SRGAP2 controls colorectal cancer chemosensitivity via regulation of mitochondrial complex I activity

Mitochondrial respiration and metabolism play an important role in the occurrence and development of colorectal cancer (CRC). In this study, we identified a functional pool of SLIT–ROBO Rho GTPase-activating protein 2 (SRGAP2) in the mitochondria of CRC cells as an important regulator of CRC chemosensitivity. We found that SRGAP2 levels were increased in CRC cells in comparison to normal colorectal cells. Loss of mitochondrial SRGAP2 led to significant decrease in mitochondrial respiration and strongly sensitized the CRC cells to chemotherapy drugs. Mechanistically, SRGAP2 physically interacts with mitochondrial complex I and positively modulates its activity. In particular, chemosensitization upon SRGAP2 loss was phenocopied by the treatment of complex I inhibitor. Thus, our results demonstrate that SRGAP2 functions as a key regulator of CRC chemosensitivity, identifying SRGAP2 as a promising therapeutic target to enhance the efficacy of chemotherapy in CRC.