JOURNAL ARTICLE

A catalytic domain variant of Mitofusin requiring a wildtype paralog for function uncouples mitochondrial outer-membrane tethering and fusion

Emily A Engelhart, Suzanne Hoppins
Journal of Biological Chemistry 2019 April 1
30936207
Mitofusins (Mfn) are dynamin-related GTPases that mediate mitochondrial outer membrane fusion, a process that is required for mitochondrial and cellular health. In Mfn1 and Mfn2 paralogs, a conserved phenylalanine (Phe-202) located in the GTPase domain on a conserved beta strand and is part of an aromatic network in the core of this domain. To gain insight into the poorly understood mechanism of Mfn-mediated membrane fusion, here we characterize a Mitofusin mutant variant etiologically linked to Charcot Marie Tooth Syndrome. From analysis of mitochondrial structure in cells and mitochondrial fusion in vitro, we found that conversion of Phe-202 to leucine in either Mfn1 or Mfn2 diminishes the fusion activity of heterotypic complexes with both Mfn1 and Mfn2 and abolishes fusion activity of homotypic complexes. Using co-immunoprecipitation and native gel analysis, we further dissect the steps of mitochondrial fusion and demonstrate that the mutant variant has normal tethering activity, but impaired higher-order nucleotide-dependent assembly. The defective coupling of tethering to membrane fusion observed here suggests that nucleotide-dependent self-assembly of Mitofusin is required after tethering to promote membrane fusion.

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