Coenzyme Q10 and Its Therapeutic Potencies Against COVID-19 and Other Similar Infections: A Molecular Review

Purpose: New lethal coronavirus disease 2019 (COVID-19), currently, has been converted to a disastrous pandemic worldwide. As there has been found no definitive treatment for the infection in this review we focused on molecular aspects of coenzyme Q10 (CoQ10) and possible therapeutic potencies of CoQ10 against COVID-19 and similar infections. Methods: This is a narrative review in which we used some authentic resources including PubMed, ISI, Scopus, Science Direct, Cochrane, and some preprint databases, the molecular aspects of CoQ10 effects, regarding to the COVID-19 pathogenesis, have been analyzed and discussed. Results: CoQ10 is an essential cofactor in the electron transport chain of the phosphorylative oxidation system. It is a powerful lipophilic antioxidant, anti-apoptotic, immunomodulatory and anti-inflammatory supplement which has been tested for the management and prevention of a variety of diseases particularly diseases with inflammatory pathogenesis. CoQ10 is a strong anti-inflammatory agent which can reduce tumor necrosis factor-α (TNF-α), interleukin (IL)- 6, C-reactive protein (CRP), and other inflammatory cytokines. The cardio-protective role of CoQ10 in improving viral myocarditis and drug induced cardiotoxicity has been determined in different studies. CoQ10 could also improve the interference in the RAS system caused by COVID-19 through exerting anti-Angiotensin II effects and decreasing oxidative stress. CoQ10 passes easily through blood–brain barrier (BBB). As a neuroprotective agent CoQ10 can reduce oxidative stress and modulate the immunologic reactions. These properties may help to reduce CNS inflammation and prevent BBB damage and neuronal apoptosis in COVID-19 patients. Conclusion: CoQ10 supplementation may prevent the COVID-19-induced morbidities with a potential protective role against the deleterious consequences of the disease, further clinical evaluations are encouraged.


Introduction
After the report of the first case of coronavirus disease 2019 (COVID-19) on 31 December 2019 in China, 1 the virus rapidly spread worldwide. The World Health Organization (WHO) officially declared COVID-19 as pandemic on 11 March 2020 and millions of people have so far died from the disease. 2 Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, and the previously known viruses SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV) are known to cause threatening epidemics with severe clinical features that mostly involve the respiratory system. 3 Coronaviridae family consists of enveloped viruses containing large positive-sense singlestranded RNA genomes which is restricted within a protein capsid and their envelope is covered with glycoprotein spikes in the shape of crowns. 2 The spikes contain receptor binding domains and facilitate the attachment and replication of the virus. 4 Angiotensin converting enzyme 2 (ACE2) is known as the mutual receptor for SARS-CoV-2 and its similar ancestor SARS-CoV. 5 ACE2 is considerably expressed in the lung epithelium, and its possible role in the pathogenesis of COVID-19 has been suggested in different studies. 6 COVID-19 is currently considered the greatest health threat internationally and there is yet no definitive treatment for the disease. Therefore, current management policy has been mainly focused on the preventive and supportive approaches. 1 As the virus continues to rapidly spread and infect millions of people, the urge to find a definite treatment intensifies and great research attempts are being conducted to solve this global concern.
Coenzyme Q 10 (CoQ 10 ) is a natural lipid soluble electron transporter found in the mitochondrial membrane. It is an essential cofactor in the electron transport chain of the phosphorylative oxidation system. This coenzyme molecule could undergo oxidation/reduction reactions, 7 and act as a powerful lipophilic antioxidant, anti-apoptotic, immunomodulatory and anti-inflammatory supplement which has been tested for the management and prevention of a variety of diseases specially diseases with inflammatory pathogenesis. 8 The role of CoQ 10 supplementation in heart failure and neurodegenerative diseases has been well established. 8,9 Other clinical applications of CoQ 10 have been tested in several clinical trials on patients with inflammatory diseases such as rheumatoid arthritis, fatty liver and diabetes. CoQ 10 supplementation has presented ameliorative effects on serum inflammatory markers. 10 Moreover, studies on critically ill and intensive care unit (ICU) patients have revealed a severe depletion of CoQ 10 levels. It may indicate that CoQ 10 supplementation solely or in combination with other micronutrients like carnitine and selenium could have a considerable positive effect on disease progression and treatment outcomes. 11 Recent studies on CoQ 10 revealed the immunomodulatory effects of this coenzyme, [12][13][14] especially in the context of viral disorders. In fact, the systemic inflammation and hypercytokinemia caused by acute viral infections may become suppressed by immunomodulatory and antiapoptotic properties of CoQ 10 . [15][16][17] Accordingly, some studies had reviewed the potential role of CoQ 10 and other mitochondrial nutrients as therapeutic options against the systemic inflammation and mitochondrial dysfunction in COVID-19. Polymeropoulos 18 in a brief opinion had reviewed the anti-inflammatory effects of CoQ 10 in various clinical situation and encouraged further researches for assessing the correlation between the levels of CoQ 10 in human body and the outcomes of COVID-19. In another comprehensive review by Pagano et al 19 the evidences supporting the role of mitochondrial nutrients, such as α-lipoic acid, CoQ 10 and carnitine, against acute and chronic inflammatory conditions were summarized. in this review we aimed to discuss the molecular aspects of CoQ 10 supplementation against COVID-19. Herein, rather than the anti-inflammatory properties of CoQ 10 , we described other various pathways that CoQ 10 supplementation could affect the disease pathogenesis including; antiviral, gene expression regulatory, immune modulatory, neuroprotective and cardiovascular protective properties of CoQ 10 . In addition, the role of CoQ10 supplementation in clinical setting particularly in critically ill patients was reviewed from a molecular point of view.

