One-Carbon Metabolism: Pulling the Strings behind Aging and Neurodegeneration

One-carbon metabolism (OCM) is a network of biochemical reactions delivering one-carbon units to various biosynthetic pathways. The folate cycle and methionine cycle are the two key modules of this network that regulate purine and thymidine synthesis, amino acid homeostasis, and epigenetic mechanisms. Intersection with the transsulfuration pathway supports glutathione production and regulation of the cellular redox state. Dietary intake of micronutrients, such as folates and amino acids, directly contributes to OCM, thereby adapting the cellular metabolic state to environmental inputs. The contribution of OCM to cellular proliferation during development and in adult proliferative tissues is well established. Nevertheless, accumulating evidence reveals the pivotal role of OCM in cellular homeostasis of non-proliferative tissues and in coordination of signaling cascades that regulate energy homeostasis and longevity. In this review, we summarize the current knowledge on OCM and related pathways and discuss how this metabolic network may impact longevity and neurodegeneration across species.

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Alterations in One-Carbon Metabolism in Celiac Disease

Nutrients ◽

10.3390/nu12123723 ◽

2020 ◽

Vol 12 (12) ◽

pp. 3723

Author(s):

Rafael Martín-Masot ◽

Natàlia Mota-Martorell ◽

Mariona Jové ◽

José Maldonado ◽

Reinald Pamplona ◽

...

Keyword(s):

Celiac Disease ◽

Carbon Metabolism ◽

Dietary Treatment ◽

Transsulfuration Pathway ◽

Healthy Control ◽

One Carbon Metabolism ◽

The One ◽

Folate Cycle ◽

First Time ◽

Metabolomic Study

Celiac disease (CD) is an autoimmune enteropathy associated with alterations of metabolism. Metabolomics studies, although limited, showed changes in choline, choline-derived lipids, and methionine concentrations, which could be ascribed to alterations in one-carbon metabolism. To date, no targeted metabolomics analysis investigating differences in the plasma choline/methionine metabolome of CD subjects are reported. This work is a targeted metabolomic study that analyzes 37 metabolites of the one-carbon metabolism in 17 children with CD, treated with a gluten-free diet and 17 healthy control siblings, in order to establish the potential defects in this metabolic network. Our results demonstrate the persistence of defects in the transsulfuration pathway of CD subjects, despite dietary treatment, while choline metabolism, methionine cycle, and folate cycle seem to be reversed and preserved to healthy levels. These findings describe for the first time, a metabolic defect in one-carbon metabolism which could have profound implications in the physiopathology and treatment of CD.

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Paving the Way for Fertilization: The Role of the Transmitting Tract

International Journal of Molecular Sciences ◽

10.3390/ijms22052603 ◽

2021 ◽

Vol 22 (5) ◽

pp. 2603

Author(s):

Ana Marta Pereira ◽

Diana Moreira ◽

Sílvia Coimbra ◽

Simona Masiero

Keyword(s):

Pollen Tube ◽

Pollen Tube Growth ◽

Current Knowledge ◽

Embryo Sac ◽

Tube Growth ◽

Signaling Cascades ◽

Secretory Cells ◽

Transmitting Tract ◽

Specialized Tissue

Angiosperm reproduction relies on the precise growth of the pollen tube through different pistil tissues carrying two sperm cells into the ovules’ embryo sac, where they fuse with the egg and the central cell to accomplish double fertilization and ultimately initiate seed development. A network of intrinsic and tightly regulated communication and signaling cascades, which mediate continuous interactions between the pollen tube and the sporophytic and gametophytic female tissues, ensures the fast and meticulous growth of pollen tubes along the pistil, until it reaches the ovule embryo sac. Most of the pollen tube growth occurs in a specialized tissue—the transmitting tract—connecting the stigma, the style, and the ovary. This tissue is composed of highly secretory cells responsible for producing an extensive extracellular matrix. This multifaceted matrix is proposed to support and provide nutrition and adhesion for pollen tube growth and guidance. Insights pertaining to the mechanisms that underlie these processes remain sparse due to the difficulty of accessing and manipulating the female sporophytic tissues enclosed in the pistil. Here, we summarize the current knowledge on this key step of reproduction in flowering plants with special emphasis on the female transmitting tract tissue.

