title: Deletion of Mitochondrial Porin Alleviates Stress Sensitivity in the Yeast Model of Shwachman-Diamond Syndrome.
abstract: 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.
authors.affiliation: Department of Pathobiology, Faculty of Science, Mahidol University, Bangkok 10400, Thailand.
authors.forename: Waruenada
authors.initials: W
authors.lastname: Kanprasoet
authors.affiliation: Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok 10400, Thailand.
authors.forename: Laran T
authors.initials: LT
authors.lastname: Jensen
authors.affiliation: Department of Pathobiology, Faculty of Science, Mahidol University, Bangkok 10400, Thailand.
authors.forename: Suwimon
authors.initials: S
authors.lastname: Sriprach
authors.affiliation: Toxicology Graduate Program, Faculty of Science, Mahidol University, Bangkok 10400, Thailand.
authors.forename: Kanate
authors.initials: K
authors.lastname: Thitiananpakorn
authors.affiliation: Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok 10400, Thailand.
authors.forename: Khanti
authors.initials: K
authors.lastname: Rattanapornsompong
authors.affiliation: Department of Pathobiology, Faculty of Science, Mahidol University, Bangkok 10400, Thailand. Electronic address: amornrat.nar@mahidol.ac.th.
authors.forename: Amornrat Naranuntarat
authors.initials: AN
authors.lastname: Jensen
mesh_terms: D001855:Bone Marrow Diseases / Q000235:genetics / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress; D010188:Exocrine Pancreatic Insufficiency / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D006358:Hot Temperature; D006801:Humans; D008068:Lipomatosis / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism; D018272:Porins / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000502:physiology*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics* / Q000378:metabolism; D000081003:Shwachman-Diamond Syndrome; D013312:Stress, Physiological
chemical_list: C580894:Por1 protein, S cerevisiae; D018272:Porins; D029701:Saccharomyces cerevisiae Proteins; C520002:Sdo1 protein, S cerevisiae
keywords: Mitochondria; Oxidative stress; Porin; Shwachman-Diamond syndrome; Yeast