Abstract 13363: Inhibition of Oxidative Modification in Mitochondrial Proteases Ameliorates Declines of Mitochondrial Respiration and Cardiac Contractility in Pressure Overload Heart Failure
Mitochondrial dysfunction is a fundamental contributor in heart failure. Our preliminary examinations on mitochondrial remodeling in TAC-operated failing heart using microarray and mitochondrial iTRAQ proteome revealed that mitochondrial electron transport chain (ETC) proteins increased even with a decrease of mRNA expression in heart failure. We investigated the underlying mechanism and pathological involvement with focus on protein quality control. Results from microarray and TRAQ indicated the possibility of abnormal protein turnover of ETC. We examined the proteolytic activity of proteasomes and mitochondrial proteases. Isolated mitochondria were incubated in ATP-containing buffer with FITC-casein or followed by immunoblotting for mitochondrial protein to assess the protease activity. Proteasome activity did not change, but protease activity was impaired in failing heart. The level of reduced cysteines of LONP1 that is the most abundant mitochondrial protease was decreased in failing heart. Immunoblot of LONP1 without reducing agent 2-mercaptoethanol exhibited disulfide dimer complex in failing heart. The exposure of isolated mitochondria to exogenous hydrogen peroxide decrease protease activity. These results suggested that oxidative stress contributes to the mitochondrial protease dysfunction in failing heart. Thus, we utilized the system that is inducible overexpression of mitochondria-targeted human catalase (mCAT) in mice hearts. We injected tamoxifen 6 weeks after TAC operation to induce mCAT and examined 2 weeks later. Abolishing oxidative stress recovered proteolytic activity and abnormal protein homeostasis in failing heart, which resulted in improved mitochondrial respiration and cardiac contractility. Treatment with MG132, a mitochondrial proteases inhibitor, partially canceled the protective effect of mCAT induction.
Conclusions: Present study suggested that oxidative stress impaired the mitochondrial protease activity and ETC proteins homeostasis. Inhibiting protein oxidation of mitochondrial proteases improved ETC activity and cardiac contractility through preserved protein quality control in pressure overload heart failure.
- © 2013 by American Heart Association, Inc.