Mitochondrial Dysfunction + Infertility: Does MTHFR play a role?

Mitochondria are organelles found in most cells that play a vital role in producing energy. They are often referred to as the “powerhouses” of the cell because they are responsible for generating most of the cell’s energy in the form of adenosine triphosphate (ATP) through a process called cellular respiration.

Mitochondria also have their own DNA, called mitochondrial DNA (mtDNA), which is distinct from the nuclear DNA found in the cell’s nucleus. Mitochondria are thought to have evolved from free-living bacteria that were engulfed by early eukaryotic cells in a process called endosymbiosis. This process gave rise to the symbiotic relationship between the mitochondria and the host cell, where the host provides the mitochondria with nutrients and the mitochondria produce energy for the host cell.

What role does Mitochondria have in Fertility?

Mitochondria play a critical role in female fertility, as they are responsible for providing the energy necessary for various processes involved in reproduction.

During oogenesis (the process of egg cell development), mitochondria accumulate in the oocyte (immature egg cell) and provide the energy required for various metabolic processes, such as meiosis and cytoplasmic maturation. Mitochondria also play a critical role in the fertilisation process, as they are involved in sperm motility and the acrosome reaction.

Mitochondrial dysfunction can have a significant impact on female fertility. In fact, the latest research suggests age-related decline in mitochondrial function is the primary reason for decreased oocyte quality and a higher incidence of chromosomal abnormalities in women in their 40’s. 

Mitochondrial DNA mutations and deletions have been associated with several fertility-related disorders, including polycystic ovary syndrome and premature ovarian failure. Furthermore, age-related decline in mitochondrial function has been linked to decreased oocyte quality and a higher incidence of chromosomal abnormalities.

On the other hand, Mitochondria play an essential role in male fertility by providing energy to the sperm cells. The production and maturation of sperm cells require a significant amount of energy, and mitochondria are responsible for generating ATP, the primary energy source for cells. Sperm cells have a high number of mitochondria, which are located in the midpiece of the sperm tail, and play a critical role in powering the flagellar movement required for sperm motility.

Research has also suggested that mitochondrial dysfunction in sperm cells can lead to male infertility. Studies have found that abnormal sperm mitochondrial function is associated with decreased sperm motility, lower sperm count, and reduced fertilisation potential. In addition, mitochondrial DNA mutations in sperm cells have been linked to male infertility and can lead to decreased sperm motility and other abnormalities in sperm function.

Overall, the healthy functioning of mitochondria is crucial for  both male and female fertility and any dysfunction can significantly impact reproductive health.

What are the signs of Mitochondrial dysfunction?

Mitochondrial dysfunction can manifest in many different ways and the signs and symptoms can vary widely depending on the severity and location of the dysfunction. Some signs and symptoms of mitochondrial dysfunction may include:

  1. Muscle weakness, fatigue, and pain
  2. Poor balance and coordination
  3. Difficulty breathing or shortness of breath
  4. Gastrointestinal issues, such as constipation, diarrhoea, or difficulty swallowing
  5. Vision and hearing problems
  6. Developmental delays in children
  7. Seizures and other neurological symptoms, such as headaches, migraines, or tremors
  8. Cardiac issues, such as arrhythmias, cardiomyopathy, and heart failure
  9. Endocrine disorders, such as diabetes or thyroid problems
  10. Immune system dysfunction, including frequent infections

It’s important to note that mitochondrial dysfunction can present differently in different individuals, and the signs and symptoms can overlap with other health conditions. Additionally, some people with mitochondrial dysfunction may not exhibit any signs or symptoms at all. If you are concerned about mitochondrial dysfunction, it’s best to consult with a qualified healthcare professional for evaluation and diagnosis.

What Causes Mitochondrial dysfunction?

