Mitochondrial Pyrophosphatase PPA2 Promotes Mitochondrial Fission and Mitophagy to Inhibit Apoptosis During Cisplatin Treatment in Oral Squamous Cell Carcinoma

Abstract

Oral Squamous cell carcinoma is one of predominant cancer in India. Mitophagy, the selective elimination of damaged mitochondria, strongly impacts the progression of diverse cancer types, including oral cancer, by favoring cell survival within the tumor microenvironment. The mitochondrial pyrophosphatase or inorganic pyrophosphatase 2 (PPA2) is a mitochondrial matrix localized protein known for maintaining mitochondrial membrane potential. We have investigated the expression of PPA2 in different grades of oral cancer and found that the PPA2 expression increased in a grade-dependent manner as well as PPA2 expression was found to be more in oral cancer tissue than in normal oral tissue. Furthermore, results showed that the cell proliferation and colonyforming potential were increased in PPA2 overexpressed cells, whereas it was reduced in PPA2 knocked down condition. The role of PPA2 in apoptosis resistance was examined, and over-expression of PPA2 rescued Cal33 cells from cisplatin-induced apoptosis, whereas the knockdown of PPA2 exaggerates the same. Then we investigated the role of PPA2 in mitophagy and found that increased mitochondrial fission and mitophagy was observed in PPA2 overexpressed Cal33 cell following CCCP treatment, whereas mitochondrial fission and mitophagy abrogates in PPA2 knocked down Cal33 cells. PPA2 over-expression also promotes the mitochondrial translocation of DRP1 and regulates mitochondrial fission in a DRP1-dependent manner. Further, the PPA2-mediated apoptosis resistance is mitophagy dependent as PPA2 overexpression fails to protect against CDDP-induced apoptosis in mitophagy-deficient conditions. In conclusion, PPA2 is over-expressed in oral cancer tissue and protects against cisplatin-induced apoptosis in a mitophagydependent manner