Mitochondrial Function is Negatively Impacted by ER stress in Obesity

Identification: Jackisch, Laura


Description

Mitochondrial Function is Negatively Impacted by ER stress in Obesity
 
L Jackisch1, PG McTernan,2, H Randeva1, G Tripathi1.,3
1Warwick Medical School, University of Warwick, UK; 2School of Science & Technology, Nottingham Trent University, UK; 3Department of Biomedical Sciences, University of Westminster, UK
 
Cellular damage in the ER and mitochondria are known to contribute to the pathology of obesity and associated comorbidities. 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 is not well characterised in human adipocytes.  Therefore, this study investigated how the induction of ER stress contributes to the development of mitochondrial inefficiency in human adipocytes.
 
Human differentiated adipocytes from 1) Chub-S7 cell line and 2) primary lean and obese abdominal subcutaneous (AbdSC) adipocytes, were treated with Tunicamycin (Tn) to induce ER stress over time. Key parameters of mitochondrial function were assessed, including oxygen consumption rate (OCR), mitochondrial membrane potential (MMP), ATP concentration fission and fusion proteins, mitochondrial dynamics and number.
 
Induction of ER stress led to a 26% (P≤0.001) increase in OCR in Chub-S7 cells in a concentration dependent manner. This increase in OCR also corresponded to diminished ATP production (26%↓; P≤0.001) and impaired MMP (32%↓; P≤0.0001), highlighting the formation of inefficient mitochondria. Morphological analysis via confocal microscopy also revealed a reduction mitochondrial elongation (16%↓; P≤0.05) and cellular area occupied by mitochondria (28%↓; P≤0.05). Additionally, Drp1, a key protein in mitochondrial fission, significantly increased (p<0.001), likely stimulating mitochondrial fragmentation as seen with the confocal analysis. Furthermore, AbdSc adipocytes from lean subjects mirrored the Chub-S7 cellular response with a 21% (p≤0.01) rise in OCR by Tn treatment. In contrast, mitochondria from obese subjects displayed 33% (p≤0.001) lower basal respiration than their lean counterparts and were not responsive to Tn, demonstrating significantly impaired respiratory function.
 
In summary, these human data suggest that adipocyte mitochondrial inefficiency is impacted by ER stress and exacerbated in obesity. Together our findings indicate the important relationship between the ER and mitochondria as a mechanism to contribute to obesity mediated T2DM.
 
 

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