Part III: Long COVID and Mitochondrial Dysregulation

In parts one and two of this series, we looked at the issues related to long COVID and its impact on the nervous and the immune systems. The effects of COVID-19 on the nervous system can present as localized effects such as loss of smell and taste to chronic fatigue, headaches, postural orthostatic tachycardia syndrome, and cognitive issues. The potential to trigger an autoimmune reaction is a very real possibility with any infection and is stimulated by molecular mimicry, bystander activation, and viral persistence. The presence of a healthy and diverse gut and lung microbiome helps to regulate the immune system and supports a robust and balanced innate immune response.

The most common reported symptom of long COVID is fatigue and the overall symptom picture resembles that of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), which is often triggered by a viral infection. Fatigue can be described as lack of energy; and when we think of energy production, we think of the mitochondria. In addition to being the powerhouses of the cell, mitochondria are also involved in maintaining cell immunity, homeostasis, cell survival, and cell death. Mitochondria also play a role in cell apoptosis (programmed cell death), calcium signaling, regulation of cellular membrane potential, and steroid synthesis [1]. SARS-CoV-2 hijacks the mitochondria and uses it for protection and viral replication, diverting resources from supporting normal cellular function to now serving as a viral factory.

Decreased mitochondrial function means less cellular energy, resulting in generalized fatigue, muscle weakness, and brain fog on a broader scale. In part three of this series, we will explore the effect of viral infection on mitochondrial function, how SARS-CoV-2 specifically affects mitochondria, resulting in symptoms of long COVID and what we can do to support mitochondrial function to prevent the long-term effects of COVID-19.

Basic Overview of Mitochondrial Function

Mitochondria are responsible for the majority of energy production in the form of adenosine triphosphate (ATP), which is readily used by cells as a source of chemical energy. Cellular respiration is the process by which mitochondria produce chemical energy from glucose. Through the process of glycolysis, one molecule of glucose is converted to two molecules of pyruvate, two molecules of nicotinamide adenine dinucleotide (NADH) and two molecules of ATP. The pyruvate enters the mitochondria where it is converted into acetyl-coenzyme-A, which enters the tricarboxylic acid (TCA or Krebs) cycle and produces two additional molecules of ATP. The energy-rich products of the TCA cycle, NADH and flavin adenine dinucleotide, undergo oxidative phosphorylation (OXPHOS) via the electron transport chain (ETC), producing water and 32 additional molecules of ATP. The entire process of cellular respiration results in approximately 36 molecules of ATP to support cellular energy needs [2].

The process of glycolysis, which is the first step in cellular respiration, occurs in the cytosol of the cell. If there is enough oxygen available for cellular respiration, the process of energy production will advance to the TCA cycle and OXPHOS along the ETC. However, if oxygen is low, glycolysis results in the production of two molecules of ATP and lactic acid. Anaerobic glycolysis can occur for quick energy production during extreme exercise or illness where oxygen delivery to cells is deficient. The reliance on anaerobic glycolysis as a means of energy production can result in fatigue and muscle pain due to the buildup of lactic acid [2].

Another form of energy production is through aerobic glycolysis also known as the Warburg effect. Once thought to occur solely in cancer cells, aerobic glycolysis may occur in specific immune cells in response to signaling events and the physiological environment. In the field of immunometabolism, it has been observed that metabolic shifts in immune cells may occur to facilitate specific immune responses, and many viruses induce metabolic reprogramming in host cells similar to the Warburg effect observed in cancer cells to produce a quick and readily available source of energy [3, 4].

Viral Influence on Mitochondrial Function

SARS-CoV-2 hijacks the mitochondria and uses it for protection and viral replication, diverting resources from supporting normal cellular function to now serving as a viral factory.

