As discussed in part one, long covid is a phenomenon which is multi factorial and symptoms experienced are varied but include breathlessness, a cough that won’t go away, joint pain, muscle aches, hearing and eyesight problems, headaches, loss of smell and taste as well as damage to the heart, lungs, kidneys and gut. However, the most common feature is significant fatigue which occurs following infection with covid19, the coronavirus SARS-CoV2. It is estimated that as many as 1.1 million people in the UK may have long COVID and the National Institute for Health Research (NIHR) released a review suggesting it could be multifactorial.
In part one we discussed the pathogenesis underlying this condition, including inflammation (and neuroinflammation), mitochondrial dysfunction, dormant viruses and the damaged caused by infection of Covid19. It also highlighted interventions which should be considered as well as nutrients associated with ameliorating these dysfunctions.
In part 2 we consider further the role of mitochondrial dysfunction. As mitochondria are the power houses of every cell, not only can damaged mitochondria affect energy levels but also the function of any of the body’s cell type, leading to suboptimal function of organ systems, therefore can contribute to multiple symptoms, as seen in long covid patients.
It has been found that long covid has many manifestations which may differ among individuals. One surprise has been that even with moderate COVID patients there are a number who find it difficult to recover. Their exercise tolerance takes a long time to return — 2 to 3 months or even longer. Some patients have residual palpitations and persistent tachycardia without any residual inflammation in the blood. Other symptoms which include neurological headache, myalgia, dizziness, and fatigue are the most common nonspecific symptoms seen in COVID-19 patients. These symptoms range from 30% to 45.5% and are more common as the disease is severe. We aim to investigate the likelihood that damage to the mitochondria may be a major factor both in the short term and in in the persistence of long covid.
It is known that increased severity of Covid19 infections is associated with a cytokine storm leading to hyperinflammation. One consequence of this is iron dysregulation which leads to hyperferritinaemia (high levels of circulating iron in the blood), caused by exhausted dying cells releasing ferritin. These high iron levels can create oxidative stress leading to an increase in reactive oxygen species (ROS). We know that high levels of oxidative stress from ROS damage mitochondrial membranes leading to mitochondrial dysfunction and or autophagy (as discussed in previous).
Although most mitochondria reside in the cytosol of cells, some are “cell-free” where they are found in non-nucleated platelets, extracellular vesicles and in extracellular space. It is thought that increased oxidative stress to platelet mitochondria may play a role in coagulation and therefore thrombus formation. The presence of thrombi, particularly in the lungs, are a consequence of severe Covid19 infection and may contribute to lung damage associated with long covid.
Inflammatory cytokines associated with covid infections, TNFα and IFγ increase mitochondrial oxidation by increasing calcium dependant mitochondrial ROS and genes which induce mitochondrial ROS generation respectively. Further exacerbating mitochondrial dysfunction.
When the mitochondria are oxidised, dysfunctional and/or apoptotic a myriad of problems occur. Firstly, there is reduced mitochondrial oxygen consumption, leading to lipid peroxidation which is associated with many pathologies including endothelial dysfunction and disrupted glucose signalling. Both may be implicated in fatigue and cardiovascular issues which are experienced in long covid.
It has also been discovered that patients with Covid19 have raised cardiolipin antibodies, which are responsible for supporting the membranes of mitochondria therefore leading to further mitochondrial instability and therefore dysfunction.
Therefore, one of the main interventions for supporting long covid is to reduce oxidative stress and support mitochondrial function and hence energy production.
As iron dysregulation appears to be a driver of oxidative stress in covid19 infection, it is prudent to avoid supplementation with high levels of iron. However, if anaemia is present and iron levels are found to be suboptimal this needs to be addressed.
The presence of poor exercise tolerance, tachycardia and palpitations may also give an indication that the cardiovascular and respiratory system are still under stress. Supporting mitochondrial function and ATP production in cardiac tissue may be useful in ameliorating these symptoms.
