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© 2013. This work is published under http://creativecommons.org/licenses/by/3.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

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 Ca2+ stores, a dramatic increase in mitochondrial Ca2+ 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.

Details

Title
Wolfram Syndrome protein, Miner1, regulates sulphydryl redox status, the unfolded protein response, and Ca 2+ homeostasis
Author
Wiley, Sandra E 1 ; Andreyev, Alexander Y 1 ; Divakaruni, Ajit S 1 ; Karisch, Robert 2 ; Perkins, Guy 3 ; Wall, Estelle A 1 ; van der Geer, Peter 4 ; Yi‐Fan Chen 5 ; Ting‐Fen Tsai 5 ; Simon, Melvin I 1 ; Neel, Benjamin G 2 ; Dixon, Jack E 6 ; Murphy, Anne N 1 

 Department of Pharmacology, University of California, San Diego, La Jolla, CA, USA 
 Campbell Family Cancer Research Institute, Ontario Cancer Institute, Princess Hospital, University Health Network and Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada 
 National Center for Imaging Research, University of California, San Diego, La Jolla, CA, USA 
 Department of Chemistry and Biochemistry, San Diego State University, San Diego, CA, USA 
 Department of Life Sciences and Institute of Genome Sciences, National Yang‐Ming University, Taipei, Taiwan 
 Department of Pharmacology, University of California, San Diego, La Jolla, CA, USA; Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA, USA; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA; Howard Hughes Medical Institute, Chevy Chase, MD, USA 
Pages
904-918
Section
Research Articles
Publication year
2013
Publication date
Jun 2013
Publisher
EMBO Press
ISSN
17574676
e-ISSN
17574684
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2299121280
Copyright
© 2013. This work is published under http://creativecommons.org/licenses/by/3.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.