Secretory Mitophagy Exports p53: A new pro-tumor survival mechanism.

Abstract

Mitochondrial dysfunction is associated with many life-threatening illnesses, from Parkinson’s disease to malignant cancers. Cells remove damaged, aged, or stressed mitochondria through a process called mitophagy. Mitophagy initiation is sensed by the molecule PINK1 triggering the isolation and packaging of the damaged mitochondrial segment for degradation through the lysosome. Our team discovered a secretory form of mitophagy where the mitochondrial segments are packaged and exported outside of the cell within extracellular vesicles (EV) derived from the interstitial fluid of breast cancer tumors. Moreover, it has been discovered that the tumor suppressor molecule p53 interacts and becomes phosphorylated by PINK1 ultimately enhancing mitophagy and carcinogenesis. Pancreatic cancer (PC) p53 mutations are associated with tumor aggressiveness. Decreased levels of intercellular p53 leads to increased genetic instability, higher tumor growth rate, and survival. We hypothesize that PC exports p53 via secretory mitophagy. We stimulated mitophagy in PANC1 and BXPC3 cells and found that phospho-p53 was elevated in small EVs. These EVs were also PINK1+.  Exported p53 was also identified within breast tumor interstitial fluid. These results support the hypothesis that exported p53 aids tumor progression particularly when the tumor cells are subjected to therapeutic oxidative stress. Altogether these results constitute a novel diagnostic method of non-invasively determining the mitochondrial health and p53 status within PC.