Phosphofructokinase deficiency impairs ATP generation, autophagy, and redox balance in rheumatoid arthritis T cells
Open accessAbstract
In the HLA class II–associated autoimmune syndrome rheumatoid arthritis (RA), CD4 T cells are critical drivers of pathogenic immunity. We have explored the metabolic activity of RA T cells and its impact on cellular function and fate. Naive CD4 T cells from RA patients failed to metabolize equal amounts of glucose as age-matched control cells, generated less intracellular ATP, and were apoptosis-susceptible. The defect was attributed to insufficient induction of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), a regulatory and rate-limiting glycolytic enzyme known to cause the Warburg effect. Forced overexpression of PFKFB3 in RA T cells restored glycolytic flux and protected cells from excessive apoptosis. Hypoglycolytic RA T cells diverted glucose toward the pentose phosphate pathway, generated more NADPH, and consumed intracellular reactive oxygen species (ROS). PFKFB3 deficiency also constrained the ability of RA T cells to resort to autophagy as an alternative means to provide energy and biosynthetic precursor molecules. PFKFB3 silencing and overexpression identified a novel extraglycolytic role of the enzyme in autophagy regulation. In essence, T cells in RA patients, even those in a naive state, are metabolically reprogrammed with insufficient up-regulation of the glycolytic activator PFKFB3, rendering them energy-deprived, ROS- and autophagy-deficient, apoptosis-sensitive, and prone to undergo senescence.
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Due to reduced production of glycolytic enzyme PFKFB3 and upregulation of G6PD, RA T cells shunt glucose toward the pentose phosphate pathway, switching from catabolic to synthetic metabolism.
“Due to reduced production of the glycolytic enzyme PFKFB3 and the upregulation of G6PD, RA T cells shunt glucose toward the pentose phosphate pathway, switching from a catabolic to a synthetic metabolism”
From Successful and Maladaptive T Cell Aging (2017) · cites this paper as Yang et al., 2013
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- Authors
- Yang, Z., Fujii, H., Mohan, S. V., Goronzy, J. J., & Weyand, C. M.
- Affiliations
- Stanford Medicine (US)
- Tohoku University (JP)
- Division of Immunology & Rheumatology, Stanford University School of Medicine, Stanford, CA 94305 1
- Corresponding author
- Weyand, Cornelia M.
- Venue
- Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2013-09-16
- Volume
- 210
- Issue
- 10
- Pages
- 2119-2134
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC3782046
- OpenAlex
- W2122624605
- Cited by
- 334
- References
- 79
- Citations by year
- 2026: 15 · 2025: 25 · 2024: 26 · 2023: 19 · 2022: 32 · 2021: 33 · 2020: 33 · 2019: 33 · 2018: 31 · 2017: 32 · 2016: 30 · 2015: 14 · 2014: 8 · 2013: 3
- FWCI
- 15.00
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- cc-by-nc-sa
- Locations
- The Journal of Experimental Medicine (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (R01AG045779)
- National Heart, Lung, and Blood Institute (P01HL058000, HL-058000)
- National Eye Institute (EY011916, R01EY011916)
- National Institute of Allergy and Infectious Diseases (R01AI044142, AI090019, R01AI108906, R56AI044142, U19AI090019, AI057266, AI044142, R01AI108891, U19AI057266)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR042547, R01AR042527, R01AR042547)
- Topics
- Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- rheumatoid arthritis, CD4+ T cells, PFKFB3, phosphofructokinase deficiency, glycolytic metabolism, Warburg effect, autophagy, reactive oxygen species, redox homeostasis, apoptosis, NADPH, pentose phosphate pathway, T cell metabolic reprogramming, cellular senescence
- MeSH terms
- Adenosine Triphosphate, Adult, Arthritis, Rheumatoid, Autophagy, Female, Glucose, Glycolysis, Humans, Male, Middle Aged, Oxidation-Reduction, Pentose Phosphate Pathway, CD4-Positive T-Lymphocytes, Gene Expression, Case-Control Studies, T-Lymphocyte Subsets, Apoptosis, Gene Silencing, Phosphofructokinase-2
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