Tunicamycin-induced ER stress mediates mitochondrial dysfunction in human adipocytes

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Jackisch, L, Murphy, A, Al-Daghri, N, McTernan, P, Randeva, H and Tripathi, G 2014. Tunicamycin-induced ER stress mediates mitochondrial dysfunction in human adipocytes. bioscientifica. https://doi.org/10.1530/endoabs.44.P193
AuthorsJackisch, L, Murphy, A, Al-Daghri, N, McTernan, P, Randeva, H and Tripathi, G
Abstract

The pathogenesis of obesity and T2DM mediates mitochondrial dysfunction which, in part, may arise as a consequence of endoplasmic reticulum (ER) stress. However, the potential impact of ER stress on mitochondria dysfunction is unclear. Therefore, we investigated whether induction of ER stress contributes to mitochondrial dysfunction in human adipocytes using 1) human differentiated adipocyte cell line (Chub-S7, n=12); and 2) primary differentiated lean and obese abdominal subcutaneous adipocytes (AbdSc Ad; n=3 respectively). ER stress was induced in post-differentiated Chub-S7 (AbdSc Ad) using tunicamycin (Tn) (0.25 μg/ml, 0.75 μg/ml) for 24 hrs, 48 hrs and 72 hrs. Assessment of mitochondrial function post Tn treatment was undertaken using the Extracellular Flux Analyser – evaluating oxygen consumption rate (OCR) and proton excretion (glycolysis; extracellular acidification rates (ECAR)). Flux stressors (oligomycin, FCCP, rotenone/antimycin A) were given to Chub-S7 adipocytes treated with Tn to measure mitochondrial response. Mitochondrial dynamics were also evaluated using RT-PCR and confocal microscopy. The Seahorse stress test identified that Tn (0.25 μg/ml, 0.75 μg/ml) induced mitochondrial stress with a 14% rise in OCR (Basal: 472 pMoles/min vs Tn: 537 pMoles/min; P=0.002) and a maximum 78% increase in ECAR (Basal: 124 mpH/minute vs Tn: 228 mpH/minute; P=0.006). This Tn induced mitochondrial stress was maintained over 72 hrs. Coupled with the observed functional data, mRNA expression analysis highlighted that fission (Drp1, Fis 1; P<0.01) and fusion (Mfn2, Opa1; P<0.01) were both increased by Tn (0.25 μg/ml, 0.75 μg/ml). Confocal microscopy was used to further verify this result. These studies highlight unfavourable changes in mitochondrial function and gene expression arise in adipocytes, in response to an inducer of ER stress; this may mimick an obese phenotype. Taken together, these results indicate that therapeutics to reduce ER stress could have a beneficial influence on alleviating mitochondrial dysfunction and its pathogenic consequences.

Year2014
JournalEndocrine Abstracts
Publisherbioscientifica
ISSN14703947
14796848
Digital Object Identifier (DOI)https://doi.org/10.1530/endoabs.44.P193
Web address (URL)http://hdl.handle.net/10545/624116
hdl:10545/624116
Publication dates01 Mar 2014
Publication process dates
Deposited09 Aug 2019, 08:51
ContributorsUniversity of Westminster
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