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Am J Physiol Heart Circ Physiol 291: H2462-H2472, 2006. First published June 9, 2006; doi:10.1152/ajpheart.01311.2005
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Alterations in oxidative phosphorylation complex proteins in the hearts of transgenic mice that overexpress the p38 MAP kinase activator, MAP kinase kinase 6

Jason A. Wall,1 Jing Wei,2 Mimi Ly,1 Peter Belmont,1 Joshua J. Martindale,1 Diem Tran,2 Jun Sun,2 Wenqiong J. Chen,2 Wen Yu,2 Paul Oeller,2 Steve Briggs,3 Asa B. Gustafsson,4 M. R. Sayen,4 Roberta A. Gottlieb,4 and Christopher C. Glembotski1

1San Diego State University Heart Institute and The Department of Biology, San Diego State University, San Diego; 2Diversa Corporation, San Diego; 3Division of Biological Sciences, University of California-San Diego, La Jolla; and 4Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California

Submitted 13 December 2005 ; accepted in final form 10 May 2006

Ischemia-reperfusion (I/R) has critical consequences in the heart. Recent studies on the functions of I/R-activated kinases, such as p38 mitogen-activated protein kinase (MAPK), showed that I/R injury is reduced in the hearts of transgenic mice that overexpress the p38 MAPK activator MAPK kinase 6 (MKK6). This protection may be fostered by changes in the levels of many proteins not currently known to be regulated by p38. To examine this possibility, we employed the multidimensional protein identification technology MudPIT to characterize changes in levels of proteins in MKK6 transgenic mouse hearts, focusing on proteins in mitochondria, which play key roles in mediating I/R injury in the heart. Of the 386 mitochondrial proteins identified, the levels of 58 were decreased, while only 2 were increased in the MKK6 transgenic mouse hearts. Among those that were decreased were 21 mitochondrial oxidative phosphorylation complex proteins, which was unexpected because p38 is not known to mediate such decreases. Immunoblotting verified that proteins in each of the five oxidative phosphorylation complexes were reduced in MKK6 mouse hearts. On assessing functional consequences of these reductions, we found that MKK6 mouse heart mitochondria exhibited 50% lower oxidative respiration and I/R-mediated reactive oxygen species (ROS) generation, both of which are predicted consequences of decreased oxidative phosphorylation complex proteins. Thus the cardioprotection observed in MKK6 transgenic mouse hearts may be partly due to decreased electron transport, which is potentially beneficial, because damaging ROS are known to be generated by mitochondrial complexes I and III during reoxygenation.

ischemia-reperfusion; mitochondrial complex proteins; mitogen-activated protein


Address for reprint requests and other correspondence: C. C. Glembotski, The SDSU Heart Institute and the Dept. of Biology, San Diego State Univ., San Diego, CA 92182 (cglembotski{at}sciences.sdsu.edu)




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