Nitration of specific tyrosines in FoF1 ATP synthase and activity loss in aging

Haynes V, Traaseth NJ, Elfering S, Fujisawa Y, Giulivi C. Nitration of specific tyrosines in FoF1 ATP synthase and activity loss in aging. Am J Physiol Endocrinol Metab 298: E978-E987, 2010. First published February 16, 2010; doi: 10.1152/ajpendo.00739.2009.-It has been reported that C-nitration of proteins occurs under nitrative/oxidative stress; however, its role in pathophysiological situations is not fully understood. In this study, we determined that nitration of Tyr(345) and Tyr(368) in the beta-subunit of the mitochondrial FoF1-ATPase is a major target for nitrative stress in rat liver under in vivo conditions. The chemical characteristics of these Tyr make them suitable for a facilitated nitration (solvent accessibility, consensus sequence, and pK(a)). Moreover, beta-subunit nitration increased significantly with the age of the rats (from 4 to 80 weeks old) and correlated with decreased ATP hydrolysis and synthesis rates. Although its affinity for ATP binding was unchanged, maximal ATPase activity decreased between young and old rats by a factor of two. These changes directly impacted the available ATP concentration in vivo, and it was expected that they would affect multiple cellular ATP-dependent processes. For instance, at least 50% of available [ATP] in the liver of older rats would have to be committed to sustain maximal Na+-K+-ATPase activity, whereas only 30% would be required for young rats. If this requirement was not fulfilled, the osmoregulation and Na+-nutrient cotransport in liver of older rats would be compromised. On the basis of our studies, we propose that targeted nitration of the beta-subunit is an early marker for nitrative stress and aging.