Mitochondrial Pathogenic Mutations and Expression Pattern of Oxidative Phosphorylation Genes in COVID-19 Patients
,
Abstract
Mitochondrial missense mutations and pathogenic variants have been implicated in the pathogenesis of COVID‐19. This study evaluated the role of mitochondrial DNA (mtDNA) mutations and changes in gene expression in the progression of COVID-19 and their correlation with clinical characteristics.
Next‐generation sequencing with high throughput was used to identify mtDNA mutations in 30 COVID-19 patients compared to 20 healthy controls. The potential impact of identified mutations on protein structure and stability was predicted using bioinformatic tools. Quantitative real-time polymerase chain reaction was employed to assess the expression levels of mtDNA-encoded genes involved in oxidative phosphorylation in COVID-19 patients and healthy controls. Correlations between gene expression levels, clinical parameters, including leukocyte, lymphocyte, neutrophil, and platelet count, as well as creatinine, alanine transaminase (ALT), aspartate transaminase (AST), and blood urea nitrogen (BUN) levels, and disease severity were analyzed.
We found 8 different mtDNA mutations in ND1, ND5, CO3, ATP6, and CYB genes, which were predicted to alter amino acids and decrease protein stability. Two missense unique mutations, C9555T in CO3 and A12418T in ND5 were identified and correlated with Complexes I and IV, respectively. This downregulation was correlated with age, elevated levels of leukocytes, lymphocytes, neutrophils, platelets, creatinine, ALT, AST, and BUN, as well as disease severity.
These findings suggest that mtDNA mutations and altered expression of oxidative phosphorylation genes contribute to mitochondrial dysfunction in COVID-19. Targeting mitochondrial dysfunction may represent a promising therapeutic strategy for COVID-19 treatment.
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5. Kernan KF, Carcillo JA. Hyperferritinemia and inflammation. Int Immunol. 2017;29(9):401-409.
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9. Costa TJ, Potje SR, Fraga-Silva TFC, Silva-Neto JA, Barros PR, Rodrigues D, et al. Mitochondrial DNA and TLR9 activation contribute to SARS-CoV-2-induced endothelial cell damage. Vasc Pharmacol. 2022;142:106946.
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11. Roubicek DA, Souza-Pinto NCD. Mitochondria and mitochondrial DNA as relevant targets for environmental contaminants. Toxicology. 2017;391:100-8.
12. Koch RE, Josefson ChC, Hill GE. Mitochondrial function, ornamentation, and immunocompetence. Biol Rev. 2017;92(3):1459-74.
13. Rouault TA, Maio N. Biogenesis and functions of mammalian iron-sulfur proteins in the regulation of iron homeostasis and pivotal metabolic pathways. Biol Chem. 2017;292(31):12744 –53.
14. Yan XJ, Yu X, Wang XP, Jiang JF, Yuan ZhY, Lu X, et al. Mitochondria play an important role in the cell proliferation suppressing activity of berberine. Sci Rep-Uk. 2017;7:1-13.
15. Kumari D, Singh Y, Singh S, Dogra V, Srivastava AK, Srivastava S, et al. Mitochondrial pathogenic mutations and metabolic alterations associated with COVID‐19 disease severity. Med Virol. 2023;92(2):e28553.
16. Singh KK, Chaubey G, Chen JY, Suravajhala P. Decoding SARS-CoV-2 hijacking of host mitochondria in COVID-19 pathogenesis. Am J Physiol-Cell Ph. 202;319(2):258-67.
17. Wu KE, Fazal FM, Parker KR, Zou J, Chang HY. RNA-GPS predicts SARS-CoV-2 RNA residency to host mitochondria and nucleolus. Cell Syst. 2020;11(1):102-108.
