This article is not intended to be medical or healthcare advice. Before attempting any health regimen seek the advice and guidance of your M.D. or primary health care provider.
This article may be of interest to you if you are interested in : oxidative stress, super oxide, anti oxidant systems in the body, fatigue, soreness, chronic fatigue syndrome, long haul covid, lipid peroxidation, detoxification of organo phosphates, detoxification of pesticides, glycine, sulfur, heme, iron, ferritin, b2, homocysteine, or mitochondrial oxidative stress.
Super Oxide, Super Oxide Dismutase, and Mitochondria
It has generally been accepted that the gene(s) primarily associated with neutralizing the free radical super oxide have been Super Oxide Dismutase (SOD), with three different types, SOD1, SOD2, and SOD3. It has also been generally accepted that SOD2 is the only SOD enzyme located inside the mitochondria, while it is also believed that the mitochondria produce around 80% of all super oxide in the body. It is no surprise that this gene has received extensive study, along with its co factor, manganese. Ron Davis, once explored how low managese levels correlated with CFS, but ended his search. Alas, for those around this game for a while, its not a singular causitive problem. If one has low manganese, perhaps before issuing an arresst warrant - we ask questions why ? Was SOD2 up regulated and working over time from too much super oxide, if so where was it coming from ? Is there poor manganese absorption from GI issues, or transport issues from the gut ? Etc. I often see two critical locations on SOD2 mutated in clients who struggle with inflammation and fatigue. Many respond well to supplements that stimulate both the activity and replication of SOD2. However, some do not......
Bring On F12, What !? What is F12 ? - Correlated to Mitochondrial SOD Concentrations!
F12 is a gene, that, wait, is correlated with mitochondrial SOD concentrations. Hmm. Well this certainly sounds important. It has other functions too, but , lets just say this got more than just a little attention from me.....
"This SNP has been strongly associated with altered mitochondrial SOD concentrations during 3 genome-wide association studies (P = 9 x 10-299) ; (P = 2 x 10-94) (P = 5 x 10-128) ." Those P- Values are quite compelling.
...One one location, "the heterozygous and homozygous variant genotype at this position has been associated with ~ 37% and 73% decreased Factor XII concentrations, compared to the homozygous major allele genotype,."
And what do you know, after perusing a handful of clients genetics who have been struggling and i couldnt wrap my head around all the reasons, you guessed it, F12 is in the field of play......but wait it gets better........
Bring on PON1 - A backup system for neutralizing Super Oxide!
Additionally, a colleague shared some literature indicating that PON1 is a backup system for neutralizing super oxide. Whoa. Yes, PON1 does many things, and it is well known as an enzyme that detoxifies pesticides, saran gas (Gulf War Syndrome anybody!?), and organo phosphates like those found in Pound-Up:). Its also implicated in MCS (Multiple Chemical Sensitivities (via Pall) , and also clears excess homocysteine (correlated to....all cause mortality). Also recent research shows it has a strong role to play in reducing lipid peroxides (um, remember GPX4!; https://www.foodforyourjeans.com/post/gpx4-key-enzyme-in-ferroptosis-long-haul-cfs). Yes, lipid peroxidation and all the nastiness that goes along with it are common in LH. Yes, PON1 has research that shows direct correlation to CVD events, no surprise here. But the final nail may be - being a back up system to SOD for detoxifying super oxide! Bam.
Bring On PPAR Alpha/Gamma!? PPAR Upregulates PON1!
"The paraoxonase (PON) group of enzymes, composed of PON1, PON2, and PON3, play an important role in decreasing oxidative stress by degrading lipid peroxides. PON1 synthesis is upregulated by PPAR. Several pharmacological compounds (acting as antioxidants and, hence, atheroprotective) stimulate both PPAR activity and PON1 expression. Recent evidence suggests that PON1 and the monocyte chemoattractant protein-1 (MCP-1) are involved in coordinating the inflammatory response in damaged tissues; PPAR may be central in the regulation of these biochemical pathways. This article reviews the state of knowledge on PON1 biochemistry and function, the influence of genetic variation, and the regulation of PON1 expression by pharmaceutical compounds that increase PPAR activity." . So, what up regulates, PPAR, our good friends Berberine and Circumin:).
So, here we have some folks who produce alot of super oxide for various reasons like: NOS Uncoupling (NOS2/NOS3 issues); upregulation of the immune system (TNFA, NFKB, IL-6) or EMF exposure or Mast Cell / Histamine activation that stimulates NOX 1,2,3,5 (and these consume NAD+ too, ugh), mutations in the ACE/ACE2/ANGT1 - angiotensin system (we have heard this before in covid land), as well challenges recycleing glutathione (GSR mutations). When the cardiolipin (see another blog article; ) get oxidized inside the innner membrane of the mitochondria, a whole world of super oxide is produced; https://www.foodforyourjeans.com/post/inner-membrane-of-the-mitochondria-cardio-lipid-phosphatidylserine-phosphatidylethanolamine. This isnt even accounting for the natural super oxide output of mitchondria under normal circumstances.
