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Journal of proteome research. 2012 Apr 6;11(4):2581-93. doi: 10.1021/pr300056m Q13.82024

C-terminal heat shock protein 90 inhibitor decreases hyperglycemia-induced oxidative stress and improves mitochondrial bioenergetics in sensory neurons

热休克蛋白90 C-末端抑制剂可降低高糖诱导的氧化应激并改善感觉神经元线粒体生物能量学 翻译改进

Liang Zhang  1, Huiping Zhao, Brian S J Blagg, Rick T Dobrowsky

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  • 1 Department of Pharmacology and Toxicology, The University of Kansas, Lawrence, Kansas 66045, United States.
  • DOI: 10.1021/pr300056m PMID: 22413817

    摘要 Ai翻译

    Diabetic peripheral neuropathy (DPN) is a common complication of diabetes in which hyperglycemia-induced mitochondrial dysfunction and enhanced oxidative stress contribute to sensory neuron pathology. KU-32 is a novobiocin-based, C-terminal inhibitor of the molecular chaperone, heat shock protein 90 (Hsp90). KU-32 ameliorates multiple sensory deficits associated with the progression of DPN and protects unmyelinated sensory neurons from glucose-induced toxicity. Mechanistically, KU-32 increased the expression of Hsp70, and this protein was critical for drug efficacy in reversing DPN. However, it remained unclear if KU-32 had a broader effect on chaperone induction and if its efficacy was linked to improving mitochondrial dysfunction. Using cultures of hyperglycemically stressed primary sensory neurons, the present study investigated whether KU-32 had an effect on the translational induction of other chaperones and improved mitochondrial oxidative stress and bioenergetics. A variation of stable isotope labeling with amino acids in cell culture called pulse SILAC (pSILAC) was used to unbiasedly assess changes in protein translation. Hyperglycemia decreased the translation of numerous mitochondrial proteins that affect superoxide levels and respiratory activity. Importantly, this correlated with a decrease in mitochondrial oxygen consumption and an increase in superoxide levels. KU-32 increased the translation of Mn superoxide dismutase and several cytosolic and mitochondrial chaperones. Consistent with these changes, KU-32 decreased mitochondrial superoxide levels and significantly enhanced respiratory activity. These data indicate that efficacy of modulating molecular chaperones in DPN may be due in part to improved neuronal mitochondrial bioenergetics and decreased oxidative stress.

    Keywords:mitochondrial bioenergetics

    Copyright © Journal of proteome research. 中文内容为AI机器翻译,仅供参考!

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    期刊名:Journal of proteome research

    缩写:J PROTEOME RES

    ISSN:1535-3893

    e-ISSN:1535-3907

    IF/分区:3.8/Q1

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    C-terminal heat shock protein 90 inhibitor decreases hyperglycemia-induced oxidative stress and improves mitochondrial bioenergetics in sensory neurons