Florfenicol-induced Mitochondrial Dysfunction Suppresses Cell Proliferation and Autophagy in Fibroblasts

Abstract

Florfenicol (FLO) is one of the most popular antibiotics used in veterinary clinic and aquaculture. FLO can inhibit both bacterial and mitochondrial protein synthesis. However, the effects of FLO on mitochondrial function and cellular homeostasis remain unclear. Here we show that FLO inhibits expression of mitochondrial DNA-encoded proteins, decreases mitochondrial membrane potential, and promotes generation of reactive oxygen species (ROS) in vitro. As a result, activities of mitochondrial respiratory chain complex I and IV and the cellular ATP level are decreased and mitochondrial morphology is damaged. FLO represses cell growth and proliferation by suppression of phosphorylation of p70S6K through AMPK/mTOR/p70S6K pathway. Furthermore, FLO also induces G0/G1 cell cycle arrest via increase of p21 levels through activating ROS/p53/p21 pathway. Moreover, the clearance of damaged mitochondria by autophagy is impaired, leading to cell proliferation inhibition and promotes cell senescence. In addition, FLO-induced upregulation of cytosolic p53 may contribute to mitophagy deficiency via regulation of Parkin recruitment. In summary, our data suggest that florfenicol is an inhibitor of mitochondrial protein synthesis that can induce noticeable cytotoxicity. Thus, these findings can be useful for guiding the proper use of FLO and the development of safe drugs.

Growth and cardiovascular development are repressed by florfenicol exposure in early chicken embryos

“…Because of the similarities between mitochondrial and bacterial ribosomes, the antibiotics developed to inhibit bacterial ribosomes inevitably inhibit mitochondrial ribosomes, leading to mitochondrial damage ( Wang et al., 2015b ). Our previous reports showed that FLO inhibits the expression of mitochondrial DNA-encoded proteins, resulting in mitochondrial damage and dysfunction ( Hu et al., 2017 ). Mitochondria are eukaryotic cellular organelles specialized for energy conversion and ATP production.…”

Efectos adversos provocados en la descendencia de Drosophila melanogaster Meigen inducidos por antibióticos usados en salmonicultura

“…El fl orfenicol afecta a nivel de la síntesis de proteínas a organelos de origen procariótico de la célula eucariótica (mitocondria y cloroplasto). Causa alteraciones estructurales graves, disfunción de mitocondrias, y como consecuencia, inhibe la proliferación celular por acumulación de daños en mitocondrias, causa un aumento de la senescencia celular en cultivos de fi broblastos de ratón (Hu et al 2017). El efecto tóxico de fl orfenicol sobre el cloroplasto, produce inhibición del crecimiento de cultivos de microalgas (Chlorella pyrenoidosa, Isochrysis galbana y Tetraselmis chui) (Wang et al 2015;Du & Liu 2012;Lai et al 2009), inhibiendo la fotosíntesis en Skeletonema costatum, a una concentración mayor o igual a 1 mg/L en 6 h (Liu et al 2012).…”

Low and high concentrations of butyrate regulate fat accumulation in chicken adipocytes via different mechanisms

“…EdU, which is a rather new thymidine analog that can be incorporated into DNA during active DNA synthesis, has widely been used to trace the cell proliferation ability [21]. In this study, subconfluent preadipocytes were treated with different SB doses for 24 h. Then, the cells were incubated with 10 µM EdU for 2 h. Cell increment could be detected via a chemical reaction with Andy FluorTM 488 Azide (green fluorescence).…”