• 文献检索
  • 文档翻译
  • 深度研究
  • 学术资讯
  • Suppr Zotero 插件Zotero 插件
  • 邀请有礼
  • 套餐&价格
  • 历史记录
应用&插件
Suppr Zotero 插件Zotero 插件浏览器插件Mac 客户端Windows 客户端微信小程序
定价
高级版会员购买积分包购买API积分包
服务
文献检索文档翻译深度研究API 文档MCP 服务
关于我们
关于 Suppr公司介绍联系我们用户协议隐私条款
关注我们

Suppr 超能文献

核心技术专利：CN118964589B侵权必究
粤ICP备2023148730 号-1Suppr @ 2026

文献检索

告别复杂PubMed语法，用中文像聊天一样搜索，搜遍4000万医学文献。AI智能推荐，让科研检索更轻松。

立即免费搜索

文件翻译

保留排版，准确专业，支持PDF/Word/PPT等文件格式，支持 12+语言互译。

免费翻译文档

深度研究

AI帮你快速写综述，25分钟生成高质量综述，智能提取关键信息，辅助科研写作。

立即免费体验

脆性 X 综合征中通过 VDAC 调节内质网-线粒体接触形成和线粒体钙稳态。

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

机构信息

Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.

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.

出版信息

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

DOI:10.1016/j.devcel.2023.03.002
PMID:37040696
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10113018/
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-Ca) homeostasis. FMRP-deficient cells feature excessive ERMCS formation and ER-to-mitochondria Ca 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 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 homeostasis as contributors to FXS and offer potential therapeutic targets.

摘要

脆性 X 信使核糖核蛋白 (FMRP) 的缺失会导致脆性 X 综合征 (FXS)，这是最常见的遗传性智力障碍形式。在这里，我们表明 FMRP 与电压依赖性阴离子通道 (VDAC) 相互作用，以调节内质网 (ER)-线粒体接触位点 (ERMCS) 的形成和功能，这些结构对于线粒体钙 (mito-Ca) 稳态至关重要。FMRP 缺陷细胞表现出过度的 ERMCS 形成和 ER 到线粒体 Ca 转移。VDAC 或其他 ERMCS 成分的遗传和药理学抑制恢复了突触结构、功能和可塑性，并挽救了果蝇 dFmr1 突变体的运动和认知缺陷。表达赋予 FMRP-VDAC 相互作用的 FMRP C 端结构域 (FMRP-C)，可挽救 FXS 患者 iPSC 衍生神经元中的 ERMCS 形成和 mito-Ca 稳态缺陷，以及 Fmr1 敲除小鼠的运动和认知缺陷。这些结果表明，改变的 ERMCS 形成和 mito-Ca 稳态是 FXS 的原因，并提供了潜在的治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ecc7/10113018/cfb246468998/nihms-1883399-f0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ecc7/10113018/3e98e2b8b2bd/nihms-1883399-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ecc7/10113018/03dceadc7916/nihms-1883399-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ecc7/10113018/56e268e711e8/nihms-1883399-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ecc7/10113018/b99480ec5b26/nihms-1883399-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ecc7/10113018/04298efabf8e/nihms-1883399-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ecc7/10113018/305efc5e5cc0/nihms-1883399-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ecc7/10113018/cfb246468998/nihms-1883399-f0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ecc7/10113018/3e98e2b8b2bd/nihms-1883399-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ecc7/10113018/03dceadc7916/nihms-1883399-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ecc7/10113018/56e268e711e8/nihms-1883399-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ecc7/10113018/b99480ec5b26/nihms-1883399-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ecc7/10113018/04298efabf8e/nihms-1883399-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ecc7/10113018/305efc5e5cc0/nihms-1883399-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ecc7/10113018/cfb246468998/nihms-1883399-f0008.jpg

