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Mitochondrial Fusion: the Machineries in and Out Trends in Cell Biology OPEN ACCESS Review Mitochondrial Fusion: The Machineries In and Out Song Gao 1,2,* and Junjie Hu 3,* Mitochondria are highly dynamic organelles that constantly undergo fission and Highlights fusion. Disruption of mitochondrial dynamics undermines their function and Crystal structures of truncated mitofusin causes several human diseases. The fusion of the outer (OMM) and inner mito- (MFN)1 and MFN2, the dynamin-like chondrial membranes (IMM) is mediated by two classes of dynamin-like protein fusogens of the outer mitochondrial membrane, reveal their structural kinship (DLP): mitofusin (MFN)/fuzzy onions 1 (Fzo1) and optic atrophy 1/mitochondria to bacterial dynamin-like protein (BDLP). genome maintenance 1 (OPA1/Mgm1). Given the lack of structural information Human MFN1 and MFN2 bear subtle on these fusogens, the molecular mechanisms underlying mitochondrial fusion differences that govern the distinct bio- remain unclear, even after 20 years. Here, we review recent advances in struc- chemical properties. tural studies of the mitochondrial fusion machinery, discuss their implication GTP-dependent dimerization and con- for DLPs, and summarize the pathogenic mechanisms of disease-causing muta- formational changes are key features of tions in mitochondrial fusion DLPs. MFNs in driving outer membrane fusion. Short optic atrophy 1/short mitochon- The Mitochondrial Fusion Machinery dria genome maintenance 1 (s-OPA1/ Mitochondria are double-membrane organelles that confer various essential cellular functions, s-Mgm1) resembles fission dynamins including energy production, metabolism, apoptosis, and innate immunity [1]. They form a highly in 3D architecture, highlighting a mech- anism of inner mitochondrial membrane fi dynamic network and constantly undergo cycles of fusion and ssion. The balance between (IMM) merging distinct from that of other fission and fusion has critical roles in maintaining mitochondrial homeostasis in response to known types of homotypic fusion. metabolic or environmental stresses, and is linked to cell division, apoptosis, and autophagy [2–5]. In particular, fusion promotes the capacity of oxidative phosphorylation and allows redistri- OPA1/Mgm1 uses multiple intermolec- ular assemblies to achieve either IMM bution of mitochondrial (mt)DNA between damaged and healthy mitochondria [6,7]. Disruptions fusion or cristae shaping. of mitochondrial dynamics are implicated in aging as well as in several human diseases, including neurodegenerative and metabolic disorders, and cancer [8,9]. Mitochondrial fusion is a two-step Structures of the mitochondrial fusion machinery provide important rules for Fzo fl MFN process; fusion of the OMM is mediated by Fzo1 in yeast, (see Glossary)in ies, and in comparing fusion DLPs with fission mammals, whereas the IMM is fused by Mgm1 in yeast and OPA1 in mammals [10,11]. DLPs. MFN and Fzo1 were identified some 20 years ago [12–15]. Mammals have two MFNs, namely MFN1 and MFN2. Functionally, MFN1 and MFN2 share not only a certain amount of redundancy, 1State Key Laboratory of Oncology in but also substantial differences [15,16]. Mice with deletion of either MFN1 or MFN2 die in utero in South China, Collaborative Innovation Center for Cancer Medicine, Sun mid-gestation [14]. MFN2 mutation accounts for most cases of Charcot-Marie-Tooth disease Yat-sen University Cancer Center, type 2A (CMT2A), a neuromuscular disorder [17]. The yeast IMM fusogen Mgm1 was initially 510060 Guangzhou, China 2 identified as a key regulator of mtDNA maintenance [18,19]. The human OPA1 gene was mapped Guangzhou Regenerative Medicine and Health Guangdong Laboratory, 510530 in genetic studies of patients with autosomal dominant optic atrophy (ADOA) [20], a hereditary Guangzhou, China neurodegenerative disease. Around the same time as the initial characterization of Fzo1 and 3National Laboratory of MFNs, Mgm1 and OPA1 were annotated as membrane-bound GTPases and subsequently Biomacromolecules, CAS Center for Excellence in Biomacromolecules, found to serve as IMM fusogens and cristae-shaping proteins [18,21,22]. Linkage of mitochon- Institute of Biophysics, Chinese Academy drial fusogen mutations to neurodegenerative diseases emphasizes the physiological importance of Sciences, Beijing 100101, China of mitochondrial membrane dynamics in neuronal cells, likely explained by the high demand for energy there [4,8]. *Correspondence: The mechanism of mitochondrial fusion is unclear, partly due to the lack of structural information [email protected] (S. Gao) and on these fusogenic proteins. Recently, several crystal and cryo-electron microscopy (EM) [email protected] (J. Hu). 