Mitochondrial one‐carbon metabolism and neural tube defects

Momb, Jessica; Appling, Dean R.

doi:10.1002/bdra.23268

Cited by 11 publications

(7 citation statements)

References 66 publications

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“…Insufficient folate intake around and during pregnancy has been associated with increased risk of neural tube defects, which is the basis for the mandatory folate fortification of foods in the US since 1998 (Momb and Appling, 2014). Strong evidence for the role of the mitochondrial folate pathway in neural tube development has been provided by a MTH FD1L-knockout mouse model, which presents neural tube defects with 100% penetrance while on a folate-proficient diet (Momb et al, 2013).…”

Section: Functions Of Folate Metabolism and Disease Connectionsmentioning

confidence: 99%

“…Many excellent reviews on folate metabolism have appeared over the past decade, some of which cover metabolic compartmentation (Tibbetts and Appling, 2010; Scotti et al, 2013), folate transport (Zhao et al, 2011), and the roles of folates in redox homeostasis (Ducker and Rabinowitz, 2017), embryonic development (Momb and Appling, 2014), cancers (Locasale, 2013; Yang and Vousden, 2016), and plants (Hanson and Gregory, 2011).…”

Section: Introductionmentioning

confidence: 99%

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Toward a better understanding of folate metabolism in health and disease

Zheng

Cantley

2018

Journal of Experimental Medicine

148

102

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Folate metabolism is crucial for many biochemical processes, including purine and thymidine monophosphate (dTMP) biosynthesis, mitochondrial protein translation, and methionine regeneration. These biochemical processes in turn support critical cellular functions such as cell proliferation, mitochondrial respiration, and epigenetic regulation. Not surprisingly, abnormal folate metabolism has been causally linked with a myriad of diseases. In this review, we provide a historical perspective, delve into folate chemistry that is often overlooked, and point out various missing links and underdeveloped areas in folate metabolism for future exploration.

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Section: Functions Of Folate Metabolism and Disease Connectionsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Toward a better understanding of folate metabolism in health and disease

Zheng

Cantley

2018

Journal of Experimental Medicine

148

102

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“…H 2 O 2 is a major ROS entity generated from mitochondrial respiratory complex I and III during stress conditions, and evidence has demonstrated that TRIM4 sensitizes cells to H 2 O 2 -induced death [41, 42]. Previous evidence showed that mitochondria-related biological processes play a role in the etiology of NTDs [43, 44]. Thus, TRIM4 might also affect NTDs through regulation of mitochondrial function.…”

Section: Discussionmentioning

confidence: 99%

TRIM4 is associated with neural tube defects based on genome-wide DNA methylation analysis

Zhang

Guo

et al. 2019

Clin Epigenet

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BackgroundNeural tube defects (NTDs) are complex abnormalities associated with gene-environment interactions. The underlying cause has not been determined.MethodsSpinal cord tissues from cases with NTDs and healthy controls were collected. Methylation patterns between cases and normal individuals were compared using 450K Infinium Methylation BeadChip Illumina. DNA methylation analysis by pyrosequencing (PyroMark Q96) and mRNA and protein expression were analyzed using real-time quantitative PCR and Western blotting, respectively. Next-generation and Sanger sequencing were used to determine genetic variants in the target genes.ResultsSpinal cord tissues from cases with NTDs had more hypomethylated than hypermethylated genes. Further evaluation showed that the exon 1 region of TRIM4 was hypomethylated, and TRIM4 mRNA and protein levels were significantly increased in NTDs compared to controls. A rare missense variant (rs76665876) in TRIM4 was found in 3 of the 14 NTD cases but was not related to TRIM4 expression. TRIM4 mRNA levels were significantly increased in cases with hypomethylation and without the rs76665876 variant.ConclusionThese findings suggest that spinal cord tissues in cases with NTDs had a different genome-wide methylation pattern compared to controls. Abnormal methylation patterns in TRIM4 in immunity pathways might be involved in NTD pathogenesis. Genetic variants in TRIM4 genes only slightly contribute to the etiology of human NTDs.Electronic supplementary materialThe online version of this article (10.1186/s13148-018-0603-z) contains supplementary material, which is available to authorized users.

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“…Most cellular formate originates from the mitochondria and is transported into the cytoplasm. Disruption of mitochondrial formate production will affect the cytoplasmic formate supply [15]. The association between maternal folate status and risk for NTDs has led to the development of a number of folate-pathway knockout mice that have been used to study the impact of folate on mammalian embryonic development [16].…”

Section: Discussionmentioning

confidence: 99%

A Common Variant in MTHFD1L is Associated with Increased Risk for Spina Biﬁda

2018

J Mol Clin Med.

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Genetic polymorphisms within folate pathway genes represent potentially meaningful risk factors for neural tube defects (NTDs).Here we investigated the association of three previously identified polymorphisms in the folate pathway gene MTHFD1L with spina bifida in a U.S. population consisting primarily of Hispanic and non-Hispanic Caucasians. MTHFD1L allele 1 was found to significantly reduce maternal risk of having a baby with spina bifida, while allele 3 significantly increased maternal risk to have a spina bifida baby. This study confirms that rs3832406 is associated with an increased risk of spina bifida.

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Mitochondrial one‐carbon metabolism and neural tube defects

Abstract: In this article, we review the evidence linking NTDs to aberrant mitochondrial one-carbon metabolism in humans and mouse models. The potential of formate, a product of mitochondrial one-carbon metabolism, to prevent NTDs is also discussed.

Cited by 11 publications

References 66 publications

Toward a better understanding of folate metabolism in health and disease

Toward a better understanding of folate metabolism in health and disease

TRIM4 is associated with neural tube defects based on genome-wide DNA methylation analysis

A Common Variant in MTHFD1L is Associated with Increased Risk for Spina Biﬁda

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