How can we support mitochondrial function?
Supporting mitochondrial function involves providing mitochondria with the nutrients required for energy production and health and reducing damage caused by oxidative stress from ROS by providing antioxidant support and reducing factors which can lead to excess oxidation.
Nutrients that support chemical energy production by mitochondria:
Benfotiamine (B1) – Co factor in the essential step which converts pyruvate into acetyl CoA
Riboflavin (B2) – Also known as FAD, accepts electrons and donates to the electron transport chain (ETC) in order to produce ATP (energy)
Nicatinomide Riboside (B3) – Also known as NADH (similar to FAD) accepts and donates electrons to ETC in order to produce ATP.
Pantothenic Acid (B5) – carrier of Coenzyme A, essential for Acetyl CoA and therefore energy production
CoQ10 (Ubiqinol) – utilised as a carrier in complex II of ETC. CoQ10 also has antioxidant properties and is found in high concentrations in the head and mid-piece of the sperm. It is considered to promote motility, foster sperm survival and provide optimal energy.
Alpha Lipoic Acid – a coenzyme of pyruvate dehydrogenase and a-ketoglutarate; enzymes responsible for reactions involved in the breakdown of fat and carbohydrate within the mitochondria
Magnesium – binds to ATP and affects its structure making energy more easily available.
All of the above nutrients are directly involved in metabolism reactions which occur in the mitochondria in order to produce energy, any deficiencies of the above nutrients can affect the rate of energy production.
There are other nutrients that are not directly involved in the chemical pathways of metabolism but are however important for energy production and maintaining mitochondrial function such as;
L-Carnitine – plays a vital role in fatty acid metabolism, transporting fatty acids into the mitochondria to be converted into energy and again a deficiency can lead to reduce energy production. Carnitine concentrations have been found to be very high in the epididymis and testes. Studies which have compared fertile and infertile men have found that fertile men have statistically significantly more carnitine in their seminal sample than infertile men. Also low levels of plasma carnitine are associated with infertility.
Omega 3 Fatty Acids – can be incorporated into the mitochondrial membrane, which aids fluidity of the membrane and therefore signalling. Omega 3 fatty acids are also very important for cell and mitochondrial membranes and hence their stability.
We can also help to protect our mitochondria by ensuring that we are consuming adequate levels of antioxidants. The antioxidant of particular importance for the mitochondria is glutathione which is our own intrinsic intracellular antioxidant. Although we are normally able to manufacture our own glutathione, when oxidative stress is in excess or if nutrients that are required to manufacture it are deficient, pathways can become overwhelmed leading to reduced levels of production. Nutrients that support production of glutathione are;
Liposomal Glutathione – this bypasses degradation within the gut and is absorbed directly across the digestive lining and can cross the blood-brain barrier.
N-Acetyl Cysteine (NAC) – regulates synthesis of and is an effective precursor to glutathione. Often used ahead of treatment with liposomal glutathione when there is a high circulating level of ROS, as encourages conjugation and elimination.
Alpha Lipoic Acid – has the ability to induce enzymes required for glutathione synthesis
Selenium – constituent of glutathione and precursor for the production of glutathione peroxidase
Vitamin C – an antioxidant in its own right but also has the ability to regenerate glutathione. Studies have also shown that supplementation can lead to an improvement in viability and motility reduced numbers of abnormal sperm and reduced sperm agglutination.
Other antioxidants have the ability to reduce oxidative stress by neutralising free radicles and could be considered to support mitochondrial function in doing so. These include carotenoids, flavonoids, vitamin E, vitamin A and zinc, this list is not exhaustive. You can ensure that you are obtaining good levels of antioxidants in the diet by:
- Eating a rainbow (different colours of fruit and vegetables contain differing phytonutrients which have antioxidant properties)
- Consume herbs and spices including turmeric, garlic and ginger.
