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Review
. 2021 Dec 23;58(1):16.
doi: 10.3390/medicina58010016.

Impaired Folate-Mediated One-Carbon Metabolism in Type 2 Diabetes, Late-Onset Alzheimer's Disease and Long COVID

Melvin R Hayden  1 , Suresh C Tyagi  2
Affiliations
Review

Impaired Folate-Mediated One-Carbon Metabolism in Type 2 Diabetes, Late-Onset Alzheimer's Disease and Long COVID

Melvin R Hayden et al. Medicina (Kaunas). .

Abstract

Impaired folate-mediated one-carbon metabolism (FOCM) is associated with many pathologies and developmental abnormalities. FOCM is a metabolic network of interdependent biosynthetic pathways that is known to be compartmentalized in the cytoplasm, mitochondria and nucleus. Currently, the biochemical mechanisms and causal metabolic pathways responsible for the initiation and/or progression of folate-associated pathologies have yet to be fully established. This review specifically examines the role of impaired FOCM in type 2 diabetes mellitus, Alzheimer's disease and the emerging Long COVID/post-acute sequelae of SARS-CoV-2 (PASC). Importantly, elevated homocysteine may be considered a biomarker for impaired FOCM, which is known to result in increased oxidative-redox stress. Therefore, the incorporation of hyperhomocysteinemia will be discussed in relation to impaired FOCM in each of the previously listed clinical diseases. This review is intended to fill gaps in knowledge associated with these clinical diseases and impaired FOCM. Additionally, some of the therapeutics will be discussed at this early time point in studying impaired FOCM in each of the above clinical disease states. It is hoped that this review will allow the reader to better understand the role of FOCM in the development and treatment of clinical disease states that may be associated with impaired FOCM and how to restore a more normal functional role for FOCM through improved nutrition and/or restoring the essential water-soluble B vitamins through oral supplementation.

Keywords: Alzheimer’s disease; COVID-19; Long COVID; MTHFR gene mutations; PASC; epigenetics; homocysteine; nutritional B vitamin deficiencies; repurposed drugs; type 2 diabetes mellitus.

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Conflict of interest statement

Both authors declare that they have no competing interests.

