An LKB1-mitochondria axis controls T_H17 effector function

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 processes⁴, including respiration and tricarboxylic acid (TCA) cycle metabolism⁵, 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_H17) cells have fused mitochondria with tight cristae. T cell-specific deletion of optic atrophy 1 (OPA1), which regulates inner mitochondrial membrane fusion and cristae morphology⁶, revealed that T_H17 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_H17 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_H17 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_H17 cell function, and uncover LKB1 as a sensor linking mitochondrial cues to effector programmes in T_H17 cells.