Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
Biomolecular Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.
Sci Rep. 2018 Jun 11;8(1):8855. doi: 10.1038/s41598-018-26949-6.
The discovery of mutations within genes associated with autosomal recessive Parkinson's disease allowed for the identification of PINK1/Parkin regulated mitophagy as an important pathway for the removal of damaged mitochondria. While recent studies suggest that AKT-dependent signalling regulates Parkin recruitment to depolarised mitochondria, little is known as to whether this can also regulate PINK1 mitochondrial accumulation and downstream mitophagy. Here, we demonstrate that inhibition of AKT signalling decreases endogenous PINK1 accumulation in response to mitochondria depolarisation, subsequent Parkin recruitment, phosphorylation of ubiquitin, and ultimately mitophagy. Conversely, we show that upon stimulation of AKT signalling via insulin, the mitophagy pathway is increased in SHSY5Y cells. These data suggest that AKT signalling is an upstream regulator of PINK1 accumulation on damaged mitochondria. Importantly, we show that the AKT pathway also regulates endogenous PINK1-dependent mitophagy in human iPSC-derived neurons.
基因突变的发现与常染色体隐性帕金森病相关，这使得 PINK1/Parkin 调节的线粒体自噬成为清除受损线粒体的重要途径。虽然最近的研究表明 AKT 依赖性信号通路调节 Parkin 募集到去极化的线粒体，但对于 AKT 是否也可以调节 PINK1 在线粒体中的积累以及下游的线粒体自噬知之甚少。在这里，我们证明 AKT 信号通路的抑制可减少内源性 PINK1 在响应线粒体去极化、随后的 Parkin 募集、泛素磷酸化以及最终的线粒体自噬时的积累。相反，我们发现通过胰岛素刺激 AKT 信号通路，SHSY5Y 细胞中的线粒体自噬途径增加。这些数据表明 AKT 信号通路是 PINK1 在受损线粒体上积累的上游调节剂。重要的是，我们表明 AKT 通路也调节人诱导多能干细胞源性神经元中内源性 PINK1 依赖性的线粒体自噬。
