Mitophagy mediated by BNIP3 and NIX critically regulates mitochondrial mass. Cellular BNIP3 and NIX levels are tightly controlled by SCF^FBXL4-mediated ubiquitination to prevent excessive mitochondrial loss and lethal disease. Here, we report that knockout of PPTC7, a mitochondrial matrix protein, hyperactivates BNIP3-/NIX-mediated mitophagy and causes perinatal lethality that is rescued by NIX knockout in mice. Biochemically, the PPTC7 precursor is trapped by BNIP3 and NIX to the mitochondrial outer membrane, where PPTC7 scaffolds assembly of a substrate-PPTC7-SCF^FBXL4 holocomplex to degrade BNIP3 and NIX, forming a homeostatic regulatory loop. PPTC7 possesses an unusually weak mitochondrial targeting sequence to facilitate its outer membrane retention and mitophagy control. Starvation upregulates PPPTC7 expression in mouse liver to repress mitophagy, which critically maintains hepatic mitochondrial mass, bioenergetics, and gluconeogenesis. Collectively, PPTC7 functions as a mitophagy sensor that integrates homeostatic and physiological signals to dynamically control BNIP3 and NIX degradation, thereby maintaining mitochondrial mass and cellular homeostasis.

BNIP3 和 NIX 介导的线粒体自噬关键性地调节线粒体质量。细胞 BNIP3 和 NIX 水平受到 SCF ^FBXL4介导的泛素化的严格控制，以防止线粒体过度丢失和致命疾病。在这里，我们报告敲除PPTC7（一种线粒体基质蛋白）会过度激活BNIP3-/NIX介导的线粒体自噬，并导致围产期死亡，而NIX敲除可挽救小鼠的围产期死亡。生物化学上，PPTC7 前体被 BNIP3 和 NIX 捕获到线粒体外膜，在线粒体外膜上，PPTC7 支架组装底物 -PPTC7-SCF ^FBXL4全复合物以降解 BNIP3 和 NIX，形成稳态调节环。 PPTC7 具有异常弱的线粒体靶向序列，以促进其外膜保留和线粒体自噬控制。饥饿会上调小鼠肝脏中的 PPPTC7 表达，从而抑制线粒体自噬，这对维持肝脏线粒体质量、生物能和糖异生至关重要。总的来说，PPTC7 充当线粒体自噬传感器，整合稳态和生理信号以动态控制 BNIP3 和 NIX 降解，从而维持线粒体质量和细胞稳态。