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

Cells

卷:8

Paul Walther¹  Enrico Calzia²  AstridS. Pfister³  Eileen Beck³  DavidP. Dannheisig³  Christian Behrends⁴ 

[1] Central Facility for Electron Microscopy, Ulm University, D-89081 Ulm, Germany;

[2] Institute of Anesthesiological Pathophysiology and Process Development, Ulm University, D-89081 Ulm, Germany;

[3] Institute of Biochemistry and Molecular Biology, Ulm University, D-89081 Ulm, Germany;

[4] Munich Cluster for Systems Neurology, Medical Faculty, Ludwig-Maximilians-University München, D-81377 Munich, Germany;

关键词: apoptosis;    autophagy;    mitochondria;    mitophagy;    nucleolus;    nucleolar stress;    Parkin;    PPAN;    ribosome;    Wnt target;   

DOI  :  10.3390/cells8080894

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown