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.

社会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。在这里，我们显示了在人类CYFIP1同源物中的果蝇突变体与自闭症和精神分裂症有关的基因，表现出线粒体过度活跃和改变的群体行为。我们确定线粒体活动的GABA可用性调节作为生物学相关的机制，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信号传导的药理和遗传操作可纠正观察到的异常。我们将Aralar确定为线粒体转运蛋白，该线粒体在线粒体活性增加时螯合GABA。这项研究增加了我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。