18. Smullen M, Meagan NO, Liam FM, Madhusoodhanan S, GuangY, Pepper D, et al. Sci Rep-Uk. 2023;13:10405.
19. Koshiba T. Mitochondrial-mediated antiviral immunity. Bba-Mol Cell Res. 2013;1833(1):225-232.
20. Dong Ch, Wei P, Jian X, Gibbs R, Boerwinkle E, Wang K, Liu X. Comparison and integration of deleteriousness prediction methods for nonsynonymous SNVs in whole exome sequencing studies. Hum Mol Genet. 2015;24(8):2125-37.
21. Sim NL, Kumar P, Hu J, Henikoff S, Schneider G, Ng PC. SIFT web server: predicting effects of amino acid substitutions on proteins. Nucleic Acids Res. 2012;40(W1):452-7.
22. Braun EL. An Evolutionary model motivated by phisicochemical properties of amino acids reveals variation among proteins. Bioinformatics. 2018;34(13):i350-i356.
23. Rodrigues CH, Pires DE, Ascher DB. DynaMut: predicting the impact of mutations on protein conformation, flexibility and stability. Nucleic Acids Res. 2018;46(W1):350-355.
24. Schon EA, DiMauro S, Hirano M. Human mitochondrial DNA: roles of inherited and somatic mutations. Nat Rev Genet. 2012;13(12):878-90.
25. Szatkowska LG, Slaska B, Rzymowska J, Brzozowska A, Floriańczyk B. Novel mitochondrial mutations in the ATP6 and ATP8 genes in patients with breast cancer. Mol Med Rep. 2014;10(4):1772-8.
26. Elesela S, Lukacs NW. Role of mitochondria in viral infections. Life. 2021;11(3):232.
27. Kauppila TES, Kauppila JHK, Larsson NG. Mammalian mitochondria and aging: an update. Cell Metab. 2017;25(1):57-71.
28. Prasun P. COVID-19: a mitochondrial perspective. DNA Cell Biol. 2021;40(6):713-719.
29. Du RH, Liang LR, Yang ChQ, Wang W, Cao TZ, Li M, et al. Predictors of mortality for patients with COVID-19 pneumonia caused by SARS-CoV-2: a prospective cohort study. Eur Respir J. 2020;55(5):2000524.
30. Zhang G, Zhang J, Wang B, Zhu X, Wang Q, Qiu Sh. Analysis of clinical characteristics and laboratory findings of 95 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a retrospective analysis. Resp Res. 2020;21(1):1-10.
31. Asanjarani B, Siri G, Hosseini SME, Abdollahi H, Hasibi M, Erfanian R, et al. Diagnostic and Prognostic Value of Routine Blood Tests in Patients with COVID-19 in Iran, Tehran. Iran J Med Council. 2021;4(3):137-44.
32. Mardani R, Ahmadi A, Zali F, Gholami A, Mousavi-Nasab SD, Kaghazian H, et al. Laboratory parameters in detection of COVID-19 patients with positive RT-PCR; a diagnostic accuracy study. Arch Acad Emerg Med. 2020;8(1):e43.
33. Mo P, Xing Y, Xiao Y, Deng L, Zhao Q, Wang H, et al. Clinical characteristics of refractory COVID-19 pneumonia in Wuhan, China. Clin infect dis. 2020;73(11):4208-13.
34. Tsegay YG, Bitew M, workneh T, Atlaw A, Aragaw M, Gemechu M, et al. The level of liver and renal function biomarker abnormalities among hospitalized COVID-19 patients in Ethiopia. medRxiv. 2022.
35. Ghahramani S, Tabrizi R, Lankarani KB, Kashani SMA, Rezaei Sh, Zeidi N, et al F. Laboratory features of severe vs. non-severe COVID-19 patients in Asian populations: a systematic review and meta-analysis. Eur J Med Res. 2020;25(1):30.
36. Qu J, Zhu HH, Huang XJ, He GF, Liu JY, Huang JJ, et al. Abnormal indexes of liver and kidney injury markers predict severity in COVID-19 patients. Infect Dru. 2021;14:3029-3040.
37. Feng G, Zheng KI, Yan QQ, Rios RS, Targher G, Byrne ChD, et al. COVID-19 and liver dysfunction: current insights and emergent therapeutic strategies. Clin Transl hepatol. 2020;8(1):18-24.
