RRC ID 27774
Author Hoshino A, Mita Y, Okawa Y, Ariyoshi M, Iwai-Kanai E, Ueyama T, Ikeda K, Ogata T, Matoba S.
Title Cytosolic p53 inhibits Parkin-mediated mitophagy and promotes mitochondrial dysfunction in the mouse heart.
Journal Nat Commun
Abstract Cumulative evidence indicates that mitochondrial dysfunction has a role in heart failure progression, but whether mitochondrial quality control mechanisms are involved in the development of cardiac dysfunction remains unclear. Here we show that cytosolic p53 impairs autophagic degradation of damaged mitochondria and facilitates mitochondrial dysfunction and heart failure in mice. Prevalence and induction of mitochondrial autophagy is attenuated by senescence or doxorubicin treatment in vitro and in vivo. We show that cytosolic p53 binds to Parkin and disturbs its translocation to damaged mitochondria and their subsequent clearance by mitophagy. p53-deficient mice show less decline of mitochondrial integrity and cardiac functional reserve with increasing age or after treatment with doxorubicin. Furthermore, overexpression of Parkin ameliorates the functional decline in aged hearts, and is accompanied by decreased senescence-associated β-galactosidase activity and proinflammatory phenotypes. Thus, p53-mediated inhibition of mitophagy modulates cardiac dysfunction, raising the possibility that therapeutic activation of mitophagy by inhibiting cytosolic p53 may ameliorate heart failure and symptoms of cardiac ageing.
Volume 4
Pages 2308
Published 2013
DOI 10.1038/ncomms3308
PII ncomms3308
PMID 23917356
MeSH Aging / pathology Animals Cellular Senescence / drug effects Cytosol / metabolism* Doxorubicin / adverse effects Embryo, Mammalian / pathology Fibroblasts / drug effects Fibroblasts / metabolism HCT116 Cells Heterozygote Humans Mice Mice, Transgenic Mitochondria / drug effects Mitochondria / metabolism* Mitochondria / ultrastructure Mitochondrial Degradation* / drug effects Myocardium / metabolism* Myocardium / pathology* Myocardium / ultrastructure Protein Binding / drug effects Protein Structure, Tertiary Protein Transport / drug effects Tumor Suppressor Protein p53 / metabolism* Ubiquitin-Protein Ligases / chemistry Ubiquitin-Protein Ligases / metabolism*
IF 12.353
Times Cited 83
Mice GFP-LC3#53(RBRC00806)