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

• Published in: EMBO molecular medicine 2013-06, Vol.5 (6), p.904-918
• Main Authors: 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.
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphate - metabolism; Animals; Antioxidants - pharmacology; calcium; Calcium - metabolism; Carrier Proteins - antagonists & inhibitors; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cell Line; endoplasmic reticulum; Glutathione - metabolism; Glutathione Disulfide - metabolism; Mice; mitochondria; Mitochondria - metabolism; Mitochondria - ultrastructure; NAD - metabolism; Nerve Tissue Proteins - antagonists & inhibitors; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Oxidation-Reduction; oxidative stress; Research Article; Sulfhydryl Compounds - chemistry; Sulfhydryl Compounds - metabolism; Unfolded Protein Response - drug effects; Wolfram Syndrome; Wolfram Syndrome - metabolism; Wolfram Syndrome - pathology
• ISSN: 1757-4676; 1757-4684
• DOI: 10.1002/emmm.201201429

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 O 2 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. Graphical Abstract Wolfram syndrome (DIDMOAD) is an incurable metabolic disease caused by mutations in Wolframin or Miner1 genes. This study reveals Miner1 biological role in cellular redox status and proposes antioxidant as therapeutic strategy against DIDMOAD.