Morgridge Institute for Research, Madison, WI, 53715, USA.
Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO, 63110, USA.
Nat Commun. 2023 Oct 13;14(1):6431. doi: 10.1038/s41467-023-42069-w.
PPTC7 is a resident mitochondrial phosphatase essential for maintaining proper mitochondrial content and function. Newborn mice lacking Pptc7 exhibit aberrant mitochondrial protein phosphorylation, suffer from a range of metabolic defects, and fail to survive beyond one day after birth. Using an inducible knockout model, we reveal that loss of Pptc7 in adult mice causes marked reduction in mitochondrial mass and metabolic capacity with elevated hepatic triglyceride accumulation. Pptc7 knockout animals exhibit increased expression of the mitophagy receptors BNIP3 and NIX, and Pptc7 mouse embryonic fibroblasts (MEFs) display a major increase in mitophagy that is reversed upon deletion of these receptors. Our phosphoproteomics analyses reveal a common set of elevated phosphosites between perinatal tissues, adult liver, and MEFs, including multiple sites on BNIP3 and NIX, and our molecular studies demonstrate that PPTC7 can directly interact with and dephosphorylate these proteins. These data suggest that Pptc7 deletion causes mitochondrial dysfunction via dysregulation of several metabolic pathways and that PPTC7 may directly regulate mitophagy receptor function or stability. Overall, our work reveals a significant role for PPTC7 in the mitophagic response and furthers the growing notion that management of mitochondrial protein phosphorylation is essential for ensuring proper organelle content and function.
PPTC7 是一种驻留在线粒体中的磷酸酶，对于维持线粒体的正常含量和功能至关重要。缺乏 Pptc7 的新生小鼠表现出异常的线粒体蛋白磷酸化，患有一系列代谢缺陷，并且在出生后一天内无法存活。使用诱导型敲除模型，我们揭示了成年小鼠中 Pptc7 的缺失导致线粒体质量和代谢能力明显降低，同时伴有肝甘油三酯积累增加。Pptc7 敲除动物表现出线粒体自噬受体 BNIP3 和 NIX 的表达增加，而 Pptc7 小鼠胚胎成纤维细胞（MEFs）显示出明显增加的线粒体自噬，这些受体缺失后会逆转这种情况。我们的磷酸蛋白质组学分析揭示了围产期组织、成年肝脏和 MEFs 之间存在一组共同的上调磷酸化位点，包括 BNIP3 和 NIX 上的多个位点，我们的分子研究表明 PPTC7 可以直接与这些蛋白质相互作用并去磷酸化它们。这些数据表明，Pptc7 的缺失通过几个代谢途径的失调导致线粒体功能障碍，并且 PPTC7 可能直接调节线粒体自噬受体的功能或稳定性。总的来说，我们的工作揭示了 PPTC7 在自噬反应中的重要作用，并进一步证明了管理线粒体蛋白磷酸化对于确保细胞器的正常含量和功能至关重要。
