A pathogenic mutation in the ALS/FTD gene VCP induces mitochondrial hypermetabolism by modulating the permeability transition pore.

IF 6.2 2区医学 Q1 NEUROSCIENCES

Acta Neuropathologica Communications Pub Date : 2024-10-10 DOI:10.1186/s40478-024-01866-0

Silke Vanderhaeghe, Jovan Prerad, Arun Kumar Tharkeshwar, Elien Goethals, Katlijn Vints, Jimmy Beckers, Wendy Scheveneels, Eveline Debroux, Katrien Princen, Philip Van Damme, Marc Fivaz, Gerard Griffioen, Ludo Van Den Bosch

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Abstract

Valosin-containing protein (VCP) is a ubiquitously expressed type II AAA⁺ ATPase protein, implicated in both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). This study aimed to explore the impact of the disease-causing VCP^R191Q/wt mutation on mitochondrial function using a CRISPR/Cas9-engineered neuroblastoma cell line. Mitochondria in these cells are enlarged, with a depolarized mitochondrial membrane potential associated with increased respiration and electron transport chain activity. Our results indicate that mitochondrial hypermetabolism could be caused, at least partially, by increased calcium-induced opening of the permeability transition pore (mPTP), leading to mild mitochondrial uncoupling. In conclusion, our findings reveal a central role of the ALS/FTD gene VCP in maintaining mitochondrial homeostasis and suggest a model of pathogenesis based on progressive alterations in mPTP physiology and mitochondrial energetics.

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ALS/FTD 基因 VCP 的致病突变通过调节通透性转换孔诱导线粒体高代谢。

含缬氨酸蛋白（VCP）是一种普遍表达的 II 型 AAA+ ATPase 蛋白，与肌萎缩侧索硬化症（ALS）和额颞叶痴呆症（FTD）都有关系。本研究旨在利用 CRISPR/Cas9 改造的神经母细胞瘤细胞系，探讨致病的 VCPR191Q/wt 突变对线粒体功能的影响。这些细胞中的线粒体增大，线粒体膜电位去极化，呼吸和电子传递链活性增加。我们的研究结果表明，线粒体代谢亢进至少部分是由钙诱导的通透性转换孔（mPTP）开放增加导致线粒体轻度解偶联引起的。总之，我们的研究结果揭示了 ALS/FTD 基因 VCP 在维持线粒体平衡中的核心作用，并提出了一种基于 mPTP 生理和线粒体能量的渐进式改变的发病模型。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Acta Neuropathologica Communications Medicine-Pathology and Forensic Medicine

CiteScore

11.20

自引率

2.80%

发文量

162

审稿时长

8 weeks

期刊介绍： "Acta Neuropathologica Communications (ANC)" is a peer-reviewed journal that specializes in the rapid publication of research articles focused on the mechanisms underlying neurological diseases. The journal emphasizes the use of molecular, cellular, and morphological techniques applied to experimental or human tissues to investigate the pathogenesis of neurological disorders. ANC is committed to a fast-track publication process, aiming to publish accepted manuscripts within two months of submission. This expedited timeline is designed to ensure that the latest findings in neuroscience and pathology are disseminated quickly to the scientific community, fostering rapid advancements in the field of neurology and neuroscience. The journal's focus on cutting-edge research and its swift publication schedule make it a valuable resource for researchers, clinicians, and other professionals interested in the study and treatment of neurological conditions.