Chronic enrichment of hepatic endoplasmic reticulum-mitochondria contact leads to mitochondrial dysfunction in obesity.
Chronic enrichment of hepatic endoplasmic reticulum-mitochondria contact leads to mitochondrial dysfunction in obesity.
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内质网（ER）和线粒体的正常功能对于细胞内稳态至关重要，并且任一位点的功能障碍与包括代谢疾病在内的病理生理状态有关。虽然ER和线粒体发挥不同的细胞作用，这些细胞器也形成物理相互作用的网站定义为线粒体相关的ER膜（MAMs），这是必不可少的钙，脂质和代谢物交换。在这里，我们表明，在肝脏中，肥胖导致MAMs的显著重组，导致线粒体Ca 2+过载，线粒体氧化能力受损和氧化应激增强。ER-线粒体相互作用的实验诱导导致氧化应激和代谢稳态受损，而PACS-2或IP 3R 1（分别对ER-线粒体束缚和钙转运重要的蛋白质）的下调改善了肥胖动物的线粒体氧化能力和胰岛素敏感性。这些发现确立了过度的ER-线粒体偶联作为肥胖中细胞器功能障碍的重要组成部分，这可能有助于代谢病理学如胰岛素抵抗的发展。
Proper function of the endoplasmic reticulum (ER) and mitochondria is critical for cellular homeostasis, and dysfunction at either site has been linked to pathophysiological states including metabolic diseases. Although ER and mitochondria play distinct cellular roles, these organelles also form physical interactions at sites defined as mitochondria associated ER-membranes (MAMs), which are essential for Ca2+, lipid and metabolite exchange. Here we show that in the liver, obesity leads to a significant reorganization of MAMs resulting in mitochondrial Ca2+ overload, compromised mitochondrial oxidative capacity and augmented oxidative stress. Experimental induction of ER-mitochondria interactions results in oxidative stress and impaired metabolic homeostasis, while down-regulation of PACS-2 or IP3R1, proteins important for ER-mitochondria tethering and calcium transport respectively, improves mitochondrial oxidative capacity and insulin sensitivity in obese animals. These findings establish excessive ER-mitochondrial coupling as an essential component of organelle dysfunction in obesity, which may contribute to the development of metabolic pathologies such as insulin resistance.
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影响因子：
120.7
作者：
Flegal, Katherine M.;Carroll, Margaret D.;Curtin, Lester R.
通讯作者：
Curtin, Lester R.
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64.5
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11.4
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