Mitochondrial Hyperacetylation Contributes with Ventricular Dysfunction as Consequence of SIRT3 Deficiency in Obesity and Metabolic Syndrome

Abstract

Cyclophilin D (CypD) mediates mitochondrial permeability transition pore (mPTP) opening, which contributes with mitochondrial dysfunction. CypD function is regulated by its acetylation state that depends on GCN5L1 acetyltransferase and SIRT3 deacetylate activity. Since obese rats with obesity and metabolic syndrome (MS) decrease SIRT3 activity and expression, we tested the hypothesis that CypD hyperacetylation promotes mitochondrial dysfunction under this pathophysiological state, which is associated with ventricular impairment and heart failure. Male rats with obesity and MS showed diastolic dysfunction and a 34% phosphocreatine reduction. Accordingly, mitochondrial from these animals was 2.5-fold prone to mPTP opening compared with controls. SIRT3 mitochondrial expression decreased 22%, concomitantly with hyperacetylated mitochondrial profile including CypD. Additionally, SIRT3 expression from human biopsies for falling hearts showed 70% decrease expression level in obese patients in comparison to non-obese patients. The hyperacetlylation profiles correlates with Body Mass Index, ventricular dysfunction and cardiac remodeling in patients with end-state of HF. Our results indicate that obesity and MS reduces SIRT3 expression and that CypD hyperacetylation increase the mPTP opening, suggesting that activation of SIRT3 might be a potential target for ventricular dysfunction and heart failure.