Besse Arnaud, Wu Ping, Bruni Francesco, Donti Taraka, Graham Brett H, Craigen William J, McFarland Robert, Moretti Paolo, Lalani Seema, Scott Kenneth L, Taylor Robert W, Bonnen Penelope E
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.
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Cell Metab. 2015 Mar 3;21(3):417-27. doi: 10.1016/j.cmet.2015.02.008.
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.
ABAT是负责主要抑制性神经递质γ-氨基丁酸（GABA）分解代谢的关键酶。我们报告了ABAT在一个看似不相关的途径——线粒体核苷补救途径中的重要作用，并证明该酶的突变会导致常染色体隐性神经代谢紊乱和线粒体DNA耗竭综合征（MDS）。我们描述了一个患有脑肌病性MDS的家系，该家系由ABAT中的纯合错义突变引起，导致受试者大脑中GABA升高，以及受试者成纤维细胞中线粒体DNA水平降低。核苷补救和免疫共沉淀实验表明，ABAT在线粒体核苷补救途径中发挥作用，促进二磷酸脱氧核苷（dNDPs）转化为三磷酸脱氧核苷（dNTPs）。通过不可逆抑制剂氨己烯酸对ABAT进行药理学抑制，导致光感受器细胞中线粒体DNA耗竭，而在细胞培养基中添加dNTPs可防止这种情况发生。这项工作揭示了ABAT是GABA代谢和核苷代谢之间的联系，并定义了一种包括MDS在内的神经代谢紊乱。
