GSH depletion, protein S-glutathionylation and mitochondrial transmembrane potential hyperpolarization are early events in initiation of cell death induced by a mixture of isothiazolinones in HL60 cells
| Autor: | Anna Di Stefano, Francesca Cherubini Di Simplicio, Simona Frosali, Anna Ettorre, Paolo Di Simplicio, Alessandra Leonini, Raffaella Priora |
|---|---|
| Rok vydání: | 2006 |
| Předmět: |
Programmed cell death
Necrosis S-glutathionylation HL-60 Cells Apoptosis Glucosephosphate Dehydrogenase Membrane Potentials chemistry.chemical_compound medicine Humans Disulfides S-Glutathionylation Cytotoxicity Molecular Biology Chromatography High Pressure Liquid Caspase Glutathione Transferase chemistry.chemical_classification Glutathione Peroxidase Reactive oxygen species Dose-Response Relationship Drug biology Preservatives Pharmaceutical Mitochondrial transmembrane potential Glutathione Cell Biology Flow Cytometry Caspase 9 Mitochondria Cell biology Enzyme Activation Kinetics Thiazoles Glutathione Reductase chemistry Caspases biology.protein Spectrophotometry Ultraviolet medicine.symptom |
| Zdroj: | Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1763(2):214-225 |
| ISSN: | 0167-4889 |
| DOI: | 10.1016/j.bbamcr.2005.12.012 |
| Popis: | We recently described that brief exposure of HL60 cells to a mixture of 5-chloro-2-methyl-4-isothiazolin-3-one (CMI) and 2-methyl-4-isothiazolin-3-one (MI) induces apoptosis at low concentrations (0.001-0.01%) and necrosis at higher concentrations (0.05-0.1%). In this study, we show that glutathione (GSH) depletion, reactive oxygen species generation, hyperpolarization of mitochondrial transmembrane potential (DeltaPsim) and formation of protein-GSH mixed disulphides (S-glutathionylation) are early molecular events that precede the induction of cell death by CMI/MI. When the cells exhibit common signs of apoptosis, they show activation of caspase-9, reduction of DeltaPsim and, more importantly, decreased protein S-glutathionylation. In contrast, necrosis is associated with severe mitochondrial damage and maximal protein S-glutathionylation. CMI/MI-induced cytotoxicity is also accompanied by decreased activity of GSH-related enzymes. Pre-incubation with L-buthionine-(S,R)-sulfoximine (BSO) clearly switches the mode of cell death from apoptosis to necrosis at 0.01% CMI/MI. Collectively, these results demonstrate that CMI/MI alters the redox status of HL60 cells, and the extent and kinetics of GSH depletion and S-glutathionylation appear to determine whether cells undergo apoptosis or necrosis. We hypothesize that S-glutathionylation of certain thiol groups accompanied by GSH depletion plays a critical role in the molecular mechanism of CMI/MI cytotoxicity. |
| Databáze: | OpenAIRE |
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