Structural and mechanistic investigation on mitochondrial fusion
Abstract
Mitochondria are key organelles that change their size, shape and
morphology undergoing a series of fusion and fission events, referred
as mitochondrial dynamics. Pivotal components mediating the fusion
and fission process of the outer/inner membrane(s) belong to the
dynamin family of GTPases named DRPs. 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 [1], [2]. 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 Like Protein from the
cyanobacteria Nostoc punctiforme [3]. 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 [3]. 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 [4]. 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. 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] Y.-L. Cao et al., MFN1 structures reveal nucleotide-triggered
dimerization critical for mitochondrial fusion, Nature, vol. 542
(2017) 372–376.
[2] Y.-J. Li et al., Structural insights of human mitofusin-2 into
mitochondrial fusion and CMT2A onset, Nat. Commun., 10 (2019)
4914.
[3] H. H. Low, J. Löwe, A bacterial dynamin-like protein, Nature,
444 (2006) 766–769.
[4] D. De Vecchis, L. Cavellini, M. Baaden, J. Hénin, M. M. Cohen,
A. Taly, A membrane-inserted structural model of the yeast mitofusin
Fzo1, Sci. Rep., 7 (2017) 10217.