Physiological Methylmalonic Acid Contributes to Cell Growth via Mitochondrial Dysfunction in Colorectal Cancer Cell Spheroids

Abstract

Methylmalonic acid (MMA) is a small molecule produced during the metabolism of branched-chain amino acids. Recently, it was reported that the blood concentration of MMA increased with age and that it also promoted lung cancer metastasis. However, little is known about how it affects cancers other than lung cancer. In this study, we examined the influences of MMA on colorectal cancer cell spheroids. We found that MMA promoted proliferation of colorectal cancer spheroids in a glutamine-dependent manner at physiological concentrations; MMA induced mitochondrial reactive oxygen species generation, which in turn affected the promotion of cell growth. Methylmalonic acid treatment also induced a metabolic shift to the glycolytic system. These results suggest that physiological concentrations of MMA may promote cancer cell proliferation by decreasing mitochondrial function and inducing a metabolic shift, and add new insights into the effect of aging on cancer.