细胞:线粒体过度活跃导致社交行为缺陷的分子机制 GABA隔

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研究揭示线粒体过度活跃导致社交行为缺陷的分子机制

作者：小柯机器人 发布时间：2020/3/23 12:31:29

本期文章：《细胞》：Volume 180 Issue 6

近日，瑞士洛桑大学Claudia Bagni研究组发现，Aralar将GABA隔离进过度活跃的线粒体，从而导致社交行为缺陷。相关论文发表在2020年3月19日出版的《细胞》杂志上。

研究人员发现，在人类CYFIP1（一个与自闭症和精神分裂症相关的基因）的同源物中，果蝇的突变体表现出线粒体过度活跃和改变的群体行为。研究人员确定线粒体活动的GABA可用性调节是生物学相关的机制，并证明其对社会行为的贡献。

具体而言，线粒体活性的增加会导致线粒体中的γ-氨基丁酸（GABA）隔离，从而降低GABA能信号传导并导致社交缺陷。线粒体活性或GABA信号的药理和遗传操作可纠正观察到的异常。

研究人员将Aralar鉴定为线粒体转运蛋白，从而线粒体活性增加时隔离GABA。这项研究增加了人们对在生理病理条件下线粒体如何调节神经元稳态和社会行为的理解。

据了解，社交障碍常常与线粒体功能障碍和神经传递改变有关。尽管线粒体功能对于大脑稳态至关重要，但线粒体破坏是否会导致社会行为缺陷尚不清楚。

附：英文原文

Title: Aralar Sequesters GABA into Hyperactive Mitochondria, Causing Social Behavior Deficits
Author: Alexandros K. Kanellopoulos, Vittoria Mariano, Marco Spinazzi, Young Jae Woo, Colin McLean, Ulrike Pech, Ka Wan Li, J. Douglas Armstrong, Angela Giangrande, Patrick Callaerts, August B. Smit, Brett S. Abrahams, Andre Fiala, Tilmann Achsel, Claudia Bagni

Issue&Volume: 2020/03/19

Abstract: Social impairment is frequently associated with mitochondrial dysfunction and alteredneurotransmission. Although mitochondrial function is crucial for brain homeostasis,it remains unknown whether mitochondrial disruption contributes to social behavioraldeficits. Here, we show that Drosophila mutants in the homolog of the human CYFIP1, a gene linked to autism and schizophrenia, exhibit mitochondrial hyperactivity andaltered group behavior. We identify the regulation of GABA availability by mitochondrialactivity as a biologically relevant mechanism and demonstrate its contribution tosocial behavior. Specifically, increased mitochondrial activity causes gamma aminobutyricacid (GABA) sequestration in the mitochondria, reducing GABAergic signaling and resultingin social deficits. Pharmacological and genetic manipulation of mitochondrial activityor GABA signaling corrects the observed abnormalities. We identify Aralar as the mitochondrialtransporter that sequesters GABA upon increased mitochondrial activity. This studyincreases our understanding of how mitochondria modulate neuronal homeostasis andsocial behavior under physiopathological conditions.

DOI: 10.1016/j.cell.2020.02.044

Source: https://www.cell.com/cell/fulltext/S0092-8674(20)30221-X

期刊信息
Cell：《细胞》，创刊于1974年。隶属于细胞出版社，最新IF：36.216
官方网址：https://www.cell.com/
投稿链接：https://www.editorialmanager.com/cell/default.aspx[url]https://www.cell.com/cell/fulltext/S0092-8674[/url](20)30221-X

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