The Antibiotic Doxycycline Impairs Cardiac Mitochondrial and Contractile Function
Tetracycline antibiotics act by inhibiting bacterial protein translation. Given the bacterial ancestry of mitochondria, we tested the hypothesis that doxycycline—which belongs to the tetracycline class—reduces mitochondrial function, and results in cardiac contractile dysfunction in cultured H9C2 ca...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-04-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/8/4100 |
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| author | Rob C. I. Wüst Bram F. Coolen Ntsiki M. Held Mariah R. R. Daal Vida Alizadeh Tazehkandi Luciënne Baks-te Bulte Marit Wiersma Diederik W. D. Kuster Bianca J. J. M. Brundel Michel van Weeghel Gustav J. Strijkers Riekelt H. Houtkooper |
| author_facet | Rob C. I. Wüst Bram F. Coolen Ntsiki M. Held Mariah R. R. Daal Vida Alizadeh Tazehkandi Luciënne Baks-te Bulte Marit Wiersma Diederik W. D. Kuster Bianca J. J. M. Brundel Michel van Weeghel Gustav J. Strijkers Riekelt H. Houtkooper |
| author_sort | Rob C. I. Wüst |
| collection | DOAJ |
| description | Tetracycline antibiotics act by inhibiting bacterial protein translation. Given the bacterial ancestry of mitochondria, we tested the hypothesis that doxycycline—which belongs to the tetracycline class—reduces mitochondrial function, and results in cardiac contractile dysfunction in cultured H9C2 cardiomyoblasts, adult rat cardiomyocytes, in <i>Drosophila</i> and in mice. Ampicillin and carbenicillin were used as control antibiotics since these do not interfere with mitochondrial translation. In line with its specific inhibitory effect on mitochondrial translation, doxycycline caused a mitonuclear protein imbalance in doxycycline-treated H9C2 cells, reduced maximal mitochondrial respiration, particularly with complex I substrates, and mitochondria appeared fragmented. Flux measurements using stable isotope tracers showed a shift away from OXPHOS towards glycolysis after doxycycline exposure. Cardiac contractility measurements in adult cardiomyocytes and <i>Drosophila melanogaster</i> hearts showed an increased diastolic calcium concentration, and a higher arrhythmicity index. Systolic and diastolic dysfunction were observed after exposure to doxycycline. Mice treated with doxycycline showed mitochondrial complex I dysfunction, reduced OXPHOS capacity and impaired diastolic function. Doxycycline exacerbated diastolic dysfunction and reduced ejection fraction in a diabetes mouse model vulnerable for metabolic derangements. We therefore conclude that doxycycline impairs mitochondrial function and causes cardiac dysfunction. |
| first_indexed | 2024-03-10T12:17:25Z |
| format | Article |
| id | doaj.art-7f8fa2633cd84842a662f204b4d64125 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T12:17:25Z |
| publishDate | 2021-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-7f8fa2633cd84842a662f204b4d641252023-11-21T15:43:59ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-04-01228410010.3390/ijms22084100The Antibiotic Doxycycline Impairs Cardiac Mitochondrial and Contractile FunctionRob C. I. Wüst0Bram F. Coolen1Ntsiki M. Held2Mariah R. R. Daal3Vida Alizadeh Tazehkandi4Luciënne Baks-te Bulte5Marit Wiersma6Diederik W. D. Kuster7Bianca J. J. M. Brundel8Michel van Weeghel9Gustav J. Strijkers10Riekelt H. Houtkooper11Laboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology, Endocrinology, and Metabolism, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The NetherlandsBiomedical Engineering and Physics, Amsterdam Cardiovascular Sciences, University of Amsterdam, Amsterdam UMC, 1105 AZ Amsterdam, The NetherlandsLaboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology, Endocrinology, and Metabolism, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The NetherlandsBiomedical Engineering and Physics, Amsterdam Cardiovascular Sciences, University of Amsterdam, Amsterdam UMC, 1105 AZ Amsterdam, The NetherlandsLaboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology, Endocrinology, and Metabolism, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The NetherlandsDepartment of Physiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, VU University Medical Center, 1081 HZ Amsterdam, The NetherlandsDepartment of Physiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, VU University Medical Center, 1081 HZ Amsterdam, The NetherlandsDepartment of Physiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, VU University Medical Center, 1081 HZ Amsterdam, The NetherlandsDepartment of Physiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, VU University Medical Center, 1081 HZ Amsterdam, The NetherlandsLaboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology, Endocrinology, and Metabolism, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The NetherlandsBiomedical Engineering and Physics, Amsterdam Cardiovascular Sciences, University of Amsterdam, Amsterdam UMC, 1105 AZ Amsterdam, The NetherlandsLaboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology, Endocrinology, and Metabolism, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The NetherlandsTetracycline antibiotics act by inhibiting bacterial protein translation. Given the bacterial ancestry of mitochondria, we tested the hypothesis that doxycycline—which belongs to the tetracycline class—reduces mitochondrial function, and results in cardiac contractile dysfunction in cultured H9C2 cardiomyoblasts, adult rat cardiomyocytes, in <i>Drosophila</i> and in mice. Ampicillin and carbenicillin were used as control antibiotics since these do not interfere with mitochondrial translation. In line with its specific inhibitory effect on mitochondrial translation, doxycycline caused a mitonuclear protein imbalance in doxycycline-treated H9C2 cells, reduced maximal mitochondrial respiration, particularly with complex I substrates, and mitochondria appeared fragmented. Flux measurements using stable isotope tracers showed a shift away from OXPHOS towards glycolysis after doxycycline exposure. Cardiac contractility measurements in adult cardiomyocytes and <i>Drosophila melanogaster</i> hearts showed an increased diastolic calcium concentration, and a higher arrhythmicity index. Systolic and diastolic dysfunction were observed after exposure to doxycycline. Mice treated with doxycycline showed mitochondrial complex I dysfunction, reduced OXPHOS capacity and impaired diastolic function. Doxycycline exacerbated diastolic dysfunction and reduced ejection fraction in a diabetes mouse model vulnerable for metabolic derangements. We therefore conclude that doxycycline impairs mitochondrial function and causes cardiac dysfunction.https://www.mdpi.com/1422-0067/22/8/4100doxycyclinemitochondrial functioncardiac contractilitycalcium handling |
| spellingShingle | Rob C. I. Wüst Bram F. Coolen Ntsiki M. Held Mariah R. R. Daal Vida Alizadeh Tazehkandi Luciënne Baks-te Bulte Marit Wiersma Diederik W. D. Kuster Bianca J. J. M. Brundel Michel van Weeghel Gustav J. Strijkers Riekelt H. Houtkooper The Antibiotic Doxycycline Impairs Cardiac Mitochondrial and Contractile Function International Journal of Molecular Sciences doxycycline mitochondrial function cardiac contractility calcium handling |
| title | The Antibiotic Doxycycline Impairs Cardiac Mitochondrial and Contractile Function |
| title_full | The Antibiotic Doxycycline Impairs Cardiac Mitochondrial and Contractile Function |
| title_fullStr | The Antibiotic Doxycycline Impairs Cardiac Mitochondrial and Contractile Function |
| title_full_unstemmed | The Antibiotic Doxycycline Impairs Cardiac Mitochondrial and Contractile Function |
| title_short | The Antibiotic Doxycycline Impairs Cardiac Mitochondrial and Contractile Function |
| title_sort | antibiotic doxycycline impairs cardiac mitochondrial and contractile function |
| topic | doxycycline mitochondrial function cardiac contractility calcium handling |
| url | https://www.mdpi.com/1422-0067/22/8/4100 |
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