Figures

Figure 1
Figure 1
Folate-Mediated One-Carbon Metabolism (FOCM). This figure illustrates both the folate and methionine interdependent cycles and supports the importance of the methyl donor S-adenosylmethionine (SAM) as well as demonstrating the importance of the essential B vitamins. Importantly, note that methionine and tetrahydrofolate (THF) are derived primarily through dietary intake to supply the methionine and folate cycles and that the enzyme methionine synthase (MS) and its essential cofactor vitamin B12 are placed in a central position of the interconnected folate and methionine cycles. FOCM comprises a network of interconnected folate-dependent metabolic pathways responsible for serine and glycine interconversion, de novo purine synthesis, de novo thymidylate synthesis and homocysteine remethylation to methionine as well as providing antioxidant defense via glutathione (GSH) production via the transsulfuration pathway. Note that the encircled methylenetetrahydrofolate reductase (MTHFR) enzyme plays and important role in the folate cycle. The most common genetic variant in MTHFR gene to date is the 677C > T polymorphism, which results in elevated levels of Hcy especially if there is deficient folate. Once Hcy is synthesized through multiple steps in the methionine cycle, it may then undergo remethylation to methionine or be eliminated through the transsulfuration pathway. Additionally, thymidylate synthase (TYMS) converts deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP) (not shown) in a 5,10-methylene-THF-dependent reaction. Importantly, cystathionine beta synthase (CBS) and cystathionine gamma lyase (CSE-CGL) do not only contribute to generate GSH (antioxidant) in the transsulfuration pathway but also are important for endothelial cell generation of hydrogen sulfide (H2S), a known gaso-transmitter and vasodilator. Elevation of Hcy from the methionine cycle may result in hyperhomocysteinemia, which is an independent risk factor for cerebro-cardiovascular diseases, accelerated atherosclerosis, thromboembolism, hypoxemia and stroke. CBS = cystathionine-beta-synthase; GCS = glutamate cysteine ligase (gamma-glutamylcysteine synthetase); GS = glutathione synthase; GSH = glutathione; MTHFR = methylenetetrahydrofolate; MS = methionine synthase; THF = tetrahydrofolate.
Figure 2
Figure 2
Compartmentalization of FOCM. Note the presence of the folate-methionine one carbon cycle metabolism in the cytoplasm (cytosol), mitochondria and nucleus. Additionally, note the importance of formate being transferred from the mitochondria to the nucleus, as well as S-adenosylmethionine (SAM) via nuclear pores. Importantly, deoxythymidine monophosphate (dTMP) synthesis occurs in the cytosol, nucleus and mitochondria, whereas purine synthesis and methionine synthesis take place within the cytosol. Mitochondrial FOCM generates formate for cytosolic and nuclear FOCM and biosynthetic precursors for mtDNA synthesis and mitochondrial protein translation. Thymidylate synthase (TYMS) converts deoxyuridine monophosphate (dUMP) to dTMP in a 5,10-methylene-THF-dependent reaction (not shown). It is important to note that mitochondrial SAM (Mt SAM) is derived from cytosolic SAM (cSAM). Additionally, the Krebs cycle also resides within the mitochondria and provides NADH and FADH2 to the electron transport chain for ATP production. ATP = adenosine triphosphate; c = cytosol; ETC = electron transport chain; FAD = flavin adenine dinucleotide; FADH = reduced flavin adenine dinucleotide; FFA = free fatty acids; HHcy = hyperhomocysteinemia; MS = methionine synthase; Mt = mitochondria; NADH = reduced nicotinamide adenine dinucleotide; T = thymidylate-thymine; U = uracil.
Figure 3
Figure 3
Chromatin Condensation in Aberrant Microglia and Oligodendrocytes in Diabetic Female db/db Models in Grey Matter—Cortical Layer III. This multipanel collage illustrates chromatin condensation in aberrant activated microglia cell(s) (aMGC) and aberrant oligodendrocytes (OL-OLG). Panels (A,D) illustrate the normal microglia cell (MGC) and oligodendrocyte in control non-diabetic models respectively. Note the abnormal aberrant mitochondria (aMt) in the microglia and neural cells in panels (B,E) respectively with aMt (highlighted yellow circles encircled in red). Panels (C,F) depict chromatin condensation (Chr Cond) within the nuclei of aberrant microglial cells and oligodendrocytes respectively. Also, note arrows in panel E depict myelin splitting and separation and arrowheads depict chromatin condensation in the nuclei (panels (C,F)). aMGCs and aberrant oligodendrocytes suggest abnormal crosstalk with abnormal myelin remodeling and impaired folate one-carbon metabolism. Magnification and scale bar varies. Images in this figure were provided and approved by CC 4.0 [32,33]. M = myelin; N = nucleus; NVU = neurovascular unit; Ol-Olig = oligodendrocyte.
Figure 4
Figure 4