Materials and Methods
The current study is a narrative molecular review. Some authentic resources including PubMed, ISI, Scopus, ScienceDirect, Cochrane, and some preprint databases such as Arxiv were searched within 2000-2021. Some sensitive keywords were used to find the most relevant articles, such as molecular, CoQ 10 , viral infection, COVID-19, SARS, and corona virus infection. Finally, the selected full-text articles were reviewed and using thematic analysis, the molecular aspects of CoQ 10 potencies against COVID-19 and other similar viral infections have been analyzed.

Molecular basis of SARS-CoV-2 infection and consequent clinical characteristics of the disease
binding of SARS-CoV-2 spike to transmembrane ACE2 is not only the first step in pathogenesis of COVID-19 but also is the most fundamental. In fact, the RNA entrance, replication and consequent cell damage is not the only pathologic concern of COVID-19. 20 As mentioned, the viral spike protein has a strong affinity to ACE2 and this is the key point of protein interaction and further deleterious clinical and pathological properties of COVID-19. 21 ACE2 is a transmembrane enzyme producing angiotensin (1)(2)(3)(4)(5)(6)(7) and a heptamer opposing the action of angiotensin II (AngII), which is correlated with the pathogenesis of several diseases like cardiovascular, renal and fibrotic diseases. Further studies about AngII revealed that besides its vasoconstrictor effect, the immunologic, inflammatory, fibrogenic and leukocyte migratory effects are also considerable aspects of this molecular axis. AngII signaling pathway is transmitted through two G-proteincoupled receptors called AT 1 and AT 2 . The most concerns is about ACE/AngII/AT 1 route through which a variety of AngII adverse effects including: (1) oxidative stress production specially through NADPH oxidase enzyme upregulation, (2) inflammatory response by the activation of NF-κB translation factor and consequent tumor necrosis factor-α (TNF-α) and interleukin (IL)-6 production, (3) activating the leukocyte migratory pathway through increasing both the endothelial adhesion molecules like VCAMs and cell adhesion molecules on leukocytes, (4) contributing to endothelial dysfunction and (5) increasing the risk of arrhythmia and fibrosis through activating the proliferating pathways of fibroblasts and smooth muscle cells. 22 Given the fact that these effects are all opposed by angiotensin (1)(2)(3)(4)(5)(6)(7) , 23 the pathophysiology of SARS-CoV-2 becomes easy to understand. The viral spike protein interaction suppresses the inhibitory effect of ACE2 on the AngII system and consequently over-activates AT 1 resulting in a propagated systemic inflammation and hypercytokinemia accompanied by immense oxidative stress in affected organs. 20 Current studies show that the secondary hemophagocytic lymphohistiocytosis as an hyperinflammatory status, which leads to hypercytokinemia, is a common reason for death after a multiorgan failure in patients infected by COVID-19. 24 These events are characterized by a cytokine storm due to the fulminant increased cytokines includes IL-2, IL-7, granulocyte colony stimulating factor, interferon-γ, inducible protein 10 (IP-10), monocyte chemo-attractant protein 1 (MCP1), macrophage inflammatory protein 1-α (MIP-1α), and TNF-α. 25 In another recent work, it was demonstrated that the CD4 + and CD8 + T cells counts in the patients with severe form of COVID-19 had been reduced in negative correlation with increased IL-6, IL-10 and TNF-α, suggesting the apoptotic effect of these factors on T cells. 26 It was also demonstrated that the apoptotic pathway triggered by IL-10, IL-6 and TNF-α passes through mitochondrial stress which is pursued by the activated caspase-9 and caspase-3. 27 The mentioned two phenomena, systemic inflammation and oxidative stress, are the main causes of almost all clinical events in COVID-19. Pneumonia in COVID-19 is not only due to the pulmonary epithelium infection but also the increased vascular permeability, leukocyte migration and vascular hyper-inflammation play an undeniable role in the pathophysiology of the disease. 28 The pathophysiology of cardiovascular effects of COVID-19 is not completely understood, but most researchers consider cytokine storm and myocardial inflammation as the key contributors to the events. 29 In very recent and novel studies, the neuro-infective properties of SARS-CoV-2 have been discussed. [30][31][32] Steardo et al 30 postulated that like SARS, MERS and other members of Coronaviridae, SARS-CoV-2 could infect the CNS and PNS causing neurologic impairment. The suggested mechanism of neuroinfection in COVID-19 is hematogenous and retrograde neuronal rout invasion to CNS. Furthermore, the systemic inflammatory state could cause the neuronal damage as made in many neuro-degenerative diseases. The first study about neurological involvement in COVID-19 patients ran in Wuhan, China, reported the neurological impairment and complications including: impaired consciousness, hyposmia, hypogeusia, dizziness, headache, and cerebrovascular accidents in severely ill patients, concluding that CNS and PNS involvement are signs of poor prognosis of the disease. 31 Li et al 33 discussed the association of respiratory failure with neuro-invasiveness of SARS-CoV-2 and demonstrated that viral invasion to the medullary cardiorespiratory centers through the root of mechanoreceptors and chemoreceptors in lower respiratory tract could cause respiratory failure in severely ill patients. (Figure 1).

