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CD4+ T cell differentiation requires metabolic reprogramming to fulfil the bioenergetic demands of proliferation and effector function, and enforce specific transcriptional programmes1-3. 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 (TH17) 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 TH17 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 landscape5,7. Our multi-omics approach revealed that the serine/threonine kinase liver-associated kinase B1 (LKB1) couples mitochondrial function to cytokine expression in TH17 cells by regulating TCA cycle metabolism and transcriptional remodelling. Mitochondrial membrane disruption activates LKB1, which restrains 1L-17 expression. LKB1 deletion restores 1L-17 expression in TH17 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 TH17 cell function, and uncover LKB1 as a sensor linking mitochondrial cues to effector programmes in TH17 cells.
Mitochondrial function is linked to mitochondrial membrane morphology4. Remodelling of the inner mitochondrial membrane and outer mitochondrial membrane (OMM) is coordinated by several GTPases that control the opposing and dynamic processes of mitochondrial fusion and fission8 (division). Mitochondrial membrane rearrangements sustain mitochondrial function by altering cristae architecture, respiratory complex organization, mtDNA metabolism and organelle distribution8. Mitochondrial membrane remodelling is especially relevant during metabolic or environmental fluctuations9 and diverse signalling pathways regulate pro-fusion and pro-fission proteins to shape mitochondrial structure and support metabolic adaptations. Conversely, mitochondria and mitochondrial membrane remodelling participate in intracellular signalling events, modulating transcription and epigenetics during cell differentiation, immune responses, tumour angiogenesis and cell death4,10,11. Given the role of mitochondrial membrane dynamics and metabolism in cell function, we investigated how mitochondrial membrane morphology affects CD4+ T cell differentiation.
TH17 cells have fused mitochondria
We polarized naive CD4+ T (TN) cells expressing a mitochondria-targeted fluorescent...