SNAP23 deficiency triggers Trim21 mitochondrial translocation to suppress TFAM-mediated oxidative metabolism and drive chemoresistance in colorectal cancer.

Chemoresistance is a major cause of poor prognosis in colorectal cancer (CRC), and its molecular mechanisms urgently need elucidation. The cell membrane protein SNAP23, known for its role in vesicle secretion, also promotes CRC cell growth. However, its role in tumor chemotherapy remains unclear. This study reveals a novel function of SNAP23, independent of vesicle transport, mediating crosstalk between the cell membrane and mitochondria to influence the chemotherapeutic response to oxaliplatin (OXA). Mechanistically, SNAP23 arrests Trim21, causing its accumulation near the cell membrane and away from mitochondria. This reduces the ubiquitination and degradation of the mitochondrial transcription factor A (TFAM), enhancing mitochondrial oxidative metabolism and increasing oxidative phosphorylation (OXPHOS) and reactive oxygen species (ROS) production, ultimately heightening the sensitivity of cancer cells to OXA. The unique regulatory function of SNAP23 in the chemotherapeutic response of colorectal cancer may provide a potential target for chemotherapy sensitization.