Project description:T helper 17 (Th17) cells are a distinct subset of CD4+ T cells necessary for maintaining gut homeostasis and have prominent roles in autoimmunity and inflammation1. Th17 cells have unique metabolic features, including a stem cell-like signature2,3 and reliance on mitochondrial respiratory chain function and tricarboxylic acid (TCA) cycle to coordinate metabolic and epigenetic remodeling4,5. Dynamic changes in mitochondrial membrane morphology are key to sustain organelle function6. However, it remains unclear whether mitochondrial membrane remodeling orchestrates metabolic and differentiation events in Th17 cells. Here we demonstrate that mitochondrial membrane fusion and tight cristae organization are required for Th17 cell function (i.e. cytokine expression) but dispensable in other T cell subsets. We find that Th17 cells rely on mitochondrial fusion as a result of their low metabolic activity. Thus, lowering metabolic activity in other T cell subsets by nutrient restriction was sufficient to increase reliance on mitochondrial fusion for effector function. Transcriptional, proteomic, and metabolomic profiling identified the serine/threonine kinase liver associated kinase B1 (LKB1) as an essential node coupling mitochondrial function to cytokine expression in T cells. By genetic and metabolomic approaches, we demonstrate that LKB1 regulates IL-17A expression by controlling TCA cycle metabolites and transcriptional remodeling. Th-17 cell-specific deletion of optic atrophy 1 (OPA1), a protein involved in mitochondrial inner membrane fusion and cristae organization, reduced autoimmune pathogenesis in a mouse model of multiple sclerosis, while additional deletion of LKB1 restored disease. Our findings highlight distinct mitochondrial requirements in CD4+ T cells, identify mitochondrial membrane fusion as a major determinant of Th17 responses, and reveal LKB1 as a sensor of mitochondrial integrity that links mitochondrial cues to effector programs in Th17 cells.

			Action	DRS
	20250519_145546_MZ_CF_MZAWAW_AW-159_Heart_Uniprotmouse10088_MZtimsTOFHT_MaxLFQ_NoImputing.sne	Other
	20250520_135156_MZ_CF_MZAWAW_AW-159_Heart_Uniprotmouse10088_MZtimsTOFHT_MaxLFQ_GlobalImputing.sne	Other
	20250520_135156_MZ_CF_MZAWAW_AW-159_Heart_Uniprotmouse10088_MZtimsTOFHT_MaxLFQ_GlobalImputing_Report_Protein_Pivot.tsv	Tabular
	20250521_111204_MZ_CF_MZAWAW_AW-159_Heart_Uniprotmouse10088_MZtimsTOFHT_MaxLFQ_NoImputing_Report_Protein_Pivot.tsv	Tabular
	MZ_CF_MZAWAW_AW-159_Heart_500ngr_iRT_44min_dia_Sample01_2025-05-17_8024.d.zip	Other

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MitoSAM-dependent lipoylation controls postnatal heart development via metabolic remodeling

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