Mitochondria Dysfunction. What Causes Long COVID? Part 3
Top 23 Potential Causes of Long COVID (LC) and other post viral infections: our mitochondria are compromised.
Years ago a single mitochondria joined with another single-celled organism in a process called endosymbiosis. Both organisms benefited from the arrangement. The mitochondria received food to make into fuel while the other cell received a bountiful source of energy.
Now, we, and most other life forms on earth, depend on mitochondria for the majority of our energy. Mitochondria live in us but they have their own separate DNA called mtDNA. You inherit your mitochondria from your mom.
Mitochondria supply us with energy in exchange for carbohydrates, fats and proteins. They make around 90% of the energy we use. So what happens if they are compromised?
Viral damage to mitochondria
Viruses can take over mitochondria and steal away the energy meant for us. Indeed some viruses may alter both mitochondrial activities and mtDNA of host cells (Gay et al. 2024).
Even after the viral infection is treated mitochondria DNA may remain damaged and listless, unable to produce sufficient energy for life. Damaged mtDNA can increase production of reactive oxygen species (ROS). ROS can damage cells and tissues. Excess ROS produced by dysfunctional mitochondria can further damage mtDNA creating a vicious cycle.
Mitochondrial impairments particularly affect the tissues with high-energy demand such muscles and brain.
In this installment of How the Long COVID Turns:
17) Your mitochondria are sickly weaklings.
18) Ill mitochondria invade the immune system to cause inflammation.
Why are your mitochondria so feeble?
Read the first and second thrilling installments in What Causes Long COVID? Part 1: Immune System Glitches and Part 2: Beyond the Immune System.
Blue Box of Science: What makes your mitochondria so feeble in Long COVID?
a) SARS-CoV-2, the virus that causes COVID-19, triggers a massive inflammatory response once it gets all cozy in the cell. This causes infected mitochondria to increase their production of reactive oxygen species (ROS). ROS are highly reactive chemicals made from oxygen; they are a by-product of cell metabolism. ROS can be helpful or harmful depending on the amount and the situation.
In this case, excess ROS prompts more pro-inflammatory cytokine and ROS production leading to a cytokine storm of inflammation. Your mitochondria have to switch from making energy (ATP) to ROS production. This means LESS energy and MORE inflammation.
In long COVID these mitochondria dysfunction may persist. SARS-CoV-2 can directly infect mitochondria and integrate their viral genome into mitochondrial DNA. This could decrease mitochondrial energy metabolism by affecting oxygen availability and utilization (Stefano et al. 2022). It damages mitochondria and causes their membranes to become more permeable which leads to cell death (apoptosis) (Saleh et al. 2020).
b) Inflammasomes are activated in the immune system. Once mitochondria are compromised, the virus can go on to activate inflammatory pathways, including inflammasomes, which are part of the innate immune system. Inflammasomes are large multiple protein complexes that live in the cell cytosol and self assemble when they sense infection or cellular stress (Dai et al. 2023). Activation of inflammasomes under the wrong conditions can lead to dysregulation of inflammasome assembly. In other words, the proteins are not put together correctly; the box picture shows a drilling rig but your body built a Jackson Pollock painting instead.
This failure to put together inflammasome proteins in the correct order is implicated in multiple diseases; including chronic inflammatory disorder, infectious diseases, and cardiovascular disorders (discussion in Dai et al. 2023). This disfunction can suppress both your innate and your adaptive immune responses.
c) Endoplasmic reticulum (ER) is stressed out. Due to excess ROS production and inflammation, coronavirus infection also causes endoplasmic reticulum (ER) stress inside the cells (Sureda et al. 2020, Georgina et al. 2023). The rough endoplasmic reticulum is a cell organelle that makes proteins, transports proteins, and folds proteins. When it is stressed, protein folding is either inhibited or done incorrectly. Improperly folded proteins are usually nonfunctional or low functioning. Since protein make everything from enzymes to cell membrane channel transport gates this is a big deal which can influence many body systems.
d) Energy production is decreased. Chronic fatigue in people with Long COVID is directly linked to problems in mitochondrial ATP production. People with LC have a lower ATP plasma level (Saito et al. 2024).
Fifty women and men with Long COVID (average age 50) exercised to exhaustion on a bicycle. VO₂ max, a measure of oxygen absorbed and used in the body during exercise, was normal in 34 people and reduced in 16 patients. However, lactate levels were increased early in the exercise process and there was reduced fatty acid oxidation. These are signs of mitochondrial dysfunction; the cell's powerhouse is unable to make energy as efficiently as it should (de Boer et al. 2022).
e) Fewer new mitochondria. There may be impaired mitochondrial biogenesis, the growth and division of mitochondria, due to impaired amino acid and nitrogen metabolism (discussion in Saito et al. 2024). This means less baby mitochondria!
f) Covid-19 downregulates mitochondria genes. Mitochondrial function is reduced during and after SARS-CoV-2 infection. The viral proteins bind to mitochondrial proteins and seem to inhibit oxidative phosphorylation (OXPHOS) while stimulating glycolysis. Oxidative phosphorylation, the metabolic process mitochondria use to generate energy, is impaired in organs like the liver, heart, kidney, and lymph nodes even after people have no signs of the COVID-19 virus (Guarnieri et al. 2023).
