Browsing by Subject "Mitochondrial folate transporter"

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Disruption of mitochondrial folate transporter gene (Slc25a32) induces embryonic lethality and neural tube defects in mice
(2017-08-09) Kim, Jimi; Finnell, Richard H.
Neural tube defects (NTDs) represent the most common class of structural congenital malformations in humans. While periconceptional supplementation with folic acid (FA) may prevent up to 70% of NTDs, a well-developed intervention strategy is required to address the remaining 30±% of NTDs that are non-responsive to folate intervention. During pregnancy, FA provides essential one carbon (1C) units for nucleotide and methyl group biosynthesis through folate mediated 1C metabolism to proper neural tube closure (NTC). Mitochondrial folate transporter (MFT, encoded by the SLC25A32 gene) transports tetrahydrofolate (THF), the bioactive form of FA, into mitochondria. We characterized a novel folate mitochondrial transport mouse model by inactivating the Slc25a32 gene. Inactivation of the Slc25a32 gene resulted in embryo-fetal lethality, as the Slc25a32[subscript gt/gt] fetuses die in utero by E12.5. Perturbation of the Slc25a32 allele exhibited abnormalities of NTC, resulting in fully penetrant NTDs of exencephaly and craniorachischisis in the Slc25a32[subscript gt/gt] embryos, as well as an increased prevalence of craniofacial defects and a reduction in embryonic growth compared to the wild-type embryos. Maternal folic acid supplementation, 5-methyl-tetrahydrofolate (5-mTHF), was ineffective in reducing the prevalence of NTDs in Slc25a32[subscript gt/gt] embryos. These NTDs were partially rescued by maternal supplementation with calcium formate, which is a downstream output product of the mitochondrial folate 1C pathway. This study proposed to utilize the Slc25a32 mouse model as a novel tool for studying the function FA in the mitochondria with respect to NTC, the mechanisms that underlie the failure of NTC in the mouse model of folate-resistant NTDs.