Abstract 10273: p53 Promotes Cardiac Aging Through The Inhibition Of Parkin Mediated Mitochondrial Quality Control
Background: The current understanding of the molecular mechanism to keep up mitochondrial integrity provokes interest in the association between aging process and mitochondrial compromise. We investigated the mechanism of cardiac aging with focus on mitochondrial quality control.
Methods and results: We performed cardiac catheterization to examine aging related changes in cardiac function. Dobutamine infusion revealed that cardiac function reserve was impaired in 20-month aged mice. Mitochondrial integrity assessed by mitochondrial DNA deletion and complexes I, II and IV driven oxygen consumption was declined in aged mice hearts. Long-term effect of doxorubicin (DOX) at a lower dose of 7.5mg/kg body weight showed that aged mice hearts were susceptible to mitochondrial damage as compared with young mice hearts. We speculated that impaired mitochondrial quality control contributes to age-related decline of mitochondrial integrity and cardiac function. Transcription of molecules associated with mitophagy and mitochondrial dynamics did not differ between young and aged mice hearts, we therefore focused on protein-protein interaction. Immunoprecipitation assay in HL-1 cells treated with 20nM DOX to induce premature senescence provided evidence of functional association between parkin and p53 which was up-regulated in aged mice hearts. p53 inhibited CCCP-induced ubiquitination of mitochondria and subsequent mitophagy in DOX treated HL-1 cells without affecting the mitochondrial translocation of parkin. In vivo, the resistance to DOX-mediated mitochondrial compromise and cardiac dysfunction in p53-/- hearts was negated in p53-/-parkin-/- hearts. Finally we examined the effect of p53-parkin interaction on cardiac aging. Mitochondrial integrity and cardiac function reserve were sustained in 20-month aged p53+/- hearts; however, those in aged p53+/-parkin+/- hearts were impaired partially to the level of aged wild-type and parkin+/- hearts.
Conclusions: This study provided evidence that p53 activation disturbed parkin-mediated mitochondrial quality control. This p53-parkin association expands our understanding of age-related mitochondrial compromise and cardiac dysfunction.
- © 2011 by American Heart Association, Inc.