Mitochondrial complex I deficiency increases protein acetylation and accelerates heart failure.
Cell Metab
; 18(2): 239-50, 2013 Aug 06.
Article
em En
| MEDLINE
| ID: mdl-23931755
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Doenças Mitocondriais
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Complexo I de Transporte de Elétrons
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Insuficiência Cardíaca
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Mitocôndrias Cardíacas
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NAD
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article