Severely reduced antioxidant and impaired mitochondrial biomarkers could be linked to post-tuberculosis lung disease in a cohort from South Africa
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Abstract
Background. Post-tuberculosis lung disease (PTLD) refers to unresolved lung damage and impaired lung function after successful treatment of tuberculosis (TB). Its pathogenesis is not fully understood, and we hypothesised that antioxidant-oxidant and mitochondrial factors may be instrumental.
Objectives. To investigate the involvement of mitochondrial and antioxidant-oxidant biomarkers in TB patients who had had more than one previous TB episode and were in the post-TB stage of disease.
Methods. Enzyme-linked immunosorbent assays were conducted on patient serum.
Results. Lipid peroxidation (measured with the thiobarbituric acid reactive substances assay) was within the normal range. In contrast, the mitochondrial regulator metallothionein-1 was 240 times lower, catalase activity 7.5 times lower, and superoxide dismutase activity 273 times lower than the normal ranges for these markers. Hypoxia-inducible factor-1-alpha (HIF-1α) was below the limit of detection. The mitochondrial markers were similar across the stratified groups after stratifying the patients based on the number of previous TB episodes. Age positively correlated with the ratio of early diastolic mitral inflow velocity to early diastolic mitral annulus velocity (E/eʹ), a marker of left ventricular filling pressure, and it marginally correlated with pulmonary artery systolic pressure, while there were no other notable correlations.
Conclusion. Our data demonstrate that antioxidant enzyme activities are extremely low in post-TB patients. A key mitochondrial protein, HIF-1α, showed no role in this context, which could suggest that these patients are not hypoxic. A novel contributor to PTLD could therefore be a limitation of antioxidant capacity and mitochondrial pathways, which is not linked to the number of previous TB episodes but may highlight the need to consider antioxidant therapy during the post-TB stage. Further research is warranted.
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1. Harshavardhan S, Vijayakumar KK, Sounderrajan V, Ramasamy P, Rajadas SE. Chapter 1 – Basics of tuberculosis disease and principles of treatment and their effects. In: Rajan M, ed. A Mechanistic Approach to Medicines for Tuberculosis Nanotherapy. Cambridge, Mass.: Academic Press, 2021:1-29. https://doi.org/10.1016/B978-0-12- 819985-5.00011-5
2. World Health Organization. Global Tuberculosis Report 2025. https://www.who. int/teams/global-programme-on-tuberculosis-and-lung-health/tb-reports/global- tuberculosis-report-2025 (accessed 4 March 2026).
3. Rachow A, Ivanova O, Wallis R, et al. TB sequel: Incidence, pathogenesis and risk factors of long-term medical and social sequelae of pulmonary TB – a study protocol. BMC Pulm Med 2019;19(1):4. https://doi.org/10.1186/s12890-018-0777-3
4. Bansal A, Yanamaladoddi VR, Sarvepalli SS, et al. Surviving pulmonary tuberculosis: Navigating the long-term respiratory effects. Cureus 2023;15(5):e38811. https://doi. org/10.7759/cureus.38811
5. Malefane L, Maarman G. Post-tuberculosis lung disease and inflammatory role players: Can we characterise the myriad inflammatory pathways involved to gain a better understanding? Chem Biol Interact 2024;387:110817. https://doi.org/10.1016/j. cbi.2023.110817
6. Jumaar C, Jacobs S, Payne C, et al. Endothelial dysfunction markers correlate with the time since completion of tuberculosis treatment and the number of previous tuberculosis episodes. Infect Dis Rep 2025;17(2):21. https://doi.org/10.3390/ idr17020021
7. Maarman GJ. Pulmonary arterial hypertension and the potential roles of metallothioneins: A focused review. Life Sci 2018;214:77-83. https://doi.org/10.1016/j. lfs.2018.10.039
8. Maarman GJ. Pulmonary hypertension and the right ventricle: The roles of mitochondrial reactive oxygen species in causing further right ventricular mitochondrial changes. In: Chakraborti S, Dhalla NS, Ganguly NK, Dikshit M, eds. Oxidative Stress in Heart Diseases. Singapore: Springer, 2019:539-549. https://doi. org/10.1007/978-981-13-8273-4_24
9. Ryanto GRT, Suraya R, Nagano T. Mitochondrial dysfunction in pulmonary hypertension. Antioxidants (Basel) 2023;12(2):372. https://doi.org/10.3390/ antiox12020372
10. Louw E, Baines N, Maarman G, et al. The prevalence of pulmonary hypertension after successful tuberculosis treatment in a community sample of adult patients. Pulm Circ 2023;13(1):e12184. https://doi.org/10.1002/pul2.12184
11. Jentzsch AM, Bachmann H, Fürst P, Biesalski HK. Improved analysis of malondialdehyde in human body fluids. Free Radic Biol Med 1996;20(2):251-256. https://doi.org/10.1016/0891-5849(95)02043-8
12. Góth L. A simple method for determination of serum catalase activity and revision of reference range. Clin Chim Acta 1991;196(2-3):143-151. https://doi.org/10.1016/0009- 8981(91)90067-m
13. MaarmanG,BlackhurstD,ThienemannF,etal.Melatoninasapreventiveandcurative therapy against pulmonary hypertension. J Pineal Res 2015;59(3):343-353. https://doi. org/10.1111/jpi.12263
14. Aguilar Diaz De Leon J, Borges CR. Evaluation of oxidative stress in biological samples using the thiobarbituric acid reactive substances assay. J Vis Exp 2020;159:10.3791/61122. https://doi.org/10.3791/61122
15. Nakazato K, Tomioka S, Nakajima K, et al. Determination of the serum metallothionein (MT)1/2 concentration in patients with Wilson’s disease and Menkes disease. J Trace Elem Med Biol 2014;28(4):441-447. https://doi.org/10.1016/j.jtemb.2014.07.013
16. Nojima M, Sakkauchi F, Mori M, et al. Relationship of serum superoxide dismutase activity and lifestyle in healthy Japanese adults. Asian Pac J Cancer Prev 2009;10(Suppl):37-40.
