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Potential Biomarkers of Mitochondrial Dysfunction Associated with COVID-19 Infection

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Application of Omic Techniques to Identify New Biomarkers and Drug Targets for COVID-19

Part of the book series: Advances in Experimental Medicine and Biology ((PMISB,volume 1412))

Abstract

Mitochondria play crucial roles in modulating immune responses, and viruses can in turn moderate mitochondrial functioning. Therefore, it is not judicious to assume that clinical outcome experienced in patients with COVID-19 or long COVID may be influenced by mitochondrial dysfunction in this infection. Also, patients who are predisposed to mitochondrial respiratory chain (MRC) disorders may be more susceptible to worsened clinical outcome associated with COVID-19 infection and long COVID. MRC disorders and dysfunction require a multidisciplinary approach for their diagnosis of which blood and urinary metabolite analysis may be utilized, including the measurement of lactate, organic acid and amino acid levels. More recently, hormone-like cytokines including fibroblast growth factor-21 (FGF-21) have also been used to assess possible evidence of MRC dysfunction. In view of their association with MRC dysfunction, assessing evidence of oxidative stress parameters including GSH and coenzyme Q10 (CoQ10) status may also provide useful biomarkers for diagnosis of MRC dysfunction. To date, the most reliable biomarker available for assessing MRC dysfunction is the spectrophotometric determination of MRC enzyme activities in skeletal muscle or tissue from the disease-presenting organ. Moreover, the combined use of these biomarkers in a multiplexed targeted metabolic profiling strategy may further improve the diagnostic yield of the individual tests for assessing evidence of mitochondrial dysfunction in patients pre- and post-COVID-19 infection.

Nadia Turton and Lauren Millichap are joint first authors.

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References

  1. Wallace DC (1999) Mitochondrial diseases in man and mouse. Science 283(5407):1482–1488

    Article  CAS  PubMed  Google Scholar 

  2. Hatefi Y (1985) The mitochondrial electron transport and oxidative phosphorylation system. Annu Rev Biochem 54:1015–1069

    Article  CAS  PubMed  Google Scholar 

  3. Burtscher J, Burtscher M, Millet GP (2021) The central role of mitochondrial fitness on antiviral defenses: An advocacy for physical activity during the COVID-19 pandemic. Redox Biol 43:101976. https://doi.org/10.1016/j.redox.2021.101976

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Saleh J, Peyssonnaux C, Singh KK, et al (2020) Mitochondria and microbiota dysfunction in COVID-19 pathogenesis. Mitochondrion 54:1–7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Yao Y, Lawrence DA (2021) Susceptibility to COVID-19 in populations with health disparities: Posited involvement of mitochondrial disorder, socioeconomic stress, and pollutants. J Biochem Mol Toxicol 35(1):e22626. https://doi.org/10.1002/jbt.22626

    Article  CAS  PubMed  Google Scholar 

  6. Haas RH, Parikh S, Falk MJ, et al (2007) Mitochondrial disease: a practical approach for primary care physicians. Pediatrics 94(1):16–37

    Google Scholar 

  7. Gorman GS, Schaefer AM, Ng Y, et al (2015) Prevalence of nuclear and mitochondrial DNA mutations related to adult mitochondrial disease. Ann Neurol 77(5):753–759

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Hargreaves IP (2003) Ubiquinone: cholesterol’s reclusive cousin. Ann Clin Biochem 40(Pt 3):207–218

    Article  CAS  PubMed  Google Scholar 

  9. Ernster L, Dallner G (1995) Biochemical, physiological and medical aspects of ubiquinone function. Biochim Biophys Acta 1271(1):195–204

    Article  PubMed  Google Scholar 

  10. Turton N, Cufflin N, Dewsbury M, et al (2022) The Biochemical Assessment of Mitochondrial Respiratory Chain Disorders. Int J Mol Sci 23(13):7487. https://doi.org/10.3390/ijms23137487

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Hargreaves IP (2018) Biochemical Assessment and Monitoring of Mitochondrial Disease. J Clin Med 7(4):66. https://doi.org/10.3390/jcm7040066

