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A TFAP4-UBC9-SUMO1 axis orchestrates pathological mitochondrial hyperfission in diabetic complications

Zhiyu Jin1, Ying Jiang1,2, Dayun Tao2

  • 1Department of Cardiology, School of Medicine, South China University of Technology, Guangzhou, 510006, China.

Acta Diabetologica
|January 28, 2026
PubMed
Abstract

Insights

The TFAP4-UBC9-SUMO1 axis drives mitochondrial damage in diabetes by promoting excessive fission and mitophagy. This pathway offers a new therapeutic target for diabetic organ complications.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Diabetology

Background:

  • Mitochondrial dysfunction is central to diabetic organ damage, characterized by excessive fission and mitophagy.
  • The upstream genetic regulators initiating these mitochondrial changes in diabetes are not fully understood.

Purpose of the Study:

  • To investigate the role of the TFAP4-UBC9-SUMO1 regulatory axis in orchestrating mitochondrial breakdown in diabetic tissues.

Main Methods:

  • Transcriptomic analysis of four independent cohorts (GEO datasets: GSE1009, GSE4745, GSE6880, GSE133598) from diabetic renal and cardiac tissues.
  • Integration of differential expression analysis with Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA) for functional enrichment.

Main Results:

  • A synchronized stress response was observed across all datasets, not isolated gene changes.
  • Diabetic tissues showed upregulated pathways in protein SUMOylation, mitochondrial organization, and ER stress.
  • Evidence indicated chronic endoplasmic reticulum protein processing and sustained mitophagy, linked to metabolic shifts.

Conclusions:

  • Transcriptomic data support TFAP4 as a transcriptional driver of UBC9 and SUMO1 expression.
  • This axis likely promotes SUMO-dependent DRP1 modification, leading to mitochondrial hyper-fission and excessive mitophagy.
  • The TFAP4-UBC9-SUMO1 axis is identified as a key driver of mitochondrial depletion in diabetes, presenting a potential therapeutic target.
Keywords:
DRP1Diabetic complicationsMitochondrial dysfunctionMitochondrial fissionMitophagySUMOylationTranscriptomic analysis

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