Tunicamycin-Induced Endoplasmic Reticulum Stress Mediates Mitochondrial Dysfunction in Human Adipocytes.

Laura Jackisch, Alice M Murphy, Sudhesh Kumar, Harpal Randeva, Gyanendra Tripathi, Philip G McTernan

The Journal of clinical endocrinology and metabolism 2020 Sep 01

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Dysfunctional endoplasmic reticulum (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 characterized 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 (24 h: 23%↑; 48 h: 68%↑, P < 0.001; 72 h: 136%↑, P < 0.001). This corresponded with mitochondrial inefficiency and diminished MMP, highlighting the formation of dysfunctional mitochondria. Morphological analysis revealed reorganization 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. © Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Citation

Laura Jackisch, Alice M Murphy, Sudhesh Kumar, Harpal Randeva, Gyanendra Tripathi, Philip G McTernan. Tunicamycin-Induced Endoplasmic Reticulum Stress Mediates Mitochondrial Dysfunction in Human Adipocytes. The Journal of clinical endocrinology and metabolism. 2020 Sep 01;105(9)