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PPTC7 maintains mitochondrial protein content by suppressing receptor-mediated mitophagy

Author

Listed:
  • Natalie M. Niemi

    (Morgridge Institute for Research
    Washington University School of Medicine)

  • 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
    National Center for Quantitative Biology of Complex Systems)

  • 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
    Institute for Molecular Bioscience
    The University of Queensland)

  • Joshua J. Coon

    (Morgridge Institute for Research
    University of Wisconsin-Madison
    University of Wisconsin-Madison
    National Center for Quantitative Biology of Complex Systems)

  • David J. Pagliarini

    (Morgridge Institute for Research
    Washington University School of Medicine
    Washington University School of Medicine
    University of Wisconsin-Madison)

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.

Suggested Citation

  • 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 , 2023. "PPTC7 maintains mitochondrial protein content by suppressing receptor-mediated mitophagy," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42069-w
    DOI: 10.1038/s41467-023-42069-w
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    References listed on IDEAS

    as
    1. Tomokazu Murakawa & Osamu Yamaguchi & Ayako Hashimoto & Shungo Hikoso & Toshihiro Takeda & Takafumi Oka & Hiroki Yasui & Hiromichi Ueda & Yasuhiro Akazawa & Hiroyuki Nakayama & Manabu Taneike & Tomofu, 2015. "Bcl-2-like protein 13 is a mammalian Atg32 homologue that mediates mitophagy and mitochondrial fragmentation," Nature Communications, Nature, vol. 6(1), pages 1-14, November.
    2. Natalie M. Niemi & Gary M. Wilson & Katherine A. Overmyer & F.-Nora Vögtle & Lisa Myketin & Danielle C. Lohman & Kathryn L. Schueler & Alan D. Attie & Chris Meisinger & Joshua J. Coon & David J. Pagli, 2019. "Pptc7 is an essential phosphatase for promoting mammalian mitochondrial metabolism and biogenesis," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    3. Corvin Walter & Adinarayana Marada & Tamara Suhm & Ralf Ernsberger & Vera Muders & Cansu Kücükköse & Pablo Sánchez-Martín & Zehan Hu & Abhishek Aich & Stefan Loroch & Fiorella Andrea Solari & Daniel P, 2021. "Global kinome profiling reveals DYRK1A as critical activator of the human mitochondrial import machinery," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
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