PPTC7 maintains mitochondrial protein content by suppressing receptor-mediated mitophagy

Natalie M. Niemi (), Lia R. Serrano, Laura K. Muehlbauer, Catherine E. Balnis, Lianjie Wei, Andrew J. Smith, Keri-Lyn Kozul, Merima Forny, Olivia M. Connor, Edrees H. Rashan, Evgenia Shishkova, Kathryn L. Schueler, Mark P. Keller, Alan D. Attie, Jonathan R. Friedman, Julia K. Pagan, Joshua J. Coon and David J. Pagliarini ()
Additional contact information
Natalie M. Niemi: Morgridge Institute for Research
Lia R. Serrano: University of Wisconsin-Madison
Laura K. Muehlbauer: University of Wisconsin-Madison
Catherine E. Balnis: University of Wisconsin-Madison
Lianjie Wei: Washington University School of Medicine
Andrew J. Smith: Washington University School of Medicine
Keri-Lyn Kozul: University of Queensland
Merima Forny: Washington University School of Medicine
Olivia M. Connor: University of Texas Southwestern Medical Center
Edrees H. Rashan: University of Wisconsin-Madison
Evgenia Shishkova: University of Wisconsin-Madison
Kathryn L. Schueler: University of Wisconsin-Madison
Mark P. Keller: University of Wisconsin-Madison
Alan D. Attie: University of Wisconsin-Madison
Jonathan R. Friedman: University of Texas Southwestern Medical Center
Julia K. Pagan: University of Queensland
Joshua J. Coon: Morgridge Institute for Research
David J. Pagliarini: Morgridge Institute for Research

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-42069-w

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