SIRT3 deficiency impairs mitochondrial bioenergetics via hyperacetylation of TCA cycle enzymes in chronic heart failure.

BACKGROUND

Mitochondrial dysfunction is a hallmark of heart failure (HF), but its upstream regulatory pathways remain incompletely understood. Sirtuin 3 (SIRT3), a mitochondrial deacetylase, is crucial for maintaining enzymatic activity through deacetylation. This study investigates whether SIRT3 downregulation leads to mitochondrial metabolic impairment in HF by enhancing acetylation of tricarboxylic acid (TCA) cycle enzymes.

METHODS

A chronic HF model was established in male C57BL/6J mice via transverse aortic constriction (TAC). Cardiac function and morphology were evaluated by echocardiography, histological staining, and transmission electron microscopy. Mitochondrial function was assessed using ATP quantification, Seahorse XF analysis, and enzymatic activity assays. Protein acetylation and SIRT3 expression were examined through Western blotting and acetyl-proteomics. Angiotensin II-treated cardiomyocytes served as an in vitro model.

RESULTS

TAC-induced HF led to cardiac remodeling and mitochondrial damage. Proteomic analysis revealed increased global protein acetylation, especially in mitochondrial proteins related to the TCA cycle. SIRT3 was significantly downregulated, corresponding with hyperacetylation and suppressed activity of pyruvate dehydrogenase (PDH), succinate dehydrogenase (SDH), and citrate synthase (CS), which was associated with impaired respiration and reduced ATP output. Ang II-treated cells showed similar changes.

CONCLUSION

SIRT3 downregulation in HF drives TCA enzyme hyperacetylation and metabolic dysfunction, suggesting a key mechanism linking protein acetylation imbalance to mitochondrial impairment in disease progression.