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Shiva, S. et al. Nitrite augments tolerance to ischemia/reperfusion injury via the modulation of mitochondrial electron transfer. J. Exp. Med. 204, 2089-2102

Vascular Medicine Branch, National Heart Lung Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Journal of Experimental Medicine (Impact Factor: 13.91). 10/2007; 204(9):2089-102. DOI: 10.1084/jem.20070198
Source: PubMed

ABSTRACT Nitrite (NO(2)(-)) is an intrinsic signaling molecule that is reduced to NO during ischemia and limits apoptosis and cytotoxicity at reperfusion in the mammalian heart, liver, and brain. Although the mechanism of nitrite-mediated cytoprotection is unknown, NO is a mediator of the ischemic preconditioning cell-survival program. Analogous to the temporally distinct acute and delayed ischemic preconditioning cytoprotective phenotypes, we report that both acute and delayed (24 h before ischemia) exposure to physiological concentrations of nitrite, given both systemically or orally, potently limits cardiac and hepatic reperfusion injury. This cytoprotection is associated with increases in mitochondrial oxidative phosphorylation. Remarkably, isolated mitochondria subjected to 30 min of anoxia followed by reoxygenation were directly protected by nitrite administered both in vitro during anoxia or in vivo 24 h before mitochondrial isolation. Mechanistically, nitrite dose-dependently modifies and inhibits complex I by posttranslational S-nitrosation; this dampens electron transfer and effectively reduces reperfusion reactive oxygen species generation and ameliorates oxidative inactivation of complexes II-IV and aconitase, thus preventing mitochondrial permeability transition pore opening and cytochrome c release. These data suggest that nitrite dynamically modulates mitochondrial resilience to reperfusion injury and may represent an effector of the cell-survival program of ischemic preconditioning and the Mediterranean diet.

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Available from: Sruti Shiva, Jul 30, 2015
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    • "Importantly, the impairment of ETC was directly confirmed by enzyme activity measurements that revealed a greatly reduced complex I activity (Fig. 4D), consistent with previous studies in mitochondria from hypoxia-sensitive species (da Silva et al., 2003; Heerlein et al., 2005; Galkin et al., 2009) that implicated a role of complex I in hypoxia/reoxygenation-induced dysfunction. Irrespective of the cause, the quintessential effect of complex I inhibition is leakage of electrons from the ETC leading to increased production of ROS (Raha et al., 2000; Turrens, 2003; Galkin and Brandt, 2005; Shiva et al., 2007; Fato et al., 2009; Murphy, 2009), with oxidative damage of not only the enzyme itself but also other mitochondrial components. We therefore tested the hypothesis that inhibition of complex-I-driven state 3 respiration was mediated by oxidative damage following over-production of ROS after hypoxia/ reoxygenation. "
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