The GABA transaminase, ABAT, is essential for mitochondrial nucleoside metabolism.
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.
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
Arnaud
A
Besse
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Ping
P
Wu
Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, The Medical School, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
Francesco
F
Bruni
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Taraka
T
Donti
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Brett H
BH
Graham
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
William J
WJ
Craigen
Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, The Medical School, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
Robert
R
McFarland
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Paolo
P
Moretti
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Seema
S
Lalani
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Kenneth L
KL
Scott
Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, The Medical School, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
Robert W
RW
Taylor
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: pbonnen@bcm.edu.
Penelope E
PE
Bonnen
D000612:4-Aminobutyrate Transaminase / Q000235:genetics / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D020125:Mutation, Missense / Q000235:genetics; D009705:Nucleosides / Q000235:genetics / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000235:genetics / Q000378:metabolism*
D004272:DNA, Mitochondrial; D009705:Nucleosides; D005680:gamma-Aminobutyric Acid; D000612:4-Aminobutyrate Transaminase