Redox mechanisms of cytoprotection by Bcl-2

Abstract

Bcl-2 is a multifunctional protein that protects against cell death induced by a wide variety of stimuli. The best characterized antiapoptotic Bcl-2 mechanism of action involves direct binding to proapoptotic proteins, e.g., Bax, inhibiting their ability to oligomerize and form pores in the mitochondrial outer membrane, through which soluble mitochondrial proapoptotic proteins, e.g., cytochrome c, are released into the cytosol. Bcl-2 also exerts antiapoptotic and antinecrotic effects that are mediated by its influence on cellular redox state and apparently independent of its interaction with proapoptotic proteins. Bcl-2 expression increases cell resistance to oxidants, augments the expression of intracellular defenses against reactive oxygen species, and may affect mitochondrial generation of superoxide radicals and hydrogen peroxide. This review focuses on the protective effects of Bcl-2 related to changes in mitochondrial redox capacity.

FIG. 1. Protection by Bcl-2 against cell death mediated by both anti-Bax and antioxidant mechanisms

CytC, cytochrome c.

FIG. 2. Bcl-2(+) mitochondria in digitonin (dig)-permeabilized PC12 cells are more resistant to membrane potential (Δψ) decreases (upper panels) and NAD(P)H oxidation (lower panels) promoted by tert-butyl hydroperoxide (t-bOOH), added at the concentrations indicated

Adapted from reference , with permission.

FIG. 3. Mitochondria isolated from GT1-7, PC12, and MM 8226 cells (as shown) were incubated in the presence of NADH-linked substrates and oligomycin, under experimental conditions similar to those described in references and

H₂O₂ release was measured by following Amplex red oxidation in the presence of horseradish peroxidase, as described in references and . Numbers in parentheses indicate H₂O₂ release rates, in nmol/min/mg of protein.