Formate Plays a Central and Formidable Role in Providing Proper Nucleus Function and Structure. Serine, glycine, methionine and choline are also necessary components to fulfill proper mitochondrial function to the nucleus in order to produce purines, thymidylate and methionine to fulfil their role in the nucleus. This figure depicts the importance of the folate dependent pathway (green coloring) for formate synthesis in the mitochondria and the central role for the formidable formate to be utilized by the nucleus for proper chromatin modeling. Note the bold and underlining of the important carbon unit in the chemical formula for formate. Also, note the folate independent pathway on the right-hand side of this figure. The concept for this slide design was derived from reference [35].
Figure 5
Figure 5
Neurovascular Unit Capillary (NVU) in control non-diabetic models. Panels (A) (cross section), (B) (longitudinal section) and (C) (cross section) depict the normal NVU composed of the endothelial cell (EC), pericyte foot processes (Pcfp), astrocyte foot processes (ACfp) and the ramified microglia cell (rMGC). Note in panel (A) that the rMGC is probing the NVU to surveil for any injury to the NVU. Note how tightly the Pcfp and the ACfp adhere and abut to the basement membrane of the ECs. Additionally, note the ACfp are pseudo colored yellow in panels (A,C) and reveal their electron lucent cytoplasm in panel (B), and the nanometer glymphatic space (gS) is pseudo colored green in panel (C). Varying magnifications upper right of each panel. Images are reproduced and modified by CC 4.0 [40].
Figure 6
Figure 6
Compilation of Abnormal Remodeling in the Cortical Grey Matter Layer III in Diabetic db/db and BTBR ob/ob Neurovascular Unit (NVU). Panel (A) is the control model and depicts the normal morphology of the NVU and the remainder of images are compiled from the diabetic db/db and BTBR ob/ob models. Panel (B1) (control with intact blood-brain barrier (BBB)) and (2–4) depicts the attenuation and or loss of the endothelial cell (EC) tight and adherens junctions (TJ/AJ) of the BBB. Panel (C1) depicts the highly electron dense endothelial glycocalyx (arrows) found in non-diabetic control models while Panel (2) depicts the attenuation and/or loss of the endothelial glycocalyx (arrows) by lanthanum nitrate perfusion fixation staining in the BTBR ob/ob diabetic model. Panel (D) depicts astrocyte foot process detachments from the endothelial neurovascular unit (NVU) with a nearby activated microglial cell (aMGC) and a labeled microbleed adjacent to the NVU in this low magnification image. Panel (E) depicts marked basement membrane thickening that is associated with the capillary NVU and note the detached astrocyte foot processes (ACfp) pseudo-colored red and the aMGC. Panel (F) depicts an aMGC (pseudo-colored red) that is encompassing the capillary NUV and note again the detached and retracted ACfp (drAC) (pseudo-colored cyan) with magnification ×2500 (not shown). These images display the remodeling changes that accompany the uncoupling of the NVU in brain grey matter in cortical layers III. Images in this compilation figure were modified with permission by CC 4.0 [27,32].
Figure 7
Figure 7
The Endothelial Glycocalyx (ecGCx). This illustration depicts the normal components of the ecGCx: a unique extracellular matrix. The ecGCx in T2DM, LOAD and Long COVID/PASC is the first component of the endothelial cell (EC) that comes into contact with the blood components of the vascular lumen. The normal components of the ecGCx include two classes of proteins that are mostly anchored proteoglycans (PGN) (purple), glycoproteins (GP) (green) and Hyaluronic acid—Hyaluronan (HA) (blue) that is an exceedingly long polymer of disaccharides that are non-sulfated glycosaminoglycans. HA may be either unattached—free floating or anchored to CD44 on the plasma membrane of ECs, or form HA–HA complexes. HA may also reversibly interact at the lumen with plasma-derived albumin, fibrinogen and soluble PGNs. The PGNs and GPs side chains consist of glycosaminoglycans (GAGs), which are covalently bound to their core proteins and are highly sulfated, which are important for giving the ecGCx its net-negative charge. The two primary PGNs are the syndecans and glypicans. The GPs consist primarily of selectins (P and E), integrins (alpha v and beta 3) and the immunoglobulin superfamily of ICAM-1, VE-CAM and PE CAM-1. Caveolae are invaginations of lipid rafts on the EC plasma membrane and contain CD44 important to anchor glycosylphosphatidylinositol (GPI) that anchor glypican-1. The GPI/glypican-1 interaction is thought to activate endothelial nitric oxide synthase (eNOS) to produce bioavailable nitric oxide (NO) via the calcium calmodulin dependent Caveolin-1 (Cav-1) protein. Note on the right-hand side of this image the numerous causes for the attenuation/shedding or loss of the ecGCx. Note that Hcy is included since it is elevated in both T2DM and Late onset Alzheimer’s disease (LOAD). Hcy may compromise the ecGCx due to its elevation, which results in hyperhomocysteinemia (HHcy), oxidative stress with elevation