USP33 alleviates FIS1-dependent mitochondrial fission and cardiac microvascular injury in diabetic cardiomyopathy via deubiquitinating and stabilizing ATG7

  • Cell Death Dis. 2026 May 30. doi: 10.1038/s41419-026-08930-8.
Yuqiong Chen  #  1 ,  Xiangyu Sun  #  2 ,  Xinyan Li  #  3 ,  Bo Guan  4 ,  Xiaopei Yan  5 ,  Chao Huang  6 ,  Nannan Zhang  7 ,  Wenjun Mao  7 ,  Yuan Tian  8 ,  Chao Chen  9 ,  Yao Lu  10 ,  Su Li  11
Affiliations
  • 1. Department of Cardiology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, China. [email protected].
  • 2. Department of Breast Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, China.
  • 3. Center for Precision Cancer Medicine & Translational Research, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China.
  • 4. Department of Geriatrics, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, China.
  • 5. Department of Respiratory Medicine, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, China.
  • 6. Ministry of Science and Technology, the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou, Jiangsu, China.
  • 7. Department of Cardiology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, China.
  • 8. Department of Cardiology, Jinshan Hospital, Fudan University, China, Shanghai, China.
  • 9. Department of Cardiology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, China. [email protected].
  • 10. XuZhou Clinical School of Xuzhou Medical University, Department of Cardiology, Xuzhou Central Hospital, XuZhou Institute of Cardiovascular Disease, Xuzhou, P.R. China. [email protected].
  • 11. Department of cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China. [email protected].
  • # Contributed equally.
PMID: 42218158 DOI: 10.1038/s41419-026-08930-8
Abstract

Endothelial dysfunction plays a key role in the development of diabetic cardiomyopathy (DCM), but the underlying mechanisms of endothelial dysfunction remain to be elucidated. Recent studies have revealed that dysregulated mitochondrial dynamics contributes to the development of cardiac microvascular dysfunction. Fission-1 (FIS1), a key effector of mitochondrial fission, functions as an outer mitochondrial membrane adapter that recruits dynamin-related protein-1 (Drp1) from the cytosol to the outer mitochondrial membrane for activating mitochondrial fission. The present study screened a library targeting deubiquitinases, and identified the regulatory role of USP33 on FIS1-dependent mitochondrial fission. We found USP33 silencing elevated FIS1 protein expression and resulted in excessive mitochondrial fission in endothelial cells, which in turn impaired mitochondrial function and worsen endothelial and cardiovascular dysfunction in DCM. Mechanistically, USP33 interacted with FIS1 at the TPR2 domain and promoted FIS1 degradation via lysosomal degradation. Further studies revealed that USP33 stabilized autophagy-related 7 (Atg7) at protein level by blocking K63-linked ubiquitination of human Atg7 at K48 (mouse K44) site. This process led to lysosomal degradation of FIS1 via ATG7-mediated Autophagy. In summary, our findings reveal that USP33 plays a critical role in endothelial dysfunction in DCM and demonstrate that ATG7-FIS1 pathway acts as one of the potential downstream mechanisms.

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