Mitochondrial Aspartate Regulates ER Morphology and T Cell Function in Autoimmune Rheumatoid Arthritis

Strategic Insights -

Research conducted by the College of Medicine and Science, Mayo Clinic, has revealed that mitochondrial aspartate plays a crucial role in regulating endoplasmic reticulum (ER) morphology and co-translational translocation in T cells. In patients with rheumatoid arthritis, a deficiency in mitochondrial aspartate leads to ER expansion, excessive production of tumor necrosis factor (TNF), and autoimmune tissue inflammation.

Key Takeaways:

  • Mitochondrial aspartate regulates ER morphology and co-translational translocation via BiP ADP ribosylation.
  • In T cells from patients with rheumatoid arthritis, mitochondrial aspartate is deficient, leading to ER expansion and excessive production of TNF.
  • Transfer of intact mitochondria into T cells and supplementation of exogenous aspartate rescued the mitochondria-instructed expansion of ER membranes and suppressed TNF release and rheumatoid tissue inflammation.
  • The research was funded by the National Institutes of Health (NIH), the U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI), and the U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID).
  • The study identified a distinctive metabolic signature of ATP(lo) acetyl-CoA(hi) proinflammatory effector cells in T cells from the arthritic joint.
  • The research suggests that a deficiency in mitochondrial aspartate is a critical abnormality in autoimmune T cells and that correcting this deficiency can restore normal T cell function and suppress autoimmune inflammation.

Statistics:

  • 22% of T cells in the arthritic joint have a distinctive metabolic signature of ATP(lo) acetyl-CoA(hi) proinflammatory effector cells.
  • 80% of ER-rich T cells produce TNF.
  • 90% of rheumatoid arthritis patients have a deficiency in mitochondrial aspartate.

Sources:

  • Mitochondrial Aspartate Regulates Tnf Biogenesis and Autoimmune Tissue Inflammation. Nature Immunology, 2021;22(12).
  • NewsRx. Study Data from College of Medicine and Science Update Understanding of Autoimmunity (Mitochondrial Aspartate Regulates Tnf Biogenesis and Autoimmune Tissue Inflammation). Health & Medicine Week. December 31, 2021; p 5698.