Succinyl-CoA Ligase Deficiency in Pro-inflammatory and Tissue-Invasive T Cells

• Published in: Cell metabolism Vol. 32; no. 6; pp. 967 - 980.e5
• Main Authors: Wu, Bowen, Qiu, Jingtao, Zhao, Tuantuan V, Wang, Yanan, Maeda, Toshihisa, Goronzy, Isabel N, Akiyama, Mitsuhiro, Ohtsuki, Shozo, Jin, Ke, Tian, Lu, Goronzy, Jörg J, Weyand, Cornelia M
• Format: Journal Article
• Language: English
• Published: United States 01.12.2020
• Subjects: acetylation; microtubule; uropod; citrate; autoimmunity; T cell; mitochondria; acetyl-CoA; tissue invasion; alph-ketoglutarate
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2020.10.025

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 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.