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

TitleThe GABA transaminase, ABAT, is essential for mitochondrial nucleoside metabolism.
Publication TypeJournal Article
Year of Publication2015
AuthorsBesse, A, Wu, P, Bruni, F, Donti, T, Graham, BH, Craigen, WJ, McFarland, R, Moretti, P, Lalani, S, Scott, KL, Taylor, RW, Bonnen, PE
JournalCell Metab
Date Published2015 Mar 3
Keywords4-Aminobutyrate Transaminase, Brain, DNA, Mitochondrial, Fibroblasts, gamma-Aminobutyric Acid, Humans, Mitochondria, Mutation, Missense, Nucleosides

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.

Alternate JournalCell Metab.
PubMed ID25738457
PubMed Central IDPMC4757431
Grant ListCA125123 / CA / NCI NIH HHS / United States
096919/Z/11/Z / / Wellcome Trust / United Kingdom
R01 GM098387 / GM / NIGMS NIH HHS / United States
AI036211 / AI / NIAID NIH HHS / United States
U54 HD083092 / HD / NICHD NIH HHS / United States
P30 CA125123 / CA / NCI NIH HHS / United States
R01NS083726 / NS / NINDS NIH HHS / United States
P30 AI036211 / AI / NIAID NIH HHS / United States
G0601943 / / Medical Research Council / United Kingdom
S10 RR024574 / RR / NCRR NIH HHS / United States
R01 NS083726 / NS / NINDS NIH HHS / United States
WT096919 / WT / WETP NIH HHS / United States
RR024574 / RR / NCRR NIH HHS / United States

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