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Tyynismaa H, Carroll CJ, Raimundo N, et al (2010) Mitochondrial myopathy induces a starvation-like response. Hum Mol Genet 19(20):3948–3958

    Article  CAS  PubMed  Google Scholar 

  13. Haas RH, Parikh S, Falk MJ, et al (2008) The in-depth evaluation of suspected mitochondrial disease. Mol Genet Metab 120(6):1326–1333

    Google Scholar 

  14. Barrientos A, Fontanesi F, Díaz F (2009) Evaluation of the mitochondrial respiratory chain and oxidative phosphorylation system using polarography and spectrophotometric enzyme assays. Curr Protoc Hum Genet Curr Protoc Hum Genet Chapter 19:Unit19.3. https://doi.org/10.1002/0471142905.hg1903s63

    Article  Google Scholar 

  15. Reisch AS, Elpeleg O (2007) Biochemical Assays for Mitochondrial Activity: Assays of TCA Cycle Enzymes and PDHc. Methods Cell Biol 80:199–222

    Article  CAS  PubMed  Google Scholar 

  16. Yubero D, Montero R, Artuch R, et al (2014) Biochemical diagnosis of coenzyme q10 deficiency. Mol Syndromol 5(3–4:147–155

    Google Scholar 

  17. Chretien D, Rustin P, Bourgeron T, et al (1994) Reference charts for respiratory chain activities in human tissues. Clin Chim Acta 228(1):53–70

    Article  CAS  PubMed  Google Scholar 

  18. Magner M, Szentiványi K, Svandová I, et al (2011) Elevated CSF-lactate is a reliable marker of mitochondrial disorders in children even after brief seizures. Eur J Paediatr Neurol 5(2):101–108

    Article  Google Scholar 

  19. Gray LR, Tompkins SC, Taylor EB (2014) Regulation of pyruvate metabolism and human disease. Cell Mol Life Sci 71(14):2577–2604

    Article  CAS  PubMed  Google Scholar 

  20. Peng M, Cai Y, Fang X, et al (2016) Rapid quantification of metabolic intermediates in blood by liquid chromatography-tandem mass spectrometry to investigate congenital lactic acidosis. Anal Chim Acta 942:50–57

    Article  CAS  PubMed  Google Scholar 

  21. Andersen LW, Mackenhauer J, Roberts JC, et al (2013) Etiology and therapeutic approach to elevated lactate levels. Mayo Clin Proc 88(10):1127–1140

    Article  CAS  PubMed  Google Scholar 

  22. Chow SL, Rooney ZJ, Cleary MA, et al (2005) The significance of elevated CSF lactate. Arch Dis Child 90(11):1188–1189

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Feldman AG, Sokol RJ, Hardison RM, et al (2017) Lactate and Lactate: Pyruvate Ratio in the Diagnosis and Outcomes of Pediatric Acute Liver Failure. J Pediatr 182:217–222.e3. https://doi.org/10.1016/j.jpeds.2016.12.031

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Clarke C, Xiao R, Place E, et al (2013) Mitochondrial respiratory chain disease discrimination by retrospective cohort analysis of blood metabolites. Mol Genet Metab 110(1–2):145–152

    Google Scholar 

  25. Bernier FP, Boneh A, Dennett X, et al (2002) Diagnostic criteria for respiratory chain disorders in adults and children. Neurology 59(9):1406–1411

    Article  CAS  PubMed  Google Scholar 

  26. Schwarz EL, Roberts WL, Pasquali M (2005) Analysis of plasma amino acids by HPLC with photodiode array and fluorescence detection. Clin Chim Acta 354(1–2):83–90

    Article  CAS  PubMed  Google Scholar 

  27. Carayol M, Licaj I, Achaintre D, et al (2015) Reliability of Serum Metabolites over a Two-Year Period: A Targeted Metabolomic Approach in Fasting and Non-Fasting Samples from EPIC. PLoS One 10(8):e0135437. https://doi.org/10.1371/journal.pone.0135437

