Identification of a mitofusin specificity region that confers unique activities to Mfn1 and Mfn2

Mol Biol Cell. 2019 Aug 1;30(17):2309-2319. doi: 10.1091/mbc.E19-05-0291. Epub 2019 Jun 12.

Abstract

Mitochondrial structure can be maintained at steady state or modified in response to changes in cellular physiology. This is achieved by the coordinated regulation of dynamic properties including mitochondrial fusion, division, and transport. Disease states, including neurodegeneration, are associated with defects in these processes. In vertebrates, two mitofusin paralogues, Mfn1 and Mfn2, are required for efficient mitochondrial fusion. The mitofusins share a high degree of homology and have very similar domain architecture, including an amino terminal GTPase domain and two extended helical bundles that are connected by flexible regions. Mfn1 and Mfn2 are nonredundant and are both required for mitochondrial outer membrane fusion. However, the molecular features that make these proteins functionally distinct are poorly defined. By engineering chimeric proteins composed of Mfn1 and Mfn2, we discovered a region that contributes to isoform-specific function (mitofusin isoform-specific region [MISR]). MISR confers unique fusion activity and mitofusin-specific nucleotide-dependent assembly properties. We propose that MISR functions in higher-order oligomerization either directly, as an interaction interface, or indirectly through conformational changes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Fibroblasts / metabolism
  • GTP Phosphohydrolases / metabolism*
  • GTP Phosphohydrolases / physiology
  • Humans
  • Membrane Fusion / physiology
  • Membrane Proteins / metabolism
  • Membrane Transport Proteins / metabolism
  • Mice
  • Mitochondria / metabolism
  • Mitochondrial Dynamics
  • Mitochondrial Membrane Transport Proteins / metabolism*
  • Mitochondrial Membrane Transport Proteins / physiology
  • Mitochondrial Membranes / metabolism*
  • Mitochondrial Proteins / metabolism*
  • Mitochondrial Proteins / physiology
  • Mutation
  • Protein Isoforms / metabolism
  • Recombinant Fusion Proteins / metabolism

Substances

  • Membrane Proteins
  • Membrane Transport Proteins
  • Mitochondrial Membrane Transport Proteins
  • Mitochondrial Proteins
  • Protein Isoforms
  • Recombinant Fusion Proteins
  • GTP Phosphohydrolases
  • MFN2 protein, human
  • Mfn1 protein, human