Depletion of WFS1 compromises mitochondrial function in hiPSC-derived neuronal models of Wolfram syndrome.
Depletion of WFS1 compromises mitochondrial function in hiPSC-derived neuronal models of Wolfram syndrome.
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DOI：
10.1016/j.stemcr.2023.04.002
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发表时间：
2023-05-09
影响因子：
5.9
通讯作者：
Sarkar, Sovan
中科院分区：
文献类型：
--
作者：
Zatyka, Malgorzata;Rosenstock, Tatiana R.;Sun, Congxin;Palhegyi, Adina M.;Hughes, Georgina W.;Lara-Reyna, Samuel;Astuti, Dewi;di Maio, Alessandro;Sciauvaud, Axel;Korsgen, Miriam E.;Stanulovic, Vesna;Kocak, Gamze;Rak, Malgorzata;Pourtoy-Brasselet, Sandra;Winter, Katherine;Varga, Thiago;Jarrige, Margot;Polveche, Helene;Correia, Joao;Frickel, Eva-Maria;Hoogenkamp, Maarten;Ward, Douglas G.;Aubry, Laetitia;Barrett, Timothy;Sarkar, Sovan
线粒体功能障碍，涉及到线粒体相关的ER膜（MAM）失调，涉及迟发性神经退行性疾病的发病机制，但了解是有限的罕见的早发性疾病。MAM驻留蛋白WFS 1的丢失导致Wolfram综合征（WS），这是一种罕见的早发性神经退行性疾病，与线粒体异常有关。在这里，我们证明了WS患者的人诱导多能干细胞衍生的神经元细胞中的线粒体功能障碍。VDAC 1被鉴定为与WFS 1相互作用，而WS细胞中这种相互作用的丧失可能损害线粒体功能。恢复WS细胞中的WFS 1水平恢复了WFS 1-VDAC 1相互作用，这与MAMs和线粒体网络的增加相关，这可能对线粒体功能产生积极影响。通过WFS 1过表达或调节线粒体功能的药理学试剂进行的遗传拯救改善了WS神经元的活力和生物能量学。我们的数据暗示了WFS 1在调节线粒体功能中的作用，并强调了WS和线粒体缺陷相关罕见疾病的治疗干预。Wolfram综合征患者来源的神经元细胞表现出线粒体功能障碍WFS 1与VDAC 1相互作用的丧失可能潜在地影响线粒体功能线粒体和细胞死亡表型通过遗传校正被拯救药理学试剂拯救线粒体缺陷并提高神经元活力在这篇文章中，Sarkar及其同事描述了Wolfram综合征患者来源的iPSC产生的神经元细胞中的线粒体功能障碍，一种罕见的早发性神经退行性疾病通过WFS 1恢复进行的遗传拯救或通过调节线粒体功能的药物进行的化学拯救改善了Wolfram综合征患者神经元的生物能量学和活力，从而为治疗干预提供了见解。
Mitochondrial dysfunction involving mitochondria-associated ER membrane (MAM) dysregulation is implicated in the pathogenesis of late-onset neurodegenerative diseases, but understanding is limited for rare early-onset conditions. Loss of the MAM-resident protein WFS1 causes Wolfram syndrome (WS), a rare early-onset neurodegenerative disease that has been linked to mitochondrial abnormalities. Here we demonstrate mitochondrial dysfunction in human induced pluripotent stem cell-derived neuronal cells of WS patients. VDAC1 is identified to interact with WFS1, whereas loss of this interaction in WS cells could compromise mitochondrial function. Restoring WFS1 levels in WS cells reinstates WFS1-VDAC1 interaction, which correlates with an increase in MAMs and mitochondrial network that could positively affect mitochondrial function. Genetic rescue by WFS1 overexpression or pharmacological agents modulating mitochondrial function improves the viability and bioenergetics of WS neurons. Our data implicate a role of WFS1 in regulating mitochondrial functionality and highlight a therapeutic intervention for WS and related rare diseases with mitochondrial defects. Wolfram syndrome patient-derived neuronal cells exhibit mitochondrial dysfunction Loss of WFS1 interaction with VDAC1 could potentially affect mitochondrial function Mitochondrial and cell death phenotypes are rescued by genetic correction Pharmacological agents rescue mitochondrial defects and improve neuronal viability In this article, Sarkar and colleagues describe mitochondrial dysfunction in neuronal cells generated from patient-derived iPSCs of Wolfram syndrome, a rare early-onset neurodegenerative disorder. Genetic rescue by WFS1 restoration or chemical rescue by drugs modulating mitochondrial function improves the bioenergetics and viability of Wolfram syndrome patient neurons, thus providing insights for therapeutic intervention.
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DOI：
10.1042/bj20081386
发表时间：
2009-01-01
期刊：
The Biochemical journal
影响因子：
--
作者：
Murphy MP
通讯作者：
Murphy MP
影响因子：
5
作者：
Ilkun O;Wilde N;Tuinei J;Pires KM;Zhu Y;Bugger H;Soto J;Wayment B;Olsen C;Litwin SE;Abel ED
通讯作者：
Abel ED
影响因子：
10.5
作者：
Chen, Yi-Fan;Kao, Cheng-Heng;Tsai, Ting-Fen
通讯作者：
Tsai, Ting-Fen
影响因子：
3.7
作者：
Horner SM;Wilkins C;Badil S;Iskarpatyoti J;Gale M Jr
通讯作者：
Gale M Jr
影响因子：
4
作者：
Camara AKS;Zhou Y;Wen PC;Tajkhorshid E;Kwok WM
通讯作者：
Kwok WM