Publication: Deletion of Mitochondrial Porin Alleviates Stress Sensitivity in the Yeast Model of Shwachman-Diamond Syndrome
3
Issued Date
2015-12-20
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ISSN
18735533
16738527
16738527
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2-s2.0-84954378574
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Mahidol University
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SCOPUS
Bibliographic Citation
Journal of Genetics and Genomics. Vol.42, No.12 (2015), 671-684
Suggested Citation
Waruenada Kanprasoet, Laran T. Jensen, Suwimon Sriprach, Kanate Thitiananpakorn, Khanti Rattanapornsompong, Amornrat Naranuntarat Jensen Deletion of Mitochondrial Porin Alleviates Stress Sensitivity in the Yeast Model of Shwachman-Diamond Syndrome. Journal of Genetics and Genomics. Vol.42, No.12 (2015), 671-684. doi:10.1016/j.jgg.2015.09.004 Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/35319
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Title
Deletion of Mitochondrial Porin Alleviates Stress Sensitivity in the Yeast Model of Shwachman-Diamond Syndrome
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Abstract
© 2015 Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, and Genetics Society of China. Shwachman-Diamond syndrome (SDS) is a multi-system disorder characterized by bone marrow failure, pancreatic insufficiency, skeletal abnormalities, and increased risk of leukemic transformation. Most patients with SDS contain mutations in the Shwachman-Bodian-Diamond syndrome gene (. SBDS), encoding a highly conserved protein that has been implicated in ribosome biogenesis. Emerging evidence also suggests a distinct role of SBDS beyond protein translation. Using the yeast model of SDS, we examined the underlying mechanisms that cause cells lacking Sdo1p, the yeast SBDS ortholog, to exhibit reduced tolerance to various stress conditions. Our analysis indicates that the environmental stress response (ESR), heat shock response (HSR), and endoplasmic reticulum unfolded protein response (UPR) of sdo1δ cells are functional and that defects in these pathways do not produce the phenotypes observed in sdo1δ yeast. Depletion of mitochondrial DNA (mtDNA) was observed in sdo1δ cells, and this is a probable cause of the mitochondrial insufficiency in SDS. Prior disruption of POR1, encoding the mitochondrial voltage dependent anion channel (VDAC), abrogated the effects of SDO1 deletion and substantially restored resistance to environmental stressors and protected against damage to mtDNA. Conversely, wild-type cells over-expressing POR1 exhibited growth impairment and increased stress sensitivity similar to that seen in sdo1δ cells. Overall, our results suggest that specific VDAC inhibitors may have therapeutic benefits for SDS patients.