Wuest 2021 Int J Mol Sci
|Wüst RCI, Coolen BF, Held NM, Daal MRR, Alizadeh Tazehkandi V, Baks-Te Bulte L, Wiersma M, Kuster DWD, Brundel BJJM, van Weeghel M, Strijkers GJ, Houtkooper RH (2021) The antibiotic doxycycline impairs cardiac mitochondrial and contractile function. Int J Mol Sci 22:4100.
Wuest Rob C I, Coolen Bram F, Held Ntsiki M, Daal Mariah R R, Tazehkandi Vida Alizadeh, Baks-Te Bulte Lucienne, Wiersma Marit, Kuster Diederik W D, Brundel Bianca J J M, van Weeghel Michel, Strijkers Gustav J, Houtkooper Riekelt H (2021) Int J Mol Sci
Abstract: 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. • Keywords: Calcium handling, Cardiac contractility, Doxycycline, Mitochondrial function • Bioblast editor: Plangger M • O2k-Network Lab: NL Amsterdam Wuest RC
Labels: MiParea: Respiration, Pharmacology;toxicology
Organism: Mouse Tissue;cell: Heart Preparation: Permeabilized tissue
Coupling state: LEAK, OXPHOS, ET Pathway: N, S, NS, ROX HRR: Oxygraph-2k