Chronic enrichment of hepatic ER-mitochondria contact sites leads to calcium dependent mitochondrial dysfunction in obesity
Pers, Benedicte Mengel
MetadataShow full item record
CitationArruda, Ana Paula, Benedicte Mengel Pers, Güneş Parlakgül, Ekin Güney, Karen Inouye, and Gökhan S. Hotamisligil. 2015. “Chronic enrichment of hepatic ER-mitochondria contact sites leads to calcium dependent mitochondrial dysfunction in obesity.” Nature medicine 20 (12): 1427-1435. doi:10.1038/nm.3735. http://dx.doi.org/10.1038/nm.3735.
AbstractProper 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.
Citable link to this pagehttp://nrs.harvard.edu/urn-3:HUL.InstRepos:17295575
- SPH Scholarly Articles