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Loss of Peter Pan (PPAN) Affects Mitochondrial Homeostasis and Autophagic Flux

1
Institute of Biochemistry and Molecular Biology, Ulm University, D-89081 Ulm, Germany
2
Institute of Anesthesiological Pathophysiology and Process Development, Ulm University, D-89081 Ulm, Germany
3
Central Facility for Electron Microscopy, Ulm University, D-89081 Ulm, Germany
4
Munich Cluster for Systems Neurology, Medical Faculty, Ludwig-Maximilians-University München, D-81377 Munich, Germany
*
Author to whom correspondence should be addressed.
Cells 2019, 8(8), 894; https://doi.org/10.3390/cells8080894
Received: 5 June 2019 / Revised: 30 July 2019 / Accepted: 10 August 2019 / Published: 14 August 2019
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Abstract

Nucleolar stress is a cellular response to inhibition of ribosome biogenesis or nucleolar disruption leading to cell cycle arrest and/or apoptosis. Emerging evidence points to a tight connection between nucleolar stress and autophagy as a mechanism underlying various diseases such as neurodegeneration and treatment of cancer. Peter Pan (PPAN) functions as a key regulator of ribosome biogenesis. We previously showed that human PPAN localizes to nucleoli and mitochondria and that PPAN knockdown triggers a p53-independent nucleolar stress response culminating in mitochondrial apoptosis. Here, we demonstrate a novel role of PPAN in the regulation of mitochondrial homeostasis and autophagy. Our present study characterizes PPAN as a factor required for maintaining mitochondrial integrity and respiration-coupled ATP production. PPAN interacts with cardiolipin, a lipid of the inner mitochondrial membrane. Down-regulation of PPAN enhances autophagic flux in cancer cells. PPAN knockdown promotes recruitment of the E3-ubiquitin ligase Parkin to damaged mitochondria. Moreover, we provide evidence that PPAN knockdown decreases mitochondrial mass in Parkin-expressing cells. In summary, our study uncovers that PPAN knockdown is linked to mitochondrial damage and stimulates autophagy. View Full-Text
Keywords: apoptosis; autophagy; mitochondria; mitophagy; nucleolus; nucleolar stress; Parkin; PPAN; ribosome; Wnt target apoptosis; autophagy; mitochondria; mitophagy; nucleolus; nucleolar stress; Parkin; PPAN; ribosome; Wnt target
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Dannheisig, D.P.; Beck, E.; Calzia, E.; Walther, P.; Behrends, C.; Pfister, A.S. Loss of Peter Pan (PPAN) Affects Mitochondrial Homeostasis and Autophagic Flux. Cells 2019, 8, 894.

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