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Dimou A, Tsimihodimos V, Bairaktari E (2022) The Critical Role of the Branched Chain Amino Acids (BCAAs) Catabolism-Regulating Enzymes, Branched-Chain Aminotransferase (BCAT) and Branched-Chain α-Keto Acid Dehydrogenase (BCKD), in Human Pathophysiology. Int J Mol Sci 23(7):4022. https://doi.org/10.3390/ijms23074022

  29. Morava E, van den Heuvel L, Hol F, et al (2006) Mitochondrial disease criteria: diagnostic applications in children. Neurology 67(10):1823–1826

    Article  CAS  PubMed  Google Scholar 

  30. Parikh S, Goldstein A, Koenig MK, et al (2015) Diagnosis and management of mitochondrial disease: a consensus statement from the Mitochondrial Medicine Society. Genet Med 17(9):689–701

    Article  CAS  PubMed  Google Scholar 

  31. Shatla HM, Tomoum HY, Elsayed SM, et al (2014) Role of plasma amino acids and urinary organic acids in diagnosis of mitochondrial diseases in children. Pediatr Neurol 51(6):820–825

    Article  PubMed  Google Scholar 

  32. Keyfi F, Lukacs Z, Varasteh A (2017) A Description of Reference Ranges for Organic Acids in Urine Samples from A Pediatric Population in Iran. Rep Biochem Mol Biol 6(1):40–50

    PubMed  PubMed Central  Google Scholar 

  33. Niwa T (1995) Mass spectrometry in disorders of organic acid metabolism. Clin Chim Acta 241–242:293–384

    PubMed  Google Scholar 

  34. Körver-Keularts I, Wang P, Waterval H, et al (2018) Fast and accurate quantitative organic acid analysis with LC-QTOF/MS facilitates screening of patients for inborn errors of metabolism. J Inherit Metab Dis 41(3):415–424

    Article  PubMed  PubMed Central  Google Scholar 

  35. Alban C, Fatale E, Joulani A, et al (2017) The Relationship between Mitochondrial Respiratory Chain Activities in Muscle and Metabolites in Plasma and Urine: A Retrospective Study. J Clin Med 6(3):31. https://doi.org/10.3390/jcm6030031

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Bennett MJ, Sheng F, Saada A (2020) Biochemical assays of TCA cycle and β-oxidation metabolites. Methods Cell Biol 155:83–120

    Article  CAS  PubMed  Google Scholar 

  37. Kumps A, Duez P, Mardens Y (2002) Metabolic, Nutritional, Iatrogenic, and Artifactual Sources of Urinary Organic Acids: A Comprehensive Table. Clin Chem 48(5):708–717

    CAS  PubMed  Google Scholar 

  38. Polymeropoulos VM (2020) A Potential Role of Coenzyme Q10 Deficiency in Severe SARS-CoV2 Infection. OBM Integrative and Complementary Medicine https://doi.org/10.21926/obm.icm.2004042

  39. Sumbalova Z, Kucharska J, Palacka P, et al (2022) Platelet mitochondrial function and endogenous coenzyme Q10 levels are reduced in patients after COVID-19. Bratisl Lek Listy 123(1):9–15

    CAS  PubMed  Google Scholar 

  40. Kalén A, Appelkvist EL, Dallner G (1989) Age-related changes in the lipid compositions of rat and human tissues. Lipids 24(7):579–84

    Article  PubMed  Google Scholar 

  41. Mantle D, Heaton RA, Hargreaves IP (2021) Coenzyme Q10 and Immune Function: An Overview. Antioxidants (Basel) 10(5):759. https://doi.org/10.3390/antiox10050759

    Article  CAS  PubMed  Google Scholar 

  42. Rodríguez-Aguilera JC, Cortés AB, Fernández-Ayala DJ, et al (2017) Biochemical Assessment of Coenzyme Q(10) Deficiency. J Clin Med 6(3):27. https://doi.org/10.3390/jcm6030027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Weber C, Bysted A, Hłlmer G (1997) The coenzyme Q10 content of the average Danish diet. Int J Vitam Nutr Res 67(2):123–129

