| First Author | Geng J | Year | 2023 |
| Journal | Dev Cell | Volume | 58 |
| Issue | 7 | Pages | 597-615.e10 |
| PubMed ID | 37040696 | Mgi Jnum | J:347471 |
| Mgi Id | MGI:7466035 | Doi | 10.1016/j.devcel.2023.03.002 |
| Citation | Geng J, et al. (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 |
| abstractText | 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. |