相似文献

1
Deregulation of ER-mitochondria contact formation and mitochondrial calcium homeostasis mediated by VDAC in fragile X syndrome.脆性 X 综合征中通过 VDAC 调节内质网-线粒体接触形成和线粒体钙稳态。
Dev Cell. 2023 Apr 10;58(7):597-615.e10. doi: 10.1016/j.devcel.2023.03.002.
2
Altered ER-mitochondria contact impacts mitochondria calcium homeostasis and contributes to neurodegeneration in vivo in disease models.内质网-线粒体接触改变影响线粒体钙离子稳态，并导致疾病模型体内的神经退行性变。
Proc Natl Acad Sci U S A. 2018 Sep 18;115(38):E8844-E8853. doi: 10.1073/pnas.1721136115. Epub 2018 Sep 5.
3
ICAM5 as a Novel Target for Treating Cognitive Impairment in Fragile X Syndrome.ICAM5 作为治疗脆性 X 综合征认知障碍的新靶点。
J Neurosci. 2020 Feb 5;40(6):1355-1365. doi: 10.1523/JNEUROSCI.2626-18.2019. Epub 2019 Dec 27.
4
Deletion of Fmr1 in parvalbumin-expressing neurons results in dysregulated translation and selective behavioral deficits associated with fragile X syndrome.在表达 Parvalbumin 的神经元中删除 Fmr1 会导致与脆性 X 综合征相关的翻译失调和选择性行为缺陷。
Mol Autism. 2022 Jun 29;13(1):29. doi: 10.1186/s13229-022-00509-2.
5
Neuron-Specific FMRP Roles in Experience-Dependent Remodeling of Olfactory Brain Innervation during an Early-Life Critical Period.神经元特异性 FMRP 在生命早期关键期嗅脑传入神经重塑中的作用。
J Neurosci. 2021 Feb 10;41(6):1218-1241. doi: 10.1523/JNEUROSCI.2167-20.2020. Epub 2021 Jan 5.
6
Calcium-Dependent Regulation of Neuronal Excitability Is Rescued in Fragile X Syndrome by a Tat-Conjugated N-Terminal Fragment of FMRP.钙依赖性调节神经元兴奋性在脆性 X 综合征中通过 FMRP 的 Tat 缀合的 N 端片段得到挽救。
J Neurosci. 2024 May 22;44(21):e0136242024. doi: 10.1523/JNEUROSCI.0136-24.2024.
7
Selective Deletion of Astroglial FMRP Dysregulates Glutamate Transporter GLT1 and Contributes to Fragile X Syndrome Phenotypes In Vivo.星形胶质细胞中脆性X智力低下蛋白的选择性缺失会使谷氨酸转运体GLT1失调，并在体内导致脆性X综合征表型。
J Neurosci. 2016 Jul 6;36(27):7079-94. doi: 10.1523/JNEUROSCI.1069-16.2016.
8
Voltage-Independent SK-Channel Dysfunction Causes Neuronal Hyperexcitability in the Hippocampus of Knock-Out Mice.电压非依赖性 SK 通道功能障碍导致敲除小鼠海马神经元过度兴奋。
J Neurosci. 2019 Jan 2;39(1):28-43. doi: 10.1523/JNEUROSCI.1593-18.2018. Epub 2018 Nov 2.
9
Disruption of GpI mGluR-Dependent Cav2.3 Translation in a Mouse Model of Fragile X Syndrome.脆性 X 综合征小鼠模型中 GpI mGluR 依赖性 Cav2.3 翻译的破坏。
J Neurosci. 2019 Sep 18;39(38):7453-7464. doi: 10.1523/JNEUROSCI.1443-17.2019. Epub 2019 Jul 26.
10
Independent role for presynaptic FMRP revealed by an FMR1 missense mutation associated with intellectual disability and seizures.与智力残疾和癫痫相关的FMR1错义突变揭示了突触前FMRP的独立作用。
Proc Natl Acad Sci U S A. 2015 Jan 27;112(4):949-56. doi: 10.1073/pnas.1423094112. Epub 2015 Jan 5.

引用本文的文献

1
: A Neurodevelopmental Factor Regulating Cell Metabolism in the Tumor Microenvironment.一种调节肿瘤微环境中细胞代谢的神经发育因子。
Biomolecules. 2025 May 28;15(6):779. doi: 10.3390/biom15060779.
2
Interactome of FMRP-N-tat therapeutic unveils key interactions for cellular function in Fragile X neurons.FMRP-N端蛋白治疗的相互作用组揭示了脆性X神经元细胞功能的关键相互作用。
J Biol Chem. 2025 Jun 4;301(7):110341. doi: 10.1016/j.jbc.2025.110341.
3
Sex-specific loss of mitochondrial membrane integrity in the auditory brainstem of a mouse model of Fragile X Syndrome.

