title: Disruption of calcium transfer from ER to mitochondria links alterations of mitochondria-associated ER membrane integrity to hepatic insulin resistance.
abstract: OBJECTIVE
  Mitochondria-associated endoplasmic reticulum membranes (MAMs) are regions of the endoplasmic reticulum (ER) tethered to mitochondria and controlling calcium (Ca(2+)) transfer between both organelles through the complex formed between the voltage-dependent anion channel, glucose-regulated protein 75 and inositol 1,4,5-triphosphate receptor (IP3R). We recently identified cyclophilin D (CYPD) as a new partner of this complex and demonstrated a new role for MAMs in the control of insulin's action in the liver. Here, we report on the mechanisms by which disruption of MAM integrity induces hepatic insulin resistance in CypD (also known as Ppif)-knockout (KO) mice.
  
  
  METHODS
  We used either in vitro pharmacological and genetic inhibition of CYPD in HuH7 cells or in vivo loss of CYPD in mice to investigate ER-mitochondria interactions, inter-organelle Ca(2+) exchange, organelle homeostasis and insulin action.
  
  
  RESULTS
  Pharmacological and genetic inhibition of CYPD concomitantly reduced ER-mitochondria interactions, inhibited inter-organelle Ca(2+) exchange, induced ER stress and altered insulin signalling in HuH7 cells. In addition, histamine-stimulated Ca(2+) transfer from ER to mitochondria was blunted in isolated hepatocytes of CypD-KO mice and this was associated with an increase in ER calcium store. Interestingly, disruption of inter-organelle Ca(2+) transfer was associated with ER stress, mitochondrial dysfunction, lipid accumulation, activation of c-Jun N-terminal kinase (JNK) and protein kinase C (PKC)ε and insulin resistance in liver of CypD-KO mice. Finally, CYPD-related alterations of insulin signalling were mediated by activation of PKCε rather than JNK in HuH7 cells.
  
  
  CONCLUSIONS
  Disruption of IP3R-mediated Ca(2+) signalling in the liver of CypD-KO mice leads to hepatic insulin resistance through disruption of organelle interaction and function, increase in lipid accumulation and activation of PKCε. Modulation of ER-mitochondria Ca(2+) exchange may thus provide an exciting new avenue for treating hepatic insulin resistance.
authors.affiliation: Inserm UMR-1060, Laboratoire CarMeN, Université Lyon 1, 165 chemin du grand Revoyet, BP12, 69921, Oullins cedex, France. jennifer.rieusset@univ-lyon1.fr.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Rieusset
authors.affiliation: Inserm U1046-CNRS UMR-9214, PhyMedExp, Université Montpellier, Montpellier, France.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Fauconnier
authors.affiliation: Inserm UMR-1060, Laboratoire CarMeN, Université Lyon 1, 165 chemin du grand Revoyet, BP12, 69921, Oullins cedex, France.
authors.forename: Melanie
authors.initials: M
authors.lastname: Paillard
authors.affiliation: Inserm UMR-1060, Laboratoire CarMeN, Université Lyon 1, 165 chemin du grand Revoyet, BP12, 69921, Oullins cedex, France.
authors.forename: Elise
authors.initials: E
authors.lastname: Belaidi
authors.affiliation: Inserm UMR-1060, Laboratoire CarMeN, Université Lyon 1, 165 chemin du grand Revoyet, BP12, 69921, Oullins cedex, France.
authors.forename: Emily
authors.initials: E
authors.lastname: Tubbs
authors.affiliation: Inserm UMR-1060, Laboratoire CarMeN, Université Lyon 1, 165 chemin du grand Revoyet, BP12, 69921, Oullins cedex, France.
authors.forename: Marie-Agnès
authors.initials: MA
authors.lastname: Chauvin
authors.affiliation: Inserm UMR-1060, Laboratoire CarMeN, Université Lyon 1, 165 chemin du grand Revoyet, BP12, 69921, Oullins cedex, France.
authors.forename: Annie
authors.initials: A
authors.lastname: Durand
authors.affiliation: Inserm UMR-1060, Laboratoire CarMeN, Université Lyon 1, 165 chemin du grand Revoyet, BP12, 69921, Oullins cedex, France.
authors.forename: Amélie
authors.initials: A
authors.lastname: Bravard
authors.affiliation: Inserm UMR-1060, Laboratoire CarMeN, Université Lyon 1, 165 chemin du grand Revoyet, BP12, 69921, Oullins cedex, France.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Teixeira
authors.affiliation: Inserm UMR-1052, Centre de recherche en Cancérologie de Lyon, Université Lyon 1, Lyon, France.
authors.forename: Birke
authors.initials: B
authors.lastname: Bartosch
authors.affiliation: Inserm UMR-1052, Centre de recherche en Cancérologie de Lyon, Université Lyon 1, Lyon, France.
authors.forename: Maud
authors.initials: M
authors.lastname: Michelet
authors.affiliation: Inserm UMR-1060, Laboratoire CarMeN, Université Lyon 1, 165 chemin du grand Revoyet, BP12, 69921, Oullins cedex, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Theurey
authors.affiliation: Inserm UMR-1060, Laboratoire CarMeN, Université Lyon 1, 165 chemin du grand Revoyet, BP12, 69921, Oullins cedex, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Vial
authors.affiliation: Inserm U1046-CNRS UMR-9214, PhyMedExp, Université Montpellier, Montpellier, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Demion
authors.affiliation: Inserm UMR-1060, Laboratoire CarMeN, Université Lyon 1, 165 chemin du grand Revoyet, BP12, 69921, Oullins cedex, France.|Hospices Civils de Lyon, Lyon, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Blond
authors.affiliation: Inserm UMR-1052, Centre de recherche en Cancérologie de Lyon, Université Lyon 1, Lyon, France.|Hospices Civils de Lyon, Lyon, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Zoulim
authors.affiliation: Inserm UMR-1060, Laboratoire CarMeN, Université Lyon 1, 165 chemin du grand Revoyet, BP12, 69921, Oullins cedex, France.
authors.forename: Ludovic
authors.initials: L
authors.lastname: Gomez
authors.affiliation: Inserm UMR-1060, Laboratoire CarMeN, Université Lyon 1, 165 chemin du grand Revoyet, BP12, 69921, Oullins cedex, France.
authors.forename: Hubert
authors.initials: H
authors.lastname: Vidal
authors.affiliation: Inserm U1046-CNRS UMR-9214, PhyMedExp, Université Montpellier, Montpellier, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Lacampagne
authors.affiliation: Inserm UMR-1060, Laboratoire CarMeN, Université Lyon 1, 165 chemin du grand Revoyet, BP12, 69921, Oullins cedex, France.|Hospices Civils de Lyon, Lyon, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Ovize
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000235:genetics / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*
chemical_list: D000081406:Peptidyl-Prolyl Isomerase F; D053496:Inositol 1,4,5-Trisphosphate Receptors; C000631446:PPIF protein, mouse; D021983:Cyclophilins; D002118:Calcium
keywords: Calcium signalling; Cyclophilin D; Endoplasmic reticulum; Inositol 1,4,5-triphosphate receptor; Insulin resistance; Liver; Mitochondria; Mitochondria-associated endoplasmic reticulum membranes; PKCε