Folate deficiency and over‐supplementation causes impaired folate metabolism: Regulation and adaptation mechanisms in <i>Caenorhabditis elegans</i>

Ortbauer, Martina; Ripper, Doris; Fuhrmann, Thomas; Lassi, Maximilian; Auernigg-Haselmaier, Sandra; Stiegler, Christina; König, Jürgen

doi:10.1002/mnfr.201500819

Cited by 18 publications

(24 citation statements)

References 36 publications

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“…The present quantification of FA analogs in the worm upon dhfr-1i treatment indi-cates that the single knockdown of dhfr-1 is sufficient to impair the whole FA cycle in the nematode, which is expected by targeting the first enzyme of the catabolic pathway. These results are in good agreement with those reported by Ortbauer et al, which indicate that the dhfr-1i dysregulates the immediate FA cycle, but also perturbs the expression of other enzymes, such as methionine synthase, which is part of the network involved in the transfer of methyl groups 15.…”

supporting

confidence: 93%

“…Caenorhabditis elegans has recently emerged as a facile model organism for studying metabolic processes, fluxes, and disorders . Remarkable metabolic homology between C. elegans and mammals has already yielded key insights into the role of FA deficiency and FA supplementation on organismal physiology, showing effects on host‐microbiome interactions, aging, lipid metabolism, and fertility . Less is known about how gene knockdown of folate cycle components or natural variation impacts global folate status and organismal physiology.…”

Section: Introductionmentioning

confidence: 99%

“…12 Remarkable metabolic homology between C. elegans and mammals has already yielded key insights into the role of FA deficiency and FA supplementation on organismal physiology, 13 showing effects on host-microbiome interactions, aging, lipid metabolism, and fertility. [14][15][16] Less is known about how gene knockdown of folate cycle components or natural variation impacts global folate status and organismal physiology. Moreover, the investigation of FA in a simple metazoan having only 959 somatic cells may expedite the discovery of new folate-like molecules.…”

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confidence: 99%

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Comparison of ESI‐MS/MS and APCI‐MS methods for the quantification of folic acid analogs in C. elegans

et al. 2019

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Folic acid (FA) plays a vital role in central metabolism, including the one carbon cycle, nucleotide, and amino acid biosynthesis. The development of sensitive, accurate analytical methods to measure FA intermediates in tissues is critical to understand their biological roles in diverse physiological and pathological contexts. Here, we developed a highly sensitive method for the simultaneous quantification of FA intermediates in the nematode Caenorhabditis elegans as a model to dissect metabolic networks. The method was further validated by analyzing the worm folate pool upon RNAi knockdown of the dihydrofolate reductase gene dhfr‐1. Comparative mass spectrometry behavior of the FA analogs using two different ion sources, electrospray ionization (ESI) and atmospheric pressure chemical ionization (APCI), revealed ESI‐MS/MS to be more sensitive, but APCI‐MS provided more detailed structure inferences, which can elucidate chemical investigation and synthesis of FA analogs. Finally, we report on the use of in vitro oxidation coupled with high‐resolution mass spectrometry as a tool to discover new endogenous FA derivatives in the nematode.

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confidence: 93%

Section: Introductionmentioning

confidence: 99%

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confidence: 99%

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Comparison of ESI‐MS/MS and APCI‐MS methods for the quantification of folic acid analogs in C. elegans

et al. 2019

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“…It has also been shown that decreased activity in one enzyme of the OCM can trigger downregulation in the gene expression for key enzymes in alternative pathways, thereby affecting the balance, e.g., between DNA methylation and synthesis [157]. In addition, there is evidence that during folate deficiency, mechanisms are in place to preserve thymidylate and consequently DNA synthesis at the expense of Hcy remethylation [158].…”

Section: Proposed Mechanisms Linking Polymorphisms Hcy B-vitaminmentioning

confidence: 99%

Potential Links between Impaired One-Carbon Metabolism Due to Polymorphisms, Inadequate B-Vitamin Status, and the Development of Alzheimer’s Disease

