The apoptotic cascade unfolds when failing mitochondria leak cytochrome c (cyt c), which then binds to and oligomerizes the caspase activator called Apaf1. Previous experiments showed that low concentrations of nucleotides, in the form of ATP or dATP, were needed for cyt c to bind to Apaf1.
The new results show that higher concentrations of ATP prevent apoptosis. At these higher levels, which match those found in healthy cells, the nucleotides bound up cyt c, thus preventing it from attaching to its Apaf1 partner.
The inhibition was overcome by artificially increasing cyt c levels or decreasing nucleotide concentrations. In healthy cells, sufficient nucleotide levels probably prevent small mitochondrial leaks from triggering death by sequestering the cyt c. Only with persistent cell death signals or unusually low nucleotide levels would cyt c overcome the nucleotide brake.
Low nucleotide levels, the group also shows, are induced by apoptotic signals and anticancer drugs such as etoposide. ATP production probably drops as a result of mitochondrial injury, but what causes the levels of the other nucleotides to drop is unclear as yet.