Biochemical and pharmacological characteristics of coenzyme Q₁₀
In 1957 Crane et al 34 reported the first time a quinone found in oxidized and reduced forms. Coenzyme Q₁₀ or CoQ₁₀ (2, 3dimethoxy-5methyl-6-decaprenyl benzoquinone) is a lipophilic vitamin-like compound which is also known as ubiquinone (oxidized) or ubiquinol (reduced). The chemical structure ( Figure 2) consists of a benzoquinone ring connected to a long side chain containing 10 isoprene units. 35 CoQ₁₀ is endogenously Figure 1. The potential protective effects of coenzyme Q 10 against COVID-19: CoQ 10 is an essential co-factor in electron transport chain of the phosphorylation oxidative system. Because of its lipophilic anti-oxidant power, it has potential ability for regenerating the VitE and VitC. Moreover, the anti-angiotensin 2 effect of CoQ 10 improve the RAS activity which is upregulated in COVID-19. The anti-apoptotic, immunomodulatory, and anti-inflammatory effects of CoQ 10 have been also confirmed through reducing TNF-a, IL-6, and CRP. The cardiovascular protective effects of CoQ 10 have been also determined, such as improving viral myocarditis and using in drug induced cardiotoxicity. Moreover, CoQ 10 has some protective effects in CNS. It can pass easily through BBB, reduce oxidative stress, and modulate the immunologic reaction. BBB: Brain blood barrier. synthesized from mevalonic acid and phenylalanine. 36 CoQ₁₀ is a well-defined physiological component of the mitochondrial respiratory chain which supports the generation of energy in the form of ATP by converting the energy in carbohydrates and fatty acids into the energyrich adenosine triphosphate. 37 It also reduces oxidative and nitrosative stress by decreasing the superoxide radicals and interfering with the production of peroxynitrite. CoQ₁₀ exists in two forms in the body: reduced form also known as ubiquinol is used by the body as an endogenous antioxidant, and oxidized or ubiquinone form is an electron carrier during mitochondrial respiration. 38 Due to several features including solubility in lipid and its role in the inhibition of lipid peroxidation, CoQ₁₀ is a very effective antioxidant against the radicals produced in the biological membranes. 39 Since the quinol form of the coenzyme Q is present in cell membranes more than the other form, it can be a very efficient antioxidant. Some enzymes such as NADH cytochrome b5 reductase, NADPH coenzyme Q reductase and NADH/NADPH oxidoreductase are effective enzymes which can keep the coenzyme Q reduced in plasma and endomembranes. 40 Recent studies show that CoQ₁₀ has numerous other roles including: gene expression modifying, protection of membranes and lipoproteins from protein oxidation and lipid peroxidation, and cell signaling. Therefore, these vital roles led us to its clinical application, especially in energy-demanding tissues involved by the disease, such as heart and liver. 41,42 CoQ₁₀ is expressed in all tissues. The body is not normally dependent on exogenous sources of CoQ 10 , but its biosynthesis is decreased with age and also many critical conditions in which the serum and tissue levels of this coenzyme are reduced by oxidative stress. In such conditions, exogenous CoQ₁₀ is required to maintain the normal blood and tissue levels. 43 CoQ₁₀ is absorbed as a lipophilic substance and its uptake increases with high fat food. The main absorption is in the small intestine without any specific receptors. In circulation, CoQ₁₀ is reduced to ubiquinol and then taken up rapidly by the liver where CoQ₁₀ is incorporated mostly into very lowdensity lipoprotein (VLDL)/low density lipoprotein (LDL) particles. CoQ₁₀ supplements have poor bioavailability in oral administration due to their insolubility in water and high molecular weight. 44 CoQ₁₀ metabolism has not been well studied in humans, but studies in animal models suggest that CoQ₁₀ is metabolized in all tissues. The main route of the elimination of CoQ₁₀ is through bile and stool excretion. A small fraction of the metabolites is phosphorylated in the cells, transported to the kidneys through blood, and excreted in the urine. 39

Coenzyme Q₁₀ and medical molecular biology
The primary physiological effect of CoQ₁₀ is described as a part of the cellular ATP synthesis system. CoQ₁₀ is a fundamental part of the oxidative phosphorylation of mitochondria. Five protein-lipid complexes situated in the inner mitochondrial membrane, which use molecular oxygen as the final electron acceptor, are engaged in oxidative phosphorylation. Complexes I-IV are responsible for the transportation of electrons to molecular oxygen. CoQ₁₀ is an electron carrier in this process. Finally, this process creates an electrochemical proton-motive force and the final complex (complex V) uses this force to form ATP. 45,46 Further studies revealed other molecular properties of CoQ₁₀ as a powerful antioxidant, gene regulator, anti-inflammatory, and immune modulating agent which are discussed as following.

