Oxidative Posttranslational Modifications Develop LONP1 Dysfunction in Pressure Overload Heart Failure
Background—Mitochondrial compromise is a fundamental contributor to heart failure. Recent studies have revealed that several surveillance systems maintain mitochondrial integrity. The present study evaluated the role of mitochondrial AAA+ protease in a mouse model of pressure overload heart failure.
Methods and Results—The FITC-casein assay and immunoblotting for endogenous mitochondrial proteins revealed a marked reduction in ATP-dependent proteolytic activity in failing heart mitochondria. The level of reduced cysteine was decreased and tyrosine nitration and protein carbonylation were promoted in Lon protease homolog (LONP1), the most abundant mitochondrial AAA+ protease, in heart failure. Comprehensive analysis revealed that electron transport chain (ETC) protein levels were increased even with a reduction in the expression of their corresponding mRNAs in heart failure, which indicated decreased protein turnover and resulted in the accumulation of oxidative damage in the ETC. The induction of catalase targeted to mitochondria (mCAT) ameliorated proteolytic activity and protein homeostasis in the ETC, leading to improvements in mitochondrial energetics and cardiac contractility even during the late-stage of pressure overload. Moreover, the infusion of mitoTEMPO, a mitochondria-targeted superoxide dismutase mimetic, recovered oxidative modifications of LONP1 and improved mitochondrial respiration capacity and cardiac function. The in vivo siRNA repression of LONP1 partially canceled the protective effects of mCAT induction and mitoTEMPO infusion.
Conclusions—Oxidative posttranslational modifications attenuate mitochondrial AAA+ protease activity, which is involved in impaired ETC protein homeostasis, mitochondrial respiration deficiency, and left ventricular contractile dysfunction. Oxidatively inactivated proteases may be an endogenous target for mitoTEMPO treatment in pressure overload heart failure.
- Received December 20, 2013.
- Accepted April 15, 2014.