Tetracycline Antibiotics Impair Mitochondrial Function and Its Experimental Use Confounds Research

Abstract

Tetracyclines, a class of antibiotics that target bacterial translation, are commonly used in research for inducible gene expression using Tet-ON/Tet-OFF systems. However, such tetracycline-inducible systems carry a risk. Given that mitochondria have a “bacterial” ancestry, these antibiotics also target mitochondrial translation and impair mitochondrial function. Indeed, treatment with doxycycline—a tetracycline derivative—disturbs mitochondrial proteostasis and metabolic activity, and induces widespread gene expression changes. Together, this affects physiology in well-established model systems ranging from cultured cells to simple organisms and to mice and plants. These changes are observed with doxycycline doses that are widely used to regulate gene expression. In light of these findings, and bearing in mind the conserved role of mitochondria in metabolism and whole organism homeostasis, we caution against the use of tetracyclines in experimental approaches. The use of newly developed tetracycline-based systems that are more sensitive could be an alternative; however, even if no overt mitochondrial toxicity is detected, widespread changes in gene expression may sensitize cells to the intended tetracycline-controlled loss- or gain-of-function, thereby introducing a “two-hit model”. This is highly relevant for cancer research, as mitochondrial metabolism holds a central position in the reallocation of nutrients for biomass production known as the Warburg effect.

Sorting out adipocyte precursors and their role in physiology and disease

“…Auwerx and colleagues (Chatzispyrou et al 2015;Moullan et al 2015) demonstrated that doxycycline negatively impacts mitochrondrial function. Doxycycline can also impact the gut microbiota in humans; the direct impact of this on adipose biology is unclear but potentially significant (Angelakis et al 2014).…”

In Vitro Chitosan Hydrogel Based Tetracycline Cytotoxicity Test on Fibroblast Viability

“…An inhibitive effect of tetracycline on protein translation, which is managed by mitochondrial DNA on mammalian cells, has been reported. This inhibition will trigger the imbalance of mitochondrial protein, which will lead to interference with growth, oxygen consumption and fertility [24,25].…”

Mitochondrial dysfunction and potential anticancer therapy

“…The cause of MDF is largely unknown but may involve genetic defects, ROS misbalance, impaired autophagy (mitophagy), alterations of signaling pathways, which regulate mitochondrial functions, retrograde pathway and mitochondrial unfolded protein response, acquired mutations in mtDNA or nDNA‐encoded mitochondrial genes, and inability of cells to overcome the consequences . A recent highlight arises from the detection of MDF in eukaryotic cells upon treatment with antibiotics . It has been demonstrated that even at low concentrations some antibiotics may inhibit mitochondrial functions and lead to detrimental changes on both molecular and physiological levels .…”