Transcriptomics analysis of colon tumors from PINK1 colon epithelial cell specific PINK1 knockout mice and wildtype controls

Mitophagy is a process by which a cell breaks down and destroys old, damaged, or abnormal mitochondria in its cytoplasm. PTEN-induced kinase 1 (PINK1) is a mitochondrial protein that mediates mitophagy. Our recent research suggests that PINK1 acts as a tumor suppressor in colorectal cancer (CRC) by modulating cellular metabolism and promoting cell death through p53 activation and reducing acetyl-CoA production. However, pharmacological modulating cellular metabolism is still challenging. To identify druggable targets in PINK1 deficient tumors, we performed an RNA-seq analysis in colon tumors from between Pink1-/-; Cdx2ERT2 ApcF/+ (KO) mice and Pink1+/+; Cdx2ERT2 ApcF/+ (WT) mice. By using Gene Set Enrichment Analysis (GSEA), we found transition metal ion transmembrane transporter activity and iron ion transmembrane transporter activity were enrich based on the Gene Ontology (GO) resource. Among these significantly changed iron ion transmembrane transporter genes, the most abundant gene Slc40a1 that encodes the iron efflux protein ferroportin was reduced, whereas the gene Slc25a28 encodes mitochondrial iron transporter 2 (Mitoferrin2, Mfrn2) was most increased in the colon tissues of KO mice. Further experiments confirmed that PINK1-deficiency can increase the accumulation of iron in the mitochondria, which may contribute to the development of colon tumors and provide a novel strategy for colon tumor therapy even with PINK1 loss