Journal Article

Mitochondrial aspartate regulates TNF biogenesis and autoimmune tissue inflammation

Goronzy, Jörg J., Jin, Ke, Weyand, Cornelia M., Zhao, Tuantuan V., Hu, Zhaolan, Abdel, Matthew P., Warrington, Ken J., Wu, Bowen

2021

Overview

Misdirected immunity gives rise to the autoimmune tissue inflammation of rheumatoid arthritis, in which excess production of the cytokine tumor necrosis factor (TNF) is a central pathogenic event. Mechanisms underlying the breakdown of self-tolerance are unclear, but T cells in the arthritic joint have a distinctive metabolic signature of ATP lo acetyl-CoA hi proinflammatory effector cells. Here we show that a deficiency in the production of mitochondrial aspartate is an important abnormality in these autoimmune T cells. Shortage of mitochondrial aspartate disrupted the regeneration of the metabolic cofactor nicotinamide adenine dinucleotide, causing ADP deribosylation of the endoplasmic reticulum (ER) sensor GRP78/BiP. As a result, ribosome-rich ER membranes expanded, promoting co-translational translocation and enhanced biogenesis of transmembrane TNF. ER rich T cells were the predominant TNF producers in the arthritic joint. Transfer of intact mitochondria into T cells, as well as supplementation of exogenous aspartate, rescued the mitochondria-instructed expansion of ER membranes and suppressed TNF release and rheumatoid tissue inflammation. 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, resulting in ER expansion and excessive production of the pro-inflammatory cytokine TNF.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/250/1619/554 / 631/250/38 / 692/699/249 / 692/699/249/1313/498 / Adenine / Adoptive Transfer / ADP-Ribosylation / Animals / Arthritis, Rheumatoid - genetics / Arthritis, Rheumatoid - immunology / Arthritis, Rheumatoid - metabolism / Arthritis, Rheumatoid - pathology / Aspartate / Aspartic Acid - metabolism / Autoimmunity / Biomedical and Life Sciences / Biomedicine / Biosynthesis / Case-Control Studies / CD4-Positive T-Lymphocytes - immunology / CD4-Positive T-Lymphocytes - metabolism / CD4-Positive T-Lymphocytes - transplantation / CD4-Positive T-Lymphocytes - ultrastructure / Cells, Cultured / Cytokines / Cytology / Development and progression / Effector cells / Endoplasmic reticulum / Endoplasmic Reticulum - immunology / Endoplasmic Reticulum - metabolism / Endoplasmic Reticulum - ultrastructure / Endoplasmic Reticulum Chaperone BiP - metabolism / Female / Health aspects / Humans / Immunological tolerance / Immunology / Infectious Diseases / Inflammation / Lymphocytes / Lymphocytes T / Male / Metabolism / Mice / Mitochondria / Mitochondria - immunology / Mitochondria - metabolism / Mitochondria - transplantation / Mitochondria - ultrastructure / NAD / Physiological aspects / Protein biosynthesis / Rheumatoid arthritis / Ribosylation / Supplements / Synovial Membrane - immunology / Synovial Membrane - metabolism / Synovial Membrane - ultrastructure / Translation / Translocation / Tumor necrosis factor / Tumor Necrosis Factor-alpha - biosynthesis / Tumor Necrosis Factor-alpha - genetics / Tumor necrosis factor-TNF