Deregulation of ER-mitochondria contact formation and mitochondrial calcium homeostasis mediated by VDAC in fragile X syndrome

Dev Cell. 2023 Apr 10;58(7):597-615.e10. doi: 10.1016/j.devcel.2023.03.002.

Abstract

Loss of fragile X messenger ribonucleoprotein (FMRP) causes fragile X syndrome (FXS), the most prevalent form of inherited intellectual disability. Here, we show that FMRP interacts with the voltage-dependent anion channel (VDAC) to regulate the formation and function of endoplasmic reticulum (ER)-mitochondria contact sites (ERMCSs), structures that are critical for mitochondrial calcium (mito-Ca2+) homeostasis. FMRP-deficient cells feature excessive ERMCS formation and ER-to-mitochondria Ca2+ transfer. Genetic and pharmacological inhibition of VDAC or other ERMCS components restored synaptic structure, function, and plasticity and rescued locomotion and cognitive deficits of the Drosophila dFmr1 mutant. Expressing FMRP C-terminal domain (FMRP-C), which confers FMRP-VDAC interaction, rescued the ERMCS formation and mito-Ca2+ homeostasis defects in FXS patient iPSC-derived neurons and locomotion and cognitive deficits in Fmr1 knockout mice. These results identify altered ERMCS formation and mito-Ca2+ homeostasis as contributors to FXS and offer potential therapeutic targets.

Keywords: ER-mitochondria contact site; ERMCS; FMRP; FXS; VDAC; fragile X messenger ribonucleoprotein; fragile X syndrome; mito-Ca(2+) homeostasis; mitochondrial calcium homeostasis; voltage-dependent anion channel.

Publication types

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

MeSH terms

  • Animals
  • Calcium / metabolism
  • Drosophila / metabolism
  • Drosophila Proteins* / metabolism
  • Endoplasmic Reticulum / metabolism
  • Fragile X Mental Retardation Protein / genetics
  • Fragile X Mental Retardation Protein / metabolism
  • Fragile X Syndrome* / genetics
  • Fragile X Syndrome* / metabolism
  • Homeostasis
  • Mice
  • Mice, Knockout
  • Mitochondria / metabolism
  • Voltage-Dependent Anion Channels / metabolism

Substances

  • Calcium
  • Fragile X Mental Retardation Protein
  • Voltage-Dependent Anion Channels
  • Fmr1 protein, mouse
  • FMR1 protein, Drosophila
  • Drosophila Proteins