RRC ID |
27774
|
著者 |
Hoshino A, Mita Y, Okawa Y, Ariyoshi M, Iwai-Kanai E, Ueyama T, Ikeda K, Ogata T, Matoba S.
|
タイトル |
Cytosolic p53 inhibits Parkin-mediated mitophagy and promotes mitochondrial dysfunction in the mouse heart.
|
ジャーナル |
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.
|
巻・号 |
4
|
ページ |
2308
|
公開日 |
2013-1-1
|
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
Mitophagy* / 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 |
12.121
|
引用数 |
216
|
WOS 分野
|
CELL BIOLOGY
|
リソース情報 |
実験動物マウス |
RBRC00806 |