Department of Cell Biology and Molecular Genetics, College of Computer, Mathematical, and Natural Sciences, University of Maryland, College Park, MD 20742, USA.
Aging (Albany NY). 2020 Mar 18;12(6):5195-5208. doi: 10.18632/aging.102941.
Peroxisomes are small, membrane-enclosed eukaryotic organelles that house various enzymes with metabolic functions. One important feature in both Hutchinson-Gilford Progeria Syndrome (HGPS) and normal aging is the elevated levels of Reactive Oxygen Species (ROS), which are generated from metabolic pathways with the capacity to cause oxidative damage to macromolecules within the cells. Although peroxisomal bioreactions can generate free radicals as their byproducts, many metabolic enzymes within the peroxisomes play critical roles as ROS scavengers, in particular, catalase. Here, we observed impaired peroxisomes-targeting protein trafficking, which suggested that the poorly assembled peroxisomes might cause high oxidative stress, contributing to the premature senescent phenotype in HGPS. We then investigated the ROS clearance efficiency by peroxisomal enzymes and found a significantly decreased expression of catalase in HGPS. Furthermore, we evaluated the effects of two promising HGPS-treatment drugs Methylene Blue and RAD001 (Everolimus, a rapamycin analog) on catalase in HGPS fibroblasts. We found that both drugs effectively reduced cellular ROS levels. MB, as a well-known antioxidant, did not affect catalase expression or activity. Interestingly, RAD001 treatment significantly upregulated catalase activity in HGPS cells. Our study presents the first characterization of peroxisomal function in HGPS and provides new insights into the cellular aspects of HGPS and the ongoing clinical trial.
过氧化物酶体是一种小型的、膜包裹的真核细胞器，其中含有各种具有代谢功能的酶。在亨廷顿舞蹈症和正常衰老中，一个重要的特征是活性氧（ROS）水平的升高，ROS 是由具有在细胞内大分子引发氧化损伤能力的代谢途径产生的。尽管过氧化物酶体的生物反应可以产生自由基作为其副产物，但过氧化物酶体中的许多代谢酶在作为 ROS 清除剂方面发挥着关键作用，特别是过氧化氢酶。在这里，我们观察到过氧化物酶体靶向蛋白转运受损，这表明组装不良的过氧化物酶体可能导致高氧化应激，导致 HGPS 中的早衰表型。然后，我们研究了过氧化物酶清除 ROS 的效率，发现 HGPS 中过氧化氢酶的表达显著降低。此外，我们评估了两种有前途的 HGPS 治疗药物亚甲蓝和 RAD001（Everolimus，一种雷帕霉素类似物）对 HGPS 成纤维细胞中过氧化氢酶的影响。我们发现这两种药物都能有效地降低细胞内 ROS 水平。MB 作为一种众所周知的抗氧化剂，不影响过氧化氢酶的表达或活性。有趣的是，RAD001 治疗显著上调了 HGPS 细胞中过氧化氢酶的活性。我们的研究首次描述了 HGPS 中过氧化物酶体功能的特征，并为 HGPS 的细胞方面以及正在进行的临床试验提供了新的见解。
