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Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Cell+Metab 2015 ; 21 (3): 417-27 Nephropedia Template TP
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The GABA transaminase, ABAT, is essential for mitochondrial nucleoside metabolism #MMPMID25738457
Besse A; Wu P; Bruni F; Donti T; Graham BH; Craigen WJ; McFarland R; Moretti P; Lalani S; Scott KL; Taylor RW; Bonnen PE
Cell Metab 2015[Mar]; 21 (3): 417-27 PMID25738457show ga
ABAT is a key enzyme responsible for catabolism of principal inhibitory neurotransmitter gamma-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.