Structural Insights of Human mitofusin-2 Into Mitochondrial Fusion and CMT2A Onset

Nat Commun. 2019 Oct 29;10(1):4914. doi: 10.1038/s41467-019-12912-0.

Abstract

Mitofusin-2 (MFN2) is a dynamin-like GTPase that plays a central role in regulating mitochondrial fusion and cell metabolism. Mutations in MFN2 cause the neurodegenerative disease Charcot-Marie-Tooth type 2A (CMT2A). The molecular basis underlying the physiological and pathological relevance of MFN2 is unclear. Here, we present crystal structures of truncated human MFN2 in different nucleotide-loading states. Unlike other dynamin superfamily members including MFN1, MFN2 forms sustained dimers even after GTP hydrolysis via the GTPase domain (G) interface, which accounts for its high membrane-tethering efficiency. The biochemical discrepancy between human MFN2 and MFN1 largely derives from a primate-only single amino acid variance. MFN2 and MFN1 can form heterodimers via the G interface in a nucleotide-dependent manner. CMT2A-related mutations, mapping to different functional zones of MFN2, lead to changes in GTP hydrolysis and homo/hetero-association ability. Our study provides fundamental insight into how mitofusins mediate mitochondrial fusion and the ways their disruptions cause disease.

Publication types

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

MeSH terms

  • Charcot-Marie-Tooth Disease / enzymology*
  • Charcot-Marie-Tooth Disease / genetics
  • Charcot-Marie-Tooth Disease / physiopathology
  • Dimerization
  • GTP Phosphohydrolases / chemistry*
  • GTP Phosphohydrolases / genetics
  • GTP Phosphohydrolases / metabolism*
  • Guanosine Triphosphate / metabolism
  • Humans
  • Mitochondria / chemistry
  • Mitochondria / enzymology
  • Mitochondria / genetics
  • Mitochondrial Dynamics*
  • Mitochondrial Membrane Transport Proteins / chemistry
  • Mitochondrial Membrane Transport Proteins / genetics
  • Mitochondrial Membrane Transport Proteins / metabolism
  • Mitochondrial Proteins / chemistry*
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism*
  • Mutation
  • Protein Domains

Substances

  • Mitochondrial Membrane Transport Proteins
  • Mitochondrial Proteins
  • Guanosine Triphosphate
  • GTP Phosphohydrolases
  • MFN2 protein, human
  • Mfn1 protein, human

Supplementary concepts

  • Charcot-Marie-Tooth disease, Type 2A