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Structure of s-Mgm1 decorating the outer surface of tubulated lipid membranes in the GTPgammaS bound stateStructure of s-Mgm1 decorating the outer surface of tubulated lipid membranes in the GTPgammaS bound state
Structural highlights
FunctionMGM1_CHATD Dynamin-related GTPase that is essential for normal mitochondrial morphology by mediating fusion of the mitochondrial inner membranes, regulating cristae morphology and maintaining respiratory chain function (PubMed:31292547). Exists in two forms: the transmembrane, long form (Dynamin-like GTPase MGM1, long form; L-MGM1), which is tethered to the inner mitochondrial membrane, and the short soluble form (Dynamin-like GTPase MGM1, short form; S-MGM1), which results from proteolytic cleavage and localizes in the intermembrane space (By similarity). Both forms (L-MGM1 and S-MGM1) cooperate to catalyze the fusion of the mitochondrial inner membrane (By similarity). The equilibrium between L-MGM1 and S-MGM1 is essential: excess levels of S-MGM1, following loss of mitochondrial membrane potential, lead to an impaired equilibrium between L-MGM1 and S-MGM1, inhibiting mitochondrial fusion (By similarity). Plays a role in the maintenance and remodeling of mitochondrial cristae, some invaginations of the mitochondrial inner membrane that provide an increase in the surface area (PubMed:31292547). Probably acts by forming helical filaments at the inside of inner membrane tubes with the shape and dimensions of crista junctions (PubMed:31292547).[UniProtKB:O60313][UniProtKB:P32266][1] Constitutes the transmembrane long form (L-MGM1) that plays a central role in mitochondrial inner membrane fusion and cristae morphology (By similarity). L-MGM1 and the soluble short form (S-MGM1) form higher-order helical assemblies that coordinate the fusion of mitochondrial inner membranes (By similarity). Inner membrane-anchored L-MGM1 molecules initiate membrane remodeling by recruiting soluble S-MGM1 to rapidly polymerize into a flexible cylindrical scaffold encaging the mitochondrial inner membrane (By similarity). Once at the membrane surface, the formation of S-MGM1 helices induce bilayer curvature (By similarity). MGM1 dimerization through the paddle region, which inserts into cardiolipin-containing membrane, promotes GTP hydrolysis and the helical assembly of a flexible MGM1 lattice on the membrane, which drives membrane curvature and mitochondrial fusion (PubMed:31292547).[UniProtKB:O60313][UniProtKB:P32266][2] Constitutes the soluble short form (S-MGM1) generated by cleavage by PCP1, which plays a central role in mitochondrial inner membrane fusion and cristae morphology (By similarity). The transmembrane long form (L-MGM1) and the S-MGM1 form higher-order helical assemblies that coordinate the fusion of mitochondrial inner membranes (By similarity). Inner membrane-anchored L-MGM1 molecules initiate membrane remodeling by recruiting soluble S-MGM1 to rapidly polymerize into a flexible cylindrical scaffold encaging the mitochondrial inner membrane (By similarity). Once at the membrane surface, the formation of S-MGM1 helices induce bilayer curvature (By similarity). MGM1 dimerization through the paddle region, which inserts into cardiolipin-containing membrane, promotes GTP hydrolysis and the helical assembly of a flexible MGM1 lattice on the membrane, which drives membrane curvature and mitochondrial fusion (PubMed:31292547). Excess levels of S-MGM1 produced by cleavage by PCP1 following stress conditions that induce loss of mitochondrial membrane potential, lead to an impaired equilibrium between L-MGM1 and S-MGM1, thereby inhibiting mitochondrial fusion (By similarity).[UniProtKB:O60313][UniProtKB:P32266][3] Publication Abstract from PubMedBalanced fusion and fission are key for the proper function and physiology of mitochondria(1,2). Remodelling of the mitochondrial inner membrane is mediated by the dynamin-like protein mitochondrial genome maintenance 1 (Mgm1) in fungi or the related protein optic atrophy 1 (OPA1) in animals(3-5). Mgm1 is required for the preservation of mitochondrial DNA in yeast(6), whereas mutations in the OPA1 gene in humans are a common cause of autosomal dominant optic atrophy-a genetic disorder that affects the optic nerve(7,8). Mgm1 and OPA1 are present in mitochondria as a membrane-integral long form and a short form that is soluble in the intermembrane space. Yeast strains that express temperature-sensitive mutants of Mgm1(9,10) or mammalian cells that lack OPA1 display fragmented mitochondria(11,12), which suggests that Mgm1 and OPA1 have an important role in inner-membrane fusion. Consistently, only the mitochondrial outer membrane-not the inner membrane-fuses in the absence of functional Mgm1(13). Mgm1 and OPA1 have also been shown to maintain proper cristae architecture(10,14); for example, OPA1 prevents the release of pro-apoptotic factors by tightening crista junctions(15). Finally, the short form of OPA1 localizes to mitochondrial constriction sites, where it presumably promotes mitochondrial fission(16). How Mgm1 and OPA1 perform their diverse functions in membrane fusion, scission and cristae organization is at present unknown. Here we present crystal and electron cryo-tomography structures of Mgm1 from Chaetomium thermophilum. Mgm1 consists of a GTPase (G) domain, a bundle signalling element domain, a stalk, and a paddle domain that contains a membrane-binding site. Biochemical and cell-based experiments demonstrate that the Mgm1 stalk mediates the assembly of bent tetramers into helical filaments. Electron cryo-tomography studies of Mgm1-decorated lipid tubes and fluorescence microscopy experiments on reconstituted membrane tubes indicate how the tetramers assemble on positively or negatively curved membranes. Our findings convey how Mgm1 and OPA1 filaments dynamically remodel the mitochondrial inner membrane. Structure and assembly of the mitochondrial membrane remodelling GTPase Mgm1.,Faelber K, Dietrich L, Noel JK, Wollweber F, Pfitzner AK, Muhleip A, Sanchez R, Kudryashev M, Chiaruttini N, Lilie H, Schlegel J, Rosenbaum E, Hessenberger M, Matthaeus C, Kunz S, von der Malsburg A, Noe F, Roux A, van der Laan M, Kuhlbrandt W, Daumke O Nature. 2019 Jul;571(7765):429-433. doi: 10.1038/s41586-019-1372-3. Epub 2019 Jul, 10. PMID:31292547[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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