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.
Ji Geng  1 ,  Tejinder Pal Khaket  1 ,  Jie Pan  1 ,  Wen Li  1 ,  Yan Zhang  2 ,  Yong Ping  2 ,  Maria Inmaculada Cobos Sillero  1 ,  Bingwei Lu  3
Affiliations
  • 1. Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • 2. Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai 200240, China; Shanghai Key Laboratory of Psychotic Disorders (No. 13dz2260500), Shanghai Mental Health Center, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China.
  • 3. Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: [email protected].
PMID: 37040696 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.
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