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

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.