An LKB1-mitochondria axis controls T <subscript>H</subscript> 17 effector function.
In: Nature, Jg. 610 (2022-10-01), Heft 7932, S. 555-561
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Zugriff:
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.
(© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)
Titel: |
An LKB1-mitochondria axis controls T <subscript>H</subscript> 17 effector function.
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Autor/in / Beteiligte Person: | Baixauli, F ; Piletic, K ; Puleston, DJ ; Villa, M ; Field, CS ; Flachsmann, LJ ; Quintana, A ; Rana, N ; Edwards-Hicks, J ; Matsushita, M ; Stanczak, MA ; Grzes, KM ; Kabat, AM ; Fabri, M ; Caputa, G ; Kelly, B ; Corrado, M ; Musa, Y ; Duda, KJ ; Mittler, G ; O'Sullivan, D ; Sesaki, H ; Jenuwein, T ; Buescher, JM ; Pearce, EJ ; Sanin, DE ; Pearce, EL |
Zeitschrift: | Nature, Jg. 610 (2022-10-01), Heft 7932, S. 555-561 |
Veröffentlichung: | Basingstoke : Nature Publishing Group ; <i>Original Publication</i>: London, Macmillan Journals ltd., 2022 |
Medientyp: | academicJournal |
ISSN: | 1476-4687 (electronic) |
DOI: | 10.1038/s41586-022-05264-1 |
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