Coenzyme Q₁₀: a powerful antioxidant and antiinflammatory agent
An antioxidant is defined as a substance that inhibits or retards oxidation. CoQ 10 is a lipid-soluble antioxidant which acts as a free radical scavenger and a membrane stabilizer, prevents phospholipid peroxidation, and regenerates vitamin E (α-tocopherol) and vitamin C (ascorbate). 47 Kagan et al 48 postulated that the vitamin E regenerative property of this coenzyme is a more effective pathway to reduce oxidative stress than the free radical scavenging characteristics of CoQ 10 . The preventive effect of CoQ 10 against lipid peroxidation also plays a role as an anti-atherosclerotic property through diminishing the oxidation of LDL. 45 CoQ 10 also upregulates some enzymatic antioxidants like superoxide dismutase (SOD) and glutathione peroxidase. 46 The ubiquinone (oxidized form of CoQ 10 ) become reduced to ubiquinol through the enzymatic actions of NADH-cytochromeb5 reductase and NAD(P)H: quinone oxidoreductase 1. 49 Researches on human body revealed that the production of CoQ 10 reduces through the ages. This contribute to the process of aging and aging related systemic inflammation. 8 Inflammation is both the cause and the consequence of oxidative stress. CoQ 10 as an immunomodulatory and an antioxidant could rationally act as a strong antiinflammatory agent. Moreover, in clinic, Various metaanalysis on RCTs strongly suggest that CoQ 10 significantly reduces TNF-α, IL-6 and C-reactive protein (CRP). 17,50 In another study CoQ 10 treatment proves to have a role in reducing the mir146-a expression which is a regulation factor of inflammatory pathways. Additionally, CoQ 10 can reduce the further release of IL-6. 51 (Figure 3) Coenzyme Q₁₀: a gene expression regulator CoQ 10 has been identified as a modulator of several biological processes like cell signaling and has a vital role in the mitochondrial respiratory chain and antioxidant activity. 52 Moreover, many in vitro and in vivo studies have demonstrated that CoQ 10 , in addition to its well-known functions, affects the expression of several human genes involved in metabolism, cell signaling, nutrient transport, cell death and cell differentiation. 53 Its diverse functions reflect its therapeutic potential as a dietary supplement for a number of diseases such as mitochondrial myopathies, migraine and cardiovascular diseases. 54 On the other hand, the conversion of Q 10 into its reduced form is accompanied by the generation of reactive oxygen species (ROS) which may also have an additional impact on gene expression. 52 A study conducted by Schmelzer et al presented that the reduced form of CoQ 10 (Q10H2) has a stronger effect on gene expression than the oxidized form CoQ 10 , primarily due to differences in bioavailability. 52 The endogenous insufficiency of CoQ 10 synthesis causes the up-regulation of oxidation reactions and the down-regulation of multiple genes which are crucial for growth such as RNA polymerase II. Exogenous CoQ 10 supplies partially restore the expression of these genes; however, the expression level of another subset of genes which are involved in some biological functions such as metabolism and cell signaling is not affected by exogenous CoQ 10 supplementation and depends solely on endogenous synthesis of CoQ 10 . 55 It has been further demonstrated that CoQ 10

