p53, PML, and P2X7 interplay at MAMs: dictating cellular fate and therapeutic outcomes

Abstract:

Mitochondria-associated membranes (MAMs) are ER-mitochondria contact sites where the tumor suppressors p53 and PML regulate Ca² signaling, autophagy, and inflammation. Our data show that P2X7R, traditionally a plasma membrane receptor, is also present at MAMs, modulating Ca² flux and inflammatory signaling. Loss of p53 or PML leads to P2X7R accumulation at MAMs, hyperactivating NLRP3 inflammasome signaling in macrophages and sustaining autophagy in tumor cells, promoting therapy resistance and tumor progression. These findings reveal an unrecognized role of P2X7R at the ER-mitochondria interface, driving cancer adaptation and immune evasion.

Hypothesis

We hypothesize that p53, PML, and P2X7R form a functional axis at MAMs, regulating Ca² homeostasis, autophagy, and inflammation. In p53/PML-deficient tumors, P2X7R accumulation at MAMs may form a pore- like structure at the ER, facilitating Ca² transfer to mitochondria and challenging IP3R3's role. This P2X7- mediated Ca² flux sustains tumor survival, metabolic adaptation, and immune suppression by activating autophagy and NLRP3-dependent inflammation. Targeting P2X7R and its downstream pathways could restore MAM homeostasis, re-sensitize tumors, and modulate immune responses.