Ganguly 2022 MitoFit

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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, Cecatto C O2k-Network Lab: IN Haldia Chakrabarti S


Labels: Pathology: Parkinson's  Stress:Cell death, Oxidative stress;RONS 

Tissue;cell: Nervous system, Neuroblastoma 

Enzyme: Complex I, Complex III  Regulation: ATP production, Inhibitor, mt-Membrane potential 



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