62 Trends in Cell Biology, January 2021, Vol. 31, No. 1 https://doi.org/10.1016/j.tcb.2020.09.008 © 2020 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Trends in Cell Biology structures of MFN and OPA1 have been reported [23–30]. In this review, we summarize these Glossary advancements and discuss the new insights in mitochondrial fusion therefrom. Amphipathic helix: an α-helix with hydrophobic residues aligning on one Structural Relationship of Mitochondrial Fusogens with the Dynamin Superfamily side and hydrophilic residues on the other side. Typically, these helices can MFNsandOPA1belongtothedynaminsuperfamily of multi-domain GTPases engaged in induce curvature by inserting their various membrane-remodeling events in eukaryotic cells [31]. Of these so-called DLPs hydrophobic face shallowly into (see Table 1 for gene names of key DLPs discussed herein), the best known function of dynamin membranes. is cleavage of clathrin-coated vesicles from the plasma membrane during endocytosis [32]. In Atlastin (ATL): an ER-resident DLP that mediates fusion of ER membranes. ATL addition, dynamin-1-like protein (DNM1L), also known as dynamin-related protein 1 (Drp1), tethers membranes by GTP-dependent mediates mitochondrial fission [33]; myxovirus-resistant (Mx) proteins and guanylate-binding dimerization and fuses them by proteins (GBPs) restrict several types of RNA virus and retrovirus [34,35]; and atlastin (ATL) conformational changes. Mutations of catalyzes endoplasmic reticulum (ER) fusion [36]; EH domain-containing proteins (EHDs) are human ATL1 causes hereditary spastic paraplegia. involved in endosomal trafficking [37], and a recently identified member, neurolastin, is a neuronal Autosomal dominant optic atrophy differentiation mediator during embryonic development [38]. In addition, bacteria also have (ADOA): a hereditary neuronal bacterial DLPs (BDLP), although their functions are not yet fully understood [39]. degenerative disease characterized by reduced visual acuity, vision loss, or vision impairment. It is caused by The DLPs all contain a GTPase (G) domain and a helical region (Figure 1A,B). Previous structural mitochondrial dysfunction that leads to and biochemical studies, especially over the past decade, revealed important common features the degeneration of optic nerve fibers. of DLPs [40–49]. First, compared with the canonical small GTPases, such as Ras and Rab, DLPs Bacterial dynamin-like protein fi (BDLP): bacterial ancestors of DLP. have an enlarged G domain that binds guanine nucleotides with weaker af nity (micromolar range The structures of BDLP resemble that of versus nanomolar range for Ras-like GTPases in terms of the dissociation constant Kd)[31]. MFN. Some BDLP appears in a tandem Second, DLPs generally do not need specific GTPase-activating proteins (GAPs) or guanine nu- manner. The functions of BDLP remain cleotide exchange factors (GEFs) during the GTP hydrolysis cycle [31,50]. Instead, their GTPase elusive. Cardiolipin: a type of phospholipid that activity is stimulated by homodimerization of the G domains [42,51], and the reloading of GTP for is enriched in, and almost exclusive to, DLPs appears to be spontaneous, in accordance with their relatively low affinity for guanine nu- IMM. It contains two phosphatidic acid cleotides [45,46,48,51]. Third, the function of DLPs relies on the relative movement between groups linked by a glycerol. the domains regulated by GTP hydrolysis [50,52,53]. MFN and OPA1 were the last members Charcot-Marie-Tooth disease type 2A (CMT2A): a hereditary neuronal of the dynamin superfamily to have information about their structure revealed [52]. For structural degenerative disease characterized by features of fission DLPs, refer to Box 1. distal weakness, atrophy, sensory loss, decreased deep-tendon reflexes, and variable foot deformity. It is caused by MFN Structures and Mitochondrial Outer Membrane Fusion mutations in MFN2. With a negatively charged OMM, mitochondrial fusion does not occur spontaneously. Genetic Fuzzy onions (Fzo): aMFNhomologin data suggest that MFN is needed on both opposing OMMs to allow fusion; thus, the trans Drosophila. Fzo was the first reported interaction between MFNs is essential [14]. In earlier studies, MFNs were depicted as a MFN [97], and its mutations disrupt mitochondrial fusion during spermatid V-shaped molecule that anchors to the OMM via two transmembrane (TM) helices [60]. The G differentiation, making the normal onion- domain and two conventionally termed heptad repeats (HR1, from residues 317-400 and like fused mitochondria (the Nebenkern) ‘fuzzy onions’. – – GDP•BeF3/GDP•AlF4: analogs used for mimicking the transition state of GTP Table 1. Gene Names of Key DLPs in Various Speciesa hydrolysis when the γ-phosphate is Function DLP name hydrolyzed
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