Mitochondrial protein acetylation and left ventricular function in a model of hypertrophic cardiomyopathy and heart failure

Indiana University-Purdue University Indianapolis (IUPUI)

Rationale: The childhood heart disease of Friedreich’s Ataxia (FRDA) is characterized by hypertrophy and failure. It is caused by loss of frataxin (FXN), a mitochondrial protein involved in energy homeostasis. FRDA model hearts have increased mitochondrial protein acetylation and impaired sirtuin 3 (SIRT3) deacetylase activity. Protein acetylation is an important regulator of cardiac metabolism and SIRT3 is protective in heart disease. The underlying pathophysiology of heart failure in FRDA is unclear. I suspect that increased acetylation in FRDA heart mitochondria damages cardiac energy homeostasis by inhibiting activity of key enzymes involved in heart metabolism. Objective: My project tested the hypothesis that altered acetylation of mitochondrial proteins contributes to the cardiomyopathy of FRDA. Methods: Conditional mouse models of FRDA cardiomyopathy with ablation of FXN (FXN KO) or FXN and SIRT3 (FXN/SIRT3 DKO) in the heart were compared to healthy controls. Hearts were evaluated using echocardiography, cardiac catheterization, histology, protein acetylation and expression. FXN KO mice were treated with NAD+ replacement therapy with nicotinamide riboside (NR), and FXN/SIRT3 DKO mice were treated with FXN protein replacement therapy. Results: Acetylation was temporally progressive and paralleled evolution of heart failure in the FXN KO model. High levels of acetylation were associated with cardiac fibrosis, mitochondrial damage, impaired fat metabolism, and diastolic and systolic dysfunction. Acetylation correlated strongly with worse heart function, and loss of SIRT3 in the FXN KO mouse resulted in significant decrease in ejection fraction and fractional shortening. Treatment of the FXN/SIRT3 DKO with FXN protein therapy reduced acetylation but was not sufficient to fully rescue heart function. Increasing NAD+ with NR-treatment in the FXN KO lead to increased mitochondrial protein acetylation and did not improve cardiac outcome. Conclusion: I found a strong negative correlation between heart function and mitochondrial protein acetylation. My findings also provide evidence that absence of SIRT3 expression in the FXN KO heart exacerbates features of heart failure, and that SIRT3 expression is necessary to rescue the FXN KO heart. These results suggest that SIRT3 inactivation and abnormal acetylation contribute to the pathophysiology of heart disease in FRDA.