Aralar Sequesters GABA into Hyperactive Mitochondria, Causing Social Behavior Deficits.

Date publication

mars 2020

Journal

Cell

Auteurs

Membres identifiés du Cancéropôle Est :
Dr GIANGRANDE Angela

Tous les auteurs :
Kanellopoulos AK, Mariano V, Spinazzi M, Woo YJ, McLean C, Pech U, Li KW, Armstrong JD, Giangrande A, Callaerts P, Smit AB, Abrahams BS, Fiala A, Achsel T, Bagni C

Lien Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/32200800

Résumé

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.

Mots clés

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

Référence

Cell. 2020 Mar 19;180(6):1178-1197.e20