Mitochondria-Associated Membranes Response to Nutrient Availability and Role in Metabolic Diseases  Pierre Theurey, Jennifer Rieusset  Trends in Endocrinology & Metabolism  Volume 28, Issue 1, Pages 32-45 (January 2017) DOI: 10.1016/j.tem.2016.09.002 Copyright © 2016 Elsevier Ltd Terms and Conditions

Figure 1 Adaptations of Mitochondrial Dynamics and Function to Nutrient Scarcity. During caloric restriction or fasting, increase in cAMP activates protein kinase A (PKA), which phosphorylates and inactivates dynamin-related protein 1 (Drp1), thereby promoting mitochondrial elongation. Nutrient deprivation also increases NAD+ levels, leading to the activation of the mitochondrial sirtuin deacetylase SIRT3 and to deacetylation of key mitochondrial proteins. Lastly, the increase in the AMP-to-ATP ratio activates AMP-activated protein kinase (AMPK), which phosphorylates both Drp1 and mitochondrial fission factor (Mff), thus promoting both antifission and profission signals, respectively. AMPK regulates SIRT1 activity impacting protein acetylation. AMPK also controls the phosphorylation of key transcription (co)activators such as peroxisomal proliferator-activated receptor-gamma coactivator 1-alpha (PGC1α) and fork-head box O (FOXO), thus regulating mitochondrial gene expression. Both PGC1α and FOXO are also targets of SIRT1-dependent deacetylation. Lastly, AMPK regulates mitophagy via direct phosphorylation of Unc-51-like autophagy activating kinase 1 (ULK1) and inhibition of mammalian target of rapamycin complex 1 (mTORC1) suppression of ULK1. Altogether, these acute and long-term regulations allow mitochondria to adapt their function to nutrient availability. Trends in Endocrinology & Metabolism 2017 28, 32-45DOI: (10.1016/j.tem.2016.09.002) Copyright © 2016 Elsevier Ltd Terms and Conditions

Figure 2 Key Figure: Regulation of Endoplasmic Reticulum (ER)–Mitochondria Interactions and Ca2+ Exchange by Cellular Energy Levels At mitochondria-associated membrane (MAM), Ca2+ transfer from the ER to mitochondria is mediated by the inositol-1,4,5-trisphosphate receptor (IP3R)–glucose-regulated protein 75 (Grp75)–voltage-dependent anion-selective channel (VDAC)–cyclophilin D (CypD) complex. Organelle interactions and Ca2+ transfer are controlled by cellular energy levels and impact mitochondria bioenergetics. Blue triangles on either side of the black line (in the broken boxes) illustrate the distance between ER and mitochondria. Left: Following fasting/nutrient deprivation, glucagon increases the phosphorylation of IP3R via the cAMP–protein kinase A (PKA) pathway, thus activating IP3R-mediated Ca2+ release. Both protein phosphatase 2A (PP2A) and phosphatase and tensin homolog (PTEN) participate in the regulation of Ca2+ release from the ER through IP3R, counteracting its Akt-mediated reduction. Fasting is also associated with an increase of ER–mitochondria interactions by an unknown mechanism. In this context, elongated mitochondria preferentially use free fatty acid (FFA) as metabolic substrate for oxidative phosphorylations (OXPHOSs). Right: In the fed state, insulin activates a signaling pathway leading to the phosphorylation and activation of Akt in two subcellular compartments: in cytoplasm near the plasma membrane and at the MAM interface. Mammalian target of rapamycin complex 2 (mTORC2) can phosphorylate and activate Akt in these two localizations. Activated Akt at MAM phosphorylates and inactivates IP3R, leading to reduced IP3R-mediated Ca2+ export from the ER. After a meal, ER–mitochondria interactions are reduced, presumably by a glucose signal. High glucose levels activate the pentose phosphate–PP2A pathway, reducing ER–mitochondria interactions and Ca2+ transfer through an unknown mechanism. This regulation may require PP2A removal from MAM in order to favor phosphorylated Akt. In this context, fragmented mitochondria preferentially use glucose metabolites as substrate for OXPHOS. CoA, coenzyme A; IRS1/2: insulin receptor substrate 1/2; PDK1: phosphoinositide-dependent kinase 1; PI3K, phosphoinositide 3-kinase. Trends in Endocrinology & Metabolism 2017 28, 32-45DOI: (10.1016/j.tem.2016.09.002) Copyright © 2016 Elsevier Ltd Terms and Conditions

Figure 3 Proposed Model for the Regulation of Metabolic Flexibility by Endoplasmic Reticulum (ER)–Mitochondria Interactions. Fasted to postprandial transition, as well as increase in glucose levels, reduces ER–mitochondria interactions through the activation of the pentose phosphate–protein phosphatase 2A (PP–PP2A) pathway, in turn inducing mitochondria fission and reducing respiration in hepatocytes. The regulation of mitochondria-associated membrane integrity and function by glucose levels should control metabolic flexibility by slowing down mitochondrial lipid oxidation (beta-oxidation) and favoring lipogenesis from excess carbohydrates, as illustrated in the broken box at the bottom of the figure. CoA, coenzyme A; OXPHOS, oxidative phosphorylation; TCA, tricarboxylic acid. Trends in Endocrinology & Metabolism 2017 28, 32-45DOI: (10.1016/j.tem.2016.09.002) Copyright © 2016 Elsevier Ltd Terms and Conditions