17. Yucel K, Aydin I, Erdem SS. Hypoxia induced factor-1α levels in patients undergoing adenoidectomy. Scand J Clin Lab Invest 2021;81(1):34-38. https://doi.org/10.1080/0 0365513.2020.1849786
18. Reis GS, Augusto VS, Silveira AP, et al. Oxidative-stress biomarkers in patients with pulmonary hypertension. Pulm Circ 2013;3(4):856-861. https://doi. org/10.1086/674764
19. AirwonmanborKO,OmonEA,OmolumenLE,AsiborE,OmolumenBA,Ikpomwosa J. Assessment of glutathione and malondialdehyde in pulmonary tuberculosis patients in Edo State, Nigeria. Trends Med Res 2024;19(1):1-12. https://doi.org/10.3923/ tmr.2024.1.12
20. Rajopadhye SH, Mukherjee SR, Chowdhary AS, Dandekar SP. Oxidative stress markers in tuberculosis and HIV/TB co-infection. J Clin Diagn Res 2017;11(8):BC24-BC28. https://doi.org/10.7860/JCDR/2017/28478.10473
21. Vidhya R, Rathnakumar K, Balu V, Pugalendi KV. Oxidative stress, antioxidant status and lipid profile in pulmonary tuberculosis patients before and after anti-tubercular therapy. Indian J Tuberc 2019;66(3):375-381. https://doi.org/10.1016/j.ijtb.2018.11.002
22. Meca AD, Turcu-Stiolica A, Stanciulescu EC, et al. Variations of serum oxidative stress biomarkers under first-line antituberculosis treatment: A pilot study. J Pers Med 2021;11(2):112. https://doi.org/10.3390/jpm11020112
23. Locatelli F, Canaud B, Eckardt KU, Stenvinkel P, Wanner C, Zoccali C. Oxidative stress in end-stage renal disease: An emerging threat to patient outcome. Nephrol Dial Transplant 2003;18(7):1272-1280. https://doi.org/10.1093/ndt/gfg074
24. Lian Y, Zhao J, Xu P, et al. Protective effects of metallothionein on isoniazid and rifampicin-induced hepatotoxicity in mice. PLoS ONE 2013;8(8):e72058. https://doi. org/10.1371/journal.pone.0072058
25. Takano H, Inoue K, Yanagisawa R, et al. Protective role of metallothionein in acute lung injury induced by bacterial endotoxin. Thorax 2004;59(12):1057-1062. https:// doi.org/10.1136/thx.2004.024232
26. Hsu E, Shi H, Jordan RM, Lyons-Weiler J, Pilewski JM, Feghali-Bostwick CA. Lung tissues in patients with systemic sclerosis have gene expression patterns unique to pulmonary fibrosis and pulmonary hypertension. Arthritis Rheum 2011;63(3):783-794. https://doi.org/10.1002/art.30159
27. Thirumoorthy N, Manisenthil Kumar KT, Shyam Sundar A, Panayappan L, Chatterjee M. Metallothionein: An overview. World J Gastroenterol 2007;13(7):993-996. https:// doi.org/10.3748/wjg.v13.i7.993
28. Golubović S, Stanković I, Ristić L, Cosić V, Dordević I, Radović M. [Antioxidant enzymes and lipid peroxidation products in patients with pulmonary tuberculosis]. Med Pregl 2010;63(7-8):450-453. https://doi.org/10.2298/mpns1008450g
29. ParchwaniD,SinghSP,PatelD.Totalantioxidantstatusandlipidperoxidesinpatients with pulmonary tuberculosis. Nat J Comm Med 2011;2(02):225-228.
