title: Mitochondria-associated endoplasmic reticulum membranes allow adaptation of mitochondrial metabolism to glucose availability in the liver.
abstract: Mitochondria-associated endoplasmic reticulum membranes (MAM) play a key role in mitochondrial dynamics and function and in hepatic insulin action. Whereas mitochondria are important regulators of energy metabolism, the nutritional regulation of MAM in the liver and its role in the adaptation of mitochondria physiology to nutrient availability are unknown. In this study, we found that the fasted to postprandial transition reduced the number of endoplasmic reticulum-mitochondria contact points in mouse liver. Screening of potential hormonal/metabolic signals revealed glucose as the main nutritional regulator of hepatic MAM integrity both in vitro and in vivo Glucose reduced organelle interactions through the pentose phosphate-protein phosphatase 2A (PP-PP2A) pathway, induced mitochondria fission, and impaired respiration. Blocking MAM reduction counteracted glucose-induced mitochondrial alterations. Furthermore, disruption of MAM integrity mimicked effects of glucose on mitochondria dynamics and function. This glucose-sensing system is deficient in the liver of insulin-resistant ob/ob and cyclophilin D-KO mice, both characterized by chronic disruption of MAM integrity, mitochondrial fission, and altered mitochondrial respiration. These data indicate that MAM contribute to the hepatic glucose-sensing system, allowing regulation of mitochondria dynamics and function during nutritional transition. Chronic disruption of MAM may participate in hepatic mitochondrial dysfunction associated with insulin resistance.
authors.affiliation: INSERM UMR-1060, CarMeN Laboratory, Lyon 1 University, INRA U1235, INSA of Lyon, Rockefeller and Charles Merieux Lyon-Sud medical Universities, F-69003 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, F-69003 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, F-69003 Lyon, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Vial
authors.affiliation: Cancer Research Center of Lyon, Centre Léon Bérard, UMR INSERM 1052, CNRS 5286, F-69373 Lyon, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Jacquemetton
authors.affiliation: INSERM UMR-1060, CarMeN Laboratory, Lyon 1 University, INRA U1235, INSA of Lyon, Rockefeller and Charles Merieux Lyon-Sud medical Universities, F-69003 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, F-69003 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, F-69003 Lyon, France.
authors.forename: Muhammad Rizwan
authors.initials: MR
authors.lastname: Alam
authors.affiliation: Cancer Research Center of Lyon, Centre Léon Bérard, UMR INSERM 1052, CNRS 5286, F-69373 Lyon, France.
authors.forename: Muriel
authors.initials: M
authors.lastname: Le Romancer
authors.affiliation: INSERM UMR-1060, CarMeN Laboratory, Lyon 1 University, INRA U1235, INSA of Lyon, Rockefeller and Charles Merieux Lyon-Sud medical Universities, F-69003 Lyon, France Hospices Civils de Lyon, Lyon-Sud Hospital, Endocrinology, Diabetology and Nutrition Service, F-69310 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, F-69003 Lyon, France Hospices Civils de Lyon, Lyon-Sud Hospital, Endocrinology, Diabetology and Nutrition Service, F-69310 Pierre Bénite, France jennifer.rieusset@univ-lyon1.fr.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Rieusset
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000473:pathology; D004721:Endoplasmic Reticulum / Q000378:metabolism* / Q000648:ultrastructure; D005947:Glucose / Q000494:pharmacology*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism; D007425:Intracellular Membranes / Q000187:drug effects / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D009752:Nutritional Status / Q000187:drug effects; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D019518:Postprandial Period / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D050995:Voltage-Dependent Anion Channel 1 / Q000378:metabolism
chemical_list: D053496:Inositol 1,4,5-Trisphosphate Receptors; D050995:Voltage-Dependent Anion Channel 1; D010749:Phosphoprotein Phosphatases; D005947:Glucose
keywords: MAM; PP2A; glucose sensing; hepatocytes; mitochondria dynamics; pentose phosphate pathway