Mitochondrial ACSS1 regulates the oncometabolite 2-hydroxyglutarate and De Novo Pyrimidine biosynthesis under nutrient-deprived conditions in lymphoma
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The mitochondrial Acetyl-CoA synthetase short-chain family member 1 (ACSS1) converts acetate, an energy source in nutrient-deprived conditions1,2, to mitochondrial acetyl-CoA. However, the specific mechanism behind this process remains unknown. Here, we show that ACSS1 is overexpressed in patients with mantle cell lymphoma (MCL), diffuse large B cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL), and Ibrutinib (IBR)-resistant cell lines. The mitochondrial stress test showed reduced oxygen consumption in ACSS1 knockdown (KD) cell lines. 13C-acetate stable isotope tracing revealed that ACSS1 knockdown (KD) in MCL cell lines attenuates the flux of mitochondrial acetate to acetyl-CoA, acetylcarnitine, and TCA cycle intermediates, including glutamine and aspartate, which are precursors for de novo pyrimidine synthesis. Consistently, there was a decrease in the labeling of glutamate, aspartate, dihydroorotate, and orotate pools in KD cell lines. Pathway analysis revealed the enrichment of de novo pyrimidine synthesis metabolites and depleting ACSS1 impaired cell growth and potential vulnerability of IBR-resistant MCL cells. Further, we discovered that acetate was used to synthesize 2-hydroxyglutarate in an ACSS1-dependent manner. These results highlight a metabolic phenotype in MCL cells, showing their ability to metabolize acetate in nutrient-deprived conditions and provide new insights into the role of ACSS1 in cancer metabolism.
