Bcl-2 prevents apoptotic mitochondrial dysfunction by regulating proton flux

AUTOR(ES)
FONTE

The National Academy of Sciences

RESUMO

We and others have recently shown that loss of the mitochondrial membrane potential (Δψ) precedes apoptosis and chemical-hypoxia-induced necrosis and is prevented by Bcl-2. In this report, we examine the biochemical mechanism used by Bcl-2 to prevent Δψ loss, as determined with mitochondria isolated from a cell line overexpressing human Bcl-2 or from livers of Bcl-2 transgenic mice. Although Bcl-2 had no effect on the respiration rate of isolated mitochondria, it prevented both Δψ 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 Δψ, suggesting that the functional target of Bcl-2 is regulation of Δψ but not PT. Bcl-2 also maintained Δψ in the presence of the protonophore SF6847, which induces proton influx, suggesting that Bcl-2 regulates ion transport to maintain Δψ. Although treatment with SF6847 in the absence of Ca2+ caused massive H+ influx in control mitochondria, the presence of Bcl-2 induced H+ efflux after transient H+ influx. In this case, Bcl-2 did not enhance K+ efflux. Furthermore, Bcl-2 enhanced H+ efflux but not K+ flux after treatment of mitochondria with Ca2+ or tert-butyl hydroperoxide. These results suggest that Bcl-2 maintains Δψ by enhancing H+ efflux in the presence of Δψ-loss-inducing stimuli.

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