The coordinate release of cytochrome c during apoptosis is rapid, complete and kinetically invariant

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Abstract
Release of cytochrome c from mitochondria triggers activation of caspase proteases and death of a cell by apoptosis. However, the mechanism and kinetics of cytochrome c release remain unknown. Here we study this event by using green fluorescent protein (GFP)-tagged cytochrome c, and find that the release of cytochrome-c–GFP always precedes exposure of phosphatidylserine and the loss of plasma-membrane integrity — characteristics of apoptotic cells. Once initiated, the release of cytochrome- c–GFP continues until all of the protein is released from all mitochondria in individual cells, within about 5 minutes, regardless of the type or strength of stimulus or the time elapsed since the stimulus was applied. Temperatures ranging from 24 °C to 37 °C do not change the duration of release, and nor does the addition of caspase inhibitors. Further, we find that the electron-transport chain can maintain the mitochondrial transmembrane potential even after cytochrome c has been released.