Mitochondrial complex I deficiency increases protein acetylation and accelerates heart failure.
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.
Mitochondria and Metabolism Center, Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, 98109, USA.
Georgios
G
Karamanlidis
Chi Fung
CF
Lee
Lorena
L
Garcia-Menendez
Stephen C
SC
Kolwicz
Wichit
W
Suthammarak
Guohua
G
Gong
Margaret M
MM
Sedensky
Philip G
PG
Morgan
Wang
W
Wang
Rong
R
Tian
D000107:Acetylation; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology; D004280:Dobutamine / Q000494:pharmacology; D042967:Electron Transport Complex I / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D005260:Female; D006333:Heart Failure / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000378:metabolism*; D028361:Mitochondrial Diseases / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism; D009243:NAD / Q000378:metabolism*; D018384:Oxidative Stress; D011247:Pregnancy; D017382:Reactive Oxygen Species / Q000378:metabolism; D056566:Sirtuin 3 / Q000378:metabolism
D002316:Cardiotonic Agents; C534449:Ndufs4 protein, mouse; D017382:Reactive Oxygen Species; C525046:Sirt3 protein, mouse; D009243:NAD; D004280:Dobutamine; D056566:Sirtuin 3; D042967:Electron Transport Complex I