    CAS  PubMed  Google Scholar 

  44. Silvagno F, Vernone A, Pescarmona GP (2020) The Role of Glutathione in Protecting against the Severe Inflammatory Response Triggered by COVID-19. Antioxidants (Basel) 9(7):624. https://doi.org/10.3390/antiox9070624

    Article  CAS  PubMed  Google Scholar 

  45. Forman HJ, Zhang H, Rinna A (2009) Glutathione: overview of its protective roles, measurement, and biosynthesis. Mol Aspects Med 0(1–2):1–12

    Article  CAS  Google Scholar 

  46. Kumar P, Osahon O, Vides DB, et al (2021) Severe Glutathione Deficiency, Oxidative Stress and Oxidant Damage in Adults Hospitalized with COVID-19: Implications for GlyNAC (Glycine and N-Acetylcysteine) Supplementation. Antioxidants (Basel) 11(1):50. https://doi.org/10.3390/antiox11010050

    Article  CAS  PubMed  Google Scholar 

  47. Zitka O, Skalickova S, Gumulec J, et al (2012) Redox status expressed as GSH:GSSG ratio as a marker for oxidative stress in paediatric tumour patients. Oncol Lett 4(6):1247–1253

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Enns GM, Cowan TM (2017) Glutathione as a Redox Biomarker in Mitochondrial Disease-Implications for Therapy. J Clin Med 6(5):50. https://doi.org/10.3390/jcm6050050

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Karkhanei B, Talebi Ghane E, Mehri F (2021) Evaluation of oxidative stress level: total antioxidant capacity, total oxidant status and glutathione activity in patients with COVID-19. New Microbes New Infect 42:100897. https://doi.org/10.1016/j.nmni.2021.100897

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Hargreaves IP, Sheena Y, Land JM, et al (2005) Glutathione deficiency in patients with mitochondrial disease: implications for pathogenesis and treatment. J Inherit Metab Dis 28(1):81–88

    Article  CAS  PubMed  Google Scholar 

  51. Enomoto AC, Schneider E, McKinnon T, et al (2020) Validation of a simplified procedure for convenient and rapid quantification of reduced and oxidized glutathione in human plasma by liquid chromatography tandem mass spectrometry analysis. Biomed Chromatogr 34(9):e4854. https://doi.org/10.1002/bmc.4854

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Giustarini D, Tsikas D, Colombo G, et al (2016) Pitfalls in the analysis of the physiological antioxidant glutathione (GSH) and its disulfide (GSSG) in biological samples: An elephant in the room. J Chromatogr B Analyt Technol Biomed Life Sci 1019:21–28

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Tipple TE, Rogers LK (2012) Methods for the determination of plasma or tissue glutathione levels. Methods Mol Biol 889:315–324

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Baldelli S, Ciccarone F, Limongi D, et al (2019) Glutathione and Nitric Oxide: Key Team Players in Use and Disuse of Skeletal Muscle. Nutrients 11(10):2318. https://doi.org/10.3390/nu11102318

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Li Y, Li S, Qiu Y, et al (2022) Circulating FGF21 and GDF15 as Biomarkers for Screening, Diagnosis, and Severity Assessment of Primary Mitochondrial Disorders in Children. Front Pediatr 10:851534. https://doi.org/10.3389/fped.2022.851534

    Article  PubMed  PubMed Central  Google Scholar 

  56. Ajaz S, McPhail MJ, Singh KK, et al (2021) Mitochondrial metabolic manipulation by SARS-CoV-2 in peripheral blood mononuclear cells of patients with COVID-19. Am J Physiol Cell Physiol 320(1):C57-C65

    Article  CAS  PubMed  Google Scholar 

  57. Babalghith AO, Al-Kuraishy HM, Al-Gareeb AI, et al (2022) The Potential Role of Growth Differentiation Factor 15 in COVID-19: A Corollary Subjective Effect or Not? Diagnostics (Basel) 12(9):2051. https://doi.org/10.3390/diagnostics12092051

    Article  CAS  PubMed  Google Scholar 

  58. Feingold KR, Grunfeld C, Heuer JG, et al (2012) FGF21 is increased by inflammatory stimuli and protects leptin-deficient ob/ob mice from the toxicity of sepsis. Endocrinology 153(6):2689–2700

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Xie T, Leung PS (2017) Fibroblast growth factor 21: a regulator of metabolic disease and health span. Am J Physiol Endocrinol Metab 313(3):E292-E302

    Article  PubMed  PubMed Central  Google Scholar 

  60. Tezze C, Romanello V, Sandri M (2019) FGF21 as Modulator of Metabolism in Health and Disease. Front Physiol 10:419. https://doi.org/10.3389/fphys.2019.00419

    Article  PubMed  PubMed Central  Google Scholar 

  61. Morovat A, Weerasinghe G, Nesbitt V, et al (2017) Use of FGF-21 as a Biomarker of Mitochondrial Disease in Clinical Practice. J Clin Med 6(8):80. https://doi.org/10.3390/jcm6080080

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Soares-Schanoski A, Sauerwald N, Goforth CW, et al (2022) Asymptomatic SARS-CoV-2 Infection Is Associated With Higher Levels of Serum IL-17C, Matrix Metalloproteinase 10 and Fibroblast Growth Factors Than Mild Symptomatic COVID-19. Front Immunol 13:821730. https://doi.org/10.3389/fimmu.2022.821730

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Woo DK, Shadel GS (2011) Mitochondrial Stress Signals Revise an Old Aging Theory. Cell 144(1):11–12

    Article  CAS  PubMed  Google Scholar 

  64. Rochette L, Zeller M, Cottin Y, et al (2021) GDF15: an emerging modulator of immunity and a strategy in COVID-19 in association with iron metabolism. Trends Endocrinol Metab 32(11):875–889

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Wischhusen J, Melero I, Fridman WH (2020) Growth/Differentiation Factor-15 (GDF-15): From Biomarker to Novel Targetable Immune Checkpoint. Front Immunol 11:951. https://doi.org/10.3389/fimmu.2020.00951

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Luan HH, Wang A, Hilliard BK, et al (2019) GDF15 Is an Inflammation-Induced Central Mediator of Tissue Tolerance. Cell 178(5):1231–1244.e11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Bams-Mengerink AM, Koelman JHTM, Waterham H, et al (2013) The neurology of rhizomelic chondrodysplasia punctata. Orphanet J Rare Dis8:174. https://doi.org/10.1186/1750-1172-8-174

  68. Johann K, Kleinert M, Klaus S (2021) The Role of GDF15 as a Myomitokine. Cells 10(11):2990. https://doi.org/10.3390/cells10112990

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Montero M, Alonso MT, Albillos A, et al (2002) Effect of inositol 1,4,5-trisphosphate receptor stimulation on mitochondrial [Ca2+] and secretion in chromaffin cells. Biochem J 365(Pt 2):451–459

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Notz Q, Schmalzing M, Wedekink F, et al (2020) Pro- and Anti-Inflammatory Responses in Severe COVID-19-Induced Acute Respiratory Distress Syndrome-An Observational Pilot Study. Front Immunol 11:581338. https://doi.org/10.3389/fimmu.2020.581338

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Varhaug KN, Hikmat O, Nakkestad HL, et al (2021) Serum biomarkers in primary mitochondrial disorders. Brain Commun 3(1):fcaa222. https://doi.org/10.1093/braincomms/fcaa222

  72. Tanno T, Noel P, Miller JL (2010) Growth differentiation factor 15 in erythroid health and disease. Curr Opin Hematol 17(3):184–190

    CAS  PubMed  PubMed Central  Google Scholar 

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Correspondence to Iain P. Hargreaves .

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Turton, N., Millichap, L., Hargreaves, I.P. (2023). Potential Biomarkers of Mitochondrial Dysfunction Associated with COVID-19 Infection. In: Guest , P.C. (eds) Application of Omic Techniques to Identify New Biomarkers and Drug Targets for COVID-19. Advances in Experimental Medicine and Biology(), vol 1412. Springer, Cham. https://doi.org/10.1007/978-3-031-28012-2_11

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