Institute of Neurogenetics, University of Luebeck, 23562 Luebeck, Germany;
Institute of Neurogenetics, University of Luebeck, 23562 Luebeck, Germany.
Proc Natl Acad Sci U S A. 2021 Oct 26;118(43). doi: 10.1073/pnas.2025347118.
Energy production via the mitochondrial electron transport chain (ETC) and mitophagy are two important processes affected in Parkinson's disease (PD). Interestingly, PINK1, mutations of which cause early-onset PD, plays a key role in both processes, suggesting that these two mechanisms are connected. However, the converging link of both pathways currently remains enigmatic. Recent findings demonstrated that lipid aggregation, along with defective mitochondria, is present in postmortem brains of PD patients. In addition, an increasing body of evidence shows that sphingolipids, including ceramide, are altered in PD, supporting the importance of lipids in the pathophysiology of PD. Here, we identified ceramide to play a crucial role in PINK1-related PD that was previously linked almost exclusively to mitochondrial dysfunction. We found ceramide to accumulate in mitochondria and to negatively affect mitochondrial function, most notably the ETC. Lowering ceramide levels improved mitochondrial phenotypes in -mutant flies and PINK1-deficient patient-derived fibroblasts, showing that the effects of ceramide are evolutionarily conserved. In addition, ceramide accumulation provoked ceramide-induced mitophagy upon PINK1 deficiency. As a result of the ceramide accumulation, β-oxidation in mutants was decreased, which was rescued by lowering ceramide levels. Furthermore, stimulation of β-oxidation was sufficient to rescue PINK1-deficient phenotypes. In conclusion, we discovered a cellular mechanism resulting from PD-causing loss of PINK1 and found a protective role of β-oxidation in ETC dysfunction, thus linking lipids and mitochondria in the pathophysiology of PINK1-related PD. Furthermore, our data nominate β-oxidation and ceramide as therapeutic targets for PD.
通过线粒体电子传递链 (ETC) 和线粒体自噬产生能量是受帕金森病 (PD) 影响的两个重要过程。有趣的是，导致早发性 PD 的 PINK1 突变在这两个过程中都起着关键作用，这表明这两种机制是相关的。然而，这两种途径的汇聚联系目前仍然是个谜。最近的发现表明，脂类聚集以及有缺陷的线粒体存在于 PD 患者的死后大脑中。此外，越来越多的证据表明，鞘脂类，包括神经酰胺，在 PD 中发生改变，支持脂质在 PD 病理生理学中的重要性。在这里，我们确定神经酰胺在以前几乎完全与线粒体功能障碍相关的 PINK1 相关 PD 中发挥关键作用。我们发现神经酰胺在线粒体中积累，并对线粒体功能产生负面影响，尤其是 ETC。降低神经酰胺水平可改善 -突变果蝇和 PINK1 缺陷型患者来源成纤维细胞的线粒体表型，表明神经酰胺的作用在进化上是保守的。此外，在 PINK1 缺陷时，神经酰胺的积累引发神经酰胺诱导的线粒体自噬。由于神经酰胺的积累，β-氧化在 突变体中减少，而降低神经酰胺水平可以挽救这一情况。此外，刺激β-氧化足以挽救 PINK1 缺陷型表型。总之，我们发现了一种源自导致 PINK1 缺失的 PD 的细胞机制，并发现β-氧化在 ETC 功能障碍中的保护作用，从而将脂质和线粒体联系起来，形成与 PINK1 相关的 PD 的病理生理学。此外，我们的数据将β-氧化和神经酰胺作为 PD 的治疗靶点。
