COENZYME Q10: A POTENTIAL BREAKTHROUGH IN PHYSIOLOGICAL DYSFUNCTIONS

COENZYME Q₁₀: A POTENTIAL BREAKTHROUGH IN PHYSIOLOGICAL DYSFUNCTIONS

Jeetendra Kumar Gupta ^*and Sushil Giri

Institute of Pharmaceutical Research, GLA University, Mathura - 281406, Uttar Pradesh, India.

ABSTRACT: Coenzyme Q₁₀ (ubiquinone) is a lipophilic benzoquinone substance. It is a pivotal component to the oxidative phosphorylation in the inner mitochondrial membrane of all aerobic cells as well as diminishes reactive oxygen species (ROS). Exogenous sources for CoQ₁₀ are grapes seed oil, walnuts, pistachios, spinach, and sesame seed. At present, it is being utilized as an antioxidant agent. Recent studies have revealed its neuroprotective action. In the present review, the comprehensive pharmacological benefits of coenzyme Q₁₀ on the central nervous system (CNS) has been revealed. Many studies were taken into considerations and compiled in accordance with their activities. Amongst those, the study using in-vitro models referring to neuronal toxicity and animal models of neurodegenerative diseases have been covered. Multiple outcomes have now evolved assisting the role of reactive oxygen species and neuroinflammation in the pathogenesis of the neurodegenerative disorder. The drug coenzyme Q₁₀ has been administered in a human subject with reference to their age and body weight. In case of increased oxidative stress and few selective cases of gene mutation, the energy production in mitochondria is highly impaired and the deficiency also happens in brain cells which is a leading cause in pathogenesis of premature aging and neurodegenerative diseases. Potential neuroprotective effects of coenzyme Q₁₀ have also been emphasized in several neurodegenerative disorders such as Parkinson’s disease (PD), Huntington’s disease and Alzheimer’s disease (AD). This article contributes a pervasive review on the utility of coenzyme Q₁₀ in the management as well as in the prevention of many illnesses as for example, hyperlipidemia, coronary artery disease, myocardial infarction and kidney disease.

Ubiquinone, Antioxidant, Anti-aging, anti-stress

INTRODUCTION: In the present scenario, the oxidative stresses are growing day by day and the bumpy lifestyles have become a matter of agitation. Many free radicals are found in nature due to environmental pollution which affects human life in many ways ^{1, 2}.

These highly reactive entities created by the pollutants can damage the vital parts of our body when they come in contact. Free radicals are repetitively being produced by both exogenous and endogenous sources.

The exogenous source is radiation, pathogens, chemical, smoking and pollutants, while the endogenous source is mitochondrial oxidative phosphorylation (during the electron transport chain mitochondria consumes almost 98% of molecular oxygen), lipid peroxidation chain reaction and other several metabolic processes. If reactive oxygen species (ROS) and nitrogen reactive species (NRS) yield in controlled form, execute imperative functions and positively involved in defense mechanism of cells and tissues against pervaded pathogens, in addition to synchronized various process including cellular growth, and proliferation glucose metabolism, activation of transcription factor, phosphorylation of specific protein ³. Apart from the serviceable effect, increased levels of ROS swiftly react with proteins, nucleic acid, and membrane lipids which disturbs ion homeostasis. It may also cause gene mutation which leads to alteration in biological and structural functions of various other molecules ^{4, 5}. In response to prevent the destructive effects of free radicals inside the normal physiological function, the body produces an endogenous substance, free-radical scavenger (CoQ₁₀) that quickly fuses with free radicals ⁶ and neutralized it. The Free radicals are unstable and deleterious molecules, freely strolling inside the cells to regain stability. The propensity and reaction rate of free radicals with different organelles inside living cells and tissues leading to cellular damage. This damage may increase chronic diseases such as cancer, tumor formation, osteoporosis and other health illness ^{7, 8}.

Coenzyme Q₁₀ & Biological System: Coenzyme Q₁₀ (CoQ₁₀) is a fat-soluble, vitamin-like naturally occurring substance. Synthesized endogenously in all respiring eukaryotic cells. CoQ₁₀ is pivotal to the oxidative phosphorylation process as an electron carrier in the inner mitochondrial membrane (energy production) as well as actively involved in diminishing of free radicals Fig. 1.

FIG. 1: FREE RADICAL SCAVENGING PROPERTY OF COENZYME Q₁₀

Source of Coenzyme Q₁₀: Predominantly it is found in the mitochondria of the heart, liver, kidney, and pancreas because these organs have the highest ATP requirement for vital physiological function. Coenzyme Q₁₀ also presents in a small amount in a wide range of foods such as grape seed oil, walnuts, pistachios, spinach, sesame seed and olive oil and with higher concentration found in organs such as liver, heart and kidney. Tissue concentration of CoQ₁₀ is maximum at about 20 years of age and progressively decreases with age ⁹.

Archives: The American biochemist Dr. Frederic L carne discovered Coenzyme Q₁₀ from bovine heart mitochondria, at the University of Wisconsin, USA. After the discovery of coenzyme Q₁₀ another scientist, Morton introduced a new compound that had the same function as coenzyme Q₁₀ from rat liver and named it as ubiquinone.

Wolf DE and Karl Folkers determined the explicit chemical structure of Coenzyme Q₁₀: 2,3 dimethoxy-5 methyl -6 decarprenyl benzoquinone at Merck laboratories