Mitochondrial Support: Other Testing and Treatment Strategies to Regenerate New Mitochondria and Optimize Your Health. Part 4
The previous 3 parts of my mitochondrial dysfunction series discussed the role of mitochondria in a broad range of symptoms and diseases, with basic testing strategies for genetic abnormalities. As you know, mitochondria play a crucial role in every biological system you need to survive.
Variants in Methylation Pathways Affect a Broad Range of Symptoms/Diseases
DNA methylation is an essential biochemical pathway since it regulates gene expression--which genes turn on and off. This is called epigenetics, where you alter your gene expression without altering your DNA. DNA methylation affects mitochondrial function and gene expression, where methylation changes in mtDNA allow mitochondria to adapt to cellular stress, such as low oxygen states (hypoxia) or exposure to pollutants. Adverse changes in mtDNA methylation have been linked to diseases including diabetes, cancer, and neurodegenerative disorders.
You can check your MTHFR status (methylenetetrahydrofolate reductase, the enzyme that plays a crucial role in folate metabolism) through a local or functional medicine laboratory to assess how much methylation support you need. I knew that I needed extra methylation support when my homocysteine (HC) level, a cardiovascular risk factor, came back elevated. I added methyl B6, methyl B12 and methyl tetrahydrofolate (methyl THF). I took Xymogen’s methyl protect, 1x/day with zinc. My HC level quickly came down to normal. I’ve been taking one methyl protect a day with a mineral supplement (MinRx, 4/day, Xymogen) for decades.
This illustrates the methylation cycle:
Notice that homocysteine breaks down into cysteine, a precursor of glutathione, your master anti-oxidant to protect against adequate stress!
Adequate Methylation Is Also Needed for Many Other Essential Biochemical Processes
DNA repair and Stability: Methylation helps prevent disease-causing mutations.
Production of Myelin Sheaths: Think of diseases like multiple sclerosis or Lyme/Bartonella with demyelination and neuropathy, where you need to remyelinate nerves to have normal neurological function.
Production of Neurotransmitters Like Serotonin, Dopamine, and Norepinephrine: Roughly half of those prescribed an SSRI like Prozac for depression find it doesn’t work well until they add methylation support. Folate is a crucial component in the synthesis of neurotransmitters like serotonin. People with depression often have lower folate levels, and supplementing with L-methylfolate, the active form of folate (I use Xaquil XR from Xymogen, with 15 mg of L-methylfolate), can improve your ability to produce these neurotransmitters, supporting mood while making SSRIs more effective. Methylation also affects an enzyme called COMT (Catechol-O-Methyltransferase) affecting neurotransmitter metabolism and your stress response. COMT is crucial for breaking down catecholamines like dopamine and norepinephrine (NE). If you can’t break down norepinephrine, one of your fight-or-flight hormones, you can develop high blood pressure, heart problems with a rapid heartbeat, and an anxiety disorder (or worsen a preexisting one).
Collagen Synthesis and Tissue Repair: Methylation supports collagen production, needed for the strength and elasticity of soft tissues like tendons, fascia, and ligaments. This can help athletes in injury prevention and recovery.
Hormone regulation: Methylation plays a role in metabolism and regulation of hormones.
Immune System and Detoxification Support: Methylation is needed for proper immune function, and is one of the 6 primary detoxification pathways in the liver phase II detoxification system, transforming toxic substances into less harmful ones. This involves the addition of a methyl group (CH3) to a molecule, making it less toxic/easier to eliminate. You eliminate heavy metals (arsenic, mercury, chromium) via methylation, also using glutathione and methyl donors like SAMe (S-adenosylmethionine).
