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: 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
• Journal: EMBO molecular medicine (EMBO Mol Med) Vol. 5 Issue 6 Pg. 904-18 (Jun 2013) ISSN: 1757-4684 [Electronic] England
• PMID: 23703906 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO.

Chemical References

• Antioxidants
• Autophagy-Related Proteins
• Carrier Proteins
• Nerve Tissue Proteins
• Noxp70 protein, mouse
• Sulfhydryl Compounds
• NAD
• Adenosine Triphosphate
• Glutathione
• Calcium
• Glutathione Disulfide

Topics

• Adenosine Triphosphate (metabolism)
• Animals
• Antioxidants (pharmacology)
• Autophagy-Related Proteins
• Calcium (metabolism)
• Carrier Proteins (antagonists & inhibitors, genetics, metabolism)
• Cell Line
• Glutathione (metabolism)
• Glutathione Disulfide (metabolism)
• Mice
• Mitochondria (metabolism, ultrastructure)
• NAD (metabolism)
• Nerve Tissue Proteins (antagonists & inhibitors, genetics, metabolism)
• Oxidation-Reduction
• Sulfhydryl Compounds (chemistry, metabolism)
• Unfolded Protein Response (drug effects)
• Wolfram Syndrome (metabolism, pathology)