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L-Carnitine in Drosophila: A Review

Antioxidants ◽

10.3390/antiox9121310 ◽

2020 ◽

Vol 9 (12) ◽

pp. 1310

Author(s):

Maria Rosaria Carillo ◽

Carla Bertapelle ◽

Filippo Scialò ◽

Mario Siervo ◽

Gianrico Spagnuolo ◽

...

Keyword(s):

Transport System ◽

Essential Role ◽

Energy Homeostasis ◽

Current Knowledge ◽

Fatty Acyl ◽

Amino Acid Derivative ◽

Carnitine Transport ◽

Human Transport ◽

Drosophila Models

L-Carnitine is an amino acid derivative that plays a key role in the metabolism of fatty acids, including the shuttling of long-chain fatty acyl CoA to fuel mitochondrial β-oxidation. In addition, L-carnitine reduces oxidative damage and plays an essential role in the maintenance of cellular energy homeostasis. L-carnitine also plays an essential role in the control of cerebral functions, and the aberrant regulation of genes involved in carnitine biosynthesis and mitochondrial carnitine transport in Drosophila models has been linked to neurodegeneration. Drosophila models of neurodegenerative diseases provide a powerful platform to both unravel the molecular pathways that contribute to neurodegeneration and identify potential therapeutic targets. Drosophila can biosynthesize L-carnitine, and its carnitine transport system is similar to the human transport system; moreover, evidence from a defective Drosophila mutant for one of the carnitine shuttle genes supports the hypothesis of the occurrence of β-oxidation in glial cells. Hence, Drosophila models could advance the understanding of the links between L-carnitine and the development of neurodegenerative disorders. This review summarizes the current knowledge on L-carnitine in Drosophila and discusses the role of the L-carnitine pathway in fly models of neurodegeneration.

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The role of H-NS in one carbon metabolism

Biochimie ◽

10.1016/0300-9084(94)90031-0 ◽

1994 ◽

Vol 76 (10-11) ◽

pp. 1063-1070 ◽

Cited By ~ 1

Author(s):

J.R. Landgraf ◽

M. Levinthal ◽

A. Danchin

Keyword(s):

Carbon Metabolism ◽

One Carbon Metabolism

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The complex functions of microRNA-150 in allergy, autoimmunity and immune tolerance

AIMS Allergy and Immunology ◽

10.3934/allergy.2021016 ◽

2021 ◽

Vol 5 (4) ◽

pp. 195-221

Author(s):

Katarzyna Nazimek ◽

Keyword(s):

Immune Responses ◽

Immune Tolerance ◽

Therapeutic Potential ◽

Current Knowledge ◽

Signaling Cascades ◽

Cell Functions ◽

Regulatory Circuits ◽

Complex Functions ◽

Genetic Level

<abstract> <p>At present, special efforts are being made to develop the strategies allowing for activation of long-lasting antigen-specific immune tolerance in therapy of allergic and autoimmune diseases. Some of these therapeutic approaches are aimed at modulating cell functions at genetic level by using miRNA-based and miRNA-targeting treatments. Simultaneously, the crucial role of extracellular vesicles as natural miRNA conveyors is highlighted for induction of antigen-specific immune tolerance, especially that they appear to be easily manipulatable for therapeutic applications. Among other immune-related miRNAs, miR-150 is getting special attention as it is differently expressed by immune cells at various stages of their maturation and differentiation. In addition, miR-150 is involved in different signaling cascades orchestrating humoral and cell-mediated mechanisms of both innate and adaptive immune responses. Therefore, miR-150 is considered a master regulator of immunity in mammals. Currently, physiological miR-150-dependent regulatory circuits and causes of their malfunctioning that underlie the pathogenesis of allergic and autoimmune disorders are being unraveled. Thus, present review summarizes the current knowledge of the role of miR-150 in the pathogenesis and complications of these diseases. Furthermore, the involvement of miR-150 in regulation of immune responses to allergens and self-antigens and in induction of antigen-specific immune tolerance is discussed with the special emphasis on the therapeutic potential of this miRNA.</p> </abstract>

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The role of dietary supplements that modulate one-carbon metabolism on stroke outcome

Current Opinion in Clinical Nutrition & Metabolic Care ◽

10.1097/mco.0000000000000743 ◽

2021 ◽

Vol Publish Ahead of Print ◽

Author(s):

Gyllian B. Yahn ◽

Jeannine Leoncio ◽

Nafisa M. Jadavji

Keyword(s):

