Wolfram Syndrome protein, Miner1, regulates sulphydryl redox status, the unfolded protein response, and Ca2+ homeostasis
نویسندگان
چکیده
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.
منابع مشابه
Wolfram Syndrome protein, Miner1, regulates sulfhydryl redox status, the unfolded protein response and Ca2+ homeostasis
Of particular relevance, a causal evidence for a direct role of Miner1 in the redox status of the cell should be provided as highlighted by Referee #1 and #2. These two reviewers also suggest performing a MitoNEET over-expression experiment to biologically address the role of MitoNEET. Referee #1 also suggests providing in vivo data to increase the physiological relevance. Finally a more thorou...
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