PDF(Pubmed)
Abstract：
Mitophagy must be carefully regulated to ensure that cells maintain appropriate numbers of functional mitochondria. The SCFFBXL4 ubiquitin ligase complex suppresses mitophagy by controlling the degradation of BNIP3 and NIX mitophagy receptors, and FBXL4 mutations result in mitochondrial disease as a consequence of elevated mitophagy. Here, we reveal that the mitochondrial phosphatase PPTC7 is an essential cofactor for SCFFBXL4-mediated destruction of BNIP3 and NIX, suppressing both steady-state and induced mitophagy. Disruption of the phosphatase activity of PPTC7 does not influence BNIP3 and NIX turnover. Rather, a pool of PPTC7 on the mitochondrial outer membrane acts as an adaptor linking BNIP3 and NIX to FBXL4, facilitating the turnover of these mitophagy receptors. PPTC7 accumulates on the outer mitochondrial membrane in response to mitophagy induction or the absence of FBXL4, suggesting a homoeostatic feedback mechanism that attenuates high levels of mitophagy. We mapped critical residues required for PPTC7-BNIP3/NIX and PPTC7-FBXL4 interactions and their disruption interferes with both BNIP3/NIX degradation and mitophagy suppression. Collectively, these findings delineate a complex regulatory mechanism that restricts BNIP3/NIX-induced mitophagy.
摘要：
必须仔细调节线粒体自噬，以确保细胞维持适当数量的功能性线粒体。SCFFBXL4泛素连接酶复合物通过控制BNIP3和NIX线粒体自噬受体的降解来抑制线粒体自噬，和FBXL4突变由于线粒体自噬升高而导致线粒体疾病。这里,我们发现线粒体磷酸酶PPTC7是SCFFBXL4介导的BNIP3和NIX破坏的重要辅因子，抑制稳态和诱导的线粒体自噬。PPTC7磷酸酶活性的破坏不会影响BNIP3和NIX的周转。相反，线粒体外膜上的PPTC7库充当将BNIP3和NIX连接到FBXL4的衔接子,促进这些线粒体自噬受体的周转。PPTC7响应于线粒体自噬诱导或FBXL4的不存在而在线粒体外膜上积累，表明具有减弱高水平的线粒体自噬的同质性反馈机制。我们绘制了PPTC7-BNIP3/NIX和PPTC7-FBXL4相互作用所需的关键残基，它们的破坏会干扰BNIP3/NIX降解和线粒体自噬抑制。总的来说，这些发现描述了限制BNIP3/NIX诱导的线粒体自噬的复杂调节机制.
