Aralar Sequesters GABA into Hyperactive Mitochondria, Causing Social Behavior Deficits

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

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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.
Original languageEnglish
Article numbere20
Pages (from-to)1178 - 1197
Number of pages41
Issue number6
Publication statusPublished - 19 Mar 2020

Keywords / Materials (for Non-textual outputs)

  • mitochondrial activity
  • mitochondrial membrane potential
  • GABA
  • social group behavior
  • Aralar
  • CYFIP1
  • autism
  • schizophrenia
  • SLC25A12 (AGC1)


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