Mitochondrial Damage as an Early Event of Monensin‐induced Cell Injury in Cultured Fibroblasts L929

Abstract

The present study was designed to identify, submicroscopically, the primary organelle or target structure for monensin in cultured murine fibroblasts L929. In addition, the effect of the drug on cell size and surface membranes of the cells were analysed; cellular proliferation, collagen secretion, and necrosis and apoptosis were re-evaluated. At the lowest concentration of monensin the foremost ultrastructural alteration occurred in the mitochondria, characterized by increased matrix density with disorganized and less distinct crystae. Incubation with monensin at higher concentrations resulted in severe mitochondrial damage and marked dilatation of the Golgi apparatus and rough endoplasmic reticulum cisternae. Fibroblasts exposed to higher concentrations of monensin were enlarged with decreased number of filopodia and hollows in the surface membrane. Moreover, monensin inhibited the cell proliferation, increased immunohistochemical positiveness for collagen type I in a dose-dependent manner, and, at high concentrations, caused cell necrosis whereas apoptosis was not induced. Taken together, these results show that monensin induces early mitochondrial damage, possibly causing an energy deficit that led to inhibition of fibroblasts proliferation and accumulation of collagen causing dilatation of Golgi apparatus and rough endoplasmic reticulum. Moreover, the mitochondrial damage would also explain the monensin-induced necrosis.

Analysis of Monensin Sensitivity in Toxoplasma gondii Reveals Autophagy as a Mechanism for Drug Induced Death

“…Perhaps monensin could have effects on host cell nutrient availability that cause nutrient stress in T. gondii , inducing TgMSH-1-mediated autophagy. Although monensin can have effects on mammalian cells, including vesicle transport [29], lysosomal pH [26], and mitochondrial damage [30], these effects occur at drug concentrations hundreds to thousands times greater than the monensin concentration used in this study. Further research will be necessary to determine precisely how monensin activates autophagy in T. gondii .…”

Monensin Induced Suicidal Erythrocyte Death

“…Thus, even though monensin leads to cell swelling, it does not trigger necrosis at the lower concentrations and shorter incubation times. At higher concentrations and extended exposure times, however, monensin is expected to trigger hemolysis and thus necrosis [22,23].…”

“…In nucleated cells, Na + entry and subsequent cell swelling may be elicited by monensin (rumensin), a well known Na + ionophore, which thus stimulates necrosis rather than apoptosis [22,23]. The effect of monensin may be due to mitochondrial damage [23] and/or weakening of the antioxidative defence [24]. Monensin intoxication leads to severe rhabdomyolysis and acute renal failure with ultimate death of the patients [22,25].…”

Novel Insights into the Interplay between Apoptosis and Autophagy

“…Monensin causes an accumulation of early forms of autophagic vacuoles and blocks the swelling of lysosomes seen in the presence of methylamine. Incubation with monensin at higher concentrations (10 and 100  μ M) resulted in severe mitochondrial damage and marked dilatation of the Golgi apparatus and rough ER cisternae [83]. Interruption of microtubules with microtubule destabilizing nocodazole impairs the conversion of LC3-I to LC3-II but does not block the degradation of LC3-II-associated autophagosomes.…”