Mitochondria and endoplasmic reticulum (ER) are two intracellular organelles that play a key role in calcium homeostasis and energy metabolism. Mitochondrial alterations, ER stress, and disruption of calcium homeostasis were independently associated with hepatic insulin resistance. Interestingly, these two organelles interact at contact points called mitochondria-associated membrane (MAM) to exchange calcium and a disruption of MAM integrity has recently been associated with hepatic insulin resistance. Therefore, a disruption of calcium transfer from ER to mitochondria could could link altered MAM integrity to alterations of insulin signaling in the liver. This is what the works of the team 3 investigated by Jennifer Rieusset, in collaboration with the team 5 managed by Pr. Michel Ovize, recently demonstrated using cyclophilin D (CypD) knock-out (KO) mice, a mice model previously used by the same teams to show that these mice had disrupted MAM integrity and hepatic insulin resistance (Tubbs E et al. Diabetes 2014).
We demonstrated that pharmacological and genetic inhibition of CypD decreased ER-mitochondria interactions, inter-organelle calcium transfer and insulin signaling in HuH7 cells. The same observations were confirmed in primary hepatocytes of CypD-KO mice. Interestingly, the disruption of calcium transfer in CypD-KO liver is associated with hepatic ER stress, decreased mitochondrial function, lipid accumulation (TG and DAG) and activation of stress kinases such as JNK and PKCe. The specific inhibition of both kinases in vitro show that it is the activation of the PKCe which is involved in the alterations of the insulin signaling associated by the inhibition of CypD. Therefore, we propose that the reduction of MAM integrity associated with the loss of CypD leads to hepatic insulin resistance through disruption of organelle calcium exchange, alterations of organelles, increase in lipid accumulation and activation of PKCε. Targetoing ER-mitochondria calcium exchange may thus provide an exciting new avenue for improving hepatic insulin resistance.