Dlat acts as a key transacetylase that induces mitochondrial protein hyperacetylation, specifically inactivating HADHA to limit fatty acid oxidation and drive heart failure with preserved ejection fraction.
Does Dlat manipulation alter mitochondrial protein acetylation, fatty acid oxidation, and HFpEF phenotypes in preclinical models?
Dlat-mediated mitochondrial protein hyperacetylation drives fatty acid oxidation inhibition and HFpEF development, identifying a novel mechanistic link and potential therapeutic target.
Increased protein acetylation is frequently observed in the failing heart, including in hearts with heart failure with preserved ejection fraction (HFpEF). However, its role in the pathogenesis of HFpEF remains insufficiently investigated. Here, we found that HFpEF hearts displayed significantly protein hyperacetylation, which were predominantly localized to mitochondria and particularly enriched in fatty acid oxidation (FAO) pathway. Notably, Dlat, a pyruvate metabolism enzyme, was identified as the key transacetylase for mitochondrial protein hyperacetylation. Dlat overexpression enhanced FAO-related protein acetylation and exacerbated cardiac lipid metabolism disturbances, whereas Dlat knockdown effectively mitigated FAO inhibition and HFpEF phenotypes. Moreover, we demonstrated that Dlat directly triggers the acetylation of alpha subunit of mitochondrial trifunctional protein (HADHA) at the K728 site, thereby inactivating HADHA enzymatic activity. Our study provides a mechanistic basis linking protein hyperacetylation, FAO inhibition, and HFpEF development. Manipulating mitochondrial protein acetylation may offer potential strategies for therapeutic intervention of HFpEF.
Wang et al. (Sat,) conducted a other in Heart failure with preserved ejection fraction (HFpEF). Dlat knockdown (AAV9-sh-Dlat) and NAD+ supplementation (Nicotinamide riboside) vs. Control / Vehicle was evaluated on Cardiac diastolic function and fatty acid oxidation capacity. Dlat acts as a key transacetylase that induces mitochondrial protein hyperacetylation, specifically inactivating HADHA to limit fatty acid oxidation and drive heart failure with preserved ejection fraction.