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Glutathione depletion enforces the mitochondrial permeability transition and causes cell death in HL60 cells that overexpress Bcl‐2
Author(s) -
Armstrong Jeffrey S.,
Jones Dean P.
Publication year - 2002
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.02-0097fje
Subject(s) - mitochondrial permeability transition pore , adenine nucleotide translocator , cytochrome c , reactive oxygen species , microbiology and biotechnology , glutathione , mitochondrion , programmed cell death , respiratory chain , apoptosis , mitochondrial respiratory chain , chemistry , mitochondrial ros , biology , biochemistry , enzyme
Bcl‐2, a protein that blocks apoptosis by inhibiting the mitochondrial permeability transition (MPT) and release of cytochrome c appears to affect normal mitochondrial function by altering electron flow and increasing rates of reactive oxygen species (ROS) production. In this study, we show that glutathione (GSH) depletion induces ROS production and selective toxicity in HL60 cells that overexpress Bcl‐2 compared with neomycin vector control cells. Toxicity was mediated by the MPT because it was blocked with the adenine nucleotide translocator (ANT) ligand bongkrekic acid and resulted in mitochondrial cytochrome c release, caspase 3 activation, and DNA fragmentation, indicating the involvement of an apoptotic pathway. Respiratory chain inhibitors stigmatellin and antimycin A, which inhibit Qo and Qi sites of respiratory chain complex III, respectively, blocked ROS production, preserved the redox state of protein thiols, and prevented cell death. These results indicate that in the absence of GSH, endogenous ROS generated at respiratory complex III induce MPT independently of Bcl‐2. The results also suggest a new model for MPT in which the central pore protein ANT is regulated by adenine nucleotide and the activity of mitochondrial respiratory complex III.