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Evidence for p53 as Guardian of the Cardiomyocyte Mitochondrial Genome Following Acute Adriamycin Treatment

Ramaneeya Nithipongvanitch, Wanida Ittarat, Joyce M. Velez, Rui Zhao, Daret K. St. Clair and Terry D. Oberley

Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin (RN,RZ,TDO); Faculty of Medical Technology, Mahidol University, Bangkok, Thailand (RN,WI); Department of Toxicology, University of Kentucky, Lexington, Kentucky (JMV,DKSC); and William S. Middleton Memorial Veterans Administration Hospital, Madison Wisconsin (TDO)

Correspondence to: Dr. Terry D. Oberley, MD, PhD, Department of Pathology and Laboratory Medicine, William S. Middleton Memorial Veterans Administration Hospital, Room A-35, 2500 Overlook Terrace, Madison, WI 53705. E-mail: toberley{at}wisc.edu. Co-corresponding author: Dr. Daret St. Clair. E-mail: dstcl00{at}pop.uky.edu

The present study is an initial analysis of whether p53 may function as guardian of the cardiomyocyte mitochondrial genome, with mitochondrial p53 localization proposed to be involved in both mitochondrial DNA (mtDNA) repair and apoptosis. Subcellular distribution, protein levels, and possible function(s) of p53 protein in the response of cardiomyocytes to adriamycin (ADR) were analyzed. Levels and subcellular localization of proteins were determined by Western blot and immunogold ultrastructural analysis techniques. Here we demonstrate that stress caused by ADR induced upregulation of p53 protein in cardiomyocyte mitochondria and nuclei between 3 and 24 hr. Increased expression of PUMA and Bax proteins, pro-apoptotic targets of p53, was documented following ADR treatment and was accompanied by increased levels of apoptotic markers, with elevation of cytosolic cytochrome c at 24 hr and subsequent caspase-3 cleavage at 3 days. Mitochondrial p53 levels correlated with mtDNA oxidative damage. Loss of p53 in knockout mouse heart resulted in a significant increase in mtDNA vulnerability to damage following ADR treatment. Our results suggest that mitochondrial p53 could participate in mtDNA repair as a first response to oxidative damage of cardiomyocyte mtDNA and demonstrate an increase of apoptotic markers as a result of mitochondrial/nuclear p53 localization. (J Histochem Cytochem 55:629–639, 2007)

Key Words: apoptosis • cardiomyopathy • doxorubicin • mitochondrial DNA • oxidative stress

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