CHCHD2-CHCHD10蛋白复合物受线粒体功能障碍调节,并改变小鼠脑内脂质稳态。

IF 9.6 1区 生物学 Q1 CELL BIOLOGY
Jule Gerlach, Paola Pireddu, Xiaoqun Zhang, Simon Wetzel, Mara Mennuni, Dusanka Milenkovic, Hendrik Nolte, Fernanda da Silva Rodrigues, Niclas Branzell, Ibrahim Kaya, Rodolfo Garcia Villegas, Diana Rubalcava-Gracia, David Alsina, Regina Feederle, Per E Andrén, Thomas Langer, Per Svenningsson, Roberta Filograna
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引用次数: 0

摘要

高度保守的CHCHD2和CHCHD10是位于膜间隙的小线粒体蛋白。最近,编码这些蛋白质的基因突变与严重的疾病有关,包括帕金森病和肌萎缩性侧索硬化症。在培养细胞中,一小部分CHCHD2和CHCHD10寡聚形成功能未知的高分子量复合物。在这里,我们产生了一个全身Chchd2敲除小鼠来研究Chchd2及其蛋白复合物在体内的作用。我们发现,CHCHD2对于维持成年雄性小鼠大脑的充分运动能力、正常纹状体多巴胺水平和脂质稳态至关重要。我们还证明,在小鼠组织中,CHCHD2和CHCHD10仅以高分子量复合物的形式存在,其水平在生理条件下被精细调节。在线粒体功能障碍的反应中,CHCHD2-CHCHD10复合物的丰度和大小增加,这是一种在不同组织中保守的机制。虽然CHCHD2的缺失并不能消除CHCHD10的寡聚化,但它增强了细胞对线粒体应激的易损性,这表明CHCHD2对线粒体损伤具有保护作用。我们的发现揭示了CHCHD2在保持组织稳态中的作用,并为CHCHD2- chchd10复合物在人类疾病中的作用提供了重要的见解。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
The CHCHD2-CHCHD10 protein complex is modulated by mitochondrial dysfunction and alters lipid homeostasis in the mouse brain.

The highly conserved CHCHD2 and CHCHD10 are small mitochondrial proteins residing in the intermembrane space. Recently, mutations in the genes encoding these proteins have been linked to severe disorders, including Parkinson's disease and amyotrophic lateral sclerosis. In cultured cells, a small fraction of CHCHD2 and CHCHD10 oligomerize to form a high molecular weight complex of unknown function. Here, we generated a whole-body Chchd2 knockout mouse to investigate the in vivo role of CHCHD2 and its protein complex. We show that CHCHD2 is crucial for sustaining full motor capacity, normal striatal dopamine levels, and lipid homeostasis in the brain of adult male mice. We also demonstrate that in mouse tissues, CHCHD2 and CHCHD10 exist exclusively as a high molecular weight complex, whose levels are finely tuned under physiological conditions. In response to mitochondrial dysfunction, the abundance and size of the CHCHD2-CHCHD10 complex increase, a mechanism conserved across different tissues. Although the loss of CHCHD2 does not abolish CHCHD10 oligomerization, it enhances cell vulnerability to mitochondrial stress, suggesting that CHCHD2 is protective against mitochondrial damage. Our findings uncover the role of CHCHD2 in preserving tissue homeostasis and provide important insights into the involvement of the CHCHD2-CHCHD10 complex in human diseases.

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来源期刊
Cell Death & Disease
Cell Death & Disease CELL BIOLOGY-
CiteScore
15.10
自引率
2.20%
发文量
935
审稿时长
2 months
期刊介绍: Brought to readers by the editorial team of Cell Death & Differentiation, Cell Death & Disease is an online peer-reviewed journal specializing in translational cell death research. It covers a wide range of topics in experimental and internal medicine, including cancer, immunity, neuroscience, and now cancer metabolism. Cell Death & Disease seeks to encompass the breadth of translational implications of cell death, and topics of particular concentration will include, but are not limited to, the following: Experimental medicine Cancer Immunity Internal medicine Neuroscience Cancer metabolism
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