Universität zu Köln

Baixauli, Francesc ORCID: 0000-0002-9676-2901, Piletic, Klara, Puleston, Daniel J., Villa, Matteo ORCID: 0000-0003-2684-0596, Field, Cameron S., Flachsmann, Lea J., Quintana, Andrea, Rana, Nisha, Edwards-Hicks, Joy, Matsushita, Mai ORCID: 0000-0001-5693-461X, Stanczak, Michal A., Grzes, Katarzyna M., Kabat, Agnieszka M., Fabri, Mario, Caputa, George, Kelly, Beth, Corrado, Mauro, Musa, Yaarub, Duda, Katarzyna J., Mittler, Gerhard, O'Sullivan, David, Sesaki, Hiromi, Jenuwein, Thomas, Buescher, Joerg M., Pearce, Edward J., Sanin, David E. and Pearce, Erika L. (2022). An LKB1-mitochondria axis controls T(H)17 effector function. Nature, 610 (7932). S. 555 - 584. BERLIN: NATURE PORTFOLIO. ISSN 1476-4687

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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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Baixauli, Francesc UNSPECIFIED orcid.org/0000-0002-9676-2901 UNSPECIFIED Piletic, Klara UNSPECIFIED UNSPECIFIED UNSPECIFIED Puleston, Daniel J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Villa, Matteo UNSPECIFIED orcid.org/0000-0003-2684-0596 UNSPECIFIED Field, Cameron S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Flachsmann, Lea J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Quintana, Andrea UNSPECIFIED UNSPECIFIED UNSPECIFIED Rana, Nisha UNSPECIFIED UNSPECIFIED UNSPECIFIED Edwards-Hicks, Joy UNSPECIFIED UNSPECIFIED UNSPECIFIED Matsushita, Mai UNSPECIFIED orcid.org/0000-0001-5693-461X UNSPECIFIED Stanczak, Michal A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Grzes, Katarzyna M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kabat, Agnieszka M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Fabri, Mario UNSPECIFIED UNSPECIFIED UNSPECIFIED Caputa, George UNSPECIFIED UNSPECIFIED UNSPECIFIED Kelly, Beth UNSPECIFIED UNSPECIFIED UNSPECIFIED Corrado, Mauro UNSPECIFIED UNSPECIFIED UNSPECIFIED Musa, Yaarub UNSPECIFIED UNSPECIFIED UNSPECIFIED Duda, Katarzyna J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Mittler, Gerhard UNSPECIFIED UNSPECIFIED UNSPECIFIED O'Sullivan, David UNSPECIFIED UNSPECIFIED UNSPECIFIED Sesaki, Hiromi UNSPECIFIED UNSPECIFIED UNSPECIFIED Jenuwein, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED Buescher, Joerg M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Pearce, Edward J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Sanin, David E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Pearce, Erika L. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-677396
DOI:	10.1038/s41586-022-05264-1
Journal or Publication Title:	Nature
Volume:	610
Number:	7932
Page Range:	S. 555 - 584
Date:	2022
Publisher:	NATURE PORTFOLIO
Place of Publication:	BERLIN
ISSN:	1476-4687
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language T-CELLS; METABOLIC-CONTROL; REGULATORY T; TH17 CELLS; LKB1; FATE; MITOCHONDRIA; RESPIRATION; FUSION; CHAIN Multiple languages Multidisciplinary Sciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/67739