¹Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA

Correspondence: JA Cidlowski, Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, National Institutes of Health, P. O. Box 12233, 111. T. W. Alexander Drive, Research Triangle Park, NC 27709, USA. Tel: (919) 541-1564; Fax: (919) 541-1367; E-mail: cidlows1@mail.nih.gov

Received 21 January 2009; Revised 20 May 2009; Accepted 4 June 2009; Published online 7 August 2009.

Abstract

Apoptosis is a conserved homeostatic process critical for organ and tissue morphogenesis, development, and senescence. This form of programmed cell death also participates in the etiology of several human diseases including cancer, neurodegenerative, and autoimmune disorders. Although the signaling pathways leading to the progression of apoptosis have been extensively characterized, recent studies highlight the regulatory role of changes in the intracellular milieu (permissive apoptotic environment) in the efficient activation of the cell death machinery. In particular, glutathione (GSH) depletion is a common feature of apoptotic cell death triggered by a wide variety of stimuli including activation of death receptors, stress, environmental agents, and cytotoxic drugs. Although initial studies suggested that GSH depletion was only a byproduct of oxidative stress generated during cell death, recent discoveries suggest that GSH depletion and post-translational modifications of proteins through glutathionylation are critical regulators of apoptosis. Here, we reformulate these emerging paradigms into our current understanding of cell death mechanisms.