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

ABSTRACT: 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.

SUBMITTER: Wu B

PROVIDER: S-EPMC7755381 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Succinyl-CoA ligase deficiency: a mitochondrial hepatoencephalomyopathy.

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2018-07-11 | MSV000082599 | MassIVE

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