Cardiomyocyte OTUD1 drives diabetic cardiomyopathy via directly deubiquitinating AMPKα2 and inducing mitochondrial dysfunction

Xue Han, Ruyi Zheng, Jiajia Zhang, Yanan Liu, Ze Li, Guoxuan Liu, Jianing Zheng, Weiqi Li, Zijun Liang, Mengyang Wang, Jie Yu, Qiaojuan Shi (), Huazhong Ying () and Guang Liang ()
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Xue Han: Hangzhou Medical College
Ruyi Zheng: Hangzhou Medical College
Jiajia Zhang: Hangzhou Medical College
Yanan Liu: Hangzhou Medical College
Ze Li: Hangzhou Medical College
Guoxuan Liu: Hangzhou Medical College
Jianing Zheng: Hangzhou Medical College
Weiqi Li: Hangzhou Medical College
Zijun Liang: Hangzhou Medical College
Mengyang Wang: Beihua University
Jie Yu: Hangzhou Medical College
Qiaojuan Shi: Hangzhou Medical College
Huazhong Ying: Hangzhou Medical College
Guang Liang: the First Affiliated Hospital, Wenzhou Medical University

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract Deubiquitinating modification of proteins is involved in the pathogenesis of diseases. Here, we investigated the role and regulating mechanism of a deubiquitinating enzyme (DUB), ovarian tumor domain-containing protein 1 (OTUD1), in diabetic cardiomyopathy (DCM). We find a significantly increased OTUD1 expression in diabetic mouse hearts, and single-cell RNA sequencing shows OTUD1 mainly distributing in cardiomyocytes. Cardiomyocyte-specific OTUD1 knockout prevents cardiac hypertrophy and dysfunction in both type 2 and type 1 diabetic male mice. OTUD1 deficiency restores cardiac AMPK activity and mitochondrial function in diabetic hearts and cardiomyocytes. Mechanistically, OTUD1 binds to AMPKα2 subunit, deubiquitinates AMPKα2 at K60/K379 sites, and then inhibits AMPKT172 phosphorylation through impeding the interaction of AMPKα2 and its upstream kinase CAMKK2. Finally, silencing AMPKα2 in cardiomyocytes abolishes the cardioprotective effects of OTUD1 deficiency in diabetic mice. In conclusion, this work identifies a direct regulatory DUB of AMPK and presents a OTUD1-AMPK axis in cardiomyocytes for driving DCM.

Date: 2025
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DOI: 10.1038/s41467-025-61901-z

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