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Title: Mitochondrial complex i deficiency increases protein acetylation and accelerates heart failure
Authors: Georgios Karamanlidis
Chi Fung Lee
Lorena Garcia-Menendez
Stephen C. Kolwicz
Wichit Suthammarak
Guohua Gong
Margaret M. Sedensky
Philip G. Morgan
Wang Wang
Rong Tian
University of Washington, Seattle
Children's Hospital and Regional Medical Center
Mahidol University
Keywords: Biochemistry, Genetics and Molecular Biology
Issue Date: 6-Aug-2013
Citation: Cell Metabolism. Vol.18, No.2 (2013), 239-250
Abstract: Mitochondrial respiratory dysfunction is linked to the pathogenesis of multiple diseases, including heart failure, but the specific mechanisms for this link remain largely elusive. We modeled the impairment of mitochondrial respiration by the inactivation of the Ndufs4 gene, a protein critical for complex I assembly, in the mouse heart (cKO). Although complex I-supported respiration decreased by >40%, the cKO mice maintained normal cardiac function in vivo and high-energy phosphate content in isolated perfused hearts. However, the cKO mice developed accelerated heart failure after pressure overload or repeated pregnancy. Decreased NAD+/NADH ratio by complex I deficiency inhibited Sirt3 activity, leading to an increase in protein acetylation and sensitization of the permeability transition in mitochondria (mPTP). NAD+precursor supplementation to cKO mice partially normalized the NAD+/NADH ratio, protein acetylation, and mPTP sensitivity. These findings describe a mechanism connecting mitochondrial dysfunction to the susceptibility to diseases and propose a potential therapeutic target. © 2013 Elsevier Inc.
ISSN: 19327420
Appears in Collections:Scopus 2011-2015

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