Our organism is daily subjected to nutritional transitions, an alternation between fasted and post-prandial states. Our organs have different hormonal and enzymatic systems to adapt their metabolism to these nutritional changes. Specifically, the liver plays a key role in the control of glucose homeostasis and has various glucose sensors to regulate its oxidative metabolism and determine whether it has to produce glucose (fasted state) or store it (post-prandial state), mainly as glycogen and fat. The works of the team 3 investigated by Jennifer Rieusset recently demonstrated that the points of contact between mitochondria and the endoplasmic reticulum (ER), called MAM (Mitochondria-associated ER membranes), is a new glucose-sensing mechanism enabling to adapt mitochondrial dynamics and function to nutritional status.
We identified that the transition from fasted to fed state reduced ER-mitochondria interactions in mouse liver. We subsequently demonstrated in vitro that this was the presence of high glucose concentrations which were responsible for the reduction of MAM integrity, via the activation of the pentose phosphate-protein phosphatase 2A pathway. Furthermore, the regulation of MAM by glucose induced mitochondria fission and impaired respiration. Indeed, the prevention of the decrease of MAM abolished glucose-induced mitochondrial alterations, whereas an experimental alteration of MAM mimicked the effect of glucose on mitochondrial dynamics and function. Interestingly, the regulation of MAM by glucose is absent in the liver of obese and diabetic mouse, characterized by chronic alteration of MAM, mitochondria fission, and reduced mitochondrial respiration. Altogether, these data indicate that MAM allow the liver to adapt the mitochondrial metabolism to glucose availability and link PP2A as an important target for modulating ER-mitochondria interactions in the liver. Finally, these data suggest that chronic disruption of MAM may participate in mitochondrial dysfunction and hepatic metabolic alterations associated with obesity and diabetes.
We propose that the regulation of MAM by glucose is a new mechanism regulating metabolic flexibility in the liver. At fasted state, the liver preferentially uses free fatty acids from adipose tissue as substrates and the maximal interaction between ER and mitochondria promotes their mitochondrial oxidation. In the fed state, the massive increase in glucose flux into the liver redirects glucose through the storage pathways into glycogen and triglycerides. Under such conditions, the decrease of interactions mitochondria-RE should contribute slowing down lipid oxidation and favoring lipogenesis.
Theurey , Tubbs E, Vial G, Jacquemetton J, Bendridi N, Chauvin MA, Alam MR, Le Romancer M, Vidal H, Rieusset J. Mitochondria-associated endoplasmic reticulum membranes allow adaptation of mitochondrial metabolism to glucose availability in the liver. J Mol Cell Biol. 2016 Apr;8(2):129-43. PubMed