38. Li Q, Guan X, Wu P, Wang X, Zhou L, Tong Y, et al. Early transmission dynamics in Wuhan, China, of novel coronavirus–infected pneumonia. New Engl J Med. 2020;382:1199-1207.
39. Park M, Nussbaum RL. Annals of Internal Medicine Recurrent Renal Cysts in a Transplanted Kidney. Ann Intern Med. 2018;169(9):657-8.
40. Levin L, Zhidkov I, Gurman Y, Hawlena H, Mishmar D. Functional recurrent mutations in the human mitochondrial phylogeny: dual roles in evolution and disease. Genome biol Evol. 2013;5(5):876-90.
41. Tranah GJ, Santaniello A, Caillier SJ, DAlfonso S, Boneschi FM, Hauser SL, et al. Mitochondrial DNA Sequence Variation in Multiple Sclerosis. Neurology. 2015;85(4):325-30.
42. Ganji R, Reddy PH. Impact of COVID-19 on mitochondrial-based immunity in aging and age-related diseases. Front Aging Neurosci. 2021;12:614650.
43. Fawcett JA, Innan H. Neutral and Non-Neutral Evolution of Duplicated Gene with Gene Conversion. Genes. 2011;2(1):191-209.
44. Koike Sh, Gaysina D, Jones PB, Wong A, Richards M. Catechol O-methyltransferase (COMT) functional haplotype in associated with recurrence of affective symptome: A prospective birth cohort study. J Affect Disorders. 2018;15(229):437-442.
45. Komar AA. SNPs, silent but not invisible. Science. 2007;315(5811):466-7.
46. Shabalina SA, Spiridonov NA, Kashina A. Sounds of silence: synonymous nucleotides as a key to biological regulation and complexity. Nucleic Acids Res. 2013;41(4):2073-94.
47. Medini H, Zirman A, Mishmar D. Immune system
cells from COVID-19 patients display compromised mitochondrial-nuclear expression co-regulation
and rewiring toward glycolysis. Iscience. 2021;24(12):103471.
48. Dirican E, Savrun ŞT, Aydın İ.E, Gülbay G, Karaman Ü. Analysis of mitochondrial DNA cytochrome‐b (CYB) and ATPase‐6 gene mutations in COVID‐19 patients. Med Virol. 2020;94(7):3138-46.
49. Rodenburg RJ. Mitochondrial complex I-linked disease. Bba Bioenergetics. 2016;1857(7):938-45.
50. Fornuskova D, Stiburek L, Wenchich L, Vinsova K, Hansikova H, Zeman J. Novel insights into the assembly and function of human nuclear-encoded cytochrome c oxidase subunits 4, 5a, 6a, 7a and 7b. Biochem J. 2010;428(3) :363-74.
51. Pereira L, Soares P, Radivojac P, Li B, Samuels DC. Comparing Phylogeny and the Predicted Pathogenicity of Protein Variations Reveals Equal Purifying Selection across the Global Human mtDNA Diversity. Am J Hum Genet. 2011;8(4):433-9.
52. Ballestar E, Farber DL, Glover S, Horwitz B, Meyer K, Nikolić M, et al. Single cell profiling of COVID-19 patients: an international data resource from multiple tissues. MedRxiv. 2020;20.20227355.
53. Mick E, Kamm J, Pisco AO, Ratnasiri K, Babik JM, Calfee CS, et al. Upper airway gene expression differentiates COVID-19 from other acute respiratory illnesses and reveals suppression of innate immune responses by SARS-CoV-2. Medrxiv. 2020;19:20105171.
54. Ryzhkova AI , Sazonova MA , Sinyov VV , Galitsyna EV, Chicheva MM , Melnichenko AA , et al. Mitochondrial diseases caused by mtDNA mutations: a mini-review. Nat Rev Genet. 2018;14:1933-42.
