Journal Article

PPTC7 maintains mitochondrial protein content by suppressing receptor-mediated mitophagy

Keller, Mark P., Pagan, Julia K., Serrano, Lia R., Attie, Alan D., Friedman, Jonathan R., Pagliarini, David J., Shishkova, Evgenia, Connor, Olivia M., Muehlbauer, Laura K., Balnis, Catherine E., Smith, Andrew J., Schueler, Kathryn L., Niemi, Natalie M., Forny, Merima, Kozul, Keri-Lyn, Rashan, Edrees H., Coon, Joshua J., Wei, Lianjie

2023

Overview

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. The mitochondrial phosphatase PPTC7 has previously been linked to the maintenance of mitochondrial content, but the mechanisms underlying this phenotype remain unclear. Here, the authors demonstrate that loss of Pptc7 results in metabolic defects and further suggest that PPTC7 is a regulator of receptor-mediated mitophagy.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13 / 13/31 / 14 / 631/443/319/333 / 631/45/475 / 631/80/39/2348 / 631/80/642/333 / 82/58 / 96 / 96/95 / Animals / BNIP3 protein / Defects / Deletion / Embryo fibroblasts / Fibroblasts / Fibroblasts - metabolism / Humanities and Social Sciences / Metabolic pathways / Metabolism / Mice / Mitochondria / Mitochondria - genetics / Mitochondria - metabolism / Mitochondrial Proteins - genetics / Mitochondrial Proteins - metabolism / Mitophagy / Mitophagy - genetics / multidisciplinary / Phenotypes / Phosphatase / Phosphoric Monoester Hydrolases - metabolism / Phosphorylation / Proteins / Receptors / Science / Science (multidisciplinary) / Triglycerides