本文引用的文献

1
GRP75 mediates endoplasmic reticulum-mitochondria coupling during palmitate-induced pancreatic β-cell apoptosis.GRP75 介导线粒体与内质网之间的偶联在棕榈酸诱导的胰岛 β 细胞凋亡过程中发挥作用。
J Biol Chem. 2021 Dec;297(6):101368. doi: 10.1016/j.jbc.2021.101368. Epub 2021 Oct 29.
2
The Role of Voltage-Dependent Anion Channel in Mitochondrial Dysfunction and Human Disease.电压门控阴离子通道在线粒体功能障碍和人类疾病中的作用。
Cells. 2021 Jul 9;10(7):1737. doi: 10.3390/cells10071737.
3
ATP Synthase c-Subunit Leak Causes Aberrant Cellular Metabolism in Fragile X Syndrome.
脆性X综合征小鼠模型听觉脑干中线粒体膜完整性的性别特异性丧失。
Open Biol. 2025 May;15(5):240384. doi: 10.1098/rsob.240384. Epub 2025 May 14.
4
Correlation of organelle interactions in the development of non-alcoholic fatty liver disease.非酒精性脂肪性肝病发生发展过程中细胞器相互作用的相关性
Front Immunol. 2025 Apr 16;16:1567743. doi: 10.3389/fimmu.2025.1567743. eCollection 2025.
5
Organelle perturbation in Alzheimer's disease: do intracellular amyloid-ß and the fragmented Golgi mediate early intracellular neurotoxicity?阿尔茨海默病中的细胞器功能紊乱：细胞内淀粉样β蛋白和破碎的高尔基体是否介导早期细胞内神经毒性？
Front Cell Dev Biol. 2025 Apr 15;13:1550211. doi: 10.3389/fcell.2025.1550211. eCollection 2025.
6
Mitochondria-organelle crosstalk in establishing compartmentalized metabolic homeostasis.线粒体-细胞器间串扰在建立区室化代谢稳态中的作用
Mol Cell. 2025 Apr 17;85(8):1487-1508. doi: 10.1016/j.molcel.2025.03.003.
7
The 40S ribosomal subunit recycling complex modulates mitochondrial dynamics and endoplasmic reticulum - mitochondria tethering at mitochondrial fission/fusion hotspots.40S核糖体亚基循环复合物在线粒体裂变/融合热点调节线粒体动力学和内质网-线粒体连接。
Nat Commun. 2025 Jan 25;16(1):1021. doi: 10.1038/s41467-025-56346-3.
8
Drug Treatments for Neurodevelopmental Disorders: Targeting Signaling Pathways and Homeostasis.神经发育障碍的药物治疗：靶向信号通路与体内平衡
Curr Neurol Neurosci Rep. 2024 Dec 6;25(1):7. doi: 10.1007/s11910-024-01394-3.
9
Dysregulation of the mTOR-FMRP pathway and synaptic plasticity in an environmental model of ASD.在自闭症谱系障碍的环境模型中，mTOR-FMRP 通路失调与突触可塑性
Mol Psychiatry. 2025 May;30(5):1937-1951. doi: 10.1038/s41380-024-02805-0. Epub 2024 Nov 27.
10
FMRP regulates MFF translation to locally direct mitochondrial fission in neurons.脆性X智力低下蛋白（FMRP）调节线粒体融合蛋白（MFF）的翻译，以在神经元中局部引导线粒体分裂。
Nat Cell Biol. 2024 Dec;26(12):2061-2074. doi: 10.1038/s41556-024-01544-2. Epub 2024 Nov 15.
ATP 合酶 c 亚基渗漏导致脆性 X 综合征细胞代谢异常。
Cell. 2020 Sep 3;182(5):1170-1185.e9. doi: 10.1016/j.cell.2020.07.008. Epub 2020 Aug 13.
4
Endoplasmic Reticulum-Mitochondria Contact Sites and Neurodegeneration.内质网-线粒体接触位点与神经退行性变
Front Cell Dev Biol. 2020 Jun 18;8:428. doi: 10.3389/fcell.2020.00428. eCollection 2020.
5
Split-TurboID enables contact-dependent proximity labeling in cells.Split-TurboID 可实现细胞内依赖接触的邻近标记。
Proc Natl Acad Sci U S A. 2020 Jun 2;117(22):12143-12154. doi: 10.1073/pnas.1919528117. Epub 2020 May 18.
6
Inefficient thermogenic mitochondrial respiration due to futile proton leak in a mouse model of fragile X syndrome.在脆性X综合征小鼠模型中，由于无效质子泄漏导致产热线粒体呼吸效率低下。
FASEB J. 2020 Jun;34(6):7404-7426. doi: 10.1096/fj.202000283RR. Epub 2020 Apr 20.
7
The role of mitochondria-associated membranes in cellular homeostasis and diseases.线粒体相关膜在细胞动态平衡和疾病中的作用。
Int Rev Cell Mol Biol. 2020;350:119-196. doi: 10.1016/bs.ircmb.2019.11.002. Epub 2019 Dec 3.
8
MERLIN: a novel BRET-based proximity biosensor for studying mitochondria-ER contact sites.MERLIN：一种新型基于 BRET 的临近生物传感器，用于研究线粒体-内质网接触位点。
Life Sci Alliance. 2019 Dec 9;3(1). doi: 10.26508/lsa.201900600. Print 2020 Jan.
9
Andrographolide alleviates Parkinsonism in MPTP-PD mice via targeting mitochondrial fission mediated by dynamin-related protein 1.穿心莲内酯通过靶向动力相关蛋白 1 介导的线粒体分裂缓解 MPTP-PD 小鼠的帕金森病。
Br J Pharmacol. 2019 Dec;176(23):4574-4591. doi: 10.1111/bph.14823. Epub 2019 Nov 14.
10
MISTERMINATE Mechanistically Links Mitochondrial Dysfunction with Proteostasis Failure.MINERVA 机制上把线粒体功能障碍与蛋白质稳态失效联系起来。
Mol Cell. 2019 Aug 22;75(4):835-848.e8. doi: 10.1016/j.molcel.2019.06.031. Epub 2019 Aug 1.