Kanellopoulos 2020 Cell
|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 (2020) Aralar sequesters GABA into hyperactive mitochondria, causing social behavior deficits. Cell 180:1178-97.|
Abstract: 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.
Copyright © 2020 Elsevier Inc. All rights reserved. • Keywords: Aralar, CYFIP1, Drosophila, GABA, SLC25A12 (AGC1), Autism, Mitochondrial activity, Mitochondrial membrane potential, Schizophrenia, Social group behavior • Bioblast editor: Plangger M • O2k-Network Lab: CH Lausanne Bagni C
Labels: MiParea: Respiration, Genetic knockout;overexpression
Organism: Drosophila Tissue;cell: Nervous system, Other cell lines Preparation: Homogenate
Coupling state: LEAK, OXPHOS, ET Pathway: N, S, CIV, NS, ROX HRR: Oxygraph-2k