Pyruvate metabolism enzyme Dlat induces mitochondria protein hyperacetylation to limit fatty acid oxidation in the HFpEF heart
Y Wang, Y Li, L HuAbstract
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.Mitochondrial protein acetylation drivesHFpEF