Dietary Supplements ◽

Carbon Metabolism ◽

Stroke Outcome ◽

One Carbon Metabolism

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The role of one-carbon metabolism and homocysteine in Parkinson’s disease onset, pathology and mechanisms

Nutrition Research Reviews ◽

10.1017/s0954422419000106 ◽

2019 ◽

Vol 32 (2) ◽

pp. 218-230 ◽

Cited By ~ 4

Author(s):

Lauren K. Murray ◽

Nafisa M. Jadavji

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Carbon Metabolism ◽

Animal Studies ◽

B Vitamins ◽

Present Review ◽

Increased Risk ◽

One Carbon Metabolism ◽

B Vitamin

AbstractParkinson’s disease (PD) is the second most common neurodegenerative disorder. It is characterised by the progressive degeneration of dopaminergic (DA) neurons. The cause of degeneration is not well understood; however, both genetics and environmental factors, such as nutrition, have been implicated in the disease process. Deficiencies in one-carbon metabolism in particular have been associated with increased risk for PD onset and progression, though the precise relationship is unclear. The aim of the present review is to determine the role of one-carbon metabolism and elevated levels of homocysteine in PD onset and pathology and to identify potential mechanisms involved. A search of PubMed, Google Scholar and Web of Science was undertaken to identify relevant human and animal studies. Case–control, prospective cohort studies, meta-analyses and non-randomised trials were included in the present review. The results from human studies indicate that polymorphisms in one-carbon metabolism may increase risk for PD development. There is an unclear role for dietary B-vitamin intake on PD onset and progression. However, dietary supplementation with B-vitamins may be beneficial for PD-affected individuals, particularly those on l-DOPA (levodopa or l-3,4-dihydroxyphenylalanine) treatment. Additionally, one-carbon metabolism generates methyl groups, and methylation capacity in PD-affected individuals is reduced. This reduced capacity has an impact on expression of disease-specific genes that may be involved in PD progression. During B-vitamin deficiency, animal studies report increased vulnerability of DA cells through increased oxidative stress and altered methylation. Nutrition, especially folates and related B-vitamins, may contribute to the onset and progression of PD by making the brain more vulnerable to damage; however, further investigation is required.

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Allosteric inhibition of MTHFR prevents futile SAM cycling and maintains nucleotide pools in one-carbon metabolism

Journal of Biological Chemistry ◽

10.1074/jbc.ra120.015129 ◽

2020 ◽

Vol 295 (47) ◽

pp. 16037-16057 ◽

Cited By ~ 1

Author(s):

Muskan Bhatia ◽

Jyotika Thakur ◽

Shradha Suyal ◽

Ruchika Oniel ◽

Rahul Chakraborty ◽

...

Keyword(s):

Carbon Metabolism ◽

Methylenetetrahydrofolate Reductase ◽

Isotope Labeling ◽

Redox Homeostasis ◽

Regulatory Region ◽

Regulatory Control ◽

Growth Defect ◽

Transsulfuration Pathway ◽

One Carbon Metabolism ◽

The Impact

Methylenetetrahydrofolate reductase (MTHFR) links the folate cycle to the methionine cycle in one-carbon metabolism. The enzyme is known to be allosterically inhibited by SAM for decades, but the importance of this regulatory control to one-carbon metabolism has never been adequately understood. To shed light on this issue, we exchanged selected amino acid residues in a highly conserved stretch within the regulatory region of yeast MTHFR to create a series of feedback-insensitive, deregulated mutants. These were exploited to investigate the impact of defective allosteric regulation on one-carbon metabolism. We observed a strong growth defect in the presence of methionine. Biochemical and metabolite analysis revealed that both the folate and methionine cycles were affected in these mutants, as was the transsulfuration pathway, leading also to a disruption in redox homeostasis. The major consequences, however, appeared to be in the depletion of nucleotides. 13C isotope labeling and metabolic studies revealed that the deregulated MTHFR cells undergo continuous transmethylation of homocysteine by methyltetrahydrofolate (CH3THF) to form methionine. This reaction also drives SAM formation and further depletes ATP reserves. SAM was then cycled back to methionine, leading to futile cycles of SAM synthesis and recycling and explaining the necessity for MTHFR to be regulated by SAM. The study has yielded valuable new insights into the regulation of one-carbon metabolism, and the mutants appear as powerful new tools to further dissect out the intersection of one-carbon metabolism with various pathways both in yeasts and in humans.

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