The antibiotic doxycycline impairs cardiac mitochondrial and contractile function

R.C.I. Wüst, B.F. Coolen, N.M. Held, M.R.R. Daal, V.A. Tazehkandi, L. Baks‐Te Bulte, M. Wiersma, D.W.D. Kuster, B.J.J.M. Brundel, M. van Weeghel, G.J. Strijkers, R.H. Houtkooper

Research output: Contribution to JournalArticleAcademicpeer-review


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.

Original languageEnglish
Article number4100
Pages (from-to)1-19
Number of pages19
JournalInternational Journal of Molecular Sciences
Issue number8
Publication statusPublished - 2 Apr 2021

Bibliographical note

Special Issue: Targeting Mitochondria in Metabolic Diseases.


  • Aging/metabolism
  • Animals
  • Anti-Bacterial Agents/pharmacology
  • Calcium/metabolism
  • Calcium Signaling/drug effects
  • Cell Respiration/drug effects
  • Cytosol/metabolism
  • Diabetes Mellitus, Experimental/pathology
  • Diastole/drug effects
  • Doxycycline/pharmacology
  • Drosophila melanogaster/drug effects
  • Electron Transport Complex I/metabolism
  • Electron Transport Complex II/metabolism
  • Glucose/metabolism
  • Glycolysis/drug effects
  • Male
  • Mice, Inbred C57BL
  • Mitochondria, Heart/drug effects
  • Mitochondrial Proteins/metabolism
  • Myocardial Contraction/drug effects
  • Myocytes, Cardiac/drug effects
  • Nuclear Proteins/metabolism
  • Oxidative Phosphorylation/drug effects
  • Rats


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