Aralar Sequesters GABA into Hyperactive Mitochondria, Causing Social Behavior Deficits
Aralar Sequesters GABA into Hyperactive Mitochondria, Causing Social Behavior Deficits
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DOI：
10.1016/j.cell.2020.02.044
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发表时间：
2020-03-19
期刊：
影响因子：
64.5
通讯作者：
Bagni, Claudia
中科院分区：
文献类型：
--
作者：
Kanellopoulos, Alexandros K.;Mariano, Vittoria;Bagni, Claudia
社交障碍通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仍不清楚。在这里，我们发现人类 CYFIP1（一种与自闭症和精神分裂症相关的基因）同源的果蝇突变体表现出线粒体过度活跃和群体行为改变。我们将线粒体活性对 GABA 可用性的调节视为一种生物学相关机制，并证明了其对社会行为的贡献。具体来说，线粒体活性增加会导致 γ 氨基丁酸 (GABA) 隔离在线粒体中，从而减少 GABA 信号传导并导致社交缺陷。对线粒体活性或 GABA 信号传导进行药理学和遗传操作可以纠正观察到的异常。我们将 Aralar 确定为线粒体转运蛋白，在线粒体活性增加时隔离 GABA。这项研究增加了我们对线粒体如何在病理生理条件下调节神经元稳态和社会行为的理解。
Social impairment is frequently associated with mitochondrial dysfunction and altered neurotransmission. Although mitochondrial function is crucial for brain homeostasis, it remains unknown whether mitochondrial disruption contributes to social behavioral deficits. Here, we show that Drosophila mutants in the homolog of the human CYFIP1, a gene linked to autism and schizophrenia, exhibit mitochondrial hyperactivity and altered group behavior. We identify the regulation of GABA availability by mitochondrial activity as a biologically relevant mechanism and demonstrate its contribution to social behavior. Specifically, increased mitochondrial activity causes gamma aminobutyric acid (GABA) sequestration in the mitochondria, reducing GABAergic signaling and resulting in social deficits. Pharmacological and genetic manipulation of mitochondrial activity or GABA signaling corrects the observed abnormalities. We identify Aralar as the mitochondrial transporter that sequesters GABA upon increased mitochondrial activity. This study increases our understanding of how mitochondria modulate neuronal homeostasis and social behavior under physiopathological conditions.