in reactive oxygen nitrogen species (RONS), inflammation and activation of matrix metalloproteinases. Note that T2DM is known to increase hyaluronidase. The impaired FOCM with hyperhomocyteinemia, oxidative stress and inflammation can be damaging to the ecGCx and contribute to endothelial cell activation and dysfunction with detrimental effects on the vascular tissue that predispose to increased vascular inflammation and a prothrombotic state and ischemia, which is also an inducer of ecGCx loss. Image provided by CC 4.0 [48]. A = albumin; AGE/RAGE = advanced glycation end products and receptor to AGE; N = nucleus; ATPIII GP = antithrombin three glycoprotein; BEC = brain endothelial cell or just endothelial cell; BM = basement membrane; CAD = cadherin; CAM = cellular adhesion molecule; CD44 = cluster of differentiation 44; ecSOD = extracellular superoxide dismutase; F = fibrinogen; FGF2 = fibroblast Growth Factor 2; FOCM = folate-mediated one-carbon metabolism; GCx = glycocalyx; ICAM-1 = intercellular adhesion molecule; Ox LDL = oxidized low-density lipoprotein; LPL = lipoprotein lipase; MMPs = matrix metalloproteinases; N = nucleus; Na+ = sodium; O = orosomucoids; Pc = vascular mural cell pericyte(s); PECAM-1 = platelet endothelial cell adhesion molecule-1. RONS = reactive oxygen species; TFPI = tissue factor pathway inhibitor; TJ/AJ = tight and adherens junctions; VCAM = Vascular cell adhesion protein; VE CAD = vascular endothelial cadherins; VEGF = vascular endothelial growth factor; XOR = xanthine oxioreductase.
Figure 8
Figure 8
Aberrant Mitochondria in Brain Endothelial cells (EC), Astrocytes (AC), Pericytes (Pc), Myelinated and Unmyelinated Neurons and Oligodendrocytes (OLIG) in the Diabetic db/db Models. The aberrant mitochondria (aMt) are pseudo-colored yellow with red outlines in order to allow for rapid identification. Panels (A–F) demonstrate aberrant mitochondria (aMt) in each of the brain cells depicted. Panel (A) depicts aMt in ECs and adjacent AC foot processes. Panel (B) depicts an aMt within the cytoplasm of an AC. Panel (C) depicts multiple aMt in the cytoplasm of a Pc. Panel (D) depicts aMt within a myelinated neuronal axon that also demonstrates separation of its lining myelin sheath. Panel (E) depicts aMt in an oligodendrocyte’s cytoplasm. Panel (F) depicts aMt with the axoplasm of an unmyelinated neuronal axon. Note that most of the aMt are hypolucent as a result of the loss of their normal electron dense matrix proteins and they share a common feature of attenuated and or loss of their crista; they are also enlarged. Magnifications are located in the upper part of each panel and the scale bars are at the bottom. The images in this figure were modified with permission by CC 4.0 [27].
Figure 9
Figure 9
Vascular Contributions to Cognitive Impairment and Dementia (VCID), LOAD and FOCM. Our current society is aging, especially in the group referred to as the baby boom generation and age-related senescence. The aging society including the baby boomers is at a much higher risk for cerebro-cardiovascular disease and stroke especially with their comorbidities of aging such as hypertension and type 2 diabetes (T2DM). This slide focuses on T2DM, LOAD and age-related senescence that is ongoing as our population ages. This image does not portray inflammation; however, it is strongly related to an excess of RONS generated by aging, T2DM, LOAD. This figure points out the nuclear chromatin condensation of the amoeboid, aberrant and activated microglia cells (aMGC) and senescence, which highlights inflammation and its co-occurrence with oxidative stress via reactive oxygen nitrogen species (RONS). Of great concern is that non-replicative senescence can be induced by a variety of factors, including DNA damage (such as chromatin condensation), inflammation, mitochondrial dysfunction, oxidative stress (RONS) and importantly epigenetic disruption as related to impaired folate one-carbon metabolism (FOCM). The importance of impaired FOCM and each of the above listed factors may contribute to the inflammatory contribution of microglia senescence and nuclear chromatin condensation as depicted from our previous discussions in Section 2, Figure 3 and hence the reason for placing images C and F within this framework as well as illustrating the folate and methionine cycles. Since we have found numerous neurovascular unit remodeling changes in the diabetic db/db models, we suggest that VCID might also be considered microvascular VCID or MVCID. Impairment of the cytosolic, mitochondria and nuclear FOCM appear to be playing a role due to excessive reactive oxygen nitrogen species (RONS). Moreover, since there is obvious ongoing senescence in T2DM and LOAD it seems appropriate to ask the following question. Could improvement of impaired FOCM be a possible therapy for senescence and possibly contribute to a synalytic therapy effect? It seems appropriate to discuss this since the field of synalytic therapies is in an emerging stage of study. AGE/RAGE = advanced glycation end products and their receptor RAGE; aMGC = aberrant-activated microglia cell; aMt = aberrant mitochondria; Chr Cond = chromatin condensation.
