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Reference: Versini R, et al. (2024) Lys716 in the transmembrane domain of yeast mitofusin Fzo1 modulates anchoring and fusion. Structure 32(11):1997-2012.e7

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Abstract

Outer mitochondrial membrane fusion, a vital cellular process, is mediated by mitofusins. However, the underlying molecular mechanism remains elusive. We have performed extensive multiscale molecular dynamics simulations to predict a model of the transmembrane (TM) domain of the yeast mitofusin Fzo1. Coarse-grained simulations of the two TM domain helices, TM1 and TM2, reveal a stable interface, which is controlled by the charge status of residue Lys716. Atomistic replica-exchange simulations further tune our model, which is confirmed by a remarkable agreement with an independent AlphaFold2 (AF2) prediction of Fzo1 in complex with its fusion partner Ugo1. Furthermore, the presence of the TM domain destabilizes the membrane, even more if Lys716 is charged, which can be an asset for initiating fusion. The functional role of Lys716 was confirmed with yeast experiments, which show that mutating Lys716 to a hydrophobic residue prevents mitochondrial fusion.

Reference Type
Journal Article
Authors
Versini R, Baaden M, Cavellini L, Cohen MM, Taly A, Fuchs PFJ
Primary Lit For
FZO1
Additional Lit For
UGO1 | fzo1-K716I | fzo1-K716V

Phenotype Annotations 4 entries for 1 gene

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GenePhenotypeExperiment TypeMutant InformationStrain BackgroundChemicalDetails
FZO1mitochondrial morphology: abnormal
classical genetics null
Allele: fzo1-K716I

K716I; transmembrane domain (TM) helix 1 mutated to an apolar residue; lysine 716 is important for TM domain structure and fusion via membrane destabilization

W303Media: glucose-containing
Details: capacity to form tubular mitochondria is lost on glucose-containing media, consistent with the essential role of fusion for wt mitochondrial morphology
FZO1mitochondrial morphology: abnormal
classical genetics null
Allele: fzo1-K716V

K716V; transmembrane domain (TM) helix 1 mutated to an apolar residue; lysine 716 is important for TM domain structure and fusion via membrane destabilization

W303Media: glucose-containing
Details: capacity to form tubular mitochondria is lost on glucose-containing media, consistent with the essential role of fusion for wt mitochondrial morphology
FZO1respiratory growth: absent
classical genetics null
Allele: fzo1-K716I

K716I; transmembrane domain (TM) helix 1 mutated to an apolar residue; lysine 716 is important for TM domain structure and fusion via membrane destabilization

W303Media: non-fermentable carbon source
Details: loss of respiratory growth on glycerol-containing media at 23, 30, and 37°C, consistent with the essential role of mitochondrial fusion for respiration
FZO1respiratory growth: absent
classical genetics null
Allele: fzo1-K716V

K716V; transmembrane domain (TM) helix 1 mutated to an apolar residue; lysine 716 is important for TM domain structure and fusion via membrane destabilization

W303Media: non-fermentable carbon source
Details: loss of respiratory growth on glycerol-containing media at 23, 30, and 37°C, consistent with the essential role of mitochondrial fusion for respiration
Showing 1 to 4 of 4 entries