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
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.