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

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83 引文 斯高帕斯(Scopus)

摘要

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.
原文英語
頁(從 - 到)904-918
頁數15
期刊EMBO Molecular Medicine
5
發行號6
DOIs
出版狀態已發佈 - 6月 2013
對外發佈

ASJC Scopus subject areas

  • 分子醫學

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