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. 2022 Oct 26;12(11):1026.
doi: 10.3390/metabo12111026.

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

Vamsi P Guntur  1   2 , Travis Nemkov  3 , Esther de Boer  1   2 , Michael P Mohning  1   2 , David Baraghoshi  4 , Francesca I Cendali  3 , Inigo San-Millán  5   6   7 , Irina Petrache  1   2 , Angelo D'Alessandro  3
Affiliations

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

Vamsi P Guntur et al. Metabolites. .

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.

Keywords: exercise intolerance; keyword post-acute sequelae of COVID-19; long COVID; metabolomics; plasma.

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Conflict of interest statement

VPG: received consultant fees from AstraZeneca and Regeneron, unrelated to this report. TN: Co-founder of Omix Technologies and Altis Biosciences, has patents unrelated to this report. ISM: Co-founder of Altis Biosciences. IP: received consultant fees from Ceramedix and Allinaire Therapeutics. Has patents unrelated to this report. Serves on the board of the American Thoracic Society. AD: Co-founder of Omix Technologies and Altis Biosciences, advisory board member of Hemanext and Forma Therapeutics, has patents unrelated to this report. All other authors declare that they have no competing interests.

Figures

Figure 1
Figure 1
Metabolomics profiles of PASC Plasma. (A) Plasma from healthy (n = 30), post-COVID without PASC (n = 16), and PASC (n = 29) individuals was collected at rest and assessed by nontargeted metabolomics using LC-MS. (B) Partial Least-Squares Discriminant Analysis (PLS-DA) of metabolomics data. (C) Variable Importance in Projection (VIP) scores of the top 15 metabolites contributing to PLS-DA clustering pattern. (D) Enriched metabolic pathways of annotated untargeted negative polarity LC-MS features. The size of each circle corresponds to its enrichment factor and color corresponds to p-value (from white to red). Fatty acid oxidation (FAO), saturated fatty acid oxidation (SFAO). (E) Heat map with top 25 metabolites significantly different among the 3 groups of individuals based on ANOVA (red color indicates higher levels and blue indicates lower levels in pairwise comparisons).Separate comparisons of plasma between healthy individuals and post-COVID (Figure 2A) or PASC (Figure 2B) revealed distinct and marked metabolic phenotypes between the groups. A direct comparison between post-COVID and PASC individuals by PLS-DA highlights that these two groups can be only subtly distinguished by untargeted metabolomics of plasma at rest (Figure 2C), with 7 significantly lower metabolites and 1 significantly higher metabolite in PASC plasma (Figure 2D).
Figure 2
Figure 2
Differences in plasma metabolite profiles in individual groups. Volcano plot comparisons to healthy plasma of (A) post-COVID without PASC and (B) PASC. C-D Comparison of post COVID without PASC vs. PASC shown by (C) PLS-DA and (D) volcano plot.
Figure 3
Figure 3
Fatty Acid Oxidation. (A) Relative levels of acylcarnitines and (B) free fatty acids are depicted as violin plots normalized to median control value. Statistically significant changes noted between * controls and post-COVID, + control and PASC, and ‡ post-COVID and PASC; FDR uncorrected * or + p < 0.05; ** or ++ p < 0.01, +++ p < 0.001, ++++ p < 0.0001.
Figure 4
Figure 4
Glycolysis and TCA Cycle. (A) A pathway map for energy metabolism is shown, along with metabolite values for (B) glycolysis, and (C) the tricarboxylic acid (TCA) cycle. FDR uncorrected * p < 0.05; ** p < 0.01, *** p < 0.001, **** p < 0.0001.
Figure 5
Figure 5
Changes in Amino Acids profiles. The relative levels of amino acids reported by single letter code are depicted as violin plots normalized to median control value. To identify significant comparisons, * healthy and COVID19 without PASC, + healthy and PASC, and ‡ COVID and PASC with FDR uncorrected * or + p < 0.05; ** or ++ p < 0.01, *** or +++ p < 0.001.
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