An LKB1-mitochondria axis controls T(H)17 effector function

Article

关键词: T-CELLS;    METABOLIC-CONTROL;    REGULATORY T;    TH17 CELLS;    LKB1;    FATE;    MITOCHONDRIA;    RESPIRATION;    FUSION;    CHAIN;   

DOI  :  10.1038/s41586-022-05264-1

来源: SCIE

【 摘 要 】

CD4(+) T cell differentiation requires metabolic reprogramming to fulfil the bioenergetic demands of proliferation and effector function, and enforce specific transcriptional programmes(1-3). Mitochondrial membrane dynamics sustains mitochondrial processes(4), including respiration and tricarboxylic acid (TCA) cycle metabolism(5), but whether mitochondrial membrane remodelling orchestrates CD4(+) T cell differentiation remains unclear. Here we show that unlike other CD4(+) T cell subsets, T helper 17 (T(H)17) cells have fused mitochondria with tight cristae. T cell-specific deletion of optic atrophy 1 (OPA1), which regulates inner mitochondrial membrane fusion and cristae morphology(6), revealed that T(H)17 cells require OPA1 for its control of the TCA cycle, rather than respiration. OPA1 deletion amplifies glutamine oxidation, leading to impaired NADH/NAD(+) balance and accumulation of TCA cycle metabolites and 2-hydroxyglutarate-a metabolite that influences the epigenetic landscape(5,7). Our multi-omics approach revealed that the serine/threonine kinase liver-associated kinase B1 (LKB1) couples mitochondrial function to cytokine expression in T(H)17 cells by regulating TCA cycle metabolism and transcriptional remodelling. Mitochondrial membrane disruption activates LKB1, which restrains IL-17 expression. LKB1 deletion restores IL-17 expression in T(H)17 cells with disrupted mitochondrial membranes, rectifying aberrant TCA cycle glutamine flux, balancing NADH/NAD(+) and preventing 2-hydroxyglutarate production from the promiscuous activity of the serine biosynthesis enzyme phosphoglycerate dehydrogenase (PHGDH). These findings identify OPA1 as a major determinant of T(H)17 cell function, and uncover LKB1 as a sensor linking mitochondrial cues to effector programmes in T(H)17 cells.

【 授权许可】

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