Institute of Cancer and Genomic Sciences, Institute of Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
Institute of Microbiology and Infection, University of Birmingham, Birmingham B15 2TT, UK.
Stem Cell Reports. 2023 May 9;18(5):1090-1106. doi: 10.1016/j.stemcr.2023.04.002.
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.
线粒体功能障碍涉及线粒体相关内质网膜（MAM）的失调与迟发性神经退行性疾病的发病机制有关，但对于罕见的早发性疾病，人们的了解有限。MAM 驻留蛋白 WFS1 的缺失会导致 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，我们在 WS 患者的诱导多能干细胞衍生神经元细胞中证明了线粒体功能障碍。鉴定出 VDAC1 与 WFS1 相互作用，而 WS 细胞中这种相互作用的缺失可能会损害线粒体功能。在 WS 细胞中恢复 WFS1 水平可恢复 WFS1-VDAC1 相互作用，这与 MAMs 和线粒体网络的增加相关，这可能会对线粒体功能产生积极影响。通过 WFS1 过表达或调节线粒体功能的药物进行基因挽救可提高 WS 神经元的活力和生物能量学。我们的数据表明 WFS1 在调节线粒体功能方面起着作用，并强调了针对 WS 和相关具有线粒体缺陷的罕见疾病的治疗干预措施。