Under the influence of a viral infection, mitochondria experience a loss of integrity in structure and function and can trigger an immune response that activates the production of inflammasomes, which may contribute to autoimmunity and ongoing inflammatory reactions [5]. Inflammasomes are intracellular proteins that trigger the activation of inflammatory cytokines. Mitochondria play a central role in the host response to viral infection and immunity, and function as a platform for immune signaling by engaging the interferon system, which operates as a liaison between the innate and adaptive immune systems [6]. SARS-CoV-2 has the ability to disable the initial immune response by inhibiting the production of interferons. Reduced interferon production delays the release of natural killer cells and stagnates T cell response. Hepatitis C, hepatitis B, adenoviruses, herpes simplex virus-I, Epstein Barr virus, cytomegalovirus, influenza A and coronaviruses have adaptations that allow them to inhibit the interferon pathway to prolong survival and evade the immune system, leaving them with a greater chance to replicate and spread [6]. Viral influence on mitochondrial activities can lead to altered energy levels by changing mitochondrial density and function, resulting in suboptimal energy output [7].

Mitochondria also produce reactive oxygen species (ROS) as a by-product of the process of oxidative phosphorylation. Once thought to have only harmful effects, it is now known that ROS function as signaling molecules, which increase the production of antioxidants, promote apoptosis, and trigger the production of new mitochondria. Mitochondrial ROS also induce mitochondrial anti-viral signaling (MAVS), resulting in induction of type I interferons, heralded as key regulators of antiviral activity [5]. ROS are a normal product of oxidative phosphorylation and can be neutralized through adequate availability of antioxidants; however, this process can become overwhelmed during infection, when ROS production increases beyond the body’s ability to control the oxidative stress. Infection can also interfere with the energy-producing pathway of the mitochondria, leaving cells and tissues with an energy deficit and an excess of ROS.

SARS-CoV-2 Hijacks Mitochondrial Function

Host response against viral infections depends on optimal mitochondrial function but the presence of SARS-CoV-2 can cause structural and metabolic changes within the mitochondria, interfering with an appropriate immune response. Host cell metabolism and activation of signaling pathways is reprogrammed by SARS-CoV-2 viral proteins [4]. SARS-CoV-2 uses its spike glycoprotein, assisted by host transmembrane serine protease 2 (TMPRSS2), to gain access to cells via the angiotensin-converting enzyme-2 (ACE2) receptor on the host cell. Binding of this receptor by the virus decreases the production of ACE2, which has a regulatory effect on mitochondrial function. Less ACE2 results in less ATP production [6].

Once the virus has entered the cell, viral RNA, RNA transcriptase, and viral open-reading frames (ORFs) enter the mitochondria to hijack and manipulate function. ORFs are segments of DNA or RNA from the virus that code for particular proteins. Viral ORFs interact with mitochondrial proteins to directly manipulate mitochondrial function to evade host cell immunity, suppress immune response, and support viral replication [6]. The presence of the virus also creates stress within the mitochondria, leading to the formation of double-walled vesicles, which give the virus a place to hide and replicate. These vesicles function like portable organelles, taking viral information to the endoplasmic reticulum to further aid in viral replication [6].

SARS-CoV-2 also promotes a metabolic shift to aerobic glycolysis to facilitate viral replication and survival. The Warburg effect appears to be involved in several processes during COVID-19 infection [4]. In response to hypoxia, the Warburg effect is induced in lung endothelial cells, which in the presence of atherosclerosis, can lead to vasoconstriction and thrombosis. Initially, aerobic glycolysis supports the activation of pro-inflammatory pathways that are needed to mobilize defenses against infections; however, a subsequent shift to the OXPHOS pathway is also needed to promote anti-inflammatory pathways that are reparative. Aging, cardiovascular disease, metabolic syndrome, type II diabetes, obesity, hypertension, and chronic kidney disease along with mitochondrial senescence contribute to a state of chronic inflammation, which promotes the Warburg effect and prevents the metabolic transition to OXPHOS to decrease inflammation and initiate repair mechanisms [4].

Aging, Comorbidities, and Mitochondrial Function

Factors that favorably contribute to the takeover of mitochondrial function by the SARS-CoV-2 virus are aging, chronic inflammation, and genetic susceptibility. The aging process results in less mitochondria and lower production of ATP with a decrease in autophagy of mitochondria, which contributes to unregulated inflammasome activity leading to chronic inflammation. The process of aging is marked by the progressive decline in cellular function, which increases susceptibility to age-related morbidity and mortality [6]. One of the hallmarks of aging is mitochondrial dysfunction, which induces senescence and contributes to the process of inflammaging. Senescence occurs when cells lose the power to divide and grow, and inflammaging is the increase in systemic inflammation as one ages. The overall effect reduces mitochondrial capacity by about 50%, resulting in fatigue and muscle weakness [6].

