Phosphofructokinase deficiency impairs atp generation, autophagy, and redox balance in rheumatoid arthritis T cells

Zhen Yang, Hiroshi Fujii, Shalini V. Mohan, Jorg J. Goronzy, Cornelia M. Weyand

Research output: Contribution to journalArticle

149 Citations (Scopus)

Abstract

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, apoptosissensitive, and prone to undergo senescence.

Original languageEnglish
Pages (from-to)2119-2134
Number of pages16
JournalJournal of Experimental Medicine
Volume210
Issue number10
DOIs
Publication statusPublished - 2013

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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