Ganguly 2022 MitoFit

Ganguly U, Bir A, Chakrabarti S (2022) Cytotoxicity of mitochondrial Complex I inhibitor rotenone: a complex interplay of cell death pathways. 2022.13. https://doi.org/10.26124/mitofit:2022-0013

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Cytotoxicity of mitochondrial Complex I inhibitor rotenone: a complex interplay of cell death pathways

Ganguly Upasana, Bir Aritri, Chakrabarti Sasanka (2022-04-19) MitoFit Prep

Abstract: Ferroptosis has been identified as a type of regulated cell death triggered by a diverse set of agents with implications in various diseases like cancer and neurodegenerative diseases. Ferroptosis is iron-dependent and accompanied by an accumulation of reactive oxygen species (ROS) and lipid oxidation products, a depletion of reduced glutathione, mitochondrial morphological alterations and the rupture of cell membrane; the process is inhibited by specific antioxidants like ferrostatin-1 and liproxstatin-1 and by other general antioxidants like the iron-chelator deferoxamine, vitamin E and N-acetylcysteine. However, the mechanism of cell death in ferroptosis subsequent to the accumulation of ROS and lipid oxidation products is not clearly established. We show here that the classical mitochondrial Complex I inhibitor rotenone (0.5 µM) causes death of SH-SY5Y cells (a human neuroblastoma cell line) over a period of 48 h accompanied by mitochondrial membrane depolarization and intracellular ATP depletion. This is associated with an intracellular accumulation of ROS and the lipid oxidation product malondialdehyde or MDA and a decrease in reduced glutathione content. All these processes are inhibited very conspicuously by specific inhibitors of ferroptosis such as ferrostatin-1 and liproxstatin-1. However, the decrease in Complex I activity upon rotenone-treatment of SH-SY5Y cells is not significantly recovered by ferrostatin-1 and liproxstatin-1. When the rotenone-treated cells are analyzed morphologically by Hoechst 33258 and propidium iodide (PI) staining, a mixed picture is noticed with densely fluorescent and condensed nuclei indicating apoptotic death of cells (Hoechst 33258) and also significant numbers of necrotic cells with bright red nuclei (PI staining). • Keywords: rotenone, mitochondria, ferroptosis, reactive oxygen species, neurodegeneration • Bioblast editor: Tindle-Solomon L • O2k-Network Lab: IN Haldia Chakrabarti S

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Bioblast 2022