NF-kappaB signaling [54] , myeloid dendritic cell activation [6] , [85] , regulation of transcription from RNA polymerase II promoter, protein localization to cilium, positive regulation of cell morphogenesis involved in differentiation, mRNA/RNA polyadenylation [102] , [5] , protein localization to cilium, phosphatidylinositol binding, optic cup structural organization [2] , endosome to plasma membrane transport vesicle, SET domain binding, negative regulation of phosphorus metabolic process [110] , regulation of fatty acid transport/ long-chain fatty acid transport [101] , [108] , [32] , [94] , positive regulation of mRNA catabolic process [87] , positive regulation of mRNA metabolic process [54] , transcription from RNA polymerase II promoter, positive regulation of cellular biosynthetic process, negative regulation of RNA metabolic process, negative regulation of nitrogen compound metabolic process [16] , [76] and negative regulation of cellular macromolecule biosynthetic process [30] .…”