Human mitochondrial MTHFD2 is a dual redox cofactor-specific methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase

Shin, Minsoo; Momb, Jessica; Appling, Dean R.

doi:10.1186/s40170-017-0173-0

Cited by 56 publications

(58 citation statements)

References 43 publications

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“…But the extent to which this reflects a coordinated action with MTHFD2 is not yet known (Bidkhori et al, 2018;Lee et al, 2017). An intriguing aspect of MTHFD2 is its ability to use both NAD + and NADP + as cofactors to generate mitochondrial NADH and NADPH, respectively, while MTHFD1 can only use NADP + (Shin et al, 2017b; Fig. 1 C).…”

Section: Introductionmentioning

confidence: 99%

The complexity of the serine glycine one-carbon pathway in cancer

Reina-Campos

Diaz-Meco

Moscat

2019

Journal of Cell Biology

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The serine glycine and one-carbon pathway (SGOCP) is a crucially important metabolic network for tumorigenesis, of unanticipated complexity, and with implications in the clinic. Solving how this network is regulated is key to understanding the underlying mechanisms of tumor heterogeneity and therapy resistance. Here, we review its role in cancer by focusing on key enzymes with tumor-promoting functions and important products of the SGOCP that are of physiological relevance for tumorigenesis. We discuss the regulatory mechanisms that coordinate the metabolic flux through the SGOCP and their deregulation, as well as how the actions of this metabolic network affect other cells in the tumor microenvironment, including endothelial and immune cells.

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Section: Introductionmentioning

confidence: 99%

The complexity of the serine glycine one-carbon pathway in cancer

Reina-Campos

Diaz-Meco

Moscat

2019

Journal of Cell Biology

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“…Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) are gonadotropins (GTHs) that signal through their cognate receptors, FSH receptor (FSHR) and LH/choriogonadotropin receptor (LHCGR), to control major gonadal events in vertebrates, including folliculogenesis and steroidogenesis in the ovary [40]. MTHFD2 is likely responsible for mitochondrial production of both NADH and NADPH in rapidly proliferating cells [41]. PAPSS2 gene plays an important role in modulating ovarian function and female fertility by control of the bioavailability of ovarian androgen [42].…”

Section: Discussionmentioning

confidence: 99%

Changes in Ovary Transcriptome and Alternative splicing at estrus from Xiang pigs with Large and Small Litter Size

Zhang

Tang

Ran

et al. 2019

Preprint

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29 30 2 1 2 Abstract 3 Background/Aims: Litter size is one of the most important reproductive traits in pig breeding, which is affected by 4 multiple genes and the environment. Ovaries are the most important reproductive organs and have a profound impact 5 on the reproduction efficiency. Therefore, genetic differences in the ovaries may contribute to the observed 6 differences in litter size. Although QTLs and candidate genes have been reported to affect the litter size in many pig 7 breeds, however, the findings cannot elucidate the marked differences of the reproductive traits between breeds. The 8 aim of present work is to elucidate the mechanisms of the differences for the reproductive traits and identify 9 candidate genes associated with litter size in Xiang pig breed. Methods: The changes in ovary transcriptome and 10 alternative splicing were investigated at estrus between Xiang pigs with large and small litter size by RNA-seq 11 technology. The RNA-seq results were confirmed by RT-qPCR method. Results: We detected 16,219 -16,285 expressed 12 genes and 12 types of alternative splicing (AS) events in Xiang pig samples. A total of 762 differentially expressed genes 13 were identified by XL (Xiang pig group with larger litter size) vs XS (Xiang pig group with small litter size) sample 14 comparisons. A total of 34 genes were upregulated and 728 genes were downregulated in XL ovary samples compared 15 with the XS samples. Alternative splicing (AS) rates in XL samples were slightly lower than that observed in XS samples. 16 Most of differentially expressed genes were differentially regulated on AS level. Eleven candidate genes were 17 potentially identified to be related to Xiang pig fecundity and litter size, which may be closely related to the gonad 18 development, oocyte maturation or embryo quality. Conclusion: The significant changes in the expression of the 19 protein-coding genes and the level of alternative splicing in estrus ovarian transcriptome between XL and XS groups 20 probably are the molecular mechanisms of phenotypic variation in litter size. 21 22

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“…The reactions catalysed by MTHFD2 and its isozyme are NAD-dependent [108]. MTHFD2 is critical in maintaining NADP/NADPH production as it showed specific redox cofactor activity with NAD and NADP [108,109]. Suppression of MTHFD2 disturbed NADPH pools and enhanced apoptosis due to accumulated oxidative stress [110].…”

Section: Methylenetetrahydrofolate Dehydrogenase (Mthfd) Maintains Namentioning

confidence: 99%

NAD- and NADPH-Contributing Enzymes as Therapeutic Targets in Cancer: An Overview

et al. 2020

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Actively proliferating cancer cells require sufficient amount of NADH and NADPH for biogenesis and to protect cells from the detrimental effect of reactive oxygen species. As both normal and cancer cells share the same NAD biosynthetic and metabolic pathways, selectively lowering levels of NAD(H) and NADPH would be a promising strategy for cancer treatment. Targeting nicotinamide phosphoribosyltransferase (NAMPT), a rate limiting enzyme of the NAD salvage pathway, affects the NAD and NADPH pool. Similarly, lowering NADPH by mutant isocitrate dehydrogenase 1/2 (IDH1/2) which produces D-2-hydroxyglutarate (D-2HG), an oncometabolite that downregulates nicotinate phosphoribosyltransferase (NAPRT) via hypermethylation on the promoter region, results in epigenetic regulation. NADPH is used to generate D-2HG, and is also needed to protect dihydrofolate reductase, the target for methotrexate, from degradation. NAD and NADPH pools in various cancer types are regulated by several metabolic enzymes, including methylenetetrahydrofolate dehydrogenase, serine hydroxymethyltransferase, and aldehyde dehydrogenase. Thus, targeting NAD and NADPH synthesis under special circumstances is a novel approach to treat some cancers. This article provides the rationale for targeting the key enzymes that maintain the NAD/NADPH pool, and reviews preclinical studies of targeting these enzymes in cancers.

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Human mitochondrial MTHFD2 is a dual redox cofactor-specific methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase

Cited by 56 publications

References 43 publications

The complexity of the serine glycine one-carbon pathway in cancer

The complexity of the serine glycine one-carbon pathway in cancer

Changes in Ovary Transcriptome and Alternative splicing at estrus from Xiang pigs with Large and Small Litter Size

NAD- and NADPH-Contributing Enzymes as Therapeutic Targets in Cancer: An Overview

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