Nitrite augments tolerance to ischemia/reperfusion injury via the modulation of mitochondrial electron transfer

• Published in: The Journal of experimental medicine 2007-09, Vol.204 (9), p.2089-2102
• Main Authors: Shiva, Sruti, Sack, Michael N, Greer, James J, Duranski, Mark, Ringwood, Lorna A, Burwell, Lindsay, Wang, Xunde, MacArthur, Peter H, Shoja, Amir, Raghavachari, Nalini, Calvert, John W, Brookes, Paul S, Lefer, David J, Gladwin, Mark T
• Format: Article
• Language: English
• Subjects: Aconitate Hydratase - metabolism; Administration, Oral; Animals; Cytochromes c - secretion; Cytoprotection - drug effects; Electron Transport - drug effects; Electron Transport Complex I - antagonists & inhibitors; Enzyme Activation - drug effects; Ion Channel Gating - drug effects; Ischemic Preconditioning; Liver - blood supply; Liver - pathology; Male; Mice; Mice, Inbred C57BL; Mitochondria - drug effects; Mitochondria - enzymology; Mitochondria - metabolism; Mitochondria - secretion; Mitochondrial Membrane Transport Proteins - metabolism; Molecular Mimicry - drug effects; Myocardial Reperfusion Injury - prevention & control; Nitrites - administration & dosage; Nitrites - pharmacology; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species - metabolism; Reperfusion Injury - prevention & control
• ISSN: 0022-1007; 1540-9538; 1892-1007
• DOI: 10.1084/jem.20070198

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.