Coenzyme Q₁₀: an immune-modulating agent
The effect of CoQ10 supplementation on the immune system is a complexity of direct and indirect impacts on the energy metabolism, cell signaling and gene expression of the immune cells. 59 The role of CoQ10 in normal ATP synthesis of mitochondria could considerably prevent the cellular stress and further apoptosis in ATP depleted activated immune cells. It is notable that the majority of immune cells involving in the regulation of the immune response use the mitochondrial pathways for ATP synthesis whereas pro-inflammatory immune cells mostly use the glycolysis pathway for ATP production. 60 In view of cell signaling and differentiation of immune cells, studies had demonstrated that CoQ10 supplementation reduced the expression of p-STAT3 and further IL-17 while upregulates the expression of p-STAT5 and further FOXP3 which leads to differentiation of CD4 + T cells into regulatory T cells rather than the pro-inflammatory T helper 17 cells. 61 In one in-vitro study, the peripheral blood mononuclear cells were exposed to CoQ₁₀ for 24 h and the secretion of some cytokines was examined including IL-1β, IL-1RA, IL-6, IL-10, IL-2, INF-γ, TNF-α and IL-2. As a result, only TNF-α and IL-2 secretion was significantly decreased.
Notably the outcome of this experiment presented that the treatment with an average concentration of 1.25µM CoQ₁₀ had the best effect, and the higher levels (up to 10µM) did not exert a significant difference. 53 The different behavior of CoQ₁₀ in lower and higher dosages is suggestive of a biphasic role for CoQ₁₀. Moreover, in another study by Gollapudi and Gupta, CoQ₁₀ presented an apoptotic protective effect on CD4 + and CD8 + which had been induced with an oxidative stressor. The selected T cells after treatment with CoQ₁₀ (under 10µM concentration) for 24 h showed a strong resistance to an oxidative stressinduced mitochondrial apoptotic pathway. It represented that CoQ₁₀ could inhibit the activation of both caspase-9 and caspase-3 in apoptotic cascades. Moreover, it can reduce the production of ROS and prevent the oxidative stress-induced mitochondrial membrane depolarization in CD4 + and CD8 + T cells. 14 Another critical step in apoptotic process that is also suppressed by CoQ₁₀ is cytochrome C release from mitochondria according to some experimental studies. 62 Furthermore, some studies demonstrated a lowered TNF-α secretion and a significant declined secretion of MIP-1α, MCP1 with CoQ₁₀ treatment on THP-1 cell line, the events which are very important in the COVID-19-induced hyper-inflammatory state. Since the monocytes are able to convert oxidized CoQ₁₀ into its reduced form, this reduction can be justified. NF-κB is a transcription factor for many genes involved in immune responses including which encode MIP-1α, MCP1, and TNF-α. It is believed that down-modulation of these factors is due to NF-κB inhibition. It has not been clearly confirmed that how CoQ₁₀ effects on NF-κB, but there are some evidences for NF-κB inhibition by antioxidant compounds 63,64 (Figure 3).

