Aralar Sequesters GABA into Hyperactive Mitochondria, Causing Social Behavior Deficits

Cell. 2020 Mar 19;180(6):1178-1197.e20. doi: 10.1016/j.cell.2020.02.044.


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.

Keywords: Aralar; CYFIP1; Drosophila; GABA; SLC25A12 (AGC1); autism; mitochondrial activity; mitochondrial membrane potential; schizophrenia; social group behavior.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Animals, Genetically Modified
  • Aspartic Acid / metabolism
  • Calcium / metabolism
  • Calcium-Binding Proteins / metabolism*
  • Calcium-Binding Proteins / physiology
  • Drosophila Proteins / metabolism*
  • Drosophila Proteins / physiology
  • Drosophila melanogaster / metabolism
  • Glucose / metabolism
  • Homeostasis
  • Humans
  • Male
  • Mitochondria / genetics
  • Mitochondria / metabolism*
  • Mitochondrial Membrane Transport Proteins / genetics
  • Mitochondrial Proteins / metabolism
  • Neurons / metabolism
  • Social Behavior
  • Synaptic Transmission
  • gamma-Aminobutyric Acid / genetics
  • gamma-Aminobutyric Acid / metabolism*


  • Adaptor Proteins, Signal Transducing
  • Aralar protein, Drosophila
  • CYFIP1 protein, human
  • Calcium-Binding Proteins
  • Drosophila Proteins
  • Mitochondrial Membrane Transport Proteins
  • Mitochondrial Proteins
  • Aspartic Acid
  • gamma-Aminobutyric Acid
  • Glucose
  • Calcium