C-Terminal Heat Shock Protein 90 Inhibitor Decreases Hyperglycemia-induced Oxidative Stress and Improves Mitochondrial Bioenergetics in Sensory Neurons

Department of Pharmacology and Toxicology, The University of Kansas, Lawrence, Kansas 66045, United States.
Journal of Proteome Research (Impact Factor: 5). 03/2012; 11(4):2581-93. DOI: 10.1021/pr300056m
Source: PubMed

ABSTRACT 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.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Diabetic neuropathy is a major complication of diabetes that involves the sensory and autonomic nervous systems and leads to significant morbidity and impact on quality of life of patients. Mitochondrial stress has been proposed as a major mediator of insulin sensitivity in skeletal muscle in type 2 diabetes and a trigger of diabetic complications such as nephropathy and cardiomyopathy in humans and animal models. Recent studies in the peripheral nervous system in type 1 and type 2 diabetic animal models suggest a role for mitochondrial dysfunction in neurodegeneration in diabetes. This chapter focuses on the nature of sensory nerve dysfunction in diabetes and presents these findings in the context of diabetes-induced nerve degeneration mediated by alterations in mitochondrial physiology. Diabetes-induced dysfunction in calcium homeostasis is discussed and causative associations with suboptimal mitochondrial physiology are developed. Comparisons are made with mitochondrial-dependent dysfunction in muscle and cardiac tissue in diabetes. It is clear that across a range of complications of diabetes mitochondrial physiology is impaired; in general, a reduction in respiratory chain capability is apparent. Where appropriate, we provide clinical evidence for mitochondrial dysfunction in the pathogenesis of complications in patients with diabetes. This abnormal activity may predispose mitochondria to generate elevated reactive oxygen species (ROS), although experimental proof remains lacking, but more importantly will deleteriously alter the bioenergetic status of neurons.
    Handbook of Clinical Neurology 01/2014; 126:353-77. DOI:10.1016/B978-0-444-53480-4.00027-8
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Human Hsp90 isoforms are molecular chaperones that are often up-regulated in malignances and represent a primary target for Hsp90 inhibitors undergoing clinical evaluation. Hsp90α is a stress-inducible isoform of Hsp90 that plays a significant role in apoptosis and metastasis. Though Hsp90α is secreted into the extracellular space under metastatic conditions, its role in cancer biology is poorly understood. We report that Hsp90α associates with the Aha1 co-chaperone and found this complex to localize in secretory vesicles and at the leading edge of migrating cells. Knockdown of Hsp90α resulted in a defect in cell migration. The functional role of Hsp90α/Aha1 was studied by treating the cells with various novobiocin-based Hsp90 C-terminal inhibitors. These inhibitors disrupted the Hsp90α/Aha1 complex, caused a cytoplasmic redistribution of Hsp90α and Aha1, and decreased cell migration. Structure-function studies determined that disruption of Hsp90α/Aha1 association and inhibition of cell migration correlated with the presence of a benzamide side chain, as an acetamide substituted analog was less effective. Our results show that disruption of Hsp90α/Aha1 interactions with novobiocin-based Hsp90 C-terminal inhibitors may limit the metastatic potential of tumors.
    ACS Chemical Biology 11/2014; 10(2). DOI:10.1021/cb5008713 · 5.36 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Peripheral sensory nervous system is composed from neurones with their axons and neuroglia that includes satellite glial cells in sensory ganglia, myelinating, non-myelinating and perisynaptic Schwann cells. Pathogenesis of peripheral diabetic polyneuropathies is associated with aberrant function of both neurones and glia. Deregulated Ca2+ homoeostasis and aberrant Ca2+ signalling in neuronal and glial elements contributes to many forms of neuropathology and is fundamental to neurodegenerative diseases. In diabetes both neurones and glia experience metabolic stress and mitochondrial dysfunction which lead to deregulation of Ca2+ homeostasis and Ca2+ signalling, which in their turn lead to pathological cellular reactions contributing to development of diabetic neuropathies. Molecular cascades responsible for Ca2+ homeostasis and signalling, therefore, can be regarded as potential therapeutic targets.
    Cell Calcium 11/2014; 56(5):362-371. DOI:10.1016/j.ceca.2014.07.005 · 4.21 Impact Factor

Full-text (2 Sources)

Available from
May 29, 2014