# p53 Interacts with VDAC1, Modulating Its Expression Level and Oligomeric State to Activate Apoptosis

## TL;DR

This paper shows that the p53 protein interacts with VDAC1, a mitochondrial channel, to control its levels and structure, promoting cell death.

## Contribution

The study reveals that p53 directly binds and modulates VDAC1, linking p53's mitochondrial role to apoptosis regulation.

## Key findings

- p53 directly binds to VDAC1, reducing its channel conductance.
- p53 increases VDAC1 expression and induces oligomerization even without stress.
- VDAC1 oligomerization is a key step in p53-mediated apoptosis.

## Abstract

The p53 tumor suppressor, a key transcription factor, acts as a cellular stress sensor that regulates hundreds of genes involved in responses to DNA damage, oxidative stress, and ischemia. Through these actions, p53 can arrest cell cycle, initiate DNA repair, or trigger cell death. In addition to its nuclear functions, p53 can translocate to mitochondria to promote apoptosis. Studies using isolated mitochondria have suggested that p53 drives the voltage-dependent anion channel (VDAC1) into high molecular mass complexes to mediate apoptosis. VDAC1 is a central regulator of cellular energy production and metabolism and also an essential player in apoptosis, induced by various apoptotic stimuli and stress conditions. We previously demonstrated that VDAC1 oligomerization, induced by various apoptosis stimuli and stress conditions, forms a large pore that enables cytochrome c release from mitochondria, thereby promoting apoptotic cell death. In this study, we show that p53 interacts with VDAC1, modulates its expression levels, and promotes VDAC1 oligomerization-dependent apoptosis. Using purified proteins, we found that p53 directly binds VDAC1, as revealed by microscale thermophoresis and by experiments using bilayer-reconstituted VDAC1, in which p53 reduced VDAC1 channel conductance. Furthermore, overexpression of p53 in p53-null cells or in cells expressing wild-type p53 increased VDAC1 expression and induced VDAC1 oligomerization even in the absence of apoptotic stimuli. Together, these findings identify VDAC1 as a direct p53 target whose expression, oligomerization, and pro-apoptotic activity are regulated by p53. They also reinforce the central role of VDAC1 oligomerization in apoptosis.