Age-associated changes in SAPK/JNK and p38 MAPK signaling in response to the generation of ROS by 3-nitropropionic acid.
Mitochondrial dysfunction has been identified as a major source of oxidative stress in aged tissues. In this study we asked whether activities of components of the SAPK/JNK and p38 MAPK stress response signaling pathways are indicative of oxidative stress in aged mouse livers and whether these pathways are responsive to oxidative stress generated by 3-nitropropionic acid (3-NPA), an inhibitor of complex II (succinic dehydrogenase). We asked whether (a) aging affects the basal activity of the SAPK/JNK stress signaling pathway; (b) specific isoforms of JNK, i.e. 46 or 54 kDa JNKs are activated by 3-NPA; (c) aging affects the response of this signaling pathway to 3-NPA; (d) there is a cross pathway activation of JNK or p38 MAPK by upstream activators. Our studies have shown that although their protein pool levels are not altered, the basal JNK activities using c-Jun as substrate is elevated. Furthermore, in aged livers, JNK activity is induced to a greater extent and takes longer to recover from 3-NPA treatment. The activities of the upstream activators of JNKs, MAP kinase kinase (MKK) 4 and 7, are also elevated in livers of aged C57BL/6 male mice. These activator kinases, which are induced (phosphorylated) by 3-NPA in young livers, are not inducible by this inhibitor in aged livers. In fact, these proteins are highly phosphorylated in the control aged livers and are dephosphorylated in response to 3-NPA. Finally, we demonstrate for the first time that MKK7 serves as an upstream activator of p38 MAPK and that MKK3 and MKK6 activates 54 kDa JNK2 in aged liver. Our studies suggest that failure to respond to 3-NPA may be indicative of the susceptibility of aged tissue to oxidative stress, supporting our hypothesis that aged tissues (especially liver) develop a state of chronic stress even in the absence of a challenge.
Hsieh
Ching-Chyuan
CC
Department of Human Biological Chemistry and Genetics, University of Texas Medical Branch, 613 Basic Science Building, Rt. 0643, Galveston, TX 77555-0643, USA.
Rosenblatt
Judah I
JI
Papaconstantinou
John
J
D000375:Aging / Q000378:metabolism*; D000818:Animals; D003292:Convulsants / Q000494:pharmacology; D008099:Liver / Q000201:enzymology; D048688:MAP Kinase Kinase 7; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D048055:Mitogen-Activated Protein Kinase 8; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009574:Nitro Compounds; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation; D011422:Propionates / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases
D003292:Convulsants; D009574:Nitro Compounds; D011422:Propionates; D017382:Reactive Oxygen Species; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048688:MAP Kinase Kinase 7; C482570:Map2k7 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases; C015392:3-nitropropionic acid