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.<Table Float="No" ID="Taba"> <tgroup cols="2"> <colspec align="left" colname="c1" colnum="1" /> <colspec align="left" colname="c2" colnum="2" /> <tbody> <row> <entry align="left" nameend="c2" namest="c1"> 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. </entry> </row> </tbody> </tgroup> </Table>

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

期刊论文
发表日期：

2025年11月20日

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Jiaxin Lei,
Yongao Wen,
Lingyi Li,
Huiyan Ji

摘要

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.