Abstract 11874: Inhibition of Cytosolic p53 Preserves Mitochondrial Integrity and Prevents Cardiac Aging
Aging is a complex process influenced by diverse molecular factors with accumulation of organellar, cellular, and organ damage, leading to functional decline and increased susceptibility to disease and death. Mitochondrial dysfunction is central to theories of aging, whereas it remains unresolved how mitochondrial quality control is involved in the process of aging. Here we show that cytosolic p53 impairs autophagic degradation of mitochondria (mitophagy) and promotes mitochondrial compromise and cardiac aging. We found that cytosolic p53 could bind to Parkin, a key modulator of mitophagy to disturb its mitochondrial translocation followed by unexecuted ubiquitination and clearance. The inhibitory interaction between p53 and Parkin was involved in impaired mitochondrial integrity and subsequent functional decline of mitochondrial respiration and cardiac functional reserve in both doxorubicin-mediated pathological aging and biological aging. In contrast, upregulation of Parkin was resistant to functional decline in cardiac aging, which interestingly ameliorated age-associated alterations including senescence-associated[[Unable to Display Character: ]]β-galactosidase activity and inflammatory state. These results provide a novel concept that p53-mediated inhibition of mitophagy provokes a vicious cycle of mitochondrial compromise, inflammation and aging, which contributes to age-dependent decline of organismal fitness and may become a novel target to prevent aging and aging related diseases.
- © 2012 by American Heart Association, Inc.