Editors' ChoiceMetabolic Syndrome

ER-Mitochondrial Communication Gets Stressful

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Science Translational Medicine  17 Dec 2014:
Vol. 6, Issue 267, pp. 267ec213
DOI: 10.1126/scitranslmed.aaa3453

Obesity leads to chronic metabolic overload and stress in cellular organelles, such as the endoplasmic reticulum (ER) and mitochondria, which serve as critical intracellular metabolic hubs. ER stress is a classic hallmark of obesity-induced metabolic dysfunction in the liver. It is also well known that human and mouse obesity is associated with mitochondrial dysfunction that leads to compromised oxidative capacity and increased oxidative stress. However, the underlying causes of these defects and the consequences of mitochondrial dysfunction for the liver and for glucose homeostasis remain unclear.

The ER forms extensive contacts with mitochondria through sites known as mitochondria-associated ER membranes (MAMs) that are highly conserved in eukaryotes. Through these sites, the ER and mitochondria exchange vital information in the form of lipids, proteins, metabolites, and Ca2+ and have a strong impact on each other’s function and on cell survival. Arruda et al. now show that metabolic stress signals can spread from one organelle to another through inter-organelle “synapses” formed between the ER and mitochondria in the liver of obese mice, resulting in the abrogation of insulin signaling. Genetic and diet-induced obesity led to marked increases in these ER-mitochondrial contacts, suggesting that stress signals could pass from one organelle to another via these contact sites. A comparison of livers from obese and lean mice revealed marked upregulation of MAM proteins involved in Ca2+ transport. Experimental manipulation of these contacts in vivo showed enhancement of ER-mitochondrial coupling. This resulted in increased Ca2+ flux from the ER to mitochondria, a concomitant increase in mitochondrial oxidative stress, and increased metabolic impairment. In contrast, uncoupling the ER from mitochondria restored functional mitochondrial oxidation and improved systemic glucose homeostasis. The researchers noted similar changes in MAM protein expression and mitochondrial morphology in the muscles of lean and obese mice, although the systemic metabolic consequences of this will require careful evaluation in future studies. The current study highlights the dynamic nature of inter-organelle communication via MAMs and their role in metabolic health. It will be important to explore whether restoring the correct number of ER-mitochondrial contacts in liver and muscle cells through targeted therapy could be potentially useful in the treatment of obesity.

A. P. Arruda et al., Chronic enrichment of hepatic endoplasmic reticulum–mitochondria contact leads to mitochondrial dysfunction in obesity. Nat. Med. 10.1038/nm.3735 (2014). [Abstract]

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