Open AccessMitochondrial aspartate regulates TNF biogenesis and autoimmune tissue inflammation
Author(s) -
Bowen Wu,
Tuantuan Zhao,
Ke Jin,
ZhaoLan Hu,
Matthew P. Abdel,
Kenneth J. Warrington,
Jörg J. Goronzy,
Cornelia M. Weyand
Publication year - 2021
Publication title -
nature immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 9.074
H-Index - 388
eISSN - 1529-2916
pISSN - 1529-2908
DOI - 10.1038/s41590-021-01065-2
Subject(s) - proinflammatory cytokine , inflammation , microbiology and biotechnology , tumor necrosis factor alpha , mitochondrion , endoplasmic reticulum , biology , unfolded protein response , mitochondrial biogenesis , cytokine , chemistry , immunology
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.