Cytosolic p53 inhibits Parkin-mediated mitophagy and promotes mitochondrial dysfunction in the mouse heart

Atsushi Hoshino, Yuichiro Mita, Yoshifumi Okawa, Makoto Ariyoshi, Eri Iwai-Kanai, Tomomi Ueyama, Koji Ikeda, Takehiro Ogata and Satoaki Matoba ()
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Atsushi Hoshino: Kyoto Prefectural University School of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku
Yuichiro Mita: Kyoto Prefectural University School of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku
Yoshifumi Okawa: Kyoto Prefectural University School of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku
Makoto Ariyoshi: Kyoto Prefectural University School of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku
Eri Iwai-Kanai: Kyoto Prefectural University School of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku
Tomomi Ueyama: Kyoto Prefectural University School of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku
Koji Ikeda: Kyoto Prefectural University School of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku
Takehiro Ogata: Kyoto Prefectural University School of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku
Satoaki Matoba: Kyoto Prefectural University School of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku

Nature Communications, 2013, vol. 4, issue 1, 1-12

Abstract: 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.

Date: 2013
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:4:y:2013:i:1:d:10.1038_ncomms3308

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DOI: 10.1038/ncomms3308

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