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Structural and mechanistic investigation on mitochondrial fusion.


Mitochondria are key organelles that change their size, shape and morphology undergoing a series of fusion and fission events, referred as mitochondrial dynamics. Dysfunctional mitochondrial dynamics are associated with major neurodegenerative disorders [1]. Pivotal components mediating the fusion and fission process of the outer/inner membrane(s) belong to the dynamin family of GTPases named DRPs [2]. While the ability of DRPs to mediate membrane fission is well documented, the mechanism of outer-membrane Fusion DRPs, named mitofusins are poorly understood. Recently this deadlock was partially circumvented with solving the truncated structures of human mitofusins MFN1 and MFN2 [3], [4]. The crystallographic structure of these mini-MFNs revealed that its fold is strikingly similar to that of the corresponding portion of BDLP, the Bacterial Dynamin Related Protein from the cyanobacteria Nostoc punctiforme [3], [5]. BDLP is a close relative of the yeast mitofusin Fzo1 (20% identity and 41% similarity). GTP binding by BDLP results in a switch from a compact structure to an ‘open’ conformation that stimulates its oligomerization and promotes its ability to shape the morphology of lipid membranes [6], [7]. It is thus likely that mitofusins undergo similar conformational rearrangements. Our group have recently demonstrated the importance of the N terminal residues 60 to 100, which are neither conserved in BDLP nor MFNs, in yeast mitofusin function [8]. Hence, structural analysis of the fragments containing these residues is pivotal to understand the role of Fzo1. Herein, we will report our effort to successfully purify and crystallize a truncated form of Fzo1 in which, the extreme C-terminal α-helix of Fzo1 is connected to the N-terminal half through a linker. This will provide fundamental insights into how Fzo1 mediates yeast mitochondrial fusion and it will allow us to further investigate the role of the residues 60 to 100. [1] D. C. Chan, “Mitochondrial Dynamics and Its Involvement in Disease,” Annu. Rev. Pathol. Mech. Dis., vol. 15, no. 1, pp. 235–259, Jan. 2020, doi: 10.1146/annurev-pathmechdis-012419-032711. [2] L. Voleman and P. Doležal, “Mitochondrial dynamics in parasitic protists,” PLoS Pathog., vol. 15, no. 11, pp. e1008008–e1008008, Nov. 2019, doi: 10.1371/journal.ppat.1008008. [3] Y.-L. Cao et al., “MFN1 structures reveal nucleotide-triggered dimerization critical for mitochondrial fusion,” Nature, vol. 542, no. 7641, pp. 372–376, 2017, doi: 10.1038/nature21077. [4] Y.-J. Li et al., “Structural insights of human mitofusin-2 into mitochondrial fusion and CMT2A onset,” Nat. Commun., vol. 10, no. 1, p. 4914, 2019, doi: 10.1038/s41467-019-12912-0. [5] Y. Qi et al., “Structures of human mitofusin 1 provide insight into mitochondrial tethering,” J. Cell Biol., vol. 215, no. 5, pp. 621–629, Dec. 2016, doi: 10.1083/jcb.201609019. [6] H. H. Low and J. Löwe, “A bacterial dynamin-like protein,” Nature, vol. 444, no. 7120, pp. 766–769, 2006, doi: 10.1038/nature05312. [7] H. H. Low, C. Sachse, L. A. Amos, and J. Löwe, “Structure of a Bacterial Dynamin-like Protein Lipid Tube Provides a Mechanism For Assembly and Membrane Curving,” Cell, vol. 139, no. 7, pp. 1342–1352, Dec. 2009, doi: 10.1016/j.cell.2009.11.003. [8] D. De Vecchis, L. Cavellini, M. Baaden, J. Hénin, M. M. Cohen, and A. Taly, “A membrane-inserted structural model of the yeast mitofusin Fzo1,” Sci. Rep., vol. 7, no. 1, p. 10217, 2017, doi: 10.1038/s41598-017-10687-2.
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hal-03972737 , version 1 (03-02-2023)


  • HAL Id : hal-03972737 , version 1


Mohammad Ozeir, Laetitia Cavellini, Thomas Chenuel, Julien Henri, Philippe Meyer, et al.. Structural and mechanistic investigation on mitochondrial fusion.. GFB 2021, Sep 2021, Virtuelle, France. ⟨hal-03972737⟩
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