title: Mitochondrial function is impaired in yeast and human cellular models of Shwachman Diamond syndrome.
abstract: Shwachman Diamond syndrome (SDS) is an inherited bone marrow failure syndrome typically characterized by neutropenia, exocrine pancreas dysfunction, metaphyseal chondrodysplasia, and predisposition to myelodysplastic syndrome and leukemia. SBDS, the gene affected in most cases of SDS, encodes a protein known to influence many cellular processes including ribosome biogenesis, mitotic spindle assembly, chemotaxis, and the regulation of reactive oxygen species production. The best characterized role for the SBDS protein is in the production of functional 60S ribosomal subunits. Given that a reduction in functional 60S subunits could impact on the translational output of cells depleted of SBDS we analyzed protein synthesis in yeast cells lacking SDO1, the ortholog of SBDS. Cells lacking SDO1 selectively increased the synthesis of POR1, the ortholog of mammalian VDAC1 a major anion channel of the mitochondrial outer membrane. Further studies revealed the cells lacking SDO1 were compromised in growth on non-fermentable carbon sources suggesting mitochondrial function was impaired. These observations prompted us to examine mitochondrial function in human cells where SBDS expression was reduced. Our studies indicate that reduced expression of SBDS decreases mitochondrial membrane potential and oxygen consumption and increases the production of reactive oxygen species. These studies indicate that mitochondrial function is also perturbed in cells expressing reduced amounts of SBDS and indicate that disruption of mitochondrial function may also contribute to SDS pathophysiology.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Louisville, Louisville, KY 40292, United States.
authors.forename: Adrianna L
authors.initials: AL
authors.lastname: Henson
authors.forename: Joseph B
authors.initials: JB
authors.lastname: Moore
authors.forename: Pascale
authors.initials: P
authors.lastname: Alard
authors.forename: Max M
authors.initials: MM
authors.lastname: Wattenberg
authors.forename: Johnson M
authors.initials: JM
authors.lastname: Liu
authors.forename: Steven R
authors.initials: SR
authors.lastname: Ellis
mesh_terms: D001855:Bone Marrow Diseases / Q000378:metabolism* / Q000473:pathology*; D002244:Carbon / Q000494:pharmacology; D002460:Cell Line; D010188:Exocrine Pancreatic Insufficiency / Q000378:metabolism* / Q000473:pathology*; D005285:Fermentation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D008068:Lipomatosis / Q000378:metabolism* / Q000473:pathology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D008954:Models, Biological; D011506:Proteins / Q000378:metabolism; D040901:Proteomics; D017382:Reactive Oxygen Species / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism; D000081003:Shwachman-Diamond Syndrome
chemical_list: D011506:Proteins; D017382:Reactive Oxygen Species; C470521:SBDS protein, human; D029701:Saccharomyces cerevisiae Proteins; C520002:Sdo1 protein, S cerevisiae; D002244:Carbon
keywords: Bone marrow failure; Mitochondria; Ribosome; Translation