Coenzyme Q₁₀: an antiviral nutrient
The viral infections, caused by RNA or DNA virus, trigger the production of reactive species (RS) and ROS including: NO, O2 .-, OH • and their by-products (such as H2O2), which interfere with normal functions of the infected cells such as gene expression and metabolism. As an instance, a higher RS level in the host cell promotes the activating of NF-κB which can lead to increased viral replication. 65 There are also some evidences that antioxidant agents can mediate viral pathogenesis through the reinforcement of cell resistance against oxidative stress. Moreover, it has been determined that the antioxidant agents exert an important role in decreasing the replication of RNA viruses such as flaviviruses, alphaviruses, and Japanese encephalitis virus through the various pathways in different stages. 66

Coenzyme Q₁₀ and anti-angiotensin II properties
The renin-angiotensin system (RAS) has been shown to play a vital role in physiological and pathophysiological events in cardiovascular system. In this cascade, ACE converts AngI to AngII, and AngII as the prime component of RAS, disrupts endothelial function by increasing the oxidative stress. On the other hand, AngII and its receptor induce the activation of NADPH oxidase whereby the synthesis of ROS is increased. When the local levels of ROS are increased, a considerable cellular damage and oxidative stress will occur by interaction with cell membranes, DNA and other molecules. 68 Some experimental studies presented that CoQ₁₀ is involved in enhancing the expression of the antioxidant enzymes and eliminating the free radicals. Treatment with antioxidant agents may remove the misbalance of RAS caused by oxidative stress. 69 Moreover, studies demonstrated the preventive effect of CoQ 10 against angiotensin induced up-regulation of NADPH oxidase enzyme. 70

Clinical implications of coenzyme Q₁₀ in COVID-19
CoQ₁₀ has been the subject of interest in a variety of diseases including cardiovascular, neurodegenerative, kidney and systemic inflammatory diseases. 8 The antioxidant, antiinflammatory, immunomodulatory and gene expression regulator properties of this molecule highlight its application as a considerable choice for nutrient therapy in the aforementioned diseases. 47 Some of these conditions such as cardiovascular diseases, hyper-inflammatory state and critical stages of illnesses like septic shock share some features with COVID-19 in pathophysiology. The following statements describe this shared features and possible effects of CoQ 10 supplementation in COVID-19 patients.

