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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...

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Autores principales: Wüst, Rob C. I., Coolen, Bram F., Held, Ntsiki M., Daal, Mariah R. R., Alizadeh Tazehkandi, Vida, Baks-te Bulte, Luciënne, Wiersma, Marit, Kuster, Diederik W. D., Brundel, Bianca J. J. M., van Weeghel, Michel, Strijkers, Gustav J., Houtkooper, Riekelt H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8071362/
https://www.ncbi.nlm.nih.gov/pubmed/33921053
http://dx.doi.org/10.3390/ijms22084100
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author Wüst, Rob C. I.
Coolen, Bram F.
Held, Ntsiki M.
Daal, Mariah R. R.
Alizadeh Tazehkandi, Vida
Baks-te Bulte, Luciënne
Wiersma, Marit
Kuster, Diederik W. D.
Brundel, Bianca J. J. M.
van Weeghel, Michel
Strijkers, Gustav J.
Houtkooper, Riekelt H.
author_facet Wüst, Rob C. I.
Coolen, Bram F.
Held, Ntsiki M.
Daal, Mariah R. R.
Alizadeh Tazehkandi, Vida
Baks-te Bulte, Luciënne
Wiersma, Marit
Kuster, Diederik W. D.
Brundel, Bianca J. J. M.
van Weeghel, Michel
Strijkers, Gustav J.
Houtkooper, Riekelt H.
author_sort Wüst, Rob C. I.
collection PubMed
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 Drosophila 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 Drosophila melanogaster 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.
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spelling pubmed-80713622021-04-26 The Antibiotic Doxycycline Impairs Cardiac Mitochondrial and Contractile Function Wüst, Rob C. I. Coolen, Bram F. Held, Ntsiki M. Daal, Mariah R. R. Alizadeh Tazehkandi, Vida Baks-te Bulte, Luciënne Wiersma, Marit Kuster, Diederik W. D. Brundel, Bianca J. J. M. van Weeghel, Michel Strijkers, Gustav J. Houtkooper, Riekelt H. Int J Mol Sci Article 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 Drosophila 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 Drosophila melanogaster 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. MDPI 2021-04-15 /pmc/articles/PMC8071362/ /pubmed/33921053 http://dx.doi.org/10.3390/ijms22084100 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Wüst, Rob C. I.
Coolen, Bram F.
Held, Ntsiki M.
Daal, Mariah R. R.
Alizadeh Tazehkandi, Vida
Baks-te Bulte, Luciënne
Wiersma, Marit
Kuster, Diederik W. D.
Brundel, Bianca J. J. M.
van Weeghel, Michel
Strijkers, Gustav J.
Houtkooper, Riekelt H.
The Antibiotic Doxycycline Impairs Cardiac Mitochondrial and Contractile Function
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 Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8071362/
https://www.ncbi.nlm.nih.gov/pubmed/33921053
http://dx.doi.org/10.3390/ijms22084100
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