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

Jackisch, L., Murphy, A.M., Kumar, S., Randeva, H., Tripathi, G. and McTernan, P.G. ORCID: 0000-0001-9023-0261, 2020. Tunicamycin-induced Endoplasmic Reticulum stress mediates mitochondrial dysfunction in human adipocytes. Journal of Clinical Endocrinology and Metabolism. ISSN 1945-7197 (Forthcoming)

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Abstract

Context: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Item Type: Journal article
Alternative Title: Effect of ER stress on mitochondria in adipocytes
Publication Title: Journal of Clinical Endocrinology and Metabolism
Creators: Jackisch, L., Murphy, A.M., Kumar, S., Randeva, H., Tripathi, G. and McTernan, P.G.
Publisher: Oxford University Press
Date: 12 May 2020
ISSN: 1945-7197
Identifiers:
NumberType
10.1210/clinem/dgaa258DOI
1324845Other
Divisions: Schools > School of Science and Technology
Depositing User: Linda Sullivan
Date Added: 13 May 2020 10:54
Last Modified: 13 May 2020 10:54
URI: http://irep.ntu.ac.uk/id/eprint/39830

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