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MTFP1 (mitochondrial fission process 1), an inner mitochondrial membrane protein, plays a crucial role in mitochondrial fission to maintain mitochondrial morphology. Our study found that MTFP1 contains a LIR (LC3-interacting region) to interact with MAP1LC3B (microtubule-associated protein 1 light chain 3 beta) and serves as a mitophagy receptor to eliminate damaged mitochondria. Interestingly, mutation of MTFP1 LIR motif (MTFP1mLIR) inhibits this interaction, decreasing mitophagy in oral cancer cells. Moreover, knockdown of PRKN (parkin RBR E3 ubiquitin protein ligase) or PINK1 (PTEN-induced kinase 1) abolished mitophagy in MTFP1-overexpressing oral cancer cells. In this setting, we observed that MTFP1mLIR-expressing cells display a decrease in TOMM20 (translocase of outer mitochondrial membrane 20) levels without affecting those of COX4 (cytochrome c oxidase subunit 4). In contrast, loss of PRKN or PINK1 caused inhibition of both TOMM20 and COX4 degradation in MTFP1mLIR-expressing cells exposed to cellular stress, suggesting that PRKN may activate the rupture of outer mitochondrial membrane in MTFP1-overexpressing cells for effective mitophagy. We also observed that MTFP1 is beneficial to oral cancer cell survival exposed to anticancer drugs, such as cisplatin, through mitophagy, since inhibition of MTFP1-dependent mitophagy induced cell death. Thus, targeting MTFP1-associated mitophagy could represent a strategy for oral cancer therapy. Abbreviations:  BBC3/PUMA, BCL2 binding component 3; BCL2L13, BCL2 like 13; BINIP3L, BCL2 interacting protein 3 like; BNIP3, BCL2 interacting protein 3; CCCP, Carbonyl cyanide m-chlorophenylhydrazone; COX4, cytochrome c oxidase subunit 4; DNM1L, dynamin 1 like;FKBP8, FKBP prolyl isomerase 8; FIS1, fission, mitochondrial 1; FUNDC1, FUN14 domain containing 1; LIR, LC3 interacting region; MTFP1, mitochondrial fission process 1; PHB2, prohibitin 2; PI3K, Phosphatidylinositol 3-kinase; PRKN, Parkin RBR E3 ubiquitin protein ligase; PINK1, PTEN induced kinase 1; TOMM20, translocase of outer mitochondrial membrane 20

MTFP1 is a mitophagy receptor that operates in PINK1/PRKN-dependent mitophagy and promotes oral cancer cell survival