Coenzyme Q₁₀ and its potential cardioprotective effects
CoQ₁₀ has a pivotal role in myocyte bioenergetics, exerts anti-inflammatory effects, and reduces oxidative stress. CoQ 10 supplementation could be beneficial for a wide spectrum of cardiovascular diseases including: heart failure, hypertension, myocardial infarction, viral myocarditis, arrhythmias, and drug-induced or idiopathic cardiomyopathies. 71 The action mechanism of this supplement, according to Greenberg and Ferishman, 69 is to not only enhance the cellular aerobic metabolism but also exert cardiovascular effects including: the modification of endothelial dysfunction, preserving the function of the NA + /K + ATPase, stabilizing the cellular membrane, reducing blood viscosity, modulating the immune system, and suppressing systemic inflammation. CoQ 10 could be helpful for cardiac patients as a supplement that contribute to increasing mitochondrial phosphate/ oxygen ratio, alleviating reperfusion injury after hypoxic conditions, modifying QRS duration abnormalities, and improve NYHA function class. 72 Moreover, CoQ 10 improves extracellular SOD and flow-mediated-dilation, 72 and protect against progressive left ventricular remodeling and fibrosis. 73 Ultimately, CoQ 10 can reduce total cardiac events and could be protective against myocardial infraction, congestive heart failure, and dilated and druginduced types of cardiomyopathies. 74 The protective role of CoQ 10 in improving viral myocarditis and drug induced cardiotoxicity introduces this supplement as an appropriate choice for the prevention of COVID-19 cardiovascular complications which is generally influenced by two factors: cytokine storm, and adverse effects of the medications. 29 The hypercytokinemia caused by SARS-COV-2 infection could lead to fulminant myocarditis, 75 a lethal condition mostly caused by hyper-inflammatory state and cytokine storms, particularly during a viral infection. 76 Evidence has demonstrated that the blood levels of inflammatory cytokines in critically ill patients in the ICU are higher than the patients not admitted to the ICU; additionally, the level of IL-6 has shown to be higher in patients with cardiac injury. 75 The anti-inflammatory, antioxidant, and immunomodulatory effects of CoQ 10 could suppress the hyper-inflammatory state, particularly through reducing IL-6, TNF-α and other inflammatory cytokines resulting in the prevention of cardiovascular events in COVID-19 patients and the alleviation of the cardiac complications caused by the cytokine storm in this disease. 74,77 Despite the fact that no definitive treatment for COVID-19 has yet been discovered, several curative and supportive medications have been suggested; the most fundamental of which include chloroquine, hydroxyl chloroquine, remdesivir, and potent antibiotics preventing bacterial super infections. 78,79 Among the adverse effects of these drugs, particularly hydroxyl chloroquine, cardiovascular complications are of great importance. 80 These drugs induce cardiotoxicity through increasing oxidative stress, triggering endothelial dysfunction and elevating tissue inflammation. 81 CoQ 10 counteracts the cardio-toxic effects of these drugs by improving the mechanism of oxidative phosphorylation, reducing oxidative stress and decreasing the inflammation of the myocardium. 82

Coenzyme Q₁₀, primary hypertension and endothelial dysfunction
The pathophysiology of primary hypertension is generally associated with the oxidative stress in the endothelium which leads to decreased available NO for the cells of vascular intima layer, mitochondrial dysfunction of the endothelium, and eventually endothelial dysfunction. 83 CoQ 10 could improve hypertension through decreasing vascular oxidative stress, improving the function of mitochondria, moderating the effects of AngII, and reducing the level of Aldosterone. 71 As mentioned, in the pathophysiology of COVID-19, the RAS system is disturbed due to the interference caused by the proteinprotein interaction of the virus spikes and ACE2, leading to the down-regulation of ACE2 which could enhance the pathologic effects of AngII and frustrate the AngII/ Ang (1)(2)(3)(4)(5)(6)(7) ratio resulting in the severe complications of COVID-19 disease. 21 Supplementation with Q10 could improve the interference in the RAS system caused by COVID-19 infection through exerting anti-AngII effects and decreasing oxidative stress. 70 The antihypertensive effects of CoQ 10 are not entirely confirmed and more well-designed clinical trials are suggested to confirm it. 84 Studies have demonstrated that CoQ 10 could not solely reduce blood pressure but could be beneficial against hypertension in the context of metabolic diseases like diabetes as an adjunctive therapy to adjust blood pressure. 82

Coenzyme Q₁₀ in critically ill and ICU patients
The molecular and cellular mechanism of sepsis has not been entirely discovered and includes different aspects. One of the most crucial elements of sepsis is severe oxidative stress accompanied by the mitochondria dysfunction. 85 The decreased levels of CoQ 10 during septic shock have also a significant importance. 86 The elevated levels of IL-6 and IL-8 which have a negative relationship with CoQ 10 levels, and the decreased LDL that is the plasma carrier of the coenzyme lead to lower CoQ 10 levels during the occurrence of septic shock. 87 The coenzyme inversely correlates with vascular endothelial biomarkers like VCAM and inflammatory cytokines like IL-10, and its decrease during septic shock, contributes to the organ failure related to the mitochondrial dysfunction. 86 Meanwhile, despite the providing stable and proper hemodynamic conditions along with the optimal oxygenation in the critically ill patients, death rates could not be reduced in these people. This clearly indicates that the substantial mitochondrial dysfunction in the critically ill patients prohibits using the oxygen to produce intracellular ATP even with proper oxygenation. 88 CoQ 10 could not only counteract the oxidative stress in sepsis as a strong mitochondrial and membranous antioxidant, but could also suppress the production of ROS, increase cellular metabolism and enhance the patient's response to oxygenation by alleviating the mitochondrial dysfunction through stabilizing the plasma membrane, sustaining the function of the NA + /K + ATPase, and regulating the oxidative phosphorylation system. Nevertheless, according to evaluations and clinical trials, supplementation with CoQ 10 could not solely benefit critically ill patients and it is advised to prescribe CoQ 10 with Selenium as a crucial component of several metabolic enzymes and selenoproteins. 11 (Figure 4).

