Folinate Supplementation Ameliorates Methotrexate Induced Mitochondrial Formate Depletion In Vitro and In Vivo

@article{Sou2021FolinateSA,
  title={Folinate Supplementation Ameliorates Methotrexate Induced Mitochondrial Formate Depletion In Vitro and In Vivo},
  author={Nga-Lai Sou and Yu-Hsuan Huang and Der-Yuan Chen and Yi-Ming Chen and Feng-Yao Tang and Hsin-An Ko and Yi-Hsuan Fan and Yi-Ying Lin and Yi-Cheng Wang and Hui-Ming Chih and Barry Shane and Wen-Nan Huang and En-Pei Isabel Chiang},
  journal={International Journal of Molecular Sciences},
  year={2021},
  volume={22}
}
(1) Background: Antifolate methotrexate (MTX) is the most common disease-modifying antirheumatic drug (DMARD) for treating human rheumatoid arthritis (RA). The mitochondrial-produced formate is essential for folate-mediated one carbon (1C) metabolism. The impacts of MTX on formate homeostasis in unknown, and rigorously controlled kinetic studies can greatly help in this regard. (2) Methods: Combining animal model (8-week old female C57BL/6JNarl mice, n = 18), cell models, stable isotopic tracer… 
3 Citations
Metformin Is a Pyridoxal-5′-phosphate (PLP)-Competitive Inhibitor of SHMT2
TLDR
It is revealed that the anti-diabetic biguanide metformin operates as a novel class of non-catalytic SHMT2 inhibitor that disrupts the pyridoxal-5′-phosphate (PLP)-dependent SHMT1-dependent oligomerization process and ultimatelySHMT2 activity.
MTHFR Knockdown Assists Cell Defense against Folate Depletion Induced Chromosome Segregation and Uracil Misincorporation in DNA
  • Ming-Tsung Wu, Wei-Ting Ye, +7 authors E. Chiang
  • Medicine
    International journal of molecular sciences
  • 2021
TLDR
In conclusion, shMTHFR in HepG2 induces cell cycle arrest in G2/M that may promote nucleotide supply and assist cell defense against folate depletion-induced chromosome segregation and uracil misincorporation in the DNA by analyzing the TCGA/GTEx datasets available within GEPIA2.
MAT2A Localization and Its Independently Prognostic Relevance in Breast Cancer Patients
TLDR
Subcellular localization of MAT2A may affect its functions, and elevated MAT2a C/N ratio in breast cancer cells is associated with increased invasiveness, which could serve as a novel independent prognostic marker for breast cancer.

References

SHOWING 1-10 OF 46 REFERENCES
Mitochondrial dysfunction and respiratory chain defects in a rodent model of methotrexate-induced enteritis
TLDR
The results of the present study suggest that MTX-induced damage to enterocyte mitochondria may play a critical role in enteritis, and methotrexate-induced alteration in mitochondrial structure may cause its dysfunction and decreases the activities of the electron chain complexes.
Low-Dose Methotrexate Inhibits Methionine S-Adenosyltransferase In Vitro and In Vivo
TLDR
It is found that methionine or folate supplementation greatly improved S-adenosylmethionine in folate-depleted cells but not in cells preexposed to methotrexate, which raises concerns on perturbed methylation reactions in humans on low-dose metotrexate.
Protective effect of lipoic acid against methotrexate-induced oxidative stress in liver mitochondria.
TLDR
It is suggested that lipoic acid has a potential role in suppressing MTX-induced mitochondrial toxicity, and it affords protection either by reversing the decline of antioxidants or by the directly scavenging the free radicals.
MTHFR C677T polymorphism increases MTX sensitivity via the inhibition of S-adenosylmethionine and de novo purine synthesis.
TLDR
Platforms are provided that help predict the genetic impact on antifolate drugs, and further delineate tissue-specific target pathway in DMARD therapies, that suggest that genetic factors should be taken into account in clinical practice.
Tracing Metabolic Fate of Mitochondrial Glycine Cleavage System Derived Formate In Vitro and In Vivo
TLDR
In healthy mice, incorporation of GCS-derived formate from glycine 2-carbon was found in serine, methionine, dTMP, and methylcytosine in bone marrow DNA, indicating that the utilization and partitioning of G CS-derived 1C unit are tissue-specific.
Long-Term Prednisolone Treatments Increase Bioactive Vitamin B6 Synthesis In Vivo
TLDR
It is concluded that long-term prednisolone treatments promoted hepatic bioactive vitamin B6 synthesis by inducing the synthesizing enzymes PDXK and PMPO and simultaneously suppressing the catabolic enzyme PDXP.
In Vivo Kinetics of Formate Metabolism in Folate-deficient and Folate-replete Rats*
TLDR
Comparison of formate production with the ingestion of dietary formate precursors showed that ∼75% of these precursor were converted to formate, indicating that formate is a significant, although underappreciated end product of choline and amino acid oxidation.
GNMT Expression Increases Hepatic Folate Contents and Folate-Dependent Methionine Synthase-Mediated Homocysteine Remethylation
TLDR
Novel findings are demonstrated that restoring GNMT assists methylfolate-dependent reactions and ameliorates the consequences of folate depletion and the regulation of specific folate dependent reactions are demonstrated.
Mitochondrial One-Carbon Pathway Supports Cytosolic Folate Integrity in Cancer Cells
TLDR
Light is shed on design features of folate metabolism, the biochemical basis for clinically observed folate deficiency in QDPR-deficient patients is provided, and the classic antifolate methotrexate causes even more extensive folate degradation in nearly all tested cancer cell lines.
Blood lipid profiles and peripheral blood mononuclear cell cholesterol metabolism gene expression in patients with and without methotrexate treatment
TLDR
Although no differences were observed in the blood lipids, the potential impacts of MTX on cholesterol metabolism should not be overlooked and the atheroprotective effects from MTX induced HY27 and ABCA1 expressions may still be present in those persons with pre-existing dyslipidemia.
...
1
2
3
4
5
...