Shwachman-Diamond syndrome (SDS) is a congenital disease that affects the bone marrow, skeletal system, and pancreas. The majority of patients with SDS have mutations in the SBDS gene, involved in ribosome biogenesis as well as other processes. A Saccharomyces cerevisiae model of SDS, lacking Sdo1p the yeast orthologue of SBDS, was utilized to better understand the molecular pathogenesis in the development of this disease. Deletion of SDO1 resulted in a three-fold over-accumulation of intracellular iron. Phenotypes associated with impaired iron-sulfur (ISC) assembly, up-regulation of the high affinity iron uptake pathway, and reduced activities of ISC containing enzymes aconitase and succinate dehydrogenase, were observed in sdo1∆ yeast. In cells lacking Sdo1p, elevated levels of reactive oxygen species (ROS) and protein oxidation were reduced with iron chelation, using a cell impermeable iron chelator. In addition, the low activity of manganese superoxide dismutase (Sod2p) seen in sdo1∆ cells was improved with iron chelation, consistent with the presence of reactive iron from the ISC assembly pathway. In yeast lacking Sdo1p, the mitochondrial voltage-dependent anion channel (VDAC) Por1p is over-expressed and its deletion limits iron accumulation and increases activity of aconitase and succinate dehydrogenase. We propose that oxidative stress from POR1 over-expression, resulting in impaired activity of ISC containing proteins and disruptions in iron homeostasis, may play a role in disease pathogenesis in SDS patients.

中文翻译：

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在 Shwachman-Diamond 综合征酵母模型中，铁稳态被破坏，铁硫簇蛋白活性受损。


什瓦赫曼-戴蒙德综合征 (SDS) 是一种影响骨髓、骨骼系统和胰腺的先天性疾病。大多数 SDS 患者的 SBDS 基因存在突变，该基因参与核糖体生物发生以及其他过程。 SDS 的酿酒酵母模型缺乏 SBDS 的酵母直系同源物 Sdo1p，可用于更好地了解该疾病发展的分子发病机制。 SDO1 的缺失导致细胞内铁过度积累三倍。在 sdo1Δ 酵母中观察到与铁硫 (ISC) 组装受损、高亲和力铁摄取途径上调以及含有乌头酸酶和琥珀酸脱氢酶的 ISC 活性降低相关的表型。在缺乏 Sdo1p 的细胞中，使用细胞不可渗透的铁螯合剂，通过铁螯合减少了活性氧 (ROS) 水平升高和蛋白质氧化。此外，sdo1Δ细胞中锰超氧化物歧化酶（Sod2p）的低活性通过铁螯合得到改善，这与ISC组装途径中活性铁的存在相一致。在缺乏 Sdo1p 的酵母中，线粒体电压依赖性阴离子通道 (VDAC) Por1p 过度表达，其缺失限制了铁积累并增加乌头酸酶和琥珀酸脱氢酶的活性。我们认为，POR1 过度表达引起的氧化应激，导致含有蛋白质的 ISC 活性受损和铁稳态破坏，可能在 SDS 患者的疾病发病机制中发挥作用。