An LKB1–mitochondria axis controls T H 17 effector function
Nature(2022)
Abstract
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.
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Key words
Energy metabolism,Lymphocyte differentiation,Science,Humanities and Social Sciences,multidisciplinary
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