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

Ramaneeya Nithipongvanitch ¹, Wanida Ittarat ¹, Joyce M. Velez ¹, Rui Zhao ¹, Daret K. St. Clair ¹ and Terry D. Oberley ^1*

¹ 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 Department of Pathology and Laboratory Medicine, William S. Middleton Memorial Veterans Administration Hospital, Madison, Wisconsin (TDO)

^* To whom correspondence should be addressed. E-mail: toberley{at}wisc.edu.

Submitted on November 12, 2006
Accepted on 2 February 2007

	Abstract

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. Herein, we demonstrate that stress caused by ADR induced up-regulation of p53 protein in cardiomyocyte mitochondria and nuclei between 3-24 h. 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 h 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.

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

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