With the combination of the potential touble spot of too much super oxide, and then systems like SOD2, PON1, that limit our ability to handle the super oxide produced by our mitochondria when we fire them up from........exercise......we officially feel, well, not well. GPX4, and other hydrogen peroxide reducing enzymes like CAT (catalase), and Thriodoxin (TRXNDR1) handle the by products of SOD2, and Pon1, so these are needed as well. GPX4 reduces hydrogen peroxide to water and helps control lipid peroxidation.....where?.....you guessed it, inside the mitochondria.
As a small aside, mutations in the genes associated with biotin delivery and utilization (SLC5A6, and BTD); may lead to excess levels of super oxide production.
Looking at folks who really, really struggle with long haul, cfs, and general malaise, at the top of the list for trouble makers, are : F12, SOD2, PON1, and GPX4. There are a handful of others too, that need to be functioning well so that these enzymes can work well (e.g. Keap1, Bach 1, NrF2, HMOX1, NQO1), but those first 4 seem to be the ones that can differentiate folks who really really struggle.
Later, I will tie together how glycine, iron, and sulfur have role to play in this mess too in a more clear well thought out way, but some food for thought for now:
PON1 is needed to support the utilization of glycine; glycine is typically converted from serine (SHMT1, SHMT2) or threonine (GCAT), unless the diet is rich in collagen.
The heme cycle needs glycine, and iron needs heme to be used by the body, and to be stored into ferritin. Hmmm this is getting interesting.
Further, guess what other enzyme is heme dependent, one of my favorites, SUOX, which is how we begin to process......sulfur. Ah yes, the folks who struggle with sulfur, and even have a reaction seeing garlic on tv:).
My favorites: Iodine, Molybdenum, Selenium are needed to make B2 functional;
B2 and molybdenum are needed for SUOX, and heme is also needed for SUOX; so we can process sulfur. Molybdenum absorption can be impacted by MOCS1, MOCS2, GPHN.
What are some of the common cofactors needed across the 8 key genes in the Heme Cycle - um, Glycine, Alpha Lipoic Acid, B2, B6, Zinc, Iron. My sulfur friends cringe:). Lead and mercury inhibit two of the key genes - noteworthy*, and IL-10 can inhibit one of the genes too. Heme is needed for Hemoglobin:). And Heme activity can be measured by a phororyns test.
B2 and glycine are needed for heme, to use iron
And all this needs HMOX1 to be functioning to : store iron into ferritin; dampen mast cell activation; stimulate SUOX; control IL-6, NFKB, and TNFA; and calm down the NOX genes (which consume NAD). What does HMOX1 need - NAD:). This sounds sorta important:).
What inhibits the SUOX-PAPSS-SULT Pathway ? Oxidized glutathione. Uh oh, our friend GSR better be working:). It only needs B2 as its cofactor:). Phenols and oxalates also constrain this pathway (SULT).
Which leads us back to PON1 and glycine as the entry point into the heme cycle never mind taking care of super oxide on the side:).
This isnt even touching the point of B2 is needed by B6 to become functional (B6 is the most common cofactor of all the B Vitamins - and of course is needed to process our sulfur friend cysteine / NAC). B2 is needed to make B12 functional as well. Oh, my. And before we get hopped up on B12, we need potassium, so better check to see if those darn angiotensin ACE/ACE2 genes are dumping potassium and stimulating the NOX genes - do your socks leave marks on your ankles when you take them off:).
If you are interested in exploring your status on these genes, or the research that shows how best to support some of these genes with compounds that stimulate them, or provide the substrate/co-factor needed to function - please consider reaching out and scheduling an appointment.
Later on i will add a series of references to support this article, in the mean time, stay warm:).
*"The CPOX protein contains a number of reduced thiol residues that render it potentially susceptible to inhibition by thiol binding agents including metals. In this regard, we have previously shown that CPOX activity is significantly impaired by mercury (Hg) as either CH3Hg+ or Hg2+ both in vivo and in vitro, and that this effect is expressed predominantly in the kidney, a principal target organ of Hg compounds. We have also demonstrated that partial inhibition of renal CPOX activity by Hg produces a characteristic change in the urinary porphyrin excretion pattern that serves as a biological indicator of Hg exposure and toxicity in both animals and humans. In more recent studies, we have found that 12–16% of human subjects respond atypically to Hg exposure in terms of porphyrin excretion and have shown that this atypical response is associated with an A814C single nucleotide polymorphism in exon 4 of the CPOX gene that results in an asparagine to histidine change at amino acid 272 (N272H) in the protein structure."
**"The discovery that IL-10 can inhibit the production of coproporphyrinogen oxidase (an enzyme involved in the synthesis of heme) may shed some lights on the mechanisms of anaemia induced by IL-10 . Petit-Bertron, A.F. et al. Adherence modifies the regulation of gene expression induced by interleukin-10.
 PPARs in Regulation of Paraoxonases: Control of Oxidative Stress and Inflammation Pathways
Jordi Camps,1Anabel García-Heredia Volume 2012 | Article ID 616371 | https://doi.org/10.1155/2012/616371