What is Endometriosis?
Endometrial tissue is usually restricted to the uterus. In endometriosis, however, endometrial tissue can grow in locations, including the ovaries and fallopian tubes, as well as in nearby and more distant tissue (bladder, rectum, etc). Consequently, endometrial tissue in these other areas can result in inflammation and scarring. Pelvic pain is usually the main
presenting symptom; being chronic in 50% of patients, with 70% experiencing pelvic pain during menstruation even during ovulation.
Infertility is common, being evident in approximately 50% of people presenting with endometriosis. Between 10% of western women and about 15% of Asian women will experience endometriosis, most typically with a first presentation at 30-40 years, often as a consequence of difficulties in conceiving.
Factors linked to endometriosis pathophysiology include: increased oxidative and nitrosative stress (O&NS), chronic immune inflammation, increased immune tolerance, autoimmunity, t helper (Th)17 cells and interleukin (IL)-17. Estrogen at the estrogen receptor-alpha (ERα) can exacerbate symptoms, with estrogen also having regulatory, symptomatic, effects via the ERβ. As both of these estrogen receptors can be mitochondria-located, there can be significant changes in mitochondria functioning in endometriosis.
As such, endometriosis shows alterations in mitochondrial functioning, oxidative stress regulation and increased trophic factors, linking endometriosis with tumor-associated pathophysiology, meaning it is viewed as a benign cancer.
Endometriosis, like a growing number of other medical conditions, shows alterations in the gut microbiome, especially via a decrease in the short-chain fatty acid (SCFA), butyrate.
What are Mitochondria:
Mitochondria are generally believed to be essential for eukaryotic life. They are termed the powerhouses of the cell as they produce most of the energy or ATP required by the cell. The mitochondria have their own genome (mtDNA) which is replicated independently of the host genome.
Mitochondrial DNA is more susceptible to damage than nuclear DNA, with a 10–20 fold higher rate of mutagenesis than the nuclear genome.
Apart from the mtDNA mutations associated with severe disease, an accumulation of mtDNA mutations has been associated with aging and age-related diseases such as neurological disorders, metabolic diseases and with several cancers.
One of the main producers of mtDNA damage is lesions due to oxidative damage and these lesions can be repaired by DNA repair pathways.
The major role of mitochondria is to generate ATP for the cell. This process relies on OXPHOS and a by-product of this process is the generation of ROS. ROS are generated almost entirely by OXPHOS (about 90%).
Mitochondrial dysfunction in endometriosis:
A number of microRNAs show alterations in endometriosis, including miR-7, miR-375 and miR-451, all of which regulate the melatonergic pathways and mitochondria functioning. Decreased miR-375 is evident in endometriosis ectopic stromal cells. Decreased miR-375 is linked to raised 14-3-3ζ levels and therefore to 14-3-3ζ-mediated arylalkylamine N-acetyltransferase (AANAT) stabilization and NAS synthesis at the start of the melatonergic pathway.
Likewise, miR-451 and miR-7 also negatively regulate 14-3-3ζ, with a downregulation of these miRNAs evident in endometriosis and endometriosis-associated ovarian cancers. Such alterations in miRNA-driven changes 14-3-3ζ-mediated melatonergic pathway initiation may also link to the data showing ectopic endometrial stromal invasion in endometriosis is 14-3-3ζ dependent.
This suggests that these miRNAs have a role in coordinating initiation of the melatonergic pathways, and therefore NAS synthesis and associated TrkB activation, with the proliferation and invasion in endometriosis, possibly priming the transition to ovarian cancers.
As the data above indicate, there are a plethora of pathophysiological changes in endometriosis. And most likely, many of these factors come into play in individual cases. Although the feminizing and some tumor effects of estrogen are mediated via ERα, the relevant effects of estrogen endometriosis may be mostly driven by mitochondria-located ERβ. In other cells ERβ forms a complex with glucose regulated protein (Grp)75, which is a mitochondria matrix chaperone. Once within the mitochondrial matrix ERβ-Grp75 complex is stable and drives a significant increase in mitochondria ATP production and alters mitochondria DNA gene expression.
There is a dramatic increase in mitochondria-located ERβ in ectopic endometriotic tissue well as in estradiol-primed endometriotic cells, which show heightened mitochondria bioenergetics coupled lower ROS, at least partly mediated by raised SOD2 levels. Heightened mitochondria ERβ levels increase migratory activity, which is attenuated by mitochondria respiration inhibition. Such data highlights the importance of mitochondria in the biological underpinnings of endometriosis, including in the changes linked to increased peritoneal estrogen levels.
Although vitamin A and retinoic acid metabolites can modulate mitochondrial functioning per se, ATRA (anti proliferative activity) can not only decrease the raised levels of peritoneal estrogen evident in endometriosis, but can also decrease levels of mitochondria ERβ in endometriotic tissue. Dysregulation of the retinoic acids, including from increased CYP26, may therefore determine the mitochondria and estrogen changes occurring in endometriosis. Such changes are likely correlate with gut dysbiosis and decreased levels of butyrate production (either from decreased vitamin A, or high circulating pro-inflammatory cytokines, or from pain-associated stress), with correlated consequences arising decrease butyrate’s immune, mitochondria and melatonin regulatory effects.
Heightened pro- and anti-inflammatory cytokine levels in endometriosis will differentially modulate the levels of activity of different immune cells, including mast cells and macrophages as well as t-cell patterning. Raised peritoneal macrophage levels are evident in endometriosis, with ERβ activation in endometrial stromal cells, leading to M2-macrophage recruitment.
Increased estrogen and mitochondria ERβ, via macrophage recruitment, may be seen as an attempt to dampen inflammation, complicated by the changes in endometrial nerves. Autocrine and paracrine effects of melatonin are crucial in shifting macrophages from a M1- M2-like phenotype, suggesting that changes in the melatonergic pathways, including within the mitochondria macrophages and neighboring cells, may be important to the nature of the immune responses in endometriosis.
The raised stress and pain levels commonly experienced in endometriosis, coupled to increases in pro-inflammatory cytokines, are highly likely to increase gut dysbiosis and permeability. It will be important to determine when this occurs, including any priming role for pre- and post-natal processes and/or whether it is secondary to symptomatic stress and pro-inflammatory cytokine induction. Lower butyrate levels, and its associated HDAC inhibition, drive these gut-associated changes, including a host of processes relevant in endometriosis pathophysiology, including mitochondria, immune, melatonin and ATRA regulation. Any role for the uterine microbiome has still to be investigated, including any possibility of a gut-uterine axis that could link alterations in butyrate to cellular processes acting to regulate the uterine microbiome.
Overall, it is clear that much of the pathophysiology of endometriosis is intimately associated with the regulation of mitochondria functioning across a host of cell types and systems. Many of the classical changes in endometriosis intimately linked to alterations in mitochondria functioning, including changes in estrogen ERβ, adiponectin, melatonin and vitamin A. Such processes are also relevant to the pathoetiology of endometriosis.
What to do to improve our mitochondria:
- Sunbathing
- Red light therapy
- Mitochondrial supplements like MitoATP, PQQ, CoQ10, NAD IVs, NADH orally, Alpha Lipoic Acid, Acetyl L Carnitine, Carnosine, Malic acid, etc
- Detoxification, treat MOLD, heavy metals, parasites, Lyme and Coinfections
- Coffee enemas
- Meditation
- Daily movement
- Sleep 8h a day
- Intermittent fasting
- Glucose stability through the day
- Anti-inflammatory diet