BCL-2 PREVENTS APOPTOTIC MITOCHONDRIAL DYSFUNCTION BY REGULATING PROTON FLUX

Citation
S. Shimizu et al., BCL-2 PREVENTS APOPTOTIC MITOCHONDRIAL DYSFUNCTION BY REGULATING PROTON FLUX, Proceedings of the National Academy of Sciences of the United Statesof America, 95(4), 1998, pp. 1455-1459
Citations number
39
Categorie Soggetti
Multidisciplinary Sciences
ISSN journal
00278424
Volume
95
Issue
4
Year of publication
1998
Pages
1455 - 1459
Database
ISI
SICI code
0027-8424(1998)95:4<1455:BPAMDB>2.0.ZU;2-V
Abstract
We and others have recently shown that lolls of the mitochondrial memb rane potential (Delta psi) precedes apoptosis and chemical-hypoxia-ind uced necrosis and is prevented by Bcl-2. In this report, we examine th e biochemical mechanism used by Bcl-2 to prevent Delta psi loss, as de termined with mitochondria isolated from a cell line overexpressing hu man Bcl-2 or from livers of Bcl-2 transgenic mice, Although Bcl-2 had no effect on the respiration rate of isolated mitochondria, it prevent ed both Delta psi loss and the permeability transition (PT) induced by various reagents, including Ca2+, H2O2, and tert-butyl hydroperoxide, Even under conditions that did not allow PT, Bcl-2 maintained Delta p si, suggesting that the functional target of Bcl-2 is regulation of De lta psi but not PT. Bcl-2 also maintained Delta psi in the presence of the protonophore SF6847, which induces proton influx, suggesting that Bcl-2 regulates ion transport to maintain Delta psi. Although treatme nt with SF6847 in the absence of Ca2+ caused massive H+ influx in cont rol mitochondria, the presence of Bcl-2 induced H+ efflux after transi ent H+ influx, In this case, Bcl-2 did not enhance K+ efflux, Furtherm ore, Bcl-2 enhanced H+ efflux but not K+ flux after treatment of mitoc hondria with Ca2+ or tert-butyl hydroperoxide, These results suggest t hat Bcl-2 maintains Delta psi by enhancing H+ efflux in the presence l af Delta psi-loss-inducing stimuli.