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Erschienen in:

01.03.2016 | Article

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

verfasst von: Jennifer Rieusset, Jeremy Fauconnier, Melanie Paillard, Elise Belaidi, Emily Tubbs, Marie-Agnès Chauvin, Annie Durand, Amélie Bravard, Geoffrey Teixeira, Birke Bartosch, Maud Michelet, Pierre Theurey, Guillaume Vial, Marie Demion, Emilie Blond, Fabien Zoulim, Ludovic Gomez, Hubert Vidal, Alain Lacampagne, Michel Ovize

Erschienen in: Diabetologia | Ausgabe 3/2016

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Abstract

Aims/hypothesis

Mitochondria-associated endoplasmic reticulum membranes (MAMs) are regions of the endoplasmic reticulum (ER) tethered to mitochondria and controlling calcium (Ca²⁺) 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 Ca²⁺ exchange, organelle homeostasis and insulin action.

Results

Pharmacological and genetic inhibition of CYPD concomitantly reduced ER–mitochondria interactions, inhibited inter-organelle Ca²⁺ exchange, induced ER stress and altered insulin signalling in HuH7 cells. In addition, histamine-stimulated Ca²⁺ 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 Ca²⁺ 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/interpretation

Disruption of IP3R-mediated Ca²⁺ 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 Ca²⁺ exchange may thus provide an exciting new avenue for treating hepatic insulin resistance.

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Titel: Disruption of calcium transfer from ER to mitochondria links alterations of mitochondria-associated ER membrane integrity to hepatic insulin resistance
verfasst von: Jennifer Rieusset
Jeremy Fauconnier
Melanie Paillard
Elise Belaidi
Emily Tubbs
Marie-Agnès Chauvin
Annie Durand
Amélie Bravard
Geoffrey Teixeira
Birke Bartosch
Maud Michelet
Pierre Theurey
Guillaume Vial
Marie Demion
Emilie Blond
Fabien Zoulim
Ludovic Gomez
Hubert Vidal
Alain Lacampagne
Michel Ovize
Publikationsdatum: 01.03.2016
Verlag: Springer Berlin Heidelberg
Erschienen in: Diabetologia / Ausgabe 3/2016
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-015-3829-8

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