Department of Cardiovascular Medicine, Kyoto Prefectural University School of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan.
Nat Commun. 2013;4:2308. doi: 10.1038/ncomms3308.
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.
累积证据表明，线粒体功能障碍在心力衰竭的进展中起作用，但线粒体质量控制机制是否参与心脏功能障碍的发展尚不清楚。在这里，我们发现细胞质 p53 会损害受损线粒体的自噬降解，从而促进小鼠的线粒体功能障碍和心力衰竭。体外和体内实验表明，衰老或阿霉素处理会减弱线粒体自噬的发生和诱导。我们发现细胞质 p53 与 Parkin 结合，并干扰其向受损线粒体的易位及其随后通过线粒体自噬的清除。p53 缺陷型小鼠在年龄增长或阿霉素处理后，线粒体完整性和心脏功能储备的下降程度较小。此外，Parkin 的过表达可改善老年心脏的功能下降，同时伴随着衰老相关β-半乳糖苷酶活性和促炎表型的减少。因此，p53 介导的抑制线粒体自噬可调节心脏功能障碍，提示通过抑制细胞质 p53 激活线粒体自噬可能改善心力衰竭和心脏老化的症状。
