Mitochondrial ACSS1 Links Acetate Metabolism to Pyrimidine Biosynthesis in Nutrient-Stressed B-Cell Lymphomas
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Acetate serves as an alternative carbon source in nutrient-limited tumors, yet its role in supporting nucleotide biosynthesis remains poorly understood. Here, we identify the mitochondrial enzyme ACSS1 as a key metabolic driver in mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), and chronic lymphocytic leukemia (CLL). ACSS1 is frequently overexpressed and catalyzes the conversion of acetate to mitochondrial acetyl-CoA, sustaining oxidative metabolism and biosynthesis under nutrient stress. Genetic silencing of ACSS1 impairs mitochondrial respiration and disrupts acetate incorporation into acetyl-CoA, TCA cycle intermediates, glutamate, and aspartate, while markedly reducing 13 C-acetate labeling of dihydroorotate and orotate, intermediates in de novo pyrimidine synthesis. Untargeted metabolomics reveal enrichment of pyrimidine biosynthesis pathways in ACSS1-high cells. Notably, acetate or uridine supplementation rescues the growth of ACSS1-deficient cells, confirming a functional link between acetate metabolism and nucleotide synthesis. These findings uncover an ACSS1-dependent mitochondrial acetate–pyrimidine axis that sustains lymphoma growth and represents a potential therapeutic vulnerability.
Statement of significance
This study identifies ACSS1 as a key metabolic vulnerability in mantle cell lymphoma (MCL), linking mitochondrial acetate metabolism to de novo pyrimidine biosynthesis. We demonstrate that ACSS1 is frequently overexpressed in MCL and is essential for converting acetate into mitochondrial acetyl-CoA, sustaining TCA cycle activity, nucleotide production, and cell survival under nutrient stress. Loss of ACSS1 disrupts this acetate–pyrimidine axis, impairing mitochondrial metabolism and reducing lymphoma cell viability. Importantly, acetate or uridine supplementation rescues the growth of ACSS1-deficient cells, highlighting a direct metabolic link with therapeutic potential. These findings reveal a novel mechanism of metabolic adaptation in MCL and suggest that targeting ACSS1-mediated acetate utilization could offer a new therapeutic approach for treating aggressive, metabolically stressed lymphomas.