- Include polyphenols found in olives, 70%+ dark chocolate (1-2 squares) and small quantities of red wine.
- Consume antioxidant containing teas such as green tea and roobosh.
D-Ribose – may be useful is it support ATP production by encouraging re-phosphorylation particularly within muscle including cardia muscle it is used effectively in chronic fatigue patients and scan also improve exercise tolerance.
It is also important to consider the way in which excess oxidative stress and occur and therefore reducing sources of oxidation can be useful.
Factors that contribute to oxidative stress include:
- High stress levels
- High sugar diet
- Consumption of trans and hydrogenated fats
- Chemicals from household products, toiletries and cosmetics
Reduction of exposure to the above can help reduce free radicals and oxidative stress.
- Excess inflammation during severe covid19 infection leads to iron dysregulation which contributes to oxidative stress and mitochondrial dysfunction, this potentially is contributing to the development of long covid.
- Poor tolerance to exercise, residual palpitations and persistent tachycardia without any residual inflammation therefore highlighting other pathologies may be at play
- Mitochondrial dysfunction affects every cell in the body and is therefore likely to play a role in long covid, particularly with fatigue as well as neurological dysfunction
- Interventions to support mitochondrial function includes providing essential nutrients utilised by the mitochondria including CoQ10, B vitamins, L-carnitine an alpha lipoic acid.
- Interventions also include anti-oxidant support such as zinc, n-acetyl cysteine, vitamin C and glutathione.
If you have questions regarding the topics that have been raised, or any other health matters, please do contact me (Helen) by phone or email at any time.
Amanda Williams and the Cytoplan Editorial Team
- Abboud H, Abboud FZ, Kharbouch H, Arkha Y, El Abbadi N, El Ouahabi A. COVID-19 and SARS-Cov-2 Infection: Pathophysiology and Clinical Effects on the Nervous System. World Neurosurg. 2020;140:49-53. doi:10.1016/j.wneu.2020.05.193
- Nile SH, Keum YS, Nile AS, Jalde SS, Patel RV (2017) ‘Antioxidant, anti-inflammatory, and enzyme inhibitory activity of natural plant flavonoids and their synthesized derivatives’, J Biochem Mol Toxicol, 32:e22002.
- Textbook of functional medicine. 2008. Institute for Functional Medicine.
- inha R, Sinha I, Calcagnotto A, Trushin N, Haley JS, Schell TD, Richie JP Jr. Oral supplementation with liposomal glutathione elevates body stores of glutathione and markers of immune function. Eur J Clin Nutr. 2018 Jan;72(1):105-111. doi: 10.1038/ejcn.2017.132. Epub 2017 Aug 30. PMID: 28853742; PMCID: PMC6389332.
- Agrawal M, Ajazuddin, Tripathi DK, Saraf S, Saraf S, Antimisiaris SG, Mourtas S, Hammarlund-Udenaes M, Alexander A. Recent advancements in liposomes targeting strategies to cross blood-brain barrier (BBB) for the treatment of Alzheimer’s disease. J Control Release. 2017 Aug 28;260:61-77. doi: 10.1016/j.jconrel.2017.05.019. Epub 2017 May 24. PMID: 28549949.
- Teitelbaum JE, Johnson C, St Cyr J. The use of D-ribose in chronic fatigue syndrome and fibromyalgia: a pilot study. J Altern Complement Med. 2006 Nov;12(9):857-62. doi: 10.1089/acm.2006.12.857. PMID: 17109576.
- Depeint F, Bruce WR, Shangari N, Mehta R, O’Brien PJ. Mitochondrial function and toxicity: role of the B vitamin family on mitochondrial energy metabolism. Chem Biol Interact. 2006 Oct 27;163(1-2):94-112. doi: 10.1016/j.cbi.2006.04.014. Epub 2006 May 1. PMID: 16765926.
Last updated on 26th July 2022 by cytoffice