Coenzyme Q10 and its potential neuroprotective effects
Most of neurodegenerative diseases like Alzheimer and Parkinson disease, despite their exclusive neurologic and molecular properties, share some common pathological aspects such as neuro-inflammation, excitotoxicity cascade induced neuronal apoptosis, and mitochondrial dysfunction in affected neurons. 89 CoQ 10 is a nutrients of interest in adjunctive therapy and the prevention of these types of age related diseases. 90 CoQ 10 with antiinflammatory, antioxidant and immunomodulatory properties, could suppress the CNS inflammation in such diseases in addition to reducing oxidative stress and enhancing mitochondrial function. 91 CoQ 10 could also prevent neuronal apoptosis trough keeping mitochondrial permeability transition pores in closed conformation and blocking the apoptosis pathway induced by N-methyl D-aspartate (NMDA) glutamate receptors or non-NMDA glutamate receptors. 92 The suggested pathophysiology of neurologic involvement in COVID-19 patient is based on three events; a retrograde trans-synaptic infection of CNS, hematogenous infection of CNS in the context of disrupted BBB due to hypercytokinemia and a systemic inflammation which causes both endothelium and astrocytes dysfunction in BBB, and the direct impact of systemic inflammation and oxidative stress on CNS and PNS causing neuronal damage and pathologic reactions in the supportive tissue of neurologic system, blood vessels, coagulation cascades and endothelium resulting in the cerebrovascular accidents. 30,32 CoQ 10 as a lipophilic antioxidant which passes easily through BBB, has a direct effect on reducing oxidative stress and modulating the immunologic reactions, which could be beneficial through suppressing the systemic inflammation, 90 preventing BBB damage, 93 and neuronal apoptosis in COVID-19 patients. 92 Accordingly, CoQ 10 supplementation could prevent the developing CNS and PNS damage and further deleterious consequences like central respiratory failure, delirium and loss of conciseness, leading to a permanent brain injury and death 31 (Figure 1).

Conclusion
COVID-19 as a pandemic lethal infection, currently, has no definite treatment. The interaction of virus-spike with ACE2 receptor leads to the down-regulation of ACE2 which could enhance the pathologic effects of AngII and disturb the AngII/Ang (1)(2)(3)(4)(5)(6)(7) ratio. It could result in a huge cytokine storm, and an extensive oxidative stress which are the molecular basis of the most complications induced by COVID-19. CoQ 10 as an essential electron transporter in the phosphorylative oxidation system is a powerful lipophilic antioxidant, anti-apoptotic, immunomodulatory and anti-inflammatory supplement which has been tested for the management and prevention of a variety of diseases specially diseases with inflammatory pathogenesis. CoQ 10 can decrease the important inflammatory cytokines and prevent the organ damages due to a huge oxidative stress. CoQ 10 can be also a cardio-protective and neuroprotective agent through reducing the viral toxicity against cardiomyocytes and CNC neurons. Accordingly, CoQ 10 supplementation could prevent the COVID-19-induced morbidities and has a potential protective role against the Figure 4. The effective role of CoQ 10 against severe oxidative stress by improving the mitochondrial dysfunction: One of the most crucial elements of sepsis infections is severe oxidative stress which is caused by mitochondrial dysfunction leading to decreasing IL-10 and VCAM. During a septic shock, a condition in which the level of CoQ 10 is decreased and it accompanies by increasing IL-6 and decreasing LDL (plasma carrier of CoQ 10 ), optimal oxygenation and as a result making proper hemodynamic condition, are supposed to improving the mitochondrial dysfunction. Although CoQ 10 has proven benefits in suppressing the production of ROS, raising the cellular metabolism, and sustaining the function of Na/K ATPas, the supplementation with CoQ 10 could not solely benefit critically for the ill advanced patients. ROS: Reactive oxygen species