Mitophagy is central to mitochondrial and cellular homeostasis and operates via the PINK1/Parkin pathway targeting mitochondria devoid of membrane potential (ΔΨm) to autophagosomes. Although mitophagy is recognized as a fundamental cellular process, selective pharmacologic modulators of mitophagy are almost nonexistent. We developed a compound that increases the expression and signaling of the autophagic adaptor molecule P62/SQSTM1 and forces mitochondria into autophagy. The compound, P62-mediated mitophagy inducer (PMI), activates mitophagy without recruiting Parkin or collapsing ΔΨmand retains activity in cells devoid of a fully functional PINK1/Parkin pathway. PMI drives mitochondria to a process of quality control without compromising the bio-energetic competence of the whole network while exposing just those organelles to be recycled. Thus, PMI circumvents the toxicity and some of the nonspecific effects associated with the abrupt dissipation of ΔΨmby ionophores routinely used to induce mitophagy and represents a prototype pharmacological tool to investigate the molecular mechanisms of mitophagy.

中文翻译：

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PMI：线粒体自噬的 ΔΨm 独立药理调节剂

Mitophagy 是线粒体和细胞稳态的核心，通过 PINK1/Parkin 通路将无膜电位 (ΔΨm) 的线粒体靶向自噬体发挥作用。尽管 mitophagy 被认为是一个基本的细胞过程，但 mitophagy 的选择性药理学调节剂几乎不存在。我们开发了一种化合物，可增加自噬衔接分子 P62/SQSTM1 的表达和信号传导，并迫使线粒体进入自噬状态。该化合物是 P62 介导的线粒体自噬诱导剂 (PMI)，可在不募集 Parkin 或折叠 ΔΨmand 的情况下激活线粒体自噬，并且在缺乏全功能 PINK1/Parkin 通路的细胞中保留活性。PMI 推动线粒体进入质量控制过程，同时不损害整个网络的生物能量能力，同时仅暴露那些待回收的细胞器。因此，