Yehuda Pen. Sleeping man with a Book 1900s.
17) Your mitochondria, which make over 90% of the energy for your body, are sick and weak:
Do you have chronic fatigue? When your mitochondria are sick, your energy levels plummet! Think of energy as your body's currency. Without energy you cannot buy or make the supplies you need to keep your system healthy.
*Lee Z. (50 something year old woman): "The worst thing for me is feeling constantly tired. I feel like I always need a nap and it is hard to get the energy to do anything. I used to have so much energy but is is gone now."
Konstantin Somov - Lady with the dog relaxing on the lawn before 1939.
Mitochondria are more than just power plants though; they are players in immune response modulation; oxidative stress; apoptosis (programmed cell death); inducing cellular senescence (when the cell's growth is stopped due to stress or other factors); and maintaining cellular and systemic homeostasis.
Just to repeat this important point: Your mitochondria make over 90% of your energy! If they are sick your energy levels plummet.
So what happens to your mitochondria in Long COVID? Mitochondrial dysfunction (the mitochondria get weak and stop working very well) is a major contributor to Long COVID symptoms. These include breathing dysfunctions, cognitive disturbances (brain fog), fatigue and muscle weakness, and cardiac symptoms (discussion in Molnar et al. 2024).
Mitochondrial dysfunctions occur through mechanisms such as inflammation and oxidative stress; immune system dysregulation; vascular and endothelial dysfunction; energy production deficits; and other metabolic disruptions including less mitochondria biogenesis (less baby mitochondria).
18) Mitochondria can prompt innate immune responses that increase inflammation.
Long COVID is highly correlated with inflammation and a dysfunctional immune response. People with Long COVID (LC) often show systemic inflammation, immune dysregulation, and decreased organ function (Madsen et al. 2024, Yin et al. 2024). In addition, decreased organ function is associated with mitochondrial dysfunction both during and after COVID-19 infection (discussion Madsen et al. 2024).
So where do mitochondria fit into this picture? When mitochondria spot dangerous invaders, they activate the innate immune system by using pattern recognition receptors (PRRs) (Madsen et al. 2024). PRRs are a type of receptor that recognizes specific molecular structures/chemicals that are found on the surface of pathogens like viruses or bacteria; called pathogen-associated molecular pattern (PAMP); or on damaged or dying cells; called damage-associated molecular patterns (DAMP). Think of PRRs as a combination of bouncers/medics - reading people's ID cards and checking them for injuries. If a dangerous individual or an injured person is detected, PRR sounds the alarm.
There are several types of PRRs including Toll-like receptors (TLRs). Membrane bound TLRs recognize the COVID-19 virus's (SARS-CoV-2) envelope, spike protein and viral RNA. TLRs are potent. They can help destroy viruses but they can also contribute to dysregulated immune functioning (Mantovani et al. 2023).
So far, so good right? But (you knew there was a but coming), immune system activation is not always a good thing.
An immune system on high alert responds with extreme violence. Put simply, the immune system responds to threats by ramping up inflammation. If the resulting inflammation is not tightly regulated it causes hyperinflammation and cytokine storms. Cytokine storms, seen in severe cases of COVID-19, are when the immune system panics and releases an excessive amount of inflammatory chemicals (cytokines). This can cause severe symptoms, organ damage, mutiple organ failure, and even death.
Did you miss the first two installments of this exciting saga?
Part 1 includes six exciting reasons your immune system may be doing you dirty after COVID:
- 1) The virus is still present and causing problem.
- 2) Your immune cells quit in mass.
- 3) Zombie virus already laying latent in your body rise up.
- 4) Immune system went full on crazy after COVID infection and started packing heat.
- 5) You start making autoantibodies that attack yourself.
- 6) Your immune system is dialed up to 150%: The interferon pathway story.
Sleeping puppy by Petrov-Vodkin (1916, priv.col).
*Names and some minor identifying details in all stories in this website are changed to protect people's privacy.
This information in this website is for informational purposes only and does not constitute medical advice, diagnosis, or treatment.
Part 2 dives into nine new and novel ways COVID-19 can screw up your heath:
- 7) COVID causes your blood to turn into sludge with abnormal blood clotting.
- 8) COVID-19 infection changes how RNA is built.
- 9) Long COVID drains your energy due to metabolomic and immune disturbances.
- 10) COVID-19 suffocates your tissues by cutting off your oxygen supply.
- 11) Don't stress though; stress makes getting Long COVID worse.
- 12) COVID decreases cortisol causing weakness and depression.
- 13) Your body is freaking out! The virus causes Autonomic Nervous System (ANS) dysfunction.
- 14) COVID hammers your gut bacteria.
- 15) Your hypothalamus-pituitary-adrenal axis (HPA axis) is disrupted.
- 16) Endothelial dysfunction drives oxidative stress and inflammation.
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