2. Zaim S, Chong JH, Sankaranarayanan V, Harky A. COVID-19 and multiorgan response. Curr Prob Cardiology. 2020;45(8):100618.
3. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Zh, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. lancet. 2020;395(10229):1054-62.
4. Moore JB, June CH. Cytokine release syndrome in severe COVID-19. Science. 2020;368(6490):473-474.
5. Kernan KF, Carcillo JA. Hyperferritinemia and inflammation. Int Immunol. 2017;29(9):401-409.
6. Phua J, Weng L, Ling L, Egi M, Lim ChM, Divatia JV, et al. Intensive care management of coronavirus disease 2019 (COVID-19): challenges and recommendations. Lancet Resp Med. 2020;8(5):506-517.
7. Varghese PM, Tsolaki AG, Yasmin H, Shastri A, Ferluga J, Vatish M, et al. Host-pathogen interaction in COVID-19: Pathogenesis, potential therapeutics and vaccination strategies. Immunobiology. 2020;225(6):152008.
8. Bhowal Ch, Ghosh S, Ghatak D, De R. Pathophysiological involvement of host mitochondria in SARS-CoV-2 infection that causes COVID-19: a comprehensive evidential insight. Mol Cell Biochem. 2022;478(6):1325-43.
9. Costa TJ, Potje SR, Fraga-Silva TFC, Silva-Neto JA, Barros PR, Rodrigues D, et al. Mitochondrial DNA and TLR9 activation contribute to SARS-CoV-2-induced endothelial cell damage. Vasc Pharmacol. 2022;142:106946.
10. Craigen WJ. Mitochondrial DNA mutations: an overview of clinical and molecular aspects. Mitochondrial Disorders: Biochem Mol Med. 2012;837:3-15.
11. Roubicek DA, Souza-Pinto NCD. Mitochondria and mitochondrial DNA as relevant targets for environmental contaminants. Toxicology. 2017;391:100-8.
12. Koch RE, Josefson ChC, Hill GE. Mitochondrial function, ornamentation, and immunocompetence. Biol Rev. 2017;92(3):1459-74.
13. Rouault TA, Maio N. Biogenesis and functions of mammalian iron-sulfur proteins in the regulation of iron homeostasis and pivotal metabolic pathways. Biol Chem. 2017;292(31):12744 –53.
14. Yan XJ, Yu X, Wang XP, Jiang JF, Yuan ZhY, Lu X, et al. Mitochondria play an important role in the cell proliferation suppressing activity of berberine. Sci Rep-Uk. 2017;7:1-13.
15. Kumari D, Singh Y, Singh S, Dogra V, Srivastava AK, Srivastava S, et al. Mitochondrial pathogenic mutations and metabolic alterations associated with COVID‐19 disease severity. Med Virol. 2023;92(2):e28553.
16. Singh KK, Chaubey G, Chen JY, Suravajhala P. Decoding SARS-CoV-2 hijacking of host mitochondria in COVID-19 pathogenesis. Am J Physiol-Cell Ph. 202;319(2):258-67.
17. Wu KE, Fazal FM, Parker KR, Zou J, Chang HY. RNA-GPS predicts SARS-CoV-2 RNA residency to host mitochondria and nucleolus. Cell Syst. 2020;11(1):102-108.
18. Smullen M, Meagan NO, Liam FM, Madhusoodhanan S, GuangY, Pepper D, et al. Sci Rep-Uk. 2023;13:10405.
19. Koshiba T. Mitochondrial-mediated antiviral immunity. Bba-Mol Cell Res. 2013;1833(1):225-232.
20. Dong Ch, Wei P, Jian X, Gibbs R, Boerwinkle E, Wang K, Liu X. Comparison and integration of deleteriousness prediction methods for nonsynonymous SNVs in whole exome sequencing studies. Hum Mol Genet. 2015;24(8):2125-37.
21. Sim NL, Kumar P, Hu J, Henikoff S, Schneider G, Ng PC. SIFT web server: predicting effects of amino acid substitutions on proteins. Nucleic Acids Res. 2012;40(W1):452-7.
