Autoimmune T cells in rheumatoid arthritis (RA) have a defect in mitochondrial oxygen consumption and ATP production. Here, we identified suppression of the GDP-forming β subunit of succinate-CoA ligase (SUCLG2) as an underlying abnormality. SUCLG2-deficient T cells reverted the tricarboxylic acid (TCA) cycle from the oxidative to the reductive direction, accumulated α-ketoglutarate, citrate, and acetyl-CoA (AcCoA), and differentiated into pro-inflammatory effector cells. In AcCoA^hi RA T cells, tubulin acetylation stabilized the microtubule cytoskeleton and positioned mitochondria in a perinuclear location, resulting in cellular polarization, uropod formation, T cell migration, and tissue invasion. In the tissue, SUCLG2-deficient T cells functioned as cytokine-producing effector cells and were hyperinflammatory, a defect correctable by replenishing the enzyme. Preventing T cell tubulin acetylation by tubulin acetyltransferase knockdown was sufficient to inhibit synovitis. These data link mitochondrial failure and AcCoA oversupply to autoimmune tissue inflammation.

类风湿性关节炎 (RA) 中的自身免疫性 T 细胞在线粒体耗氧量和 ATP 产生方面存在缺陷。在这里，我们确定抑制琥珀酸辅酶 A 连接酶 (SUCLG2) 的 GDP 形成 β 亚基是潜在的异常。SUCLG2 缺陷型 T 细胞将三羧酸 (TCA) 循环从氧化方向逆转为还原方向，积累 α-酮戊二酸、柠檬酸和乙酰辅酶 A (AcCoA)，并分化为促炎效应细胞。在AcCoA^喜RA T 细胞、微管蛋白乙酰化稳定了微管细胞骨架并将线粒体定位在核周位置，导致细胞极化、尾足类动物形成、T 细胞迁移和组织侵袭。在组织中，SUCLG2 缺陷的 T 细胞作为产生细胞因子的效应细胞发挥作用，并且是高炎症性的，这种缺陷可以通过补充酶来纠正。通过微管蛋白乙酰转移酶敲低防止 T 细胞微管蛋白乙酰化足以抑制滑膜炎。这些数据将线粒体衰竭和 AcCoA 供过于求与自身免疫组织炎症联系起来。