Ganguly 2022 MitoFit

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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. β€” 2022-11-22 published in Bioenerg Commun 2022.14.

Β» MitoFit Preprints 2022.13.v2.

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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) MitoFit Prep


Version 2 (v2) 2022-11-10
Version 1 (v1) 2022-04-19 Β»Link to all versionsΒ«

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 Β΅M) 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).

β€’ Keywords: rotenone, mitochondria, ferroptosis, reactive oxygen species, neurodegeneration β€’ Bioblast editor: Tindle-Solomon L, Cecatto C β€’ O2k-Network Lab: IN Haldia Chakrabarti S

Author reviewer discussion

Author reviewer dicussions pdf
Reviewer comments leading from MitoFit Preprint version 1 to version 2

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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