WBSCR16 Is a Guanine Nucleotide Exchange Factor Important for Mitochondrial Fusion

Cell Rep. 2017 Jul 25;20(4):923-934. doi: 10.1016/j.celrep.2017.06.090.

Abstract

Regulated inter-mitochondrial fusion/fission is essential for maintaining optimal mitochondrial respiration and control of apoptosis and autophagy. In mammals, mitochondrial fusion is controlled by outer membrane GTPases MFN1 and MFN2 and by inner membrane (IM) GTPase OPA1. Disordered mitochondrial fusion/fission contributes to various pathologies, and MFN2 or OPA1 mutations underlie neurodegenerative diseases. Here, we show that the WBSCR16 protein is primarily associated with the outer face of the inner mitochondrial membrane and is important for mitochondrial fusion. We provide evidence of a WBSCR16/OPA1 physical interaction in the intact cell and of a WBSCR16 function as an OPA1-specific guanine nucleotide exchange factor (GEF). Homozygosity for a Wbscr16 mutation causes early embryonic lethality, whereas neurons of mice heterozygous for the mutation have mitochondria with reduced membrane potential and increased susceptibility to fragmentation upon exposure to stress, suggesting roles for WBSCR16 deficits in neuronal pathologies.

Keywords: GEF; GTPase; OPA1; WBSCR16; Williams-Beuren syndrome; fusion; granine nucleotide exchange factor; mitochondria.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Apoptosis / physiology
  • Cell Cycle / genetics
  • Cell Cycle / physiology
  • Cell Proliferation / genetics
  • Cell Proliferation / physiology
  • Female
  • GTP Phosphohydrolases / genetics
  • GTP Phosphohydrolases / metabolism
  • Guanine Nucleotide Exchange Factors / genetics
  • Guanine Nucleotide Exchange Factors / metabolism*
  • HeLa Cells
  • Humans
  • Immunoprecipitation
  • Male
  • Mice
  • Mice, Mutant Strains
  • Mitochondrial Dynamics / genetics
  • Mitochondrial Dynamics / physiology
  • Mitochondrial Membranes / metabolism
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism
  • Protein Binding

Substances

  • Guanine Nucleotide Exchange Factors
  • Mitochondrial Proteins
  • GTP Phosphohydrolases