Chronic enrichment of hepatic endoplasmic reticulum-mitochondria contact leads to mitochondrial dysfunction in obesity

Nat Med. 2014 Dec;20(12):1427-35. doi: 10.1038/nm.3735. Epub 2014 Nov 24.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Video-Audio Media

MeSH terms

  • Animals
  • Calcium / metabolism*
  • Calnexin / metabolism
  • Disease Models, Animal
  • Down-Regulation
  • Endoplasmic Reticulum / metabolism*
  • Endoplasmic Reticulum / ultrastructure
  • Endoplasmic Reticulum Stress / physiology
  • GTP Phosphohydrolases / metabolism
  • Glucose / metabolism*
  • Hepatocytes / metabolism*
  • Hepatocytes / ultrastructure
  • Inositol 1,4,5-Trisphosphate Receptors / metabolism
  • Lipid Metabolism / physiology*
  • Liver / metabolism*
  • Liver / ultrastructure
  • Mice
  • Microscopy, Electron, Transmission
  • Mitochondria / metabolism*
  • Mitochondria / ultrastructure
  • Obesity / metabolism*
  • Oxidative Stress / physiology*
  • Vesicular Transport Proteins / metabolism


  • Inositol 1,4,5-Trisphosphate Receptors
  • Ip3r2 protein, mouse
  • Itpr1 protein, mouse
  • Pacs2 protein, mouse
  • Vesicular Transport Proteins
  • Calnexin
  • GTP Phosphohydrolases
  • Mfn2 protein, mouse
  • Glucose
  • Calcium