Mitofusins, from Mitochondria to Metabolism Emilie Schrepfer, Luca Scorrano  Molecular Cell  Volume 61, Issue 5, Pages 683-694 (March 2016) DOI: 10.1016/j.molcel.2016.02.022 Copyright © 2016 Elsevier Inc. Terms and Conditions

Figure 1 Regulation of Mitochondrial Morphology and Bioenergetic Efficiency in Response to Nutrient Oversupply or Undersupply Cellular metabolic homeostasis is under the control of the balance between nutrient supply and demand. Perturbation in nutrient supply drives cellular adaptations to re-equilibrate the balance. Metabolic oversupply is followed by fragmentation of mitochondrial network, which leads to a decrease of mitochondrial bioenergetic efficiency that, in association with an increase in nutrient storage, will avoid energy waste. Conversely, under metabolic undersupply, mitochondria elongate in order to increase mitochondrial bioenergetic efficiency and sustain the energy need. Molecular Cell 2016 61, 683-694DOI: (10.1016/j.molcel.2016.02.022) Copyright © 2016 Elsevier Inc. Terms and Conditions

Figure 2 Mfn2 in the Regulation of Mitochondrial Biogenesis (A) Mfn2 gene encodes for a 757-amino-acid protein containing several well-conserved domains: a GTPase domain (with five G motifs), two coiled-coil domains (HR1 and HR2), a proline rich domain (PR), and a bipartite transmembrane domain (TM), which allows Mfn2 anchorage in the OMM. Depending on Mfn2 expression level, the mitochondrial metabolism is affected. Molecules/complexes or narrows represented in green are upregulated, whereas those in red are downregulated. (B) Upon Mfn2 overexpression, mitochondrial metabolism is activated. In particular, glucose oxidation, Kreb’s cycle, and proton leak are enhanced, in association with an increase of the mitochondrial membrane potential (ΔΨm) and of the respiratory chain. The respiratory chain constitutes five complexes, which couple electron (e−) transfer from electron donors to oxygen (which is reduced in water [H2O]) with transfer of protons (H+) across the membrane and lead to ATP synthesis. Mfn2 overexpression increased expression of several subunits of complexes I, IV, and V. (C) Upon Mfn2 depletion, glucose oxidation is decreased, concomitantly with an increase of glucose uptake and glycogen synthesis (glycogenesis). Fatty acid β oxidation and amino acid oxidation are also decreased. Loss of Mfn2 also induces a decrease in proton leak, ΔΨm, oxygen consumption, and mitochondrial respiration, with a downregulation of several subunits of complexes I, II, III, and V. Molecular Cell 2016 61, 683-694DOI: (10.1016/j.molcel.2016.02.022) Copyright © 2016 Elsevier Inc. Terms and Conditions

Figure 3 BDLP cis-Oligomers Are Involved in Membrane Curvature and Formation of a Tube Structure between Two Liposomes BDLP crystal structure revealed that BDLP is composed of a head (dark blue), a neck (light blue), a trunk (violet), and a hydrophobic paddle (orange) inserted in the membrane. Upon GTP association, BDLP changes its conformation and induces membranes curvature. cis-oligomers are then able to form a tube and connect two liposomes. Molecular Cell 2016 61, 683-694DOI: (10.1016/j.molcel.2016.02.022) Copyright © 2016 Elsevier Inc. Terms and Conditions

Figure 4 Mitofusins Modulate Cell Fate Mfns are involved in the regulation of macroautophagy. Through the elongation of mitochondria, they protect against specific mitophagy. Moreover, Mfn2 allows the supply of lipids for autophagosome formation via the regulation of MAMs. In turn, Mfn2 depletion inhibits the autophagic flux and finally leads to a bioenergetics crisis upon starvation. Mfns also interfere in cell cycle progression, decreasing cell proliferation. They are also involved in stress-induced senescence and, once senescence occurs, are important players to maintain mitochondrial biogenesis capacity. Lastly, Mfns sustain either pro-apoptotic or anti-apoptotic functions, depending on cellular status and environment. Molecular Cell 2016 61, 683-694DOI: (10.1016/j.molcel.2016.02.022) Copyright © 2016 Elsevier Inc. Terms and Conditions

Figure 5 Mitofusin-Dependent Metabolic Adaptation to Environmental Stimuli In response to exogenous stimuli, Mfns are involved in the transduction of metabolic signaling in different organs in order to maintain the whole-body energy homeostasis. In particular, in response to food intake, changes in temperature, stress, or exercise, the BAT, brain, heart, or skeletal muscles adapt their metabolism to control feeding, body weight, contractile functions, antioxidant response, or insulin sensitivity. (A) Adiposity signal (leptin/insulin) induces different behavior in two subsets of hypothalamic neurons (Agrp and POMC neurons). In orexigenic Agrp neurons, overfeeding triggers an Mfn1/2-dependant elongation of mitochondria, leading to an increase in food intake and fat gain. Conversely, overfeeding leads to an impairment of anorexigenic POMC neurons through a decrease in Mfn2 expression level, associated with a decrease of mito-ER tethering. This reduction of POMC neuron activity leads to a decrease in energy expenditure, leptin resistance, and obesity. (B) In the heart, besides their crucial functions in preserving cardiomyocyte homeostasis and function, Mfn1/2 have also been involved in the decrease of cardiomyocyte viability upon cell-death stimuli (Ca2+ stimulation, ROS generation). However, depletion of both Mfn1 and Mfn2 has been associated with heart failure. (C) In skeletal muscles, changes in temperature, adrenergic stimulation, and high energy expenditure lead to a PGC1α-dependent increase of Mfn2. In turn, an increase in Mfn2 causes OXPHOS subunit transcription and stimulated mitochondrial respiration and limits ROS generation, ER stress, and JNK pathway activation, eventually contributing to maintain insulin sensitivity. Because of these crucial regulations, Mfn2 depletion is associated with obesity and/or diabetes. Molecular Cell 2016 61, 683-694DOI: (10.1016/j.molcel.2016.02.022) Copyright © 2016 Elsevier Inc. Terms and Conditions