CNC – Center for Neuroscience and Cell Biology, Institute of Biology, University of Coimbra, Coimbra, Portugal.
Hum Mol Genet. 2012 Nov 1;21(21):4680-702. doi: 10.1093/hmg/dds309. Epub 2012 Jul 27.
Abnormal presence of autophagic vacuoles is evident in brains of patients with Parkinson's disease (PD), in contrast to the rare detection of autophagosomes in a normal brain. However, the actual cause and pathological significance of these observations remain unknown. Here, we demonstrate a role for mitochondrial metabolism in the regulation of the autophagy-lysosomal pathway in ex vivo and in vitro models of PD. We show that transferring mitochondria from PD patients into cells previously depleted of mitochondrial DNA is sufficient to reproduce the alterations in the autophagic system observed in PD patient brains. Although the initial steps of this pathway are not compromised, there is an increased accumulation of autophagosomes associated with a defective autophagic activity. We prove that this functional decline was originated from a deficient mobilization of autophagosomes from their site of formation toward lysosomes due to disruption in microtubule-dependent trafficking. This contributed directly to a decreased proteolytic flux of α-synuclein and other autophagic substrates. Our results lend strong support for a direct impact of mitochondria in autophagy as defective autophagic clearance ability secondary to impaired microtubule trafficking is driven by dysfunctional mitochondria. We uncover mitochondria and mitochondria-dependent intracellular traffic as main players in the regulation of autophagy in PD.
帕金森病（PD）患者的大脑中明显存在自噬空泡异常，而在正常大脑中很少检测到自噬体。然而，这些观察结果的实际原因和病理意义仍然未知。在这里，我们在 PD 的离体和体外模型中证明了线粒体代谢在调控自噬溶酶体途径中的作用。我们表明，将来自 PD 患者的线粒体转移到先前耗尽线粒体 DNA 的细胞中，足以重现 PD 患者大脑中观察到的自噬系统的改变。尽管该途径的初始步骤没有受到损害，但与自噬活性缺陷相关的自噬体的积累增加。我们证明，这种功能下降源于自噬体从形成部位向溶酶体的迁移由于微管依赖性运输的中断而受损，导致自噬体的功能下降。这直接导致α-突触核蛋白和其他自噬底物的蛋白水解通量减少。我们的研究结果为线粒体对自噬的直接影响提供了有力支持，因为由于微管运输受损导致的自噬清除能力缺陷是由功能失调的线粒体驱动的。我们发现线粒体和依赖线粒体的细胞内运输是 PD 中自噬调节的主要参与者。
