Heart specific knockout of Ndufs4 ameliorates ischemia reperfusion injury

Journal of Molecular and Cellular Cardiology
Huiliang ZhangWang Wang

Abstract

Ischemic heart disease (IHD) is a leading cause of mortality. The most effective intervention for IHD is reperfusion, which ironically causes ischemia reperfusion (I/R) injury mainly due to oxidative stress-induced cardiomyocyte death. The exact mechanism and site of reactive oxygen species (ROS) generation during I/R injury remain elusive. We aim to test the hypothesis that Complex I-mediated forward and reverse electron flows are the major source of ROS in I/R injury of the heart. We used a genetic model of mitochondrial Complex I deficiency, in which a Complex I assembling subunit, Ndufs4 was knocked out in the heart (Ndufs4H-/-). The Langendorff perfused Ndufs4H-/- hearts exhibited significantly reduced infarct size (45.3 ± 5.5% in wild type vs 20.9 ± 8.1% in Ndufs4H-/-), recovered contractile function, and maintained mitochondrial membrane potential after no flow ischemia and subsequent reperfusion. In cultured adult cardiomyocytes from Ndufs4H-/- mice, I/R mimetic treatments caused minimal cell death. Reintroducing Ndufs4 in Ndufs4H-/- cardiomyocytes abolished the protection. Mitochondrial NADH declined much slower in Ndufs4H-/- cardiomyocytes during reperfusion suggesting decreased forward electron flow. Mitochondrial fl...Continue Reading

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Citations

Sep 6, 2019·Apoptosis : an International Journal on Programmed Cell Death·Mengqiu WuZhanjun Jia
Jul 3, 2020·Frontiers in Physiology·J SnyderP Y Sato
Mar 14, 2019·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·Maurizio ForteSperanza Rubattu
May 21, 2020·Frontiers in Pharmacology·Leonardo MacielJose Hamilton Matheus Nascimento
Jan 10, 2019·Journal of Molecular and Cellular Cardiology·Sundararajan VenkateshCarolyn K Suzuki

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