Recent insights into the structure and function of Mitofusins in mitochondrial fusion

Abstract

Mitochondria undergo frequent fusion and fission events to adapt their morphology to cellular needs. Homotypic docking and fusion of outer mitochondrial membranes are controlled by Mitofusins, a set of large membrane-anchored GTPase proteins belonging to the dynamin superfamily. Mitofusins include, in addition to their GTPase and transmembrane domains, two heptad repeat domains, HR1 and HR2. All four regions are crucial for Mitofusin function, but their precise contribution to mitochondrial docking and fusion events has remained elusive until very recently. In this commentary, we first give an overview of the established strategies employed by various protein machineries distinct from Mitofusins to mediate membrane fusion. We then present recent structure–function data on Mitofusins that provide important novel insights into their mode of action in mitochondrial fusion.

A Molecular Perspective on Mitochondrial Membrane Fusion: From the Key Players to Oligomerization and Tethering of Mitofusin

“…Therefore, it might still be possible for the human as well as other vertebrates to adopt two different topologies (Cohen and Tareste, 2018). This duality may facilitate the coordination between OM and IM during fusion and supply the function that Ugo1 has in yeast (Cohen and Tareste, 2018), perhaps in concert with the recently identified SLC25A46 (Abrams et al 2015).…”

“…Clear examples are widely discussed in recent review works (Friedman et al 2018;Marrink et al 2019;Corradi et al 2019). The involvement of mitofusins in mitochondrial fusion was also recently reviewed (Cohen and Tareste 2018). Here, we thus review and discuss recent observations on mitofusin oligomerization and dynamics in their native membrane environment based on computational approaches such as molecular modeling and molecular dynamics (MD) simulation.…”

“…They are far from being isolated and indeed very dynamic during cell life. Mitochondria continuously move on cytoskeletal tracks, divide and fuse, forming shapes that range from isolated corpuscles to filamentous networks (Braun and Westermann 2011, Chan 2012, Cohen and Tareste, 2018, Tilokani et al, 2018. This precisely controlled process is known as mitochondrial dynamics for which they evolved a dedicated set of protein machineries Nunnari.…”

“…OPA1(optic atrophy 1) and its yeast homologue Mgm1 (mitochondrial genome maintenance 1) mediate the fusion of the mitochondrial inner membrane (IM) and participate in cristae organization (Wong et al 2000;Frezza et al 2006). The fusion of the mitochondrial OM is triggered by the mitofusins Mfn1 and Mfn2 in mammals and by the fuzzy onion Fzo1 protein in yeast (Hales and Fuller 1997;Cohen and Tareste 2018). Notably, the phylogenetically related group of atlastin (and its yeast homologue Sey1p), functions in fusion of ER tubules (Hu et al 2009;Orso et al 2009).…”

Mitochondrial Surveillance by Cdc48/p97: MAD vs. Membrane Fusion

“…In addition, their activity is fine-tuned by assembly with coregulatory proteins and by posttranslational modifications [187]. In regards to the OMM, fusion depends on ubiquitylation of mitofusins [188,189].…”