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    Diminished Superoxide Generation Is Associated With Respiratory Chain Dysfunction and Changes in the Mitochondrial Proteome of Sensory Neurons From Diabetic Rats

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    Issue Date
    2011-09-28
    Author
    Akude, Eli
    Zherebitskaya, Elena
    Chowdhury, Subir K. Roy
    Smith, Darrell R.
    Dobrowsky, Rick T.
    Fernyhough, Paul
    Publisher
    American Diabetes Association
    Type
    Article
    Article Version
    Scholarly/refereed, publisher version
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    Abstract
    OBJECTIVE Impairments in mitochondrial function have been proposed to play a role in the etiology of diabetic sensory neuropathy. We tested the hypothesis that mitochondrial dysfunction in axons of sensory neurons in type 1 diabetes is due to abnormal activity of the respiratory chain and an altered mitochondrial proteome. RESEARCH DESIGN AND METHODS Proteomic analysis using stable isotope labeling with amino acids in cell culture (SILAC) determined expression of proteins in mitochondria from dorsal root ganglia (DRG) of control, 22-week-old streptozotocin (STZ)-diabetic rats, and diabetic rats treated with insulin. Rates of oxygen consumption and complex activities in mitochondria from DRG were measured. Fluorescence imaging of axons of cultured sensory neurons determined the effect of diabetes on mitochondrial polarization status, oxidative stress, and mitochondrial matrix-specific reactive oxygen species (ROS). RESULTS Proteins associated with mitochondrial dysfunction, oxidative phosphorylation, ubiquinone biosynthesis, and the citric acid cycle were downregulated in diabetic samples. For example, cytochrome c oxidase subunit IV (COX IV; a complex IV protein) and NADH dehydrogenase Fe-S protein 3 (NDUFS3; a complex I protein) were reduced by 29 and 36% (P < 0.05), respectively, in diabetes and confirmed previous Western blot studies. Respiration and mitochondrial complex activity was significantly decreased by 15 to 32% compared with control. The axons of diabetic neurons exhibited oxidative stress and depolarized mitochondria, an aberrant adaption to oligomycin-induced mitochondrial membrane hyperpolarization, but reduced levels of intramitochondrial superoxide compared with control. CONCLUSIONS Abnormal mitochondrial function correlated with a downregulation of mitochondrial proteins, with components of the respiratory chain targeted in lumbar DRG in diabetes. The reduced activity of the respiratory chain was associated with diminished superoxide generation within the mitochondrial matrix and did not contribute to oxidative stress in axons of diabetic neurons. Alternative pathways involving polyol pathway activity appear to contribute to raised ROS in axons of diabetic neurons under high glucose concentration.
    Description
    Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
    URI
    http://hdl.handle.net/1808/13488
    DOI
    https://doi.org/10.2337/db10-0818
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    • Pharmacy Scholarly Works [235]
    Citation
    Akude, Eli, Elena Zherebitskaya, Subir K Roy Chowdhury, Darrell R Smith, Rick T Dobrowsky, and Paul Fernyhough. 2011. “Diminished Superoxide Generation Is Associated With Respiratory Chain Dysfunction and Changes in the Mitochondrial Proteome of Sensory Neurons From Diabetic Rats.” Diabetes 60 (1): 288–97. http://dx.doi.org/10.2337/db10-0818

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    Contact KU ScholarWorks
    785-864-8983
    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    Image Credits
     

     

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