Wolfram Syndrome protein, Miner1, regulates sulphydryl redox status, the unfolded protein response, and Ca2+ homeostasis

Sandra E. Wiley, Alexander Y. Andreyev, Ajit S. Divakaruni, Robert Karisch, Guy Perkins, Estelle A. Wall, Peter van der Geer, Yi Fan Chen, Ting Fen Tsai, Melvin I. Simon, Benjamin G. Neel, Jack E. Dixon, Anne N. Murphy

Research output: Contribution to journalArticle

49 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)904-918
Number of pages15
JournalEMBO Molecular Medicine
Volume5
Issue number6
DOIs
Publication statusPublished - Jun 2013
Externally publishedYes

Fingerprint

Wolfram Syndrome
Unfolded Protein Response
NAD
Oxidation-Reduction
Homeostasis
Deaf-Blind Disorders
Fibroblasts
Adenosine Triphosphate
Reactive Nitrogen Species
Inborn Genetic Diseases
Glutathione Disulfide
Metabolic Diseases
Reducing Agents
Acetylcysteine
Rare Diseases
Oxidants
Adenosine Diphosphate
Reactive Oxygen Species
Mitochondria
Proteins

Keywords

  • Calcium
  • Endoplasmic reticulum
  • Mitochondria
  • Oxidative stress
  • Wolfram Syndrome

ASJC Scopus subject areas

  • Molecular Medicine

Cite this

Wiley, S. E., Andreyev, A. Y., Divakaruni, A. S., Karisch, R., Perkins, G., Wall, E. A., ... Murphy, A. N. (2013). Wolfram Syndrome protein, Miner1, regulates sulphydryl redox status, the unfolded protein response, and Ca2+ homeostasis. EMBO Molecular Medicine, 5(6), 904-918. https://doi.org/10.1002/emmm.201201429

Wolfram Syndrome protein, Miner1, regulates sulphydryl redox status, the unfolded protein response, and Ca2+ homeostasis. / Wiley, Sandra E.; Andreyev, Alexander Y.; Divakaruni, Ajit S.; Karisch, Robert; Perkins, Guy; Wall, Estelle A.; van der Geer, Peter; Chen, Yi Fan; Tsai, Ting Fen; Simon, Melvin I.; Neel, Benjamin G.; Dixon, Jack E.; Murphy, Anne N.

In: EMBO Molecular Medicine, Vol. 5, No. 6, 06.2013, p. 904-918.

Research output: Contribution to journalArticle

Wiley, SE, Andreyev, AY, Divakaruni, AS, Karisch, R, Perkins, G, Wall, EA, van der Geer, P, Chen, YF, Tsai, TF, Simon, MI, Neel, BG, Dixon, JE & Murphy, AN 2013, 'Wolfram Syndrome protein, Miner1, regulates sulphydryl redox status, the unfolded protein response, and Ca2+ homeostasis', EMBO Molecular Medicine, vol. 5, no. 6, pp. 904-918. https://doi.org/10.1002/emmm.201201429
Wiley, Sandra E. ; Andreyev, Alexander Y. ; Divakaruni, Ajit S. ; Karisch, Robert ; Perkins, Guy ; Wall, Estelle A. ; van der Geer, Peter ; Chen, Yi Fan ; Tsai, Ting Fen ; Simon, Melvin I. ; Neel, Benjamin G. ; Dixon, Jack E. ; Murphy, Anne N. / Wolfram Syndrome protein, Miner1, regulates sulphydryl redox status, the unfolded protein response, and Ca2+ homeostasis. In: EMBO Molecular Medicine. 2013 ; Vol. 5, No. 6. pp. 904-918.
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