USP28 Serves as a Key Suppressor of Mitochondrial Morphofunctional Defects and Cardiac Dysfunction in the Diabetic Heart
Authors' conclusion
Our findings provide a USP28-modulated mitochondria homeostasis mechanism that involves the PPARα-Mfn2 axis in diabetic hearts
Study context
- Population
- T2DM mouse models (db/db and HFD/STZ) and diabetic-mimicking cardiomyocytes in vitro
- Comparison
- USP28 cardiac knockout or AAV9-USP28 overexpression vs controls in diabetic mice
Methodological detailsdb/db and HFD/STZ T2DM mouse models, cardiac-specific USP28 knockout, AAV9-USP28 overexpression, NRVMs and hiPSC-derived cardiomyocytes in vitro
- Db/db and HFD/STZ T2DM mouse models
- Cardiac-specific USP28 knockout
- AAV9-USP28 overexpression
- NRVMs and hiPSC-derived cardiomyocytes in vitro
Main finding
As reported in the abstract
- Diabetic ventricle (db/db mice and diabetic patients) showed significant reduction in USP28 expression
- Diabetic USP28 cardiac knockout: more severe progressive cardiac dysfunction, lipid accumulation and mitochondrial disarrangement vs controls
- USP28 overexpression improved systolic and diastolic dysfunction and ameliorated cardiac hypertrophy and fibrosis in the diabetic heart
- AAV9-USP28 diabetic mice: less lipid storage, reduced ROS formation and mitochondrial impairment vs AAV9-null
- USP28 overexpression attenuated cardiac remodeling, dysfunction, lipid accumulation and mitochondrial impairment in HFD/STZ T2DM mice; confirmed in NRVMs and hiPSC-derived cardiomyocytes
- USP28 directly interacted with PPARα, deubiquitinating and stabilizing it (Lys152) to promote Mfn2 transcription
- Cardioprotective benefits of USP28 largely abrogated with PPARα deletion and conditional Mfn2 loss-of-function in db/db mice
Original publication
USP28 Serves as a Key Suppressor of Mitochondrial Morphofunctional Defects and Cardiac Dysfunction in the Diabetic Heart. Circulation. Published 23 November 2023. doi:10.
Summarised from the published abstract; every number is checked against it