22. Braun EL. An Evolutionary model motivated by phisicochemical properties of amino acids reveals variation among proteins. Bioinformatics. 2018;34(13):i350-i356.
23. Rodrigues CH, Pires DE, Ascher DB. DynaMut: predicting the impact of mutations on protein conformation, flexibility and stability. Nucleic Acids Res. 2018;46(W1):350-355.
24. Schon EA, DiMauro S, Hirano M. Human mitochondrial DNA: roles of inherited and somatic mutations. Nat Rev Genet. 2012;13(12):878-90.
25. Szatkowska LG, Slaska B, Rzymowska J, Brzozowska A, Floriańczyk B. Novel mitochondrial mutations in the ATP6 and ATP8 genes in patients with breast cancer. Mol Med Rep. 2014;10(4):1772-8.
26. Elesela S, Lukacs NW. Role of mitochondria in viral infections. Life. 2021;11(3):232.
27. Kauppila TES, Kauppila JHK, Larsson NG. Mammalian mitochondria and aging: an update. Cell Metab. 2017;25(1):57-71.
28. Prasun P. COVID-19: a mitochondrial perspective. DNA Cell Biol. 2021;40(6):713-719.
29. Du RH, Liang LR, Yang ChQ, Wang W, Cao TZ, Li M, et al. Predictors of mortality for patients with COVID-19 pneumonia caused by SARS-CoV-2: a prospective cohort study. Eur Respir J. 2020;55(5):2000524.
30. Zhang G, Zhang J, Wang B, Zhu X, Wang Q, Qiu Sh. Analysis of clinical characteristics and laboratory findings of 95 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a retrospective analysis. Resp Res. 2020;21(1):1-10.
31. Asanjarani B, Siri G, Hosseini SME, Abdollahi H, Hasibi M, Erfanian R, et al. Diagnostic and Prognostic Value of Routine Blood Tests in Patients with COVID-19 in Iran, Tehran. Iran J Med Council. 2021;4(3):137-44.
32. Mardani R, Ahmadi A, Zali F, Gholami A, Mousavi-Nasab SD, Kaghazian H, et al. Laboratory parameters in detection of COVID-19 patients with positive RT-PCR; a diagnostic accuracy study. Arch Acad Emerg Med. 2020;8(1):e43.
33. Mo P, Xing Y, Xiao Y, Deng L, Zhao Q, Wang H, et al. Clinical characteristics of refractory COVID-19 pneumonia in Wuhan, China. Clin infect dis. 2020;73(11):4208-13.
34. Tsegay YG, Bitew M, workneh T, Atlaw A, Aragaw M, Gemechu M, et al. The level of liver and renal function biomarker abnormalities among hospitalized COVID-19 patients in Ethiopia. medRxiv. 2022.
35. Ghahramani S, Tabrizi R, Lankarani KB, Kashani SMA, Rezaei Sh, Zeidi N, et al F. Laboratory features of severe vs. non-severe COVID-19 patients in Asian populations: a systematic review and meta-analysis. Eur J Med Res. 2020;25(1):30.
36. Qu J, Zhu HH, Huang XJ, He GF, Liu JY, Huang JJ, et al. Abnormal indexes of liver and kidney injury markers predict severity in COVID-19 patients. Infect Dru. 2021;14:3029-3040.
37. Feng G, Zheng KI, Yan QQ, Rios RS, Targher G, Byrne ChD, et al. COVID-19 and liver dysfunction: current insights and emergent therapeutic strategies. Clin Transl hepatol. 2020;8(1):18-24.
38. Li Q, Guan X, Wu P, Wang X, Zhou L, Tong Y, et al. Early transmission dynamics in Wuhan, China, of novel coronavirus–infected pneumonia. New Engl J Med. 2020;382:1199-1207.
39. Park M, Nussbaum RL. Annals of Internal Medicine Recurrent Renal Cysts in a Transplanted Kidney. Ann Intern Med. 2018;169(9):657-8.
