Changes in intramitochondrial and cytosolic pH: early events that modulate caspase activation during apoptosis.

摘要: Mitochondria trigger apoptosis by releasing caspase activators, including cytochrome c (cytC). Here we show, using a pH-sensitive green fluorescent protein (GFP), that mitochondria-dependent apoptotic stimuli (such as Bax, staurosporine and ultraviolet irradiation) induce rapid, Bcl-2-inhibitable mitochondrial alkalinization cytosol acidification, followed cytC release, activation swelling depolarization. These events are not induced mitochondria-independent stimuli, such Fas. Activation of cytosolic caspases in vitro is minimal at neutral pH, but maximal acidic indicating mitochondria-induced acidification the may be important for activation; this finding supported results obtained from cells protonophores. Cytosol release suppressed oligomycin, FoF1-ATPase/H +-pump inhibitor, inhibitors. Ectopic expression Bax wild-type, FoF1/H+-pump-deficient, yeast similarly matrix alkalinization, cell death. findings indicate mitochondria-mediated alteration intracellular pH an early event regulates pathway apoptosis.