p53 can kill cells by transcription-dependent means, and it can enhance this effect by inducing death by a transcription-independent mitochondrial pathway. Reporting in Molecular Cell, Ute Moll's group show that p53 does this by translocating to mitochondria, and inducing permeabilization of the outer mitochondrial membrane (OMM) and the release of cytochrome c.

Previously, the authors saw that a fraction of p53 translocates rapidly to mitochondria after apoptotic stimuli (DNA damage and hypoxia) in malignant and immortal cells. So they γ-irradiated mouse thymocytes to see if this also occurs in primary cells. Within 1 h of treatment, p53 moved to the mitochondria.

By targeting p53 directly to mitochondria of p53-null cells and using several sensitive transcriptional assays, Moll's group could discount the involvement of p53's transactivation activity during the ensuing apoptosis.

Because p53 translocates to the surface of mitochondria, the authors looked for a link with the anti-apoptotic mediators Bcl2 and BclXL, which are anchored constitutively at the OMM, and found that p53 formed a specific complex with Bcl2 and BclXL.

Death-stimulus-induced mitochondrial translocation of p53 precedes the release of cytochrome c, and the authors next showed that purified p53 could release cytochrome c from mitochondria in a dose-dependent manner. It does this by forming inhibitory complexes with BclXL (which stabilizes the OMM) and by conformationally changing, and thereby indirectly activating, Bak and Bax proteins (which are the ultimate effectors of cytochrome c release).

The authors propose that p53, by moving rapidly to the mitochondria, effectively 'jump starts' and amplifies its slower-starting transcription-dependent effect on apoptosis. From a cancer aspect, some p53 mutants can't interact with BclXL to promote cytochrome c release, so mutations that are selected for during human tumorigenesis might represent 'double-hit' mutations that inhibit both the transcriptional and mitochondrial apoptotic activites of p53.