30. Dai DF, Chen T, Wanagat J, et al. Age-dependent cardiomyopathy in mitochondrial mutator mice is attenuated by overexpression of catalase targeted to mitochondria. Aging Cell 2010;9(4):536-544. https://doi.org/10.1111/j.1474-9726.2010.00581.x
31. DaiDF,RabinovitchP.Mitochondrialoxidativestressmediatesinductionofautophagy and hypertrophy in angiotensin-II treated mouse hearts. Autophagy 2011;7(8):917- 918. https://doi.org/10.4161/auto.7.8.15813
32. Dai DF, Santana LF, Vermulst M, et al. Overexpression of catalase targeted to mitochondria attenuates murine cardiac aging. Circulation 2009;119(21):2789-2797. https://doi.org/10.1161/CIRCULATIONAHA.108.822403
33. Rubinstein L, Schreurs A-S, Torres SM, et al. Overexpression of catalase in mitochondria mitigates changes in hippocampal cytokine expression following simulated microgravity and isolation. NPJ Microgravity 2021;7(1):24. https://doi. org/10.1038/s41526-021-00152-w
34. Cupido G, Günther G. Post tuberculosis lung disease and tuberculosis sequelae: A narrative review. Indian J Tuberc 2024;71(1):64-72. https://doi.org/10.1016/j. ijtb.2023.04.001
35. Li C, Wang J, Xu JF, Pi J, Zheng B. Roles of HIF-1α signaling in Mycobacterium tuberculosis infection: New targets for anti-TB therapeutics? Biochem Biophys Res Commun 2024;711:149920. https://doi.org/10.1016/j.bbrc.2024.149920
36. Rong B, Liu Y, Li M, Fu T, Gao W, Liu H. Correlation of serum levels of HIF-1α and IL-19 with the disease progression of COPD: A retrospective study. Int J Chron Obstruct Pulm Dis 2018;13:3791-3803. https://doi.org/10.2147/COPD.S177034
37. Belton M, Brilha S, Manavaki R, et al. Hypoxia and tissue destruction in pulmonary TB. Thorax 2016;71(12):1145-1153. https://doi.org/10.1136/thoraxjnl-2015-207402
38. Nan Y, Wang Y, Dong Y, et al. Impact of hypoxia-inducible factor-1α on host immune metabolism and tissue damage during Mycobacterium bovis infection. J Infect Dis 2024;231(2):355-365. https://doi.org/10.1093/infdis/jiae305
39. Li H-S, Zhou Y-N, Li L, et al. HIF-1α protects against oxidative stress by directly targeting mitochondria. Redox Biol 2019;25:101109. https://doi.org/10.1016/j. redox.2019.101109
40. Mohareer K, Banerjee S. Mycobacterial infection alters host mitochondrial activity. Int Rev Cell Mol Biol 2023;377:87-119. https://doi.org/10.1016/bs.ircmb.2023.01.007 41. El-Benhawy SA, Sakr OA, Fahmy EI, et al. Assessment of serum hypoxia biomarkers pre- and post-radiotherapy in patients with brain tumors. J Mol Neurosci
2022;72(11):2303-2312. https://doi.org/10.1007/s12031-022-02065-z
42. FockEM,ParnovaRG.Protectiveeffectofmitochondria-targetedantioxidantsagainst inflammatory response to lipopolysaccharide challenge: A review. Pharmaceutics
2021;13(2):144. https://doi.org/10.3390/pharmaceutics13020144
43. Madebo T, Lindtjørn B, Aukrust P, Berge RK. Circulating antioxidants and lipid peroxidation products in untreated tuberculosis patients in Ethiopia. Am J Clin Nutr
2003;78(1):117-122. https://doi.org/10.1093/ajcn/78.1.117
44. Kachour N, Beever A, Owens J, et al. Liposomal glutathione helps to mitigate
Mycobacterium tuberculosis infection in the lungs. Antioxidants (Basel) 2022;11(4):673.
https://doi.org/10.3390/antiox11040673
45. Karamchand S, Williams M, Naidoo P, Decloedt E, Allwood B. Post-tuberculous lung disease: Should we be using theophylline? J Thorac Dis 2021;13(2):1230-1238. https:// doi.org/10.21037/jtd-20-1298
46. Mapamba DA, Sauli E, Mrema L, et al. Impact of N-acetyl cysteine (NAC) on tuberculosis (TB) patients – a systematic review. Antioxidants (Basel) 2022;11(11):2298. https://doi.org/10.3390/antiox11112298