Abstract 9949: NADH/NAD+ Sensitive Protein Hyper-acetylation Links Mitochondrial Dysfunction to Cardiac Susceptibility to Stress
Mitochondrial dysfunction is a recognized player in heart failure progression although the underlying molecular mechanisms are largely unknown. Using a mouse model with Complex I-deficiency (cardiac Ndufs4-KO, cKO), we had shown that impairment of mitochondrial function led to increases in NADH/NAD+ ratio and inhibition of sirtuin activity. The resultant mitochondrial lysine acetylation (LysAc) sensitized the mitochondrial permeability transition pore (mPTP) opening and exacerbated heart failure progression. Here, we show that elevation of cardiac NAD+ levels pharmacologically or genetically normalized LysAc levels and rescued cardiac dysfunction in cKO mice under stresses. Furthermore, pressure overload in control mice also led to increases in cardiac NADH/NAD+ ratio, mitochondrial LysAc levels and mPTP sensitivity. All of them were normalized by increasing cardiac NAD+ levels. Together with the elevated LysAc levels in human failing hearts, these data support the roles of LysAc in human heart failure progression. Interestingly, proteomics analysis revealed increased LysAc of proteins in the mitochondria as well as in the cytosol and nucleus from cKO hearts without changes in the total protein amount. We identified LysAc of mitochondrial malate aspartate shuttle (MAS) as a mechanism for communicating elevated NADH/NAD+ ratio in the mitochondria to the cytosol, resulting in hyperacetylation of non-mitochondrial proteins. Furthermore, increased LysAc sensitized the mPTP to stress by promoting the binding of cyclophilin D (CypD) to the ATP synthase complex via increased interaction with oligomycin-sensitive conferring protein (OSCP). In silico docking calculation revealed an interaction interface between CypD and OSCP in ATP synthase complex, and their interaction can be facilitated via acetylation of the specific lysine residues identified by the acetylome analysis. This study unveils novel mechanisms by which mitochondrial dysfunction modulates protein modification and the propensity to cardiac dysfunction during stress. The results also identify NADH/NAD+ ratio as a therapeutic target for the progression of heart failure.
Author Disclosures: C. Lee: None. L. Garcia-Menendez: None. Y. Choi: None. N.D. Roe: None. J.D. Chavez: None. J.E. Bruce: None. J.S. Edgar: None. Y. Goo: None. D.R. Goodlett: None. R. Tian: None.
- © 2015 by American Heart Association, Inc.