Polyamines directly induce release of cytochrome c from heart mitochondria

Cytochrome c release from mitochondria to the cytosol represents a critical step in apoptosis, correlated to the activation of the caspase cascade. In this report, we show that addition of micromolar concentrations of polyami nes to isolated rat heart mitochondria induces the release of cytochrome c. Spermine, which is effective at concentrations of 10-100 mu M, is more pot ent than spermidine, whereas putrescine has no effect up to 1 mM. The relea se of cytochrome c caused by spermine is a rapid, saturable and selective p rocess that is independent of mitochondria damage. Spermine, unlike polylys ine, is able to release a discrete amount of cytochrome c from intact, func tional mitochondria. The cytochrome c-releasing power of spermine is not af fected by cyclosporin A, differently from the effect of permeability transi tion inducers. In a cardiac cell-free model of apoptosis, the latent caspas e activity of cytosolic extracts from cardiomyocytes could be activated by cytochrome c released from spermine-treated heart mitochondria. These data indicate a novel mechanism of cytochrome c release from the mitochondrion, and suggest that prolonged and sustained elevation of polyamines, character istic of some pathologies such as heart hypertrophy, could be involved in t he development of apoptosis.