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

Area of Science:

• Biochemistry
• Molecular Biology
• Cardiology

Background:

• Protein deubiquitination is crucial in disease pathogenesis.
• Diabetic cardiomyopathy (DCM) involves complex molecular mechanisms.
• Ovarian tumor domain-containing protein 1 (OTUD1) is a deubiquitinating enzyme (DUB).

Purpose of the Study:

• Investigate the role of OTUD1 in diabetic cardiomyopathy (DCM).
• Elucidate the regulatory mechanism of OTUD1 in cardiac function during diabetes.
• Determine the OTUD1-AMPK signaling axis in DCM pathogenesis.

Main Methods:

• Assessed OTUD1 expression in diabetic mouse hearts using quantitative methods.
• Utilized single-cell RNA sequencing to identify OTUD1 localization in cardiomyocytes.
• Performed cardiomyocyte-specific OTUD1 knockout in diabetic mouse models.
• Analyzed AMPK activity, phosphorylation, and mitochondrial function.
• Investigated protein-protein interactions between OTUD1, AMPKα2, and CAMKK2.

Main Results:

• OTUD1 expression is significantly increased in diabetic mouse hearts, primarily in cardiomyocytes.
• Cardiomyocyte-specific OTUD1 knockout ameliorated cardiac hypertrophy and dysfunction in diabetic mice.
• OTUD1 deficiency restored cardiac AMPK activity and mitochondrial function.
• OTUD1 directly binds and deubiquitinates AMPKα2, inhibiting its phosphorylation by CAMKK2.
• Silencing AMPKα2 abrogated the cardioprotective effects of OTUD1 deficiency.

Conclusions:

• OTUD1 acts as a direct regulator of AMPK in cardiomyocytes.
• A novel OTUD1-AMPK signaling axis contributes to the pathogenesis of DCM.
• Targeting OTUD1 may offer a therapeutic strategy for diabetic cardiomyopathy.