The inhibition of TXNRD1 by methylglyoxal impairs the intracellular control of Mycobacterium tuberculosis
Type 2 diabetes (DM) is a risk factor for development of tuberculosis (TB). Methylglyoxal (MGO), a reactive carbonyl increased during DM targets diverse macromolecules. Here we discovered that MGO converted the mammalian selenoprotein thioredoxin reductase 1 (TXNRD1) to a NADPH oxidase, activating t...
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Elsevier
2025-09-01
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| Series: | Redox Biology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S221323172500254X |
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| author | Hanxiong Li Ruining Liu Gokul Raj Kathamuthu Radosveta Gencheva Zhen Gong Axel Tobias Scholz Mohammad Alzrigat Lucia Coppo Elias S.J. Arnér Martin E. Rottenberg |
| author_facet | Hanxiong Li Ruining Liu Gokul Raj Kathamuthu Radosveta Gencheva Zhen Gong Axel Tobias Scholz Mohammad Alzrigat Lucia Coppo Elias S.J. Arnér Martin E. Rottenberg |
| author_sort | Hanxiong Li |
| collection | DOAJ |
| description | Type 2 diabetes (DM) is a risk factor for development of tuberculosis (TB). Methylglyoxal (MGO), a reactive carbonyl increased during DM targets diverse macromolecules. Here we discovered that MGO converted the mammalian selenoprotein thioredoxin reductase 1 (TXNRD1) to a NADPH oxidase, activating the NRF2 transcription factor in bone marrow macrophages (BMM). NRF2 signaling hampered the production of immune molecules by BMM, thus allowing intracellular growth of M. tuberculosis (Mtb). The overexpression of NRF2 was sufficient to increase the Mtb growth. Several inhibitors of TXNRD1 mimicked the effects of MGO on Mtb growth in BMM. MGO and the TXNRD1 inhibitor auranofin also increased the susceptibility of mice to Mtb infection. Finally, IFN-γ abrogated the MGO-triggered suppression of the protective responses to Mtb in BMM, by epigenetic regulation of immune genes, without impairing NRF2 activation. Thus, metabolic alterations in DM may have a causative role in TB-DM comorbidity, by activating NRF2 responses that impair immune protective responses. |
| format | Article |
| id | doaj-art-a275cef4e4db44669934ebb42ed69c65 |
| institution | Kabale University |
| issn | 2213-2317 |
| language | English |
| publishDate | 2025-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj-art-a275cef4e4db44669934ebb42ed69c652025-08-24T05:12:25ZengElsevierRedox Biology2213-23172025-09-018510374110.1016/j.redox.2025.103741The inhibition of TXNRD1 by methylglyoxal impairs the intracellular control of Mycobacterium tuberculosisHanxiong Li0Ruining Liu1Gokul Raj Kathamuthu2Radosveta Gencheva3Zhen Gong4Axel Tobias Scholz5Mohammad Alzrigat6Lucia Coppo7Elias S.J. Arnér8Martin E. Rottenberg9Dept Microbiology, Tumor and Cell Biology, Stockholm, SwedenDept Microbiology, Tumor and Cell Biology, Stockholm, SwedenDept Microbiology, Tumor and Cell Biology, Stockholm, SwedenDivision of Biochemistry, Dept of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, SwedenDept Microbiology, Tumor and Cell Biology, Stockholm, SwedenDivision of Biochemistry, Dept of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, SwedenDept Microbiology, Tumor and Cell Biology, Stockholm, SwedenDivision of Biochemistry, Dept of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, SwedenDivision of Biochemistry, Dept of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden; Dept of Selenoprotein Research and National Tumor Biology Laboratory, National Institute of Oncology, Budapest, HungaryDept Microbiology, Tumor and Cell Biology, Stockholm, Sweden; Corresponding author. Dept. Microbiology, Tumor and Cell Biology, Karolinska Institutet, S17177, Stockholm, Sweden.Type 2 diabetes (DM) is a risk factor for development of tuberculosis (TB). Methylglyoxal (MGO), a reactive carbonyl increased during DM targets diverse macromolecules. Here we discovered that MGO converted the mammalian selenoprotein thioredoxin reductase 1 (TXNRD1) to a NADPH oxidase, activating the NRF2 transcription factor in bone marrow macrophages (BMM). NRF2 signaling hampered the production of immune molecules by BMM, thus allowing intracellular growth of M. tuberculosis (Mtb). The overexpression of NRF2 was sufficient to increase the Mtb growth. Several inhibitors of TXNRD1 mimicked the effects of MGO on Mtb growth in BMM. MGO and the TXNRD1 inhibitor auranofin also increased the susceptibility of mice to Mtb infection. Finally, IFN-γ abrogated the MGO-triggered suppression of the protective responses to Mtb in BMM, by epigenetic regulation of immune genes, without impairing NRF2 activation. Thus, metabolic alterations in DM may have a causative role in TB-DM comorbidity, by activating NRF2 responses that impair immune protective responses.http://www.sciencedirect.com/science/article/pii/S221323172500254XTuberculosisDiabetesMacrophageMethylglyoxalThioredoxin reductaseNRF2 |
| spellingShingle | Hanxiong Li Ruining Liu Gokul Raj Kathamuthu Radosveta Gencheva Zhen Gong Axel Tobias Scholz Mohammad Alzrigat Lucia Coppo Elias S.J. Arnér Martin E. Rottenberg The inhibition of TXNRD1 by methylglyoxal impairs the intracellular control of Mycobacterium tuberculosis Redox Biology Tuberculosis Diabetes Macrophage Methylglyoxal Thioredoxin reductase NRF2 |
| title | The inhibition of TXNRD1 by methylglyoxal impairs the intracellular control of Mycobacterium tuberculosis |
| title_full | The inhibition of TXNRD1 by methylglyoxal impairs the intracellular control of Mycobacterium tuberculosis |
| title_fullStr | The inhibition of TXNRD1 by methylglyoxal impairs the intracellular control of Mycobacterium tuberculosis |
| title_full_unstemmed | The inhibition of TXNRD1 by methylglyoxal impairs the intracellular control of Mycobacterium tuberculosis |
| title_short | The inhibition of TXNRD1 by methylglyoxal impairs the intracellular control of Mycobacterium tuberculosis |
| title_sort | inhibition of txnrd1 by methylglyoxal impairs the intracellular control of mycobacterium tuberculosis |
| topic | Tuberculosis Diabetes Macrophage Methylglyoxal Thioredoxin reductase NRF2 |
| url | http://www.sciencedirect.com/science/article/pii/S221323172500254X |
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