Mitochondrial aspartate regulates TNF biogenesis and autoimmune tissue inflammation
Open accessAbstract
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.
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In vitro transfer of healthy mitochondria to CD4+ T cells from RA patients can restore aspartate metabolism and decrease TNF production compared with untreated controls.
“Moreover, the in vitro transfer of healthy mitochondria to CD4+ T cells from patients with RA can restore aspartate metabolism and decrease the production of TNF, compared with untreated controls286–288.”
From The role of mitochondria in rheumatic diseases (2022) · cites this paper as [288]
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Research works printed but not linked: 3
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Cited by
Sorted by citations
The role of mitochondria in rheumatic diseases
Becker, Y. L. C., Duvvuri, B., Fortin, P. R., Lood, C., & Boilard, E. (2022) · Nature Reviews Rheumatology · doi:10.1038/s41584-022-00834-z · Cited by 81 · see citing works
- Authors
- Wu, B., Zhao, T. V., Jin, K., Hu, Z., Abdel, M. P., Warrington, K. J., Goronzy, J. J., & Weyand, C. M.
- Affiliations
- Mayo Clinic (US)
- Corresponding author
- Weyand, Cornelia M.
- ORCID
- Venue
- Nature Immunology
- Published
- 2021-11-22
- Volume
- 22
- Issue
- 12
- Pages
- 1551-1562
- ISSN
- 1529-2908 (ISSN-L)
- 1529-2916
- PMC
- PMC8756813
- OpenAlex
- W3216944928
- Cited by
- 141
- References
- 68
- Citations by year
- 2026: 25 · 2025: 37 · 2024: 30 · 2023: 24 · 2022: 24 · 2021: 1
- FWCI
- 14.88
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Immunology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (R01HL142068, P01HL129941)
- U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (R01AI108906)
- U.S. Department of Health & Human Services | National Institutes of Health (R01AR042527)
- Topics
- Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Keywords
- rheumatoid arthritis, T cell metabolism, endoplasmic reticulum expansion, cotranslational translocation, NAD+ regeneration, mitochondrial transfer
- MeSH terms
- ADP-Ribosylation, Endoplasmic Reticulum Chaperone BiP, Animals, Arthritis, Rheumatoid, Aspartic Acid, Cells, Cultured, Endoplasmic Reticulum, Female, Humans, Male, Mitochondria, Synovial Membrane, Tumor Necrosis Factor-alpha, CD4-Positive T-Lymphocytes, Autoimmunity, Case-Control Studies, Adoptive Transfer, Mice
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