title: Mitochondria-associated endoplasmic reticulum membrane (MAM) integrity is required for insulin signaling and is implicated in hepatic insulin resistance.
abstract: Mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) are functional domains between both organelles involved in Ca(2+) 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 Ca(2+) 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.
authors.affiliation: INSERM UMR-1060, CarMeN Laboratory, Lyon 1 University, INRA U1235, INSA of Lyon, Rockefeller and Charles Merieux Lyon-Sud Medical Universities, Lyon, France.
authors.forename: Emily
authors.initials: E
authors.lastname: Tubbs
authors.affiliation: INSERM UMR-1060, CarMeN Laboratory, Lyon 1 University, INRA U1235, INSA of Lyon, Rockefeller and Charles Merieux Lyon-Sud Medical Universities, Lyon, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Theurey
authors.affiliation: INSERM UMR-1060, CarMeN Laboratory, Lyon 1 University, INRA U1235, INSA of Lyon, Rockefeller and Charles Merieux Lyon-Sud Medical Universities, Lyon, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Vial
authors.affiliation: INSERM UMR-1060, CarMeN Laboratory, Lyon 1 University, INRA U1235, INSA of Lyon, Rockefeller and Charles Merieux Lyon-Sud Medical Universities, Lyon, France.
authors.forename: Nadia
authors.initials: N
authors.lastname: Bendridi
authors.affiliation: INSERM UMR-1060, CarMeN Laboratory, Lyon 1 University, INRA U1235, INSA of Lyon, Rockefeller and Charles Merieux Lyon-Sud Medical Universities, Lyon, France.
authors.forename: Amélie
authors.initials: A
authors.lastname: Bravard
authors.affiliation: INSERM UMR-1060, CarMeN Laboratory, Lyon 1 University, INRA U1235, INSA of Lyon, Rockefeller and Charles Merieux Lyon-Sud Medical Universities, Lyon, France.
authors.forename: Marie-Agnès
authors.initials: MA
authors.lastname: Chauvin
authors.affiliation: INSERM UMR-1060, CarMeN Laboratory, Lyon 1 University, INRA U1235, INSA of Lyon, Rockefeller and Charles Merieux Lyon-Sud Medical Universities, Lyon, France.
authors.forename: Jingwei
authors.initials: J
authors.lastname: Ji-Cao
authors.affiliation: INSERM UMR-1052, Cancer Research Center of Lyon, Lyon 1 University, Hospices Civils de Lyon, Lyon, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Zoulim
authors.affiliation: INSERM UMR-1052, Cancer Research Center of Lyon, Lyon 1 University, Hospices Civils de Lyon, Lyon, France.
authors.forename: Birke
authors.initials: B
authors.lastname: Bartosch
authors.affiliation: INSERM UMR-1060, CarMeN Laboratory, Lyon 1 University, INRA U1235, INSA of Lyon, Rockefeller and Charles Merieux Lyon-Sud Medical Universities, Lyon, France Hospices Civils de Lyon, Louis Pradel Hospital, Cardiovascular Functional Explorations Service and CIC of Lyon, Lyon, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Ovize
authors.affiliation: INSERM UMR-1060, CarMeN Laboratory, Lyon 1 University, INRA U1235, INSA of Lyon, Rockefeller and Charles Merieux Lyon-Sud Medical Universities, Lyon, France Hospices Civils de Lyon, Lyon-Sud Hospital, Endocrinology, Diabetology, and Nutrition Service, Pierre-Bénite, France.
authors.forename: Hubert
authors.initials: H
authors.lastname: Vidal
authors.affiliation: INSERM UMR-1060, CarMeN Laboratory, Lyon 1 University, INRA U1235, INSA of Lyon, Rockefeller and Charles Merieux Lyon-Sud Medical Universities, Lyon, France Hospices Civils de Lyon, Lyon-Sud Hospital, Endocrinology, Diabetology, and Nutrition Service, Pierre-Bénite, France.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Rieusset
mesh_terms: D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology*; D007425:Intracellular Membranes / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D007328:Insulin