Geng, J., Khaket, T.P., Pan, J., Li, W., Zhang, Y., Ping, Y., Cobos Sillero, M.I., Lu, B. (2023). Deregulation of ER-mitochondria contact formation and mitochondrial calcium homeostasis mediated by VDAC in fragile X syndrome.  Dev. Cell 58(7): 597--615.e10.

FBrf0256267

Research paper

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-Ca[2+]) homeostasis. FMRP-deficient cells feature excessive ERMCS formation and ER-to-mitochondria Ca[2+] 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-Ca[2+] 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-Ca[2+] homeostasis as contributors to FXS and offer potential therapeutic targets.

PMC10113018 (PMC) (EuropePMC)