The role of the Bcl-2 family in the regulation of outer mitochondrial membrane permeability

Abstract

Mitochondria are well known as sites of electron transport and generators of cellular ATP. Mitochondria also appear to be sites of cell survival regulation. In the process of programmed cell death, mediators of apoptosis can be released from mitochondria through disruptions in the outer mitochondrial membrane; these mediators then participate in the activation of caspases and of DNA degradation. Thus the regulation of outer mitochondrial membrane integrity is an important control point for apoptosis. The Bcl-2 family is made up of outer mitochondrial membrane proteins that can regulate cell survival, but the mechanisms by which Bcl-2 family proteins act remain controversial. Most metabolites are permeant to the outer membrane through the voltage dependent anion channel (VDAC), and Bcl-2 family proteins appear to be able to regulate VDAC function. In addition, many Bcl-2 family proteins can form channels in vitro, and some pro-apoptotic members may form multimeric channels large enough to release apoptosis promoting proteins from the intermembrane space. Alternatively, Bcl-2 family proteins have been hypothesized to coordinate the permeability of both the outer and inner mitochondrial membranes through the permeability transition (PT) pore. Increasing evidence suggests that alterations in cellular metabolism can lead to pro-apoptotic changes, including changes in intracellular pH, redox potential and ion transport. By regulating mitochondrial membrane physiology, Bcl-2 proteins also affect mitochondrial energy generation, and thus influence cellular bioenergetics.

Protective Effects of Glycyrrhizin against .BETA.2-Adrenergic Receptor Agonist-Induced Receptor Internalization and Cell Apoptosis

“…49,50) It was reported that changes in the ratio of proapoptotic and antiapoptotic members of the Bcl-2 family, rather than the absolute expression level of any single Bcl-2 member protein, could determine apoptotic sensitivity. 51) In the present study, we found that treatment with glycyrrhizin increased ratio of Bcl-2/Bax (Fig. 10).…”

Resistance to apoptosis, increased growth potential, and altered gene expression in cells that survived genotoxic hexavalent chromium [Cr(VI)] exposure

“…Alterations in VDAC function lead to the mitochondrial membrane permeability transition, which results in the release of the inter-membrane space components into the cytosol (reviewed in [83][84][85][86]). Our studies have verified that release of cytochrome c from the mitochondria is the point of no return for Cr(VI)-induced apoptosis, which can be inhibited by cyclosporin A [87].…”

The N-Terminal Domain of Bcl-xL Reversibly Binds Membranes in a pH-Dependent Manner

“…K x is the partition coefficient for the protonated Bclx L ΔTM to partition into the lipid vesicles. This framework has four assumptions: (i) only protonated Bcl-x L ΔTM [protein(0) above] binds to the lipid vesicles, (ii) membrane-bound protein is not involved in the protonation-deprotonation equilibrium, (iii) the protonation sites are equal and independent, and (iv) no significant contribution arises from the protonationdeprotonation equilibria of the ionizable lipid headgroups in this pH range (3)(4)(5)(6)(7)(8). This last assumption is well-founded (32).…”