The Antibiotic Doxycycline Impairs Cardiac Mitochondrial and Contractile Function.

Michel Van Weeghel,Gustav J Strijkers,Mariah R R Daal,Marit Wiersma,Rob C I Wüst,Bianca J J M Brundel,Bram F Coolen,Diederik W D Kuster,Ntsiki M Held,Luciënne Baks-Te Bulte,Vida Alizadeh Tazehkandi,Riekelt H Houtkooper

doi:10.3390/ijms22084100

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.

Highlights

In the heart, a high constant energy utilization rate is coupled to constant energy production by mitochondrial oxidative phosphorylation (OXPHOS) [1,2,3,4]
Its inhibiting effect on mitochondrial protein synthesis has long been acknowledged [11], and even helped scientists unravel the bacterial ancestry of mitochondria [6], very few studies have focused on the possible toxic effects of antibiotics on cell metabolism and function
We report the negative effects of doxycycline antibiotics on mitochondrial function by showing that it reduced OXPHOS and impairs contractile function in various animal models

Summary

Introduction

A high constant energy utilization rate is coupled to constant energy production by mitochondrial oxidative phosphorylation (OXPHOS) [1,2,3,4]. Mitochondria serve a crucial role for optimal cardiac functioning, and they sustain their physiological role by forming physically connected (sub)networks that provide a rapid conductive path for energy distribution [5]. An important feature of mitochondria is their bacterial ancestry [6]. Throughout evolution, the vast majority of genes encoding mitochondrial proteins have moved to the nuclear DNA (nDNA), and these nuclear-encoded proteins need to be imported into the mitochondria. Mitochondria still retain their own circular DNA (mtDNA), encoding the mitochondrial 16S and 12S rRNA, 22 tRNAs and 13 core subunits of the OXPHOS system, including seven crucial subunits of mitochondrial complex I [7,8]. The stoichiometric balance between both genomes is tightly regulated, and this mitonuclear protein balance is crucial for optimal mitochondrial function [9,10]

Methods

Results

Conclusion