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    Tunicamycin-induced Endoplasmic Reticulum stress mediates mitochondrial dysfunction in human adipocytes.

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    JCEM-May2020-ER stress.pdf
    Embargo:
    2021-05-15
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    Authors
    Jackisch, Laura
    Murphy, Alice M
    Kumar, Sudhesh
    Randeva, Harpal
    Tripathi, Gyanendra
    McTernan, Philip G
    Affiliation
    University of Warwick
    Nottingham Trent University
    University of Derby
    Issue Date
    2020-05-15
    
    Metadata
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    Abstract
    Dysfunctional ER and mitochondria are known to contribute to the pathology of metabolic disease. This damage may occur, in part, as a consequence of ER-mitochondria cross-talk in conditions of nutrient excess such as obesity. To date insight into this dynamic relationship has not been characterised in adipose tissue. Therefore, this study investigated whether ER stress contributes to the development of mitochondrial inefficiency in human adipocytes from lean and obese participants. Human differentiated adipocytes from Chub-S7 cell line and primary abdominal subcutaneous adipocytes from lean and obese participants were treated with tunicamycin to induce ER stress. Key parameters of mitochondrial function were assessed, including mitochondrial respiration, membrane potential (MMP) and dynamics. ER stress led to increased respiratory capacity in a model adipocyte system (Chub-S7 adipocytes) in a concentration and time dependent manner (24hr: 23%↑; 48hr: 68%↑, (p<0.001); 72hr: 136%↑, (p<0.001)). This corresponded with mitochondrial inefficiency and diminished MMP, highlighting the formation of dysfunctional mitochondria. Morphological analysis revealed reorganisation of mitochondrial network, specifically mitochondrial fragmentation. Furthermore, p-DRP1, a key protein in fission, significantly increased (p<0.001). Additionally, adipocytes from obese subjects displayed lower basal respiration (49%↓, p<0.01) and were unresponsive to tunicamycin in contrast to their lean counterparts, demonstrating inefficient mitochondrial oxidative capacity. These human data suggest that adipocyte mitochondrial inefficiency is driven by ER stress and exacerbated in obesity. Nutrient excess induced ER stress leads to mitochondrial dysfunction that may therefore shift lipid deposition ectopically and thus have further implications on the development of related metabolic disorders.
    Citation
    Jackisch, L., Murphy, A.M., Kumar, S., Randeva, H., Tripathi, G. and McTernan, P.G., (2020). 'Tunicamycin-induced Endoplasmic Reticulum stress mediates mitochondrial dysfunction in human adipocytes'. The Journal of Clinical Endocrinology & Metabolism, pp. 1-41.
    Publisher
    Oxford University Press
    Journal
    The Journal of clinical endocrinology and metabolism
    URI
    http://hdl.handle.net/10545/624887
    DOI
    10.1210/clinem/dgaa258
    PubMed ID
    32413131
    Additional Links
    https://academic.oup.com/jcem/advance-article-abstract/doi/10.1210/clinem/dgaa258/5837767
    Type
    Article
    Language
    en
    EISSN
    1945-7197
    ae974a485f413a2113503eed53cd6c53
    10.1210/clinem/dgaa258
    Scopus Count
    Collections
    School of Human Sciences

    entitlement

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