How Emotional Trauma and Stress Affect Mitochondrial Dysfunction
Trauma can result in neuroendocrine activation with increased production of catecholamines (adrenaline, NE) as well as cortisol. High levels of cortisol impair glucose metabolism, which can result in insulin resistance and ROS production. High catecholamine levels also produce ROS, adversely affecting ATP production and efficiency. Mind-body techniques like calm-abiding meditation have been shown to lower inflammation, indirectly supporting mitochondrial health, while influencing your genetics and extending your telomeres (the caps at the ends of your DNA involved in longevity). This link explains more:
Testing Your Emotional Genetic Pathways
Apart from checking your MTHFR status, have you ever wondered why some people have a difficult time getting over trauma, where others are incredibly resilient? There are 3 genes involved in your stress response that can be checked via genetic testing. The COMT gene has a ‘worrier’ vs ‘warrior’ allele. The ‘worrier’ has decreased COMT activity increasing NE and dopamine. The ‘warrior’ allele has increased COMT activity, clearing catecholamines more easily under stress. Then there are other genes that regulate NE release and uptake. Norepinephrine is needed for attention, memory and emotional responses. Those with a certain SNP in the ADRA-2B gene (alpha-2 B adrenergic receptor) where they can’t uptake NE properly are more sensitive to stress and have stronger encoding of trauma and recall. Many with PTSD have this genetic variant. The third gene, a serotonin transporter gene (5HTRPR) has a short allele where serotonin stays in our synapses without proper uptake into our cells. In that case, you would be more sensitive to stress, anxiety, depression and PTSD. If you had the long allele, with higher transport of serotonin into the cells, you would normally be more resilient to stress. You can check these genetic variants through labs like DNA company and Nutrigenomics. You can also check overall mitochondrial function with a cheek swab (Mitoswab), although every time I have ordered it, it shows mitochondrial dysfunction!
Making New, Healthy Mitochondria: Mitochondrial Biogenesis
We need to make new healthy mitochondria and get rid of damaged mitochondria to stay healthy. New mitochondria are made by a process called fission and fusion. Fission is where a single mitochondrion divides into two or more smaller mitochondria while segregating damaged mitochondria which are removed by autophagy (mitophagy). Autophagy is the process of clearing out dead and damaged cells, whereas mitophagy is clearing out damaged mitochondria. A lack of proper autophagy and mitophagy can lead to a buildup of damaged cellular components, including dysfunctional mitochondria, which contribute to various disease states and accelerates aging. Defective autophagy has been linked to neurodegenerative disorders (like Alzheimer's and Parkinson's), cancer, cardiovascular diseases, and metabolic disorders. Impaired mitophagy also leads to mitochondrial dysfunction, reduced ATP production, oxidative stress and cell death. So fission, making new mitochondria, with balanced autophagy and mitophagy are essential for long-term health. Lifestyle modifications listed below like intermittent fasting and reduced caloric diets help support autophagy and mitophagy.
Mitochondrial fusion on the other hand is where two or more mitochondria combine to form a single, larger mitochondrion. Fusion allows for the mixing of mitochondrial contents, which can be beneficial for repairing damaged mitochondria and for sharing resources between mitochondria. An imbalance can lead to various diseases. Excessive fission can lead to a fragmented mitochondrial network, while a lack of fission and increased fusion can result in elongated, hyperfused mitochondria, impacting cellular metabolism and function. See the image below:
Inflammation Interferes with Mitochondrial Regeneration—So How Do You Turn On Mitochondrial Production?
All inflammatory factors on the MSIDS model need to be addressed because they will interfere with mitochondrial biogenesis. How do you form new mitochondria?
There is a switch inside your cells called PGC-1α. It is the master regulator of mitochondrial biogenesis and function.
The basic lifestyle factors for turning on/off PGC-1α include:
A Mediterranean, anti-inflammatory diet with optimized nutrition.
Caloric restriction with intermittent fasting and time restricted eating.
Targeted physical exercise, especially cardiovascular, resistance training and High Intensity Interval training [HIIT].
Getting good quality sleep.
Cold exposure increases mitochondrial biogenesis; cold showers affect brown adipose tissue and increase non-shivering thermogenesis. As does heat with saunas, which increase heat shock proteins, lowering oxidative stress.
In this image, factors highlighted with green are some that increase mitochondrial biogenesis; factors highlighted in brown (too much insulin, inflammation, aging) decrease it.
Why Are Ketogenic Diets and Intermittent Fasting with Low Calorie Diets So Good for Mitochondrial Function?
Switching your fuel source from glucose to fat and ketones triggers adaptive responses that increase mitochondrial function. Intermittent fasting decreases insulin sensitivity, improves glucose and lipid metabolism, improves your microbiome, decreases abdominal fat (a significant source of inflammatory cytokines), lowers blood pressure, and increases disease resistance and resilience.
Ketones like beta hydroxy butyrate (βHB) formed during intermittent fasting and calorie restriction are also helpful because:
They are highly efficient fuel sources that help you to make more ATP, and are cleaner fuels, decreasing ROS. They also increase mitochondrial fission and fusion.
βHB upregulates mitochondrial enzymes like SOD and GPX2, decreasing free radicals.
βHB upregulates anti-inflammatory pathways like Nrf2. This increases your antioxidant defenses and detoxification enzymes.
βHB improves metabolic flexibility, decreasing dependency on glucose as an energy source (for those who suffer from significant reactive hypoglycemia).
