Mitochondria, oxygen metabolism and the regulation of cell death

Abstract

Factors required for cell survival include molecular oxygen and various antioxidants in the appropriate proportions. A perturbation of this delicate intracellular redox (reduction–oxidation) balance may result in oxidative cell injury and subsequent apoptotic or necrotic cell death, depending on the severity of the insult. In the current paradigm for apoptotic cell death, the activity of a family of caspases orchestrates the multiple downstream events that comprise apoptosis. In TNF- and Fas-mediated apoptosis, the proteolytic cascade is triggered directly by pro-caspase-8 binding to the activated plasma membrane receptor complex. In other forms of apoptosis, the mechanisms of activation of the proteolytic cascade are less well established but may involve other proteases, or factors released from mitochondria. Such as cytochrome c, which serves to activate dormant caspases in the cytosol. One of the most reproducible inducers of apoptosis is mild oxidative stress. Oxidants can promote caspase activation by either upregulation of the Fas system or by stimulating cytochrome c release from miroclondria. Conversely, a variety of anti-oxidants are known to inhibit the death process. In fact, the cellular redox status can directly effect virtually all the known components of the apoptotic machinery, including proteases, transcription factors, and phospholipid signaling. This chapter will address mechanisms by which this redox modulation of apoptotic components occurs.