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

EMBO Molecular Medicine

Sandra E. Wiley¹  Alexander Y. Andreyev¹  Ajit S. Divakaruni¹  Robert Karisch²  Guy Perkins⁴  Estelle A. Wall¹  Peter van der Geer⁶  Yi-Fan Chen³  Ting-Fen Tsai³  Melvin I. Simon¹  Benjamin G. Neel²  Jack E. Dixon⁵ 

[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;Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei, Taiwan;National Center for Imaging Research, University of California, San Diego, La Jolla, CA, USA;E-mail address: 关键词: calcium;    endoplasmic reticulum;    mitochondria;    oxidative stress;    Wolfram Syndrome;   

DOI  :  10.1002/emmm.201201429

来源: Wiley

【 摘 要 】

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.

【 授权许可】

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Copyright © 2013 EMBO Molecular Medicine

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