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

Summary

OTUD1 is upregulated in diabetic mouse hearts and primarily expressed in cardiomyocytes. Cardiomyocyte-specific OTUD1 deletion prevents hypertrophy and dysfunction in type 1 and type 2 diabetes by restoring AMPK activity and mitochondrial function; OTUD1 directly deubiquitinates AMPKα2 at K60/K379, suppressing AMPK signaling.

Key Findings

• OTUD1 expression is significantly increased in diabetic mouse hearts and predominantly localized to cardiomyocytes by scRNA-seq.
• Cardiomyocyte-specific OTUD1 knockout prevents cardiac hypertrophy and dysfunction in both type 1 and type 2 diabetic male mice.
• OTUD1 deficiency restores AMPK activity and mitochondrial function in diabetic hearts and cardiomyocytes.
• OTUD1 binds AMPKα2 and deubiquitinates it at K60/K379, thereby inhibiting AMPK signaling.

Clinical Implications

Targeting the OTUD1–AMPK axis (e.g., DUB inhibition or AMPK activation) may prevent or reverse diabetic cardiomyopathy; OTUD1 expression could serve as a biomarker for disease activity.

Limitations

• Findings are preclinical and primarily in male mice; sex differences and human relevance need validation
• Therapeutic modulation of OTUD1 or AMPK was not tested clinically

Future Directions

Validate OTUD1–AMPK signaling in human cardiac tissue; develop selective OTUD1 inhibitors and test AMPK activators in diabetic cardiomyopathy models with both sexes.