Nutrition is a very important part of methylation and the transsulfuration connection to mitochondrial function. Be thinking of Total Mitochondria, Homocysteine Redux, Alpha Lipoic Acid and Super-ox as this complicated story unfolds.

Mitochondria lose their ability to resuscitate due to oxidative damage. This is naturally accelerated with age and is universally recognized as a major contributing factor to a wide range of functional decline and tissue deterioration. This further causes damage to proteins in their formation. Much of this research was reported by Bruce Ames’ in the American Journal of Clinical Nutrition (2002 April;75 4 616-58.)

Aging in general and nutrient deficiency has been shown to cause a decreased binding affinity for co-enzymes and nutrient co-factors for enzymes, thus causing a decrease in mitochondrial function. Ames’ research has demonstrated that increasing the availability of acetyl L-carnitine, the substrate for the enzyme acetyl-L-carnitine transferase, (which plays a key role in transporting long-chain fatty acids into the mitochondria for β oxidation and ATP production), along with α-lipoic acid, (a mitochondrial antioxidant that also serves as a cofactor for two key enzymes in the Krebs cycle, pyruvate dehydrogenase and α-ketoglutarate dehydrogenase), restores the velocity of the reactions. This research has been further substantiated by other studies of TM Hagen and published in the National Academy of Science (U S A. 1997 Apr 1;94 7 :3064-9.)

I have discussed the genetic changes called SNPs many times in previous Puzzle Pieces. Certain Single Nucleotide Polymorphisms plus the aging-associated accumulation of oxidative damage, may promote premature aging. As many as one-third of all mutations in a gene result in the corresponding enzyme having a decreased binding affinity for a coenzyme. This yields a lower rate of reaction and causes uncoupling.

One well-researched example demonstrating its impact on mitochondrial function is the 677CàT SNP of methylenetetrahydrofolate reductase (MTHFR). This is a key enzyme in the methylation cycle. MTHFR is responsible for the conversion of folic acid into methionine synthase, which, along with B12, recycles homocysteine to methionine.

Another fairly common SNP is the 677CàT variant (~30-40% incidence), thymine is substituted for cytosine in the gene, resulting in production of a slow variant of the MTHFR enzyme in which valine is substituted for alanine at position 222 (for which reason this SNP is also labeled Ala222Val). In individuals in whom both alleles have this SNP (i.e., individuals homozygous for the TT genotype of MTHFR, (~10% of the North American population), the resulting enzyme expressed has only 50% of the activity of the wild (more common) CC type. This study was reported by JA Schneider, DC Rees, YT Liu and JB Clegg in the American Journal of Human Genetic in 1998.

Similar to the way in which providing supplemental acetyl-L-carnitine restores normal enzyme activity for acetyl-L-carnitine transferase, providing supplemental folate, the substrate for MTHFR, may help compensate for the drop in MTHFR activity that will otherwise occur in carriers of this SNP. Another way of looking at this is that carriers of the MTHFR 677CàT SNP have an increased requirement for folate to optimize the activity of this enzyme, and thus require more folate for normal methylation. This is why many patients that show a need for Homocysteine Redux, which has these nutrients within, become a lifetime necessity. This may also be true for Total Mitochondria.

Nutritional deficiencies and genetic inheritance are shown to cause decrease in MTHFR activity. Therefore restoring normal levels of MTHFR activity is essential for optimal function in aging mitochondria. When MTHFR is compromised, not only is methylation impaired, but unmetabolized homocysteine accumulates in the cell and effluxes into the bloodstream. In both, homocysteine will react with reactive oxygen intermediates, greatly increasing the rate of antioxidant consumption, including that of GSH, an antioxidant critical for neutralizing mitochondrial reactive oxygen species (ROS).

High levels of homocysteine have been shown to increase lipid peroxidation in the endothelium, liver, kidney and brain. In addition to decreasing antioxidant defenses and total thiol content (Thiols are compounds that contain the functional group [–SH], aka a sulfhydryl or thiol group. [–SH] is the sulfur analogue of an alcohol group [–OH]. Key compounds in mitochondrial energy production, coenzyme A, cysteine, GSH, and α-lipoic acid are all thiols), hyperhomocystenemia has been shown to disrupt the activity of all three key mitochondrial antioxidant enzymes (superoxide dismutase [which neutralizes superoxide radical (O2−)], catalase [which neutralizes hydrogen peroxide (H2O2)] and glutathione peroxidase (GPx) [which reduces H2O2 and lipid peroxides]).

In this discussion we have linked Homocysteine metabolism, methylation, transsulfuration and Mitochondrial Function to genetic predisposition that can be influenced widely by supported nutrition. Of course TOTAL MITOCHONDRIA has the all of the nutrients researched and clinically tested to allow maximum mitochondrial function and resuscitation, including Acetyl-L-Carnitine. TOTAL ALPHA LIPOIC ACID gives us further anti-oxidant production, as does SUPER-OX. HOMOCYSTIENE REDUX is the key to reducing homocysteine levels.

The decreased MTHFR activity we have been discussing impairs the methylation cycle, resulting in increasing levels of homocysteine, increased ROS production, decreased S-adenosylmethionine (SAM) production, and increased oxidative stress, which greatly increases the rate of glutathione (GSH) depletion.

Homocysteine is also involved in transsulfuration as the precursor to cysteine, the rate-limiting factor for the production of GSH, which is a powerful endogenous antioxidant.

Thus compromised methylation results in increased homocysteine into plasma, where it is highly susceptible to being oxidized, increasing the formation of superoxide radical (O2−) and hydrogen peroxide (H2O2).

The answer again is proper nutrition and supplementation with TOTAL MITOCHONDRIA, HOMOCYSTEINE REDUX, SUPER-OX and ALPHA LIPOIC ACID, along with proper diet and any other nutrition that tests by a Total Scan, blood tests, Saliva testing, hair analysis, questionnaires etc.

I hope you enjoyed this more technical approach as to why we need specific nutritional support and why increase levels may be necessary for individuals carrying specific SNPs. I always read this type of research and information to enable proper formulation of products; but have rarely presented it for your enjoyment as I did in this Puzzle Piece.

Yours In Health and Wellness,


John W Brimhall, DC and the Wellness Team