Many of the conditions that are considered comorbidities for SARS-CoV-2 contribute to a state of chronic inflammation. Diabetes, heart disease, obesity, and metabolic diseases are commonly present with mitochondrial dysfunction. Mitochondrial genetic mutations may also be a contributing factor in determining the severity of post-viral sequelae related to mitochondrial function. While there are no studies on the long-term effects of SARS-COV-2 on mitochondrial function, past studies on ME/CFS strongly implicate mitochondrial dysfunction as a central cause of ME/CFS symptoms [8, 9]. A renewed interest in the causes of post-viral syndromes will likely be forthcoming as we progress through this pandemic.

Mitochondrial Issues in Post-Viral Syndromes and ME/CFS

Mitochondria play a central role in the host response to viral infection and immunity, and function as a platform for immune signaling by engaging the interferon system, which operates as a liaison between the innate and adaptive immune systems.

Although no single cause has been associated with ME/CFS, viral infections have often been cited to trigger the onset of this disorder. In the case of SARS-CoV-2 and other viruses, there may be a direct impact on mitochondrial function from the virus itself [10]. The oxidative stress that occurs during an infection can leave mitochondria in a state of dysfunction. The mitochondria of our cells are responsible for the production of ATP and produce 90-95% of the body’s total energy [11]. ATP drives all the necessary chemical reactions in the body and if there is a shortage of ATP production, basic biochemical reactions may not be optimized. As a point of comparison, mitochondrial diseases associated with genetic mutations manifest as fatigue, muscle weakness, and cognitive decline along with waxing and waning energy patterns typical of ME/CFS.

While there are no definitive markers to identify ME/CFS specifically, there are a range of different markers that can be used to assess mitochondrial function including mitochondrial proteins, production of ATP, and oxygen consumption of live plated cells. The earliest evidence of the relationship between ME/CFS and mitochondrial issues was seen in structural changes of skeletal muscle cell mitochondria in peripheral blood mononuclear cells. Also noted was the decrease in OXPHOS and an increase in aerobic glycolysis, resulting in less ATP production in ME/CFS patients as compared to controls. As reported by the Journal of Translational Medicine, Sweetman et al concluded that mitochondrial dysfunction can happen via oxidative damage as might occur during an extreme inflammatory reaction to an infection [12].

In a 2019 article in Mitochondrion, Robert Naviaux, MD, PhD, discusses the cell danger response (CDR) and its connection to environmental health, mitochondrial function, and chronic illness. The CDR is a universal response to environmental threat, stress, infection or injury, and it is the mitochondria that sense and respond to changes in the cellular environment and mediate the regulators of the CDR that signal safety or danger within the cell. Once initiated, the CDR cannot be turned off and must cycle through to completion to effectively resolve the danger response. If the CDR persists abnormally, whole body metabolism, the gut microbiome, and multiple organ systems become impaired and chronic disease can emerge. Previous illness, stress, environmental toxins, chronic inflammatory illnesses, hormonal imbalances, autoimmune disorders, and allergies can impede the process of resolution of the CDR [13]. As much of the CDR is mediated by the mitochondria, supporting mitochondrial function, and employing general habits of good health can support a healthy CDR and potentially resolve chronic illness.

Mitochondrial Support

To offset the production of ROS within the mitochondria, enzymes, and coenzymes such as vitamin E and CoQ10 (ubiquinone) help to remove ROS to prevent damage. If essential nutrients, such as vitamin E and CoQ10 are deficient, removal of the ROS is impaired and damage through oxidative stress occurs. CoQ10 is the only lipid-soluble antioxidant that is produced endogenously in humans [11]. Ubiquinol is the reduced form of CoQ10 and acts as an antioxidant by reducing ROS and regenerating other antioxidants. It is also found in the highest concentration in the most metabolically active tissues such as the heart, liver, and muscle.