Figure 10
Figure 10
Clinical Signs and Symptoms of LC/PASC. This illustration shares at least 14 of the most common symptoms reported by LC/PASC individuals. Note that the symptoms that are related to neurological manifestations are underlined and appear in white bold font and preceded by asterisks. Additionally, note that fatigue and dysphoria are at the top of the list at the heading of the ‘standing man’ to the right-hand side of this figure as one of most aggravating clinical signs and symptoms of the remaining neurological manifestations. Further, note that this ‘standing man’ is portrayed as being a muscular robust individual that is not frail or old. In many cases, the individuals who have LC/PASC are very healthy and even young.
Figure 11
Figure 11
The Homocysteine Wheel. This illustration depicts the central importance of homocysteine (Hcy) in its hyperhomocysteine (HHcy) state as it relates to the multiorgan tissue damage and associated multiple clinical diseases, which now includes the COVID-19 post-viral syndrome of LC/PASC. HHcy generates damage to proteins, lipids and nucleic acids as result of oxidative redox stress and the generation of excessive reactive oxygen nitrogen species (RONS). In HHcy, Hcy undergoes autoxidation, formation of Hcy mixed disulfides, interaction of Hcy thiolactones and protein homocysteinylation reactions, which result in damage and dysfunction to proteins, tissues and organs. Note the large asterisk at the central bottom of this illustration where the effects of HHcy promotes the uncoupling of the endothelial nitric oxide synthase enzyme (eNOS) by oxidizing the tetrahydrobiopterin (BH4) co-enzyme of eNOS and thus promotes an even further production of superoxide while it concurrently decreases the bioavailability of nitric oxide (NO), thus important to normal endothelial cell dysfunction. As a result, the endothelium undergoes activation and dysfunction and becomes a proinflammatory, prothrombotic endothelium due to increased generation of RONS. While this review has focused primarily on COVID-19 and LC/PASC, this illustration demonstrates that HHcy affects many other tissues, organs and clinical diseases. This modified image is reproduced with permission by CC 4.0 [6]. CHF = congestive heart failure; COVID-19 = coronavirus disease-19; CVD = cebro-cardiovascular disease; HTN = hypertension; MetS = metabolic syndrome; MMPs = matrix metalloproteinases; NTD = neural tube defects; LC/PASC = Long COVID/post-acute sequelae of SARS-CoV-2; LOAD = late-onset Alzheimer’s disease; T2DM = type 2 diabetes mellitus.
Figure 12
Figure 12
Possible Damaging Effects of Elevated Homocysteine (Hcy). There are at least 14 possible damaging effects of hyperhomocysteinemia (HHcy) to cells, tissues and organs. The possible damaging effects (1–13) are supported in reference [6], while the possible damaging effect of HHcy in number 14 is developed in the current review. Additionally, circulating monocytic SARS-CoV-2 spike protein remnants may also induce toxic cytokine/chemokine production in endothelial cells. CD14lo = cluster of differentiation 14 low; CD16+ = cluster of differentiation 16 positive; EC = endothelial cell; ecGCx = endothelial cell glycocalyx; eNOS = endothelial nitric oxide synthase; IFNγ = interferon gamma; LDL = low-density lipoprotein cholesterol; NO = nitric oxide; Ox = oxidative stress; RONS = reactive oxygen nitrogen species; NFkappaB = nuclear factor kappa B; RBCs = red blood cells; TNFα = tumor necrosis factor alpha.
Figure 13
Figure 13
Impaired FOCM and Elevated Hcy (HHcy) Results in an Activated Endothelium that Promotes Activated Fractalkine (CX3CL1). This collection of transmission electron micrographs from the female diabetic db/db models and diabetic BTBR ob/ob models in cortical grey matter (layer III) allow for illustrative and representative images that may also be present in Long COVID/post-acute sequelae of SARS-CoV-2 (LC/PASC). Impaired FOCM is associated with hyperhomocysteinemia (HHcy) and results in an activated endothelium with an attenuation and/or loss of endothelial glycocalyx (ecGCx) (yellows arrows pointing to lanthanum nitrate positively stained ecGCx) in the control model (panel (A)), which predisposes to the attenuation and/or loss of the ecGCx in diabetic BTBR ob/ob models and the development of microclots and microthrombi (panel (B)). Additionally, impaired FOCM with HHcy is associated with endothelial activation and dysfunction resulting in adhesion of red blood cell(s) (RBCs) (panel (C)) and adhesion of leukocytes such as lymphocytes (panel (D)) and monocytes (which may include the non-classical monocyte (CD14Lo, CD16+) (panel (E)). Magnifications vary and scale bars are included. This modified multi-panel figure is reproduced with permission by CC 4.0 [6,27,32,41].
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