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The mitochondrial pyruvate carrier regulates antitumor function and memory T cell differentiation

ABSTRACT: The mitochondrial pyruvate carrier regulates antitumor function and memory T cell differentiation

PROVIDER: PRJNA765936 | ENA |

REPOSITORIES: ENA

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The mitochondrial pyruvate carrier regulates antitumor function and memory T cell differentiation

Project description:Effector CD8+ T cells engage glycolysis for both lactate fermentation and pyruvate oxidation, the latter requiring the mitochondrial pyruvate carrier (MPC). How mitochondrial pyruvate metabolism impacts T cell function and fate, remains incompletely understood. We found that genetic deletion of MPC drives CD8+ T cell differentiation towards a memory phenotype. Metabolic flexibility induced by MPC inhibition in a nutrient-rich environment allowed for increased acetyl-coenzyme-A production by glutamine and fatty acid oxidation. This correlated with histone acetylation and chromatin accessibility on pro-memory genes. However, in a nutrient-deprived tumor microenvironment, MPC is essential for sustaining lactate oxidation that limits the metabolic suppression of CD8+ T cell anti-tumor function. To optimally translate these findings, we used a small molecule MPC inhibitor to imprint a stable memory phenotype during chimeric antigen receptor (CAR) T manufacturing, and demonstrated that infusing metabolically conditioned MPC WT CAR T cells resulted in superior and long-lasting anti-tumor activity.

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Mitochondrial Pyruvate Carrier 1 (MPC1) enforces T cell homeostasis by enabling pyruvate oxidation in the mitochondria

Project description:The transporter which uptakes pyruvate into the mitochondria during pyruvate oxidation, called the Mitochondrial Pyruvate Carrier (MPC), was only recently identified. While the MPC has been studied in a variety of cell types, including cancer cells and stem cells, very little is known about the importance of MPC in immune cells. Here, we delete MPC from hematopoietic cells and measure its impact on T cell gene expression.

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Loss of the mitochondrial pyruvate carrier promotes stem cell gene expression in colon adenomas.

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Mitochondrial carrier homolog 2 (MTCH2) regulates the differentiation of AML cells by controlling pyruvate entry into the mitochondria, nuclear localization of pyruvate dehydrogenase complex and H3 and H4 histone acetylation

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ATAC-sequencing of primary basal-derived mouse prostate organoids treated with vehicle, the mitochondrial pyruvate carrier inhibitor UK5099, or lactate supplementation

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Mitochondrial Pyruvate Carrier 1 (MPC1) enforces T cell homeostasis by enabling pyruvate oxidation in the mitochondria

Project description:Mitochondrial Pyruvate Carrier 1 (MPC1) enforces T cell homeostasis by enabling pyruvate oxidation in the mitochondria

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Mitochondrial carrier homolog 2 (MTCH2) is necessary for AML survival

Project description:Through a CRISPR screen to identify mitochondrial genes necessary for the growth of AML cells, we identified the mitochondrial outer membrane protein MTCH2 (Mitochondrial Carrier Homolog 2). In AML, knockdown of MTCH2 decreased growth, reduced engraftment potential of stem cells and induced differentiation. Inhibiting MTCH2 altered in AML cells increased nuclear pyruvate and pyruvate dehydrogenase that induced histone acetylation and subsequently promoted the differentiation of AML cells. Thus, we have defined a new mechanism by which mitochondria and metabolism regulate AML stem cells and gene expression.

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RNA sequencing of PTEN,Rb1 double knockout (DKO) mouse prostate organoids treated with vehicle or the small molecule mitochondrial pyruvate carrier (MPC) inhibitor UK5099

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Loss of the mitochondrial pyruvate carrier promotes stem cell gene expression in colon adenomas.

Project description:Loss of the mitochondrial pyruvate carrier promotes stem cell gene expression in colon adenomas.

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