Institute of Biochemistry and Molecular Biology, Ulm University, D-89081 Ulm, Germany.
Institute of Anesthesiological Pathophysiology and Process Development, Ulm University, D-89081 Ulm, Germany.
Cells. 2019 Aug 14;8(8):894. doi: 10.3390/cells8080894.
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.
核仁应激是细胞对核糖体生物发生或核仁破坏的抑制的反应，导致细胞周期停滞和/或细胞凋亡。新出现的证据表明，核仁应激与自噬之间存在紧密联系，自噬是神经退行性疾病和癌症治疗等各种疾病的潜在机制。Peter Pan（PPAN）是核糖体生物发生的关键调节因子。我们之前曾表明，人 PPAN 定位于核仁线粒体，并且 PPAN 敲低会触发 p53 非依赖性核仁应激反应，最终导致线粒体凋亡。在这里，我们证明了 PPAN 在调节线粒体稳态和自噬中的新作用。本研究将 PPAN 表征为维持线粒体完整性呼吸偶联 ATP 产生所需的因子。PPAN 与心磷脂相互作用，心磷脂是线粒体内部膜的脂质。PPAN 的下调增强了癌细胞中的自噬通量。PPAN 敲低促进了 E3-泛素连接酶 Parkin 到受损线粒体的募集。此外，我们提供的证据表明，PPAN 敲低会减少 Parkin 表达细胞中的线粒体质量。总之，我们的研究揭示了 PPAN 敲低与线粒体损伤有关，并刺激自噬。
