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KAT6A acetylation regulates AMPK function and hypertrophic remodeling in the heart
Mariko Aoyagi Keller1, Andreas Ivessa1, Tong Liu2
1Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers-New Jersey Medical School, 185 South Orange Ave, Newark, NJ 07103, USA.
Molecular Metabolism
|August 27, 2025
Summary
Ketogenic diets impact heart health by altering KAT6A acetylation, a modification crucial for mitochondrial function and cell growth. This acetylation influences AMPK signaling, offering potential therapeutic targets for cardiac conditions.
Area of Science:
- Cardiovascular Biology
- Metabolic Regulation
- Molecular Cardiology
Background:
- Dietary interventions, such as ketogenic diets, significantly influence host metabolism and disease susceptibility.
- Lysine acetyltransferases (KATs) are key regulators of cellular processes, utilizing acetyl-CoA.
- Previous studies indicated ketogenic diets alleviate cardiac pathology, but underlying mechanisms require elucidation.
Purpose of the Study:
- To investigate the role of KAT6A acetylation in cardiac function and metabolism under ketogenic diet conditions.
- To elucidate the molecular mechanisms linking KAT6A acetylation to mitochondrial function and cell growth.
- To determine the impact of KAT6A K816 acetylation on AMPK signaling in cardiomyocytes.
Main Methods:
- Proteomic analysis to identify KAT6A acetylation sites in mouse hearts under ketogenic diet and hypertension.
- RNA-sequencing to assess the effects of KAT6A acetylation-mimetic mutants on cardiomyocyte signaling.
- Generation and analysis of KAT6A-K816R acetylation-resistant knock-in mice.
Main Results:
- KAT6A acetylation at K816 was identified in hearts on a ketogenic diet, enhancing interaction with AMPK subunits.
- KAT6A acetylation mimicked by a mutant stimulated AMPK signaling and mitigated mitochondrial dysfunction and hypertrophy in cardiomyocytes.
- KAT6A-K816R knock-in mice showed smaller hearts, enhanced AMPK activity, and protection against cardiac remodeling.
Conclusions:
- KAT6A acetylation at K816 is critical for regulating mitochondrial function and cell growth.
- KAT6A modulates AMPK activity through K816-acetylation, impacting cardiac metabolism and hypertrophy in a cell-type-specific manner.
- These findings highlight KAT6A acetylation as a key mediator of ketogenic diet effects on cardiac health.
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