Permeabilization of the mitochondrial inner membrane during apoptosis: impact of the adenine nucleotide translocator

Abstract

Mitochondrial membrane permeabilization can be a rate limiting step of apoptotic as well as necrotic cell death. Permeabilization of the outer mitochondrial membrane (OM) and/or inner membrane (IM) is, at least in part, mediated by the permeability transition pore complex (PTPC). The PTPC is formed in the IM/OM contact site and contains the two most abundant IM and OM proteins, adenine nucleotide translocator (ANT, in the IM) and voltage-dependent anion channel (VDAC, in the OM), the matrix protein cyclophilin D, which can interact with ANT, as well as apoptosis-regulatory proteins from the Bax/Bcl-2 family. Here we discuss that ANT has two opposite functions. On the one hand, ANT is a vital, specific antiporter which accounts for the exchange of ATP and ADP on IM. On the other hand, ANT can form a non-specific pore, as this has been shown by electrophysiological characterization of purified ANT reconstituted into synthetic lipid bilayers or by measuring the permeabilization of proteoliposomes containing ANT. Pore formation by ANT is induced by a variety of different agents (e.g. Ca 2+ , atractyloside, thiol oxidation, the pro-apoptotic HIV-1 protein Vpr, etc.) and is enhanced by Bax and inhibited by Bcl-2, as well as by ADP. In isolated mitochondria, pore formation by ANT leads to an increase in IM permeability to solutes up to 1500 Da, swelling of the mitochondrial matrix, and OM permeabilization, presumably due to physical rupture of OM. Although alternative mechanisms of mitochondrial membrane permeabilization may exist, ANT emerges as a major player in the regulation of cell death.

Unconjugated bilirubin induces apoptosis in colon cancer cells by triggering mitochondrial depolarization

“…That bilirubin is capable of directly causing depolarization of isolated mitochondria, as has previously been proposed by Rodrigues et al, 64 is supported by our light-scattering and rhodamine fluorescence data. Our finding that bilirubin-induced large-amplitude swelling is not blocked by cyclosporin A, an established inhibitor of the mitochondrial PTP, 58,77 in conjunction with data from Rodrigues et al indicating that bilirubin alters mitochondrial lipid polarity, 23,78 further suggests that bilirubin is capable of exerting a direct effect on mitochondrial membrane integrity.…”

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].…”

BCL-2 in the crosshairs: tipping the balance of life and death

“…In order to overcome cell impermeability, cell penetrating peptides were synthesized by tagging the BH3 domain with moieties that facilitate uptake, including Antennapedia [119][120][121] and poly-D-arginine 57 amino-acid sequences, and fatty acids such as decanoic acid. 122 Despite their cell permeability, several drawbacks of these derivatized peptides include loss of a-helical structure, protease sensitivity, low cellular potency, and in certain circumstances apoptosis induction independent of BCL-2 targeting.…”