One-Carbon metabolism in ME

ME patients have dysregulated one-carbon metabolism (1).

One-carbon metabolism has thoroughly been described in ref 2.

An easy to read description of one-carbon metabolism is found in ref 3.

Figure from ref 3:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5518849/figure/fig1/

The plasma level of serine was increased in male ME patients, and purine synthesis was decreased in both male and female ME patients. (1). We may hypothesize that serine was not turned into methylene-THF, methyl-THF and formyl-THF in adequate amounts.

Bao et al have shown that mitochondrial dysfunction is able to remodel the one-carbon metabolism in human cell. The researchers induced mitochondrial dysfunction (mtDNA deletion) in a cellular model. They showed (4):

• an ATF4-mediated starvation-like transcription response
• expression of serine synthesis genes: PHGDH, PSAT1 and PSPH
• an increase in serine synthesis and a  decrease in serine consumption
• an impaired mitochondrial production of formate from serine
• detection of sulfane sulfur species
• increased H2S production
• the damage may be rescued with purine or formate supplementation

Formate is an essential metabolite and a potential toxic molecule (5).

May the dysregulated one-carbon metabolism in a ME be rescued with supplementation?

The genes PHGDH, PSAT1, MTHFD1 and MTHFD1L were differentially methylated in peripheral blood mononuclear cells (PBMC) from ME patients subtypes (6).

The gene ALDH1L2 encodes metochondrial 10-formyltetrahydrofolate dehydrogenase. ALDH1L2 was hypomethylated (genic region: 3'UTR) in PBMC from ME patients (7).

The gene AMT encodes one of four components of the glycine cleavage system, which is important to one-carbon metabolism. The AMT gene promotor was hypomethylated in PBMC from ME patients (7). AMT was differentially methylated in four different genic regions in PBMC from ME patient subtypes (6).

Oxidation of the sulfur of methionine results in methionine sulfoxide or methionine sulfone. The sulfur-containing amino acids methionine and cysteine are more easily oxidized than the other amino acids. Unlike oxidation of other amino acids, the oxidation of methionine can be reversed by enzymatic action, specifically by enzymes in the methionine sulfoxide reductase family of enzymes. The three known methionine sulfoxide reductases are MsrA, MsrB, and fRmsr. (8).

Methionine sulfoxide was increased in plasma from male ME patients (1). Methionine sulfone was increased in plasma from female ME patients (9).

The genes MSRA and MSRB3 were hypomethylated in PBMC from ME patients (7), and MSRA was differentially methylated in PBMC from ME patient subtypes (6).

Formate and serine in ME

Serum levels of formate (10):
Physiological level:   32,8  +/-13,3
Control:   36,9  +/-26,1
ME/CFS:   23,8   +/-5,1
p=0,08

Serum levels of serine (10):

Physiological level:   159,8  +/-26,6
Control:   155   +/-55,2
ME/CFS:   134   +/-34,5
p=0,34

Further reading: 

Mitochondrial translation requires folate-dependent tRNA methylation https://www.ncbi.nlm.nih.gov/pubmed/29364879

5,10-methenyltetrahydrofolate synthetase deficiency causes a neurometabolic disorder associated with microcephaly, epilepsy, and cerebral hypomyelination https://www.ncbi.nlm.nih.gov/pubmed/30031689

Use of 13C315N1-Serine or 13C515N1-Methionine for Studying Methylation Dynamics in Cancer Cell Metabolism and Epigenetics.https://www.ncbi.nlm.nih.gov/pubmed/30725450

Serine Is an Essential Metabolite for Effector T Cell Expansion https://www.ncbi.nlm.nih.gov/pubmed/28111214

References:

1) Naviaux RK, Naviaux JC, Li K, Bright AT, Alaynick WA, Wang L, Baxter A, Nathan N et al (2016) Metabolic features of chronic fatigue syndrome. Proc Natl Acad Sci U S A 113:E5472–E5480. https://doi.org/10.1073/pnas.1607571113

2) Cell Metab. 2017 Jan 10;25(1):27-42. doi: 10.1016/j.cmet.2016.08.009. Epub 2016 Sep 15.
One-Carbon Metabolism in Health and Disease.
Ducker GS1, Rabinowitz JD2. https://www.ncbi.nlm.nih.gov/pubmed/27641100

3) Br J Cancer. 2017 Jun 6;116(12):1499-1504. doi: 10.1038/bjc.2017.118. Epub 2017 May 4.
One-carbon metabolism in cancer. https://www.ncbi.nlm.nih.gov/pubmed/3072545

4) Elife. 2016 Jun 16;5. pii: e10575. doi: 10.7554/eLife.10575.
Mitochondrial dysfunction remodels one-carbon metabolism in human cells. https://www.ncbi.nlm.nih.gov/pubmed/27307216
Bao XR1,2,3, Ong SE3, Goldberger O1, Peng J1,3, Sharma R1, Thompson DA3, Vafai SB1,3, Cox AG4, Marutani E5, Ichinose F5, Goessling W3,4, Regev A3,6, Carr SA3, Clish CB3, Mootha VK1,2,3.

5) Clin Chem Lab Med. 2013 Mar 1;51(3):571-8. doi: 10.1515/cclm-2012-0552.
Formate: an essential metabolite, a biomarker, or more?
Lamarre SG1, Morrow G, Macmillan L, Brosnan ME, Brosnan JT. https://www.ncbi.nlm.nih.gov/pubmed/23241677

6) de Vega et al: Integration of DNA methylation & health scores identifies subtypes in ME/CFS. Epigenomics 2018, 10, 5 https://www.futuremedicine.com/doi/full/10.2217/epi-2017-01

7) Trivedi et al: Identification of ME/CFS - associated DNA methylation patternsPlos One 2018, 13, 7 https://journals.plos.org/plosone/article?id=10.1371/journal.pone.02010

8) Wikipedia: Methionine sulfoxid

9) Germain et al: Prospective Biomarkers from Plasma Metabolomics of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Implicate Redox Imbalance in Disease Symptomatology. Metabolites. 2018 Dec 6;8(4). pii: E90. doi: 10.3390/metabo8040090.https://www.ncbi.nlm.nih.gov/pubmed/30563204

10) lin Chim Acta. 2012 Oct 9;413(19-20):1525-31. doi: 10.1016/j.cca.2012.06.022. Epub 2012 Jun 21. NMR metabolic profiling of serum identifies amino acid disturbances in chronic fatigue syndrome. Armstrong CW1, McGregor NR, Sheedy JR, Buttfield I, Butt HL, Gooley PR.

https://www.ncbi.nlm.nih.gov/pubmed/22728138