Reference - Detail
| 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 | 2013-1-1 |
| 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 |
| Times Cited | 216 |
| WOS Category | CELL BIOLOGY |
| Altmetric score |
オルトメトリクス指標項目
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| The most frequently cited source | X(Twitter) |
| Total number of mentions | 5 |
| Altmetric score changes over past 6months | 0.0 |
| Resource | |
| Mice | RBRC00806 |