βHB improves microbiome diversity, lowering inflammation.
βHB decreases mTOR, the Mammalian Target of Rapamycin, which regulates cell growth, metabolism, and aging. Lowering mTOR increases autophagy, mitophagy, and DNA repair, and can help prevent Alzheimer’s disease, cancer, cardiovascular disease and diabetes.
What Stops Mitochondrial Biogenesis and Turning on PGC 1 Alpha?
The opposite of what’s on this list! As well as turning on NFkappaB (NF-κB), the switch inside our nucleus that turns on inflammatory cytokines (MSIDS factors), as you can see:
Targeted Mitochondrial Nutrition/Supplementation
There are 3 different types of nutritional supplements that can positively affect PGC-1α:
L-arginine: An essential amino acid, it improves mitochondrial function by increasing nitric oxide (NO). Beets, nuts (walnuts, almonds, pecans), and seeds as well as nutritional supplements with L-arginine increase NO.
Alpha-lipoic acid (ALA): Through food or supplements, it can turn on an enzyme called AMPK (AMP-activated protein kinase). AMPK acts as a metabolic master switch; it regulates the cellular uptake of glucose for energy production and the formation of new mitochondria. When ATP levels go down with exercise, AMPK is stimulated, helping replenish it. I take Alamax 600 mg (Xymogen) 1-2x/ day, although those with hypoglycemia need to be careful.
Resveratrol: Through foods or supplements, it activates sirtuin genes (SIRT1), stimulating PGC-1α. Sirtuin genes help preserve the lives of cells, and influence age-related diseases such as cancer, heart disease, osteoporosis, diabetes, and neurodegeneration. Resveratrol from grapes and berries, and quercetin found in fruits, vegetables, and tea, both activate SIRT1 and the sirtuin genes of longevity. Resveratrol can also increase mitochondrial production and enhance exercise tolerance. To date, it is the only supplement known to do this. I take Resveratrin Plus and Quercetin 20x + (Xymogen) 1x/day.
You also need to replace damaged mitochondrial membranes from various sources of inflammation (infections, toxins) with lipid replacement therapy and provide essential cofactors needed to produce ATP.
Mitochondrial targeted supplements also include:
CoQ 10 (Researched Nutritionals, Co-Q power, 400 mg each): I take 1x/day.
ATP 360 (Researched Nutritionals): 3x/day provides comprehensive mitochondrial support with NT factors.
NADH (ENADA): I take 5 mg 1x/day. In those suffering with Myalgic Encephalomyelitis, doses up to 10 mg 2x/day have been shown to be helpful.
Acetyl-L-carnitine (Carnitex, Xymogen): Each capsule contains 500 mg. Doses go up to 2 capsules 2x/day (2000 mg). Not for those with alpha gal allergy.
Essential Vitamins and Minerals: B vitamins, and a good multimineral with magnesium, manganese, and copper provide mitochondrial co-factors.
MitoNR (Designs for Health): 2x/day. Nicotinamide riboside (NR) supports mitochondrial function by boosting levels of NAD+, a crucial molecule involved in energy production and cellular health.
Mitoprime: 1x/day (Xymogen). Contains L-ergothioneine, which combats oxidative stress and helps regenerate glutathione.
Fiber, like MGP-Fiber, one scoop a day (Orthomolecular): Fiber supports a healthy microbiome and increases anti-inflammatory short chain fatty acids.
Urolithin A: This is a natural compound produced in the gut when bacteria break down ellagitannins and ellagic acid, found in foods like pomegranates, berries, and nuts. It’s a post-biotic created by your gut microbiome. Some individuals prefer to take it as a supplement (Mitopure, 500 mg, 2x/day). I eat lots of organic berries!
Other Lipid Replacement Therapy: I use Bio PC Pro (Orthomolecular) one scoop 2x/day to push toxins out of the cell membranes during mold detoxification, as well as Xymogen’s Phosphaline 4:1 with phosphatidylcholine. See this link:
Acquired mitochondrial disorders are common due to multiple overlapping causes of inflammation affecting all of us, and the diet, exercise and nutraceuticals I’ve listed are part of my daily routine. There are also new cutting edge techniques for genetic mitochondrial disorders that recently made headlines. See below:
Eight healthy babies were born in the UK using this new IVF technique that successfully reduced their risk of inheriting genetic mitochondrial diseases from their mothers. This breakthrough gives hope to women with mitochondrial DNA mutations that they could one day have children without passing on the debilitating or fatal mitochondrial diseases to the children!
We are making progress…Wishing you excellent health and longevity!