If the mitochondria are already in a state of dysfunction due to preexisting health issues and oxidative stress from low-level inflammation, their ability to keep up with energy demands becomes severely compromised.

Deficiencies of CoQ10 can occur with less endogenous production as we age and can be depleted with certain medications like statins to reduce cholesterol. CoQ10 deficiency may also be associated with dysfunctional OXPHOS, which can occur in ME/CFS. A study of 58 ME/CFS participants and 22 healthy controls, showed that the ME/CFS participants had lower overall levels of CoQ10, and their degree of fatigue was associated with a lower concentration of CoQ10 in plasma. It was also noted that ATP levels were significantly decreased while lipid peroxidation was increased, indicating mitochondrial dysfunction [11].

In a study out of Spain, Castro-Marrero et al evaluated the effects of CoQ10 and reduced NADH supplementation on the symptoms associated with ME/CFS. Seventy-three female participants were randomized to either the CoQ10+NADH or placebo group. In addition to improvements in fatigue according to the Fatigue Impact Scale, after eight weeks supplementing with 200 mg of CoQ10 and 20 mg of NADH, participants in the supplement group showed a decrease in oxidative damage, improvement in mitochondrial function, and enhanced energy [14]. CoQ10 and NADH can stimulate energy production by replenishing depleted cellular stores of ATP, and together they can act as free radical scavengers that can reduce lipid peroxidation and DNA damage caused by oxidative stress. Mitochondria are very susceptible to environmental toxins, nutrient deficiencies, and oxidative stress [15]. Additional support for mitochondrial function includes acetyl-L-carnitine, pyrroloquinoline quinone, vitamin C, choline, α-lipoic acid, α-ketoglutaric acid, resveratrol, N-acetyl cysteine, magnesium, and a quality multivitamin and mineral complex. Several professional product lines have mitochondrial support products that include most of the above-listed nutrients.

In Summary

Age and health status prior to infection can be a predictor of outcomes and may help us to determine who will develop long COVID. Metabolic issues associated with aging, obesity, and a sedentary lifestyle are not supportive of mitochondrial health. Viruses can manipulate the energy-producing pathway of the mitochondria to favor glycolysis over OXPHOS. If the mitochondria are already in a state of dysfunction due to preexisting health issues and oxidative stress from low-level inflammation, their ability to keep up with energy demands becomes severely compromised [10]. The hijacking of the mitochondria to serve the needs of the virus structurally and functionally changes the mitochondria, resulting in ongoing inflammation and a reduced ability to support the energy needs of cells. Symptoms such as fatigue and weakness, are often the result of these cellular changes.

COVID-19 long-haulers may experience excessive oxidative damage in response to extreme inflammation generated by the infection; however, poor mitochondrial status and deficiencies in nutrients that are needed to quench ROS may also be prevalent among those who experienced only mild to moderate illness. This might explain why the severity of COVID-19 does not seem to predict who experiences post-viral syndrome or long COVID. Having less metabolic reserve due to stress, inadequate sleep, hypothalamic-pituitary-adrenal (HPA) axis dysfunction, poor diet, chronic inflammation, a constant low level of oxidative stress, and the existence of comorbidities may lead to the development of long COVID even if the acute infection is mild to moderate. 

Assessing Key Markers with ZRT Testing

ZRT Laboratory can offer a number laboratory tests to assess a variety of markers related to inflammation, metabolic health, nutrient status, sex hormones, adrenal hormones, neurotransmitters, heavy metals, and minerals. The CDC suspects about 30% of COVID-19 survivors may go on to develop persistent symptoms after recovery from the acute illness. While the trigger for the onset of post-viral syndromes may be a singular event, the effects are broad and involve multiple systems. As we face the burgeoning issue of long COVID, the approach to treatment will involve addressing inflammation and dysregulation within the CNS, autoimmune issues, mitochondrial function, and hormone and HPA axis dysregulation. In the fourth and final installment on long COVID, we will explore issues related to HPA axis dysfunction and its relationship to post-viral syndrome.

ZRT Tests to Consider

Related Sources


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