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

Abstract

Autoimmune Tcells 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 Tcells 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 AcCoAhi RA Tcells, tubulin acetylation stabilized the microtubule cytoskeleton and positioned mitochondria in a perinuclear location, resulting in cellular polarization, uropod formation, Tcell migration, and tissue invasion. In the tissue, SUCLG2-deficient Tcells functioned as cytokine-producing effector cells and were hyperinflammatory, a defect correctable by replenishing the enzyme. Preventing Tcell tubulin acetylation by tubulin acetyltransferase knockdown was sufficient to inhibit synovitis. These data link mitochondrial failure and AcCoA oversupply to autoimmune tissue inflammation.