title: Cytosolic p53 inhibits Parkin-mediated mitophagy and promotes mitochondrial dysfunction in the mouse heart.
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.
authors.affiliation: Department of Cardiovascular Medicine, Kyoto Prefectural University School of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Hoshino
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Mita
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Okawa
authors.forename: Makoto
authors.initials: M
authors.lastname: Ariyoshi
authors.forename: Eri
authors.initials: E
authors.lastname: Iwai-Kanai
authors.forename: Tomomi
authors.initials: T
authors.lastname: Ueyama
authors.forename: Koji
authors.initials: K
authors.lastname: Ikeda
authors.forename: Takehiro
authors.initials: T
authors.lastname: Ogata
authors.forename: Satoaki
authors.initials: S
authors.lastname: Matoba
mesh_terms: D000375:Aging / Q000473:pathology; D000818:Animals; D016922:Cellular Senescence / Q000187:drug effects; D003600:Cytosol / Q000378:metabolism*; D004317:Doxorubicin / Q000009:adverse effects; D004622:Embryo, Mammalian / Q000473:pathology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D045325:HCT116 Cells; D006579:Heterozygote; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D063306:Mitophagy / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology* / Q000648:ultrastructure; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000378:metabolism*
chemical_list: D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein