Disruption of calcium transfer from ER to mitochondria links alterations of mitochondria-associated ER membrane integrity to hepatic insulin resistance

Autor: Maud Michelet, Amélie Bravard, Alain Lacampagne, Guillaume Vial, Hubert Vidal, Marie-Agnès Chauvin, Annie Durand, Elise Belaidi, Melanie Paillard, Pierre Theurey, Jennifer Rieusset, Marie Demion, Jérémy Fauconnier, Emily Tubbs, Fabien Zoulim, Geoffrey Teixeira, Emilie Blond, Birke Bartosch, Michel Ovize, Ludovic Gomez
Přispěvatelé: Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Service d'Explorations Fonctionnelles Cardiovasculaires (SEFC), Hospices Civils de Lyon (HCL), Virologie humaine, École normale supérieure - Lyon (ENS Lyon)-IFR128-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Cancérologie de Lyon (CRCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Physiopathologie moléculaire et nouveaux traitements des hépatites virales, Université de Lyon-Université de Lyon-IFR62-Institut National de la Santé et de la Recherche Médicale (INSERM), Cardioprotection, Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Jazyk: angličtina
Rok vydání: 2016
Předmět:
Male
0301 basic medicine
Endocrinology
Diabetes and Metabolism
medicine.medical_treatment
[SDV]Life Sciences [q-bio]
Mitochondrion
Biology
Cell Line
Cyclophilins
Mice
03 medical and health sciences
Insulin resistance
5-triphosphate receptor
Internal Medicine
medicine
Mitochondria-associated endoplasmic reticulum membranes
Animals
Humans
Inositol 1
4
5-Trisphosphate Receptors
[SDV.BBM]Life Sciences [q-bio]/Biochemistry
Molecular Biology
ComputingMilieux_MISCELLANEOUS
Protein kinase C
Calcium signaling
Mice
Knockout
PKCε
Endoplasmic reticulum
Insulin
Calcium signalling
STIM1
[SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism
medicine.disease
Inositol 1
Cell biology
Mitochondria
030104 developmental biology
Liver
Inositol 1 4 5-triphosphate receptor
Hepatocytes
Unfolded protein response
Calcium
Cyclophilin D
Zdroj: Diabetologia
Diabetologia, Springer Verlag, 2016, 59 (3), pp.614-623. ⟨10.1007/s00125-015-3829-8⟩
ISSN: 0012-186X
1432-0428
DOI: 10.1007/s00125-015-3829-8⟩
Popis: 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.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.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.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.
Databáze: OpenAIRE
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