There are many factors that can cause mitochondrial dysfunction, including:

  1. Genetic mutations: Mitochondrial disorders can be caused by mutations in the mitochondrial DNA (mtDNA),  in nuclear genes that encode mitochondrial proteins or the genes involved in the metabolism of nutrients needed in the mitochondria.
  2. Environmental toxins: Exposure to environmental toxins such as pesticides, heavy metals, and industrial chemicals can damage mitochondria and impair their function.
  3. Ageing: Mitochondrial function declines with age, and this is thought to contribute to the ageing process.
  4. Poor nutrition: A diet that is deficient in essential nutrients can impair mitochondrial function.
  5. Infections: Certain infections, such as viral infections, can damage mitochondria and impair their function.
  6. Medications: Some medications, such as certain antibiotics and chemotherapy drugs, can cause mitochondrial dysfunction.
  7. Chronic stress: Chronic stress can lead to oxidative stress and inflammation, which can damage mitochondria and impair their function.
  8. Physical trauma: Traumatic injuries can damage mitochondria and impair their function.

What impact can MTHFR variations play?

There is some evidence to suggest that genetic variants in the MTHFR (methylenetetrahydrofolate reductase) gene may affect mitochondrial function, although the exact mechanism is not fully understood.

MTHFR is involved in the metabolism of folate, a B-vitamin that is important for the synthesis of nucleotides, DNA, and proteins. MTHFR converts 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, which is required for the conversion of homocysteine to methionine. Genetic variants in the MTHFR gene can affect the function of this enzyme and may lead to elevated levels of homocysteine in the blood.

Elevated homocysteine levels have been associated with mitochondrial dysfunction, as homocysteine can interfere with mitochondrial respiration and contribute to oxidative stress. Additionally, folate and other B-vitamins are involved in the synthesis of coenzymes that are required for mitochondrial energy production, so deficiencies in these vitamins can also affect mitochondrial function.

MTHFR variations have also been associated with increased amounts of unmetabolised folic acid in the blood. 

There is some evidence to suggest that unmetabolized folic acid (UMFA) may have negative effects on mitochondrial function, although the exact mechanisms are not fully understood. UMFA is a form of folate that is not converted into its active form in the body and can accumulate in the bloodstream.

One study published in the American Journal of Clinical Nutrition found that supplementation with high doses of folic acid, particularly in individuals with specific genetic variants, can lead to accumulation of UMFA and decreased mitochondrial DNA content in skeletal muscle cells. This study suggests that high doses of folic acid may interfere with mitochondrial function by inhibiting DNA synthesis and repair.

Other studies have also suggested that UMFA may have negative effects on immune function, cognitive function, and cancer risk. More research is needed to fully understand the potential effects of UMFA on health and mitochondrial function.

It’s worth noting that folic acid is a synthetic form of folate that is commonly added to fortified foods and dietary supplements. It’s generally recommended to obtain folate from natural dietary sources, such as leafy greens, beans, and whole grains, rather than relying on supplements. 

Carolyn recently authored an article on the topic of excess folic acid. You can read the article here.

Impact of Folate and B12 deficiencies

Both vitamin B12 and folate deficiencies can impact mitochondrial function. These vitamins play important roles in the synthesis of nucleotides, DNA, and proteins, which are required for mitochondrial biogenesis, energy production, and function.

Vitamin B12 is involved in the metabolism of amino acids and fatty acids, which are important energy substrates for the mitochondria. It is also required for the synthesis of methionine, which is involved in the methylation of DNA and RNA. Deficiencies in vitamin B12 can lead to impaired mitochondrial function, as well as a range of neurological, reproductive and hematological symptoms.

Folate is required for the synthesis of nucleotides and DNA, which are required for mitochondrial biogenesis (i.e creation) and function. Deficiencies in folate can lead to impaired mitochondrial function, as well as a range of hematological, neurological, reproductive and cardiovascular symptoms.

Both vitamin B12 and folate deficiencies can lead to elevated levels of homocysteine, an amino acid that has been associated with mitochondrial dysfunction and oxidative stress. Additionally, deficiencies in these vitamins can lead to impaired DNA synthesis and repair, which can contribute to mitochondrial dysfunction.

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