Disruption in iron homeostasis and impaired activity of iron-sulfur cluster containing proteins in the yeast model of Sh
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(2020) 10:105 Jain et al. Cell Biosci https://doi.org/10.1186/s13578-020-00468-2
Open Access
RESEARCH
Disruption in iron homeostasis and impaired activity of iron‑sulfur cluster containing proteins in the yeast model of Shwachman‑Diamond syndrome Ayushi Jain1, Phubed Nilatawong1,2, Narinrat Mamak3, Laran T. Jensen4 and Amornrat Naranuntarat Jensen1,5,6*
Abstract Background: 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. Results: 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 overexpressed and its deletion limits iron accumulation and increases activity of aconitase and succinate dehydrogenase. Conclusions: 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. Keywords: Shwachman-diamond syndrome, Iron overload, Yeast, Iron sulfur cluster, POR1 overexpression Background Shwachman-Diamond syndrome (SDS) is an autosomal recessive disorder characterized as a ribosomopathy [1–4]. Defects in ribosome biogenesis, due to mutations in ribosomal proteins and assembly factors, can lead to a wide range of clinical phenotypes [5]. Patients with SDS suffer from bone marrow failure, exocrine pancreatic *Correspondence: [email protected] 1 Department of Pathobiology, Faculty of Science, Mahidol University, 272 Rama 6 Road, Bangkok 10400, Thailand Full list of author information is available at the end of the article
dysfunction, skeletal abnormalities, and have a high risk of malignant transformation [6–11]. Even though SDS is a rare genetic disorder, it is a common cause of inherited exocrine pancreatic dysfunction and bone marrow failure [12–15]. The majority of SDS patients have loss of function mutations in SBDS (SDS1, OMIM #260400) [16]. The best characterized function of SBDS is its role in the release and recycling of eIF6 from pre-60S ribosomes, a proces
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