Key result
Dlat knockdown restores cardiac function in HFpEF mice by reviving fatty acid oxidation.
Why the study?
Myocardial metabolic impairments and increased protein acetylation occur in HFpEF, but how protein acetylation contributes to cardiac metabolic impairments in the pathogenesis of HFpEF has not been fully investigated.
Does targeting Dlat-mediated mitochondrial protein hyperacetylation or reactivating HADHA restore cardiac fatty acid oxidation capacity and prevent cardiac dysfunction in a mouse model of HFpEF?
Does targeting Dlat-mediated mitochondrial protein hyperacetylation or reactivating HADHA restore cardiac fatty acid oxidation capacity and prevent cardiac dysfunction in a mouse model of HFpEF?
In a preclinical mouse model of HFpEF, the pyruvate metabolism enzyme Dlat induces mitochondrial protein hyperacetylation—specifically inactivating HADHA at the K728 site to limit fatty acid oxidation—identifying mitochondrial deacetylation and HADHA reactivation as potential therapeutic targets for HFpEF.
May support Dlat-HADHA targeting in HFpEF; leaves open translation from mouse models to patients.
Background Myocardial metabolic impairments were known to play a significant role in the development of heart failure with preserved ejection fraction (HFpEF), while the pathogenic mechanisms remain largely unknown. Increased protein acetylation was frequently detected in the failing heart including HFpEF hearts. Nonetheless, how protein acetylation was involved in cardiac metabolic impairments in the pathogenesis of HFpEF has not been fully investigated. Methods A 2-hit strategy (high-fat diet and Nω-nitrol-arginine methyl ester) was used to induce HFpEF model in mice. mitochondrial respiratory function measurement and metabolomics test were performed to reflect cardiac metabolic alteration. Genetically engineered mouse models and various cellular and molecular techniques including acetylome profiling analysis and enzymatic activity assay was employed to investigate the underlying mechanisms. Results Significant cardiac diastolic functional impairment, pathological cardiac remodeling, as well as boosted protein hyperacetylation was observed in the heart of 2-hit HFpEF mice. Results of acetylome profiling revealed that the hyperacetylated protein was mainly located in mitochondria and enriched in metabolic pathways, especially in fatty acid oxidation (FAO). Meanwhile, HFpEF heart also displayed reduced FAO capacity and aberrant lipid accumulation. Activation of protein deacetylation restored FAO capacity and attenuated cardiac dysfunction in the HFpEF heart, while inhibition of mitochondrial deacetylase activity directly induced lipid metabolism disorder in the cardiomyocytes. Next, we identify Dlat, a pyruvate metabolism enzyme, as the key transacetylase for mitochondrial protein hyperacetylation in HFpEF heart. Overexpression of Dlat boosted FAO-related protein acetylation and further impeded cardiac lipid metabolism, thereby inducing pathological changes which mimicked HFpEF phenotype. In contrast, Dlat knockdown showed a reliable effect in mitigating FAO inhibition and functional impairment in 2-hit HFpEF mice. Through discovery-driven approaches, we uncovered that Dlat directly binds with the alpha subunit of mitochondrial trifunctional protein (HADHA) and triggers its acetylation at K728 site to inactivate HADHA enzymatic activity. Reactivating HADHA by cardiac-specific HADHA overexpression or an oral biogenic polyamine was able to boost cardiac FAO capacity and prevented the development of HFpEF. Conclusion Our study provided a mechanistic basis that directly linked protein hyperacetylation, FAO inhibition and development of HFpEF. Activating mitochondrial deacetylase or cardiac FAO capacity might represent novel approaches to restore cardiac metabolic hemostasis and cardiac function in HFpEF.
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Wang et al. (2026) studied Heart failure with preserved ejection fraction (HFpEF). Dlat knockdown, HADHA overexpression, or oral biogenic polyamine vs. 2-hit HFpEF mice or Dlat overexpression was evaluated on Mitochondrial fatty acid oxidation capacity and cardiac diastolic function. Dlat acetylates HADHA at K728 to inhibit fatty acid oxidation in 2-hit HFpEF mice, while Dlat knockdown or HADHA reactivation restores cardiac function.
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