2. Academic Validation
  3. High glucose-induced mitophagy accelerates premature aging of T cells in patients with rheumatoid arthritis

High glucose-induced mitophagy accelerates premature aging of T cells in patients with rheumatoid arthritis

  • Clin Rheumatol. 2025 Nov 20. doi: 10.1007/s10067-025-07815-z.
Jiaxin Lei 1 2,  Yongao Wen 3,  Lingyi Li 4 5,  Huiyan Ji 6 7
Affiliations

Affiliations

  • 1 Institutes of Biology and Medical Sciences, The Fourth Affiliated Hospital of Soochow University, Suzhou Medical College of Soochow University, Soochow University, Suzhou, Jiangsu, 215123, China. [email protected].
  • 2 Jiangsu Key Laboratory of Infection and Immunity, MOE Key Laboratory of Geriatric Diseases and Immunology, Soochow University, Suzhou, China. [email protected].
  • 3 Suzhou Foreign Language School, Suzhou, China.
  • 4 Institutes of Biology and Medical Sciences, The Fourth Affiliated Hospital of Soochow University, Suzhou Medical College of Soochow University, Soochow University, Suzhou, Jiangsu, 215123, China.
  • 5 Jiangsu Key Laboratory of Infection and Immunity, MOE Key Laboratory of Geriatric Diseases and Immunology, Soochow University, Suzhou, China.
  • 6 Institutes of Biology and Medical Sciences, The Fourth Affiliated Hospital of Soochow University, Suzhou Medical College of Soochow University, Soochow University, Suzhou, Jiangsu, 215123, China. [email protected].
  • 7 Jiangsu Key Laboratory of Infection and Immunity, MOE Key Laboratory of Geriatric Diseases and Immunology, Soochow University, Suzhou, China. [email protected].
PMID: 41261244 DOI: 10.1007/s10067-025-07815-z
Abstract

Objectives: Premature T cell aging, marked by telomere shortening and cell cycle arrest, plays a key role in the pathogenesis of rheumatoid arthritis (RA). Growing evidence suggests that high glucose-induced metabolic dysfunction critically regulates both cellular aging and RA progression. This study explores how high glucose exacerbates T cell aging, providing novel insights into the mechanisms underlying RA development.

Methods: CD4+ T cells isolated from RA patients and healthy controls, along with HC-derived CD4+ T cells cultured in either low- or high-glucose conditions, were analyzed for aging markers including telomere length and cell cycle regulatory proteins to evaluate glucose-dependent effects. Cellular metabolism was characterized through: (1) glucose uptake (2-NBDG assay), (2) mitochondrial respiration (oxygen consumption rate analysis), and (3) Mitophagy activity (DRP1/PINK1/parkin protein levels by immunoblotting). Mechanistic studies employed both pharmacological interventions (2-DG for glycolysis inhibition, succinyl phosphonate for OGDH inhibition, Mdivi-1 for DRP1 blockade) and genetic manipulation (DRP1 knockdown and overexpression) to delineate the roles of glucose metabolism and DRP1-mediated Mitophagy in T cell aging.

Results: RA-derived CD4+ T cells exhibited increased glucose uptake and mitochondrial dysfunction. Enhanced Mitophagy accelerated T-cell aging in RA. Mechanistically, high glucose promoted succinate accumulation, a key TCA cycle metabolite, leading to succinylation of Zinc Finger Protein 76 (ZNF76), a DRP1 transcription factor. This activated ZNF76, upregulating DRP1-mediated Mitophagy and driving T-cell aging. Targeting glucose uptake and Mitophagy may thus reverse T-cell dysfunction and ameliorate RA severity.

Conclusion: Elevated Mitophagy induced by high glucose represents a cell-autonomous mechanism driving premature T cell aging in RA, presenting a novel therapeutic avenue for disease management. Key Points • Dysregulated glucose metabolism is a key driver of T cell aging and RA pathogenesis. • High glucose exposure triggers metabolic reprogramming, leading to succinate accumulation. • Accumulated succinate induces ZNF76 succinylation and enhances DRP1-dependent mitophagy-a phenotype consistently observed in CD4+ T cells from RA patients. • DRP1-dependent Mitophagy drives T cell aging in RA.

Keywords

CD4+ T cells; DRP1; Rheumatoid Arthritis; Succinylation.

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