40. Levin L, Zhidkov I, Gurman Y, Hawlena H, Mishmar D. Functional recurrent mutations in the human mitochondrial phylogeny: dual roles in evolution and disease. Genome biol Evol. 2013;5(5):876-90.
41. Tranah GJ, Santaniello A, Caillier SJ, DAlfonso S, Boneschi FM, Hauser SL, et al. Mitochondrial DNA Sequence Variation in Multiple Sclerosis. Neurology. 2015;85(4):325-30.
42. Ganji R, Reddy PH. Impact of COVID-19 on mitochondrial-based immunity in aging and age-related diseases. Front Aging Neurosci. 2021;12:614650.
43. Fawcett JA, Innan H. Neutral and Non-Neutral Evolution of Duplicated Gene with Gene Conversion. Genes. 2011;2(1):191-209.
44. Koike Sh, Gaysina D, Jones PB, Wong A, Richards M. Catechol O-methyltransferase (COMT) functional haplotype in associated with recurrence of affective symptome: A prospective birth cohort study. J Affect Disorders. 2018;15(229):437-442.
45. Komar AA. SNPs, silent but not invisible. Science. 2007;315(5811):466-7.
46. Shabalina SA, Spiridonov NA, Kashina A. Sounds of silence: synonymous nucleotides as a key to biological regulation and complexity. Nucleic Acids Res. 2013;41(4):2073-94.
47. Medini H, Zirman A, Mishmar D. Immune system
cells from COVID-19 patients display compromised mitochondrial-nuclear expression co-regulation
and rewiring toward glycolysis. Iscience. 2021;24(12):103471.
48. Dirican E, Savrun ŞT, Aydın İ.E, Gülbay G, Karaman Ü. Analysis of mitochondrial DNA cytochrome‐b (CYB) and ATPase‐6 gene mutations in COVID‐19 patients. Med Virol. 2020;94(7):3138-46.
49. Rodenburg RJ. Mitochondrial complex I-linked disease. Bba Bioenergetics. 2016;1857(7):938-45.
50. Fornuskova D, Stiburek L, Wenchich L, Vinsova K, Hansikova H, Zeman J. Novel insights into the assembly and function of human nuclear-encoded cytochrome c oxidase subunits 4, 5a, 6a, 7a and 7b. Biochem J. 2010;428(3) :363-74.
51. Pereira L, Soares P, Radivojac P, Li B, Samuels DC. Comparing Phylogeny and the Predicted Pathogenicity of Protein Variations Reveals Equal Purifying Selection across the Global Human mtDNA Diversity. Am J Hum Genet. 2011;8(4):433-9.
52. Ballestar E, Farber DL, Glover S, Horwitz B, Meyer K, Nikolić M, et al. Single cell profiling of COVID-19 patients: an international data resource from multiple tissues. MedRxiv. 2020;20.20227355.
53. Mick E, Kamm J, Pisco AO, Ratnasiri K, Babik JM, Calfee CS, et al. Upper airway gene expression differentiates COVID-19 from other acute respiratory illnesses and reveals suppression of innate immune responses by SARS-CoV-2. Medrxiv. 2020;19:20105171.
54. Ryzhkova AI , Sazonova MA , Sinyov VV , Galitsyna EV, Chicheva MM , Melnichenko AA , et al. Mitochondrial diseases caused by mtDNA mutations: a mini-review. Nat Rev Genet. 2018;14:1933-42.
| Files | ||
| Issue | Vol 23 No 4 (2024) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijaai.v23i4.16212 | |
| Keywords | ||
| COVID-19 Mitochondria Mitochondrial DNA Mutation Oxidative stress | ||
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How to Cite
1.
Shokuhi Nia M, Kordi Tamandani D, Momeni M kazem, Bameri Z. Mitochondrial Pathogenic Mutations and Expression Pattern of Oxidative Phosphorylation Genes in COVID-19 Patients. Iran J Allergy Asthma Immunol. 2024;23(4):374-392.
