Mar 5, 2015

The GABA transaminase, ABAT, is essential for mitochondrial nucleoside metabolism

Cell Metabolism
Arnaud BessePenelope E Bonnen

Abstract

ABAT is a key enzyme responsible for catabolism of principal inhibitory neurotransmitter γ-aminobutyric acid (GABA). We report an essential role for ABAT in a seemingly unrelated pathway, mitochondrial nucleoside salvage, and demonstrate that mutations in this enzyme cause an autosomal recessive neurometabolic disorder and mtDNA depletion syndrome (MDS). We describe a family with encephalomyopathic MDS caused by a homozygous missense mutation in ABAT that results in elevated GABA in subjects' brains as well as decreased mtDNA levels in subjects' fibroblasts. Nucleoside rescue and co-IP experiments pinpoint that ABAT functions in the mitochondrial nucleoside salvage pathway to facilitate conversion of dNDPs to dNTPs. Pharmacological inhibition of ABAT through the irreversible inhibitor Vigabatrin caused depletion of mtDNA in photoreceptor cells that was prevented through addition of dNTPs in cell culture media. This work reveals ABAT as a connection between GABA metabolism and nucleoside metabolism and defines a neurometabolic disorder that includes MDS.

Mentioned in this Paper

Photoreceptors
Embryo
Metabolic Process, Cellular
Real-Time Polymerase Chain Reaction
DNDPglucose 4,6-dehydratase
Inborn Errors of Metabolism
Biochemical Pathway
Gamma-aminobutyric Acid Metabolic Process
Polyvinylidene fluoride
Tissue Membrane

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