Troesch¹,

Weber²,

Mohajeri³

2016

Nutrients

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Alzheimer’s disease (AD) is the major cause of dementia and no preventive or effective treatment has been established to date. The etiology of AD is poorly understood, but genetic and environmental factors seem to play a role in its onset and progression. In particular, factors affecting the one-carbon metabolism (OCM) are thought to be important and elevated homocysteine (Hcy) levels, indicating impaired OCM, have been associated with AD. We aimed at evaluating the role of polymorphisms of key OCM enzymes in the etiology of AD, particularly when intakes of relevant B-vitamins are inadequate. Our review indicates that a range of compensatory mechanisms exist to maintain a metabolic balance. However, these become overwhelmed if the activity of more than one enzyme is reduced due to genetic factors or insufficient folate, riboflavin, vitamin B6 and/or vitamin B12 levels. Consequences include increased Hcy levels and reduced capacity to synthetize, methylate and repair DNA, and/or modulated neurotransmission. This seems to favor the development of hallmarks of AD particularly when combined with increased oxidative stress e.g., in apolipoprotein E (ApoE) ε4 carriers. However, as these effects can be compensated at least partially by adequate intakes of B-vitamins, achieving optimal B-vitamin status for the general population should be a public health priority.

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“…However, differences in gene expression analysis indicated that, although similar, the damage seems to arise following different pathways. The exact mechanism that the cell employs in response to nutritional deficits has been studied in Caenorhabditis elegans [91]. Folate deficiency also seems to be an enhancing factor of DNA damage resulting from radiation in vivo [92], which led to the investigation of folic acid acting as a radioprotective agent in vitro [93].…”

Section: Folate Deficiency and Genomic Damagementioning

confidence: 99%

Folate deficiency as predisposing factor for childhood leukaemia: a review of the literature

et al. 2017

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BackgroundFolic acid and its derivates, known as folates, are chemoprotective micronutrients of great interest because of their essential role in the maintenance of health and genomic integrity. The supplementation of folic acid during pregnancy has long been known to reduce the risk of neural tube defects (NTDs) in the foetus. Folate metabolism can be altered by many factors, including adequate intake through diet. Folate deficiency can compromise the synthesis, repair and methylation of DNA, with deleterious consequences on genomic stability and gene expression. These processes are known to be altered in chronic diseases, including cancer and cardiovascular diseases.Main bodyThis review focuses on the association between folate intake and the risk of childhood leukaemia. Having compiled and analysed studies from the literature, we show the documented effects of folates on the genome and their role in cancer prevention and progression with particular emphasis on DNA methylation modifications. These changes are of crucial importance during pregnancy, as maternal diet has a profound impact on the metabolic and physiological functions of the foetus and the susceptibility to disease in later life. Folate deficiency is capable of modifying the methylation status of certain genes at birth in both animals and humans, with potential pathogenic and tumorigenic effects on the progeny. Pre-existing genetic polymorphisms can modify the metabolic network of folates and influence the risk of cancer, including childhood leukaemias. The protective effects of folic acid might be dose dependent, as excessive folic acid could have the adverse effect of nourishing certain types of tumours.ConclusionOverall, maternal folic acid supplementation before and during pregnancy seems to confer protection against the risk of childhood leukaemia in the offspring. The optimal folic acid requirements and supplementation doses need to be established, especially in conjunction with other vitamins in order to determine the most successful combinations of nutrients to maintain genomic health and wellbeing. Further research is therefore needed to uncover the role of maternal diet as a whole, as it represents a main factor capable of inducing permanent changes in the foetus.

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Folate deficiency and over‐supplementation causes impaired folate metabolism: Regulation and adaptation mechanisms in Caenorhabditis elegans

Abstract: Single gene silencing alters gene expression in both cycles and disrupts folate homeostasis. Folate over-supplementation and deficiency favors TS over MS cycle and causes prophase DNA damage.

Cited by 18 publications

References 36 publications

Comparison of ESI‐MS/MS and APCI‐MS methods for the quantification of folic acid analogs in C. elegans

Comparison of ESI‐MS/MS and APCI‐MS methods for the quantification of folic acid analogs in C. elegans

Potential Links between Impaired One-Carbon Metabolism Due to Polymorphisms, Inadequate B-Vitamin Status, and the Development of Alzheimer’s Disease

Folate deficiency as predisposing factor for childhood leukaemia: a review of the literature

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