Loss of mitochondrial aconitase promotes colorectal cancer progression via SCD1-mediated lipid remodeling.

Abstract Objective Mitochondrial aconitase (ACO2) is an essential enzyme that bridges the TCA cycle and lipid metabolism. However, its role in cancer development remains to be elucidated. The metabolic subtype of colorectal cancer (CRC) was recently established. We investigated ACO2's potential role in CRC progression through mediating metabolic alterations. Methods We compared the mRNA and protein expression of ACO2 between paired CRC and non-tumor tissues from 353 patients. Correlations between ACO2 levels and clinicopathological features were examined. CRC cell lines with knockdown or overexpression of ACO2 were analyzed for cell proliferation and tumor growth. Metabolomics and stable isotope tracing analyses were used to study the metabolic alterations induced by loss of ACO2. Results ACO2 decreased in >50% of CRC samples compared with matched non-tumor tissues. Decreased ACO2 levels correlated with advanced disease stage (P  Conclusions Our study demonstrated that the rewiring metabolic pathway maintains CRC survival during compromised TCA cycles and characterized the therapeutic vulnerability of lipid desaturation in a meaningful subset of CRC with mitochondrial dysfunction.