Abstract: Objective: To explore the mechanism of mitochondrial fission regulator 1 (MTFR1)-mediated mitochondrial fission involved in the malignant biological behavior of colon cancer. Methods: The expression of MTFR1 in colon cancer and its association with colon cancer prognosis were analyzed using the Gepia database.The human colon cancer cell line Lovo cells were divided into vector group (Vector),MTFR1 overexpression plasmid group (MTFR1) or MTFR1 knockdown group (sh-MTFR1),and control group (sh-NC).MTFR1 in cells was detected by quantitative real-time PCR.Cell migration was assessed by Transwell assay,and mitochondrial interconnectivity in cells was detected by MitoTracker Red staining.The protein expressions of ERK1/2 and peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α) were detected by Western blotting. Results: Gepia analysis showed that higher MTFR1 RNA expression levels were observed in colon adenocarcinoma tissues (P<0.01),and elevated MTFR1 expression levels predicted poor prognosis in colon adenocarcinoma patients (P<0.01).Compared with the Vector group,the number of Lovo cell metastasis and invasion in the MTFR1 group increased significantly (P<0.01 and P<0.05) and the length of mitochondrial branches decreased significantly (P<0.05).Compared with sh-NC group,the number of Lovo cell metastasis and invasion in sh-MTFR1 group decreased significantly (P<0.01) and the length of mitochondrial branch increased significantly (P<0.05).In addition,compared with the Vector group,both p-ERK1/2 and PGC-1α were up-regulated in the MTFR1 group (P<0.05).With increasing concentration of PD0325901,phosphorylation-dependent inhibition of p-ERK1/2 (P<0.01),and PGC-1α gradual decrease(P<0.01) were observed in Lovo cells overexpressing MTFR1. Conclusions: MTFR1-mediated mitochondrial fission is involved in the malignant biological behavior of colon cancer.This effect is attributed at least in part to ERK1/2-PGC-1α pathway activation.