Mitochondria-Associated Endoplasmic Reticulum Membrane (MAM) Integrity Is Required for Insulin Signaling and Is Implicated in Hepatic Insulin Resistance

  1. Jennifer Rieusset1,4
  1. 1INSERM UMR-1060, CarMeN Laboratory, Lyon 1 University, INRA U1235, INSA of Lyon, Rockefeller and Charles Merieux Lyon-Sud Medical Universities, Lyon, France
  2. 2INSERM UMR-1052, Cancer Research Center of Lyon, Lyon 1 University, Hospices Civils de Lyon, Lyon, France
  3. 3Hospices Civils de Lyon, Louis Pradel Hospital, Cardiovascular Functional Explorations Service and CIC of Lyon, Lyon, France
  4. 4Hospices Civils de Lyon, Lyon-Sud Hospital, Endocrinology, Diabetology, and Nutrition Service, Pierre Bénite, France
  1. Corresponding author: Jennifer Rieusset, jennifer.rieusset{at}univ-lyon1.fr.

Abstract

Mitochondria-associated endoplasmic reticulum (ER) membranes (MAM) are functional domains between both organelles involved in Ca2+ exchange, through the voltage-dependent anion channel (VDAC)-1/glucose-regulated protein 75 (Grp75)/inositol 1,4,5-triphosphate receptor (IP3R)-1 complex, and regulating energy metabolism. Whereas mitochondrial dysfunction, ER stress, and altered Ca2+ homeostasis are associated with altered insulin signaling, the implication of MAM dysfunctions in insulin resistance is unknown. Here we validated an approach based on in situ proximity ligation assay to detect and quantify VDAC1/IP3R1 and Grp75/IP3R1 interactions at the MAM interface. We demonstrated that MAM integrity is required for insulin signaling and that induction of MAM prevented palmitate-induced alterations of insulin signaling in HuH7 cells. Disruption of MAM integrity by genetic or pharmacological inhibition of the mitochondrial MAM protein, cyclophilin D (CypD), altered insulin signaling in mouse and human primary hepatocytes and treatment of CypD knockout mice with metformin improved both insulin sensitivity and MAM integrity. Furthermore, ER-mitochondria interactions are altered in liver of both ob/ob and diet-induced insulin-resistant mice and improved by rosiglitazone treatment in the latter. Finally, increasing organelle contacts by overexpressing CypD enhanced insulin action in primary hepatocytes of diabetic mice. Collectively, our data reveal a new role of MAM integrity in hepatic insulin action and resistance, providing a novel target for the modulation of insulin action.

Footnotes

  • P.T. and G.V. contributed equally to this work.

  • Received November 18, 2013.
  • Accepted April 30, 2014.

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