title: Wolfram Syndrome protein, Miner1, regulates sulphydryl redox status, the unfolded protein response, and Ca2+ homeostasis.
abstract: Miner1 is a redox-active 2Fe2S cluster protein. Mutations in Miner1 result in Wolfram Syndrome, a metabolic disease associated with diabetes, blindness, deafness, and a shortened lifespan. Embryonic fibroblasts from Miner1(-/-) mice displayed ER stress and showed hallmarks of the unfolded protein response. In addition, loss of Miner1 caused a depletion of ER Ca(2+) stores, a dramatic increase in mitochondrial Ca(2+) load, increased reactive oxygen and nitrogen species, an increase in the GSSG/GSH and NAD(+)/NADH ratios, and an increase in the ADP/ATP ratio consistent with enhanced ATP utilization. Furthermore, mitochondria in fibroblasts lacking Miner1 displayed ultrastructural alterations, such as increased cristae density and punctate morphology, and an increase in O2 consumption. Treatment with the sulphydryl anti-oxidant N-acetylcysteine reversed the abnormalities in the Miner1 deficient cells, suggesting that sulphydryl reducing agents should be explored as a treatment for this rare genetic disease.
authors.affiliation: Department of Pharmacology, University of California, San Diego, La Jolla, CA, USA.
authors.forename: Sandra E
authors.initials: SE
authors.lastname: Wiley
authors.forename: Alexander Y
authors.initials: AY
authors.lastname: Andreyev
authors.forename: Ajit S
authors.initials: AS
authors.lastname: Divakaruni
authors.forename: Robert
authors.initials: R
authors.lastname: Karisch
authors.forename: Guy
authors.initials: G
authors.lastname: Perkins
authors.forename: Estelle A
authors.initials: EA
authors.lastname: Wall
authors.forename: Peter
authors.initials: P
authors.lastname: van der Geer
authors.forename: Yi-Fan
authors.initials: YF
authors.lastname: Chen
authors.forename: Ting-Fen
authors.initials: TF
authors.lastname: Tsai
authors.forename: Melvin I
authors.initials: MI
authors.lastname: Simon
authors.forename: Benjamin G
authors.initials: BG
authors.lastname: Neel
authors.forename: Jack E
authors.initials: JE
authors.lastname: Dixon
authors.forename: Anne N
authors.initials: AN
authors.lastname: Murphy
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D000071183:Autophagy-Related Proteins; D002118:Calcium / Q000378:metabolism*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D005978:Glutathione / Q000378:metabolism; D019803:Glutathione Disulfide / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000378:metabolism / Q000648:ultrastructure; D009243:NAD / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D013438:Sulfhydryl Compounds / Q000737:chemistry* / Q000378:metabolism; D056811:Unfolded Protein Response / Q000187:drug effects; D014929:Wolfram Syndrome / Q000378:metabolism / Q000473:pathology
chemical_list: D000975:Antioxidants; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins; D009419:Nerve Tissue Proteins; C515811:Noxp70 protein, mouse; D013438:Sulfhydryl Compounds; D009243:NAD; D000255:Adenosine Triphosphate; D005978:Glutathione; D002118:Calcium; D019803:Glutathione Disulfide