How Low Methylation Destroys Your Energy Metabolism
In How Energy Deficiency Hurts Methylation, I covered the ways that low ATP and a low NAD+/NADH ratio will sap your methylation, and the patterns to look for on a Genova Methylation Panel to verify this is happening.
It turns out low methylation can also destroy your energy metabolism.
This is not simply a result of decreasing creatine synthesis. As I covered in Your Cells Are Starving for Creatine, 45% of methylation is used for creatine synthesis, and for most people this falls far short of providing optimal creatine concentrations. Everyone needs their creatine stores saturated, and most people need one or two pounds of meat per day or a creatine supplement to achieve that. People who do not respond well to creatine should use Handling Creatine Side Effects to navigate the process of reaching saturated creatine stores.
While 45% of methylation is used for creatine synthesis and 45% is used for phosphatidylcholine synthesis, among the many roles of the other 10% is constructing a properly functioning mitochondrial respiratory chain.
The proof of principle for this is that pathogenic mutations in SLC25A6, the mitochondrial S-adenosyl-methionine (SAM) transporter, leads to combined oxidative phosphorylation deficiency. This means it leads to a deficiency of multiple respiratory chain complexes.
The methylation cycle occurs in the cytosol and has as its aim to produce SAM, the universal methylation donor for methylation reactions.
SLC25A6 brings SAM from the cytosol into the mitochondria.
As I covered in Does CoQ10 Deserve a Spot in Your Longevity Plan, CoQ10 synthesis requires two methylations that occur in the mitochondria, meaning they require the transport of SAM through SLC25A6 to occur.
Mitochondrial methylation is also needed to synthesize lipoic acid, which is needed to burn pyruvate, branched-chain amino acids, alpha-ketoglutarate, and glycine for energy.
Methylation is also required for the production of all of the mitochondrial proteins that are synthesized within the mitochondria, and for the regulation of numerous mitochondrial proteins, including those that transport ADP into the mitochondria and ATP out. Complex II is the only respiratory chain complex that is completely synthesized by the nuclear genome, and is the only complex that appears to be spared in SLC25A6 deficiency, supporting the role of mitochondrial protein synthesis.
A case report of three patients with respiratory chain deficiency due to SLC25A6 deficiency was published in 2015.
It follows straightforwardly that if SAM transport into the mitochondrion is needed for the function of the respiratory chain, then so is production of SAM in the first place. Transport of SAM that doesn’t exist isn’t going to support your respiratory chain.
Thus, optimizing methylation with my MTHFR Protocol, the Genova Methylation Panel, and my Guide to Interpreting the Genova Methylation Panel is an important step in optimizing your energy metabolism.
The key sign that you need to optimize your energy metabolism is that you aren’t dead yet.
Energy Metabolism Governs Everything, and energy is the only thing keeping you in that state, so optimizing it will optimize for staying alive and healthy.
Fascinating post. Appreciate brushing back up on this topic - I'd forgotten how supplementing with creatine and sunflower lecithin can ease the methylation demand in our body and allow SAM to be used for other purposes. Interesting to hear about the need to transport SAM into the mitochondria and how important methylation is to the production of all mitochondrial proteins that are synthesized within the mitochondria. Also fascinating that all of complex ii is synthesized by the nuclear genome. Thanks very much as always!
I've actually started the base methylation protocol last week and two very interesting things happened:
1. My sleep has instantly improved by an incredible degree. No night wake ups, feeling good sleepiness, remembering lots of dreams suddenly, and not awaking up in the morning feeling like i have been run over by a car. (Note: my sleep improved with glycine alone in the past but never this much and it become worse after a few days so i stopped)
2. I became absolutely massively depressed within a day. Zero motivation, no energy, instantly overwhelmed by everything, high anxiety/irritability, and everything feels wrong. The worse i've had it in a long time.
So i was taking 2 x 500mg TMG, around 3-5g of creatine, 2x 200mg of Magnesium Glycinate, 100mg of b2 (since it is lowest capsule, but also tried swapping with 25mg riboflavin 5 phosphate and couldn't tell a difference), and 2 x 400mcg of methylfolate L-5-MTHF/DFE.
I then saw tweets by Dr Walsh (and a few mentions on reddit) that methylfolate increases the serotonin reuptake transporter, which for people with low serotonin could perhaps cause/increase depressive symptoms.
Yesterday i removed the folate from the protocol and today i feel significantly better, but my sleep last night was not as good.
Chris, I'm curious if this explanation tracks for you or if you think there is another reason for the sudden sharp depressive symptoms. And if it is the folate (for SERT expression reasons or other), what would be an alternative if any, or how should the protocol change to accommodate? Would just glycine, b2, tmg, and creatine be work fine without the folate? Any insights in general would be appreciated.