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内质网
细胞生物学
氧化应激
氧化磷酸化
胰岛素抵抗
生物
细胞器
未折叠蛋白反应
钙
内分泌学
内科学
化学
生物化学
胰岛素
医学
作者
Ana Paula Arruda,Benedicte Mengel Pers,Güneş Parlakgül,Ekin Güney,Karen Inouye,Gökhan S. Hotamışlıgil
出处
期刊:Nature Medicine
[Springer Nature]
日期:2014-11-24
卷期号:20 (12): 1427-1435
被引量:496
摘要
Obesity-induced mitochondria stress and dysfunction results from disorganized mitochondria-associated ER membranes and excess calcium flux. Proper function of the endoplasmic reticulum (ER) and mitochondria is crucial for cellular homeostasis, and dysfunction at either site has been linked to pathophysiological states, including metabolic diseases. Although the ER and mitochondria play distinct cellular roles, these organelles also form physical interactions with each other at sites defined as mitochondria-associated ER membranes (MAMs), which are essential for calcium, lipid and metabolite exchange. Here we show that in the liver, obesity leads to a marked reorganization of MAMs resulting in mitochondrial calcium overload, compromised mitochondrial oxidative capacity and augmented oxidative stress. Experimental induction of ER-mitochondria interactions results in oxidative stress and impaired metabolic homeostasis, whereas downregulation of PACS-2 or IP3R1, proteins important for ER-mitochondria tethering or calcium transport, respectively, improves mitochondrial oxidative capacity and glucose metabolism in obese animals. These findings establish excessive ER-mitochondrial coupling as an essential component of organelle dysfunction in obesity that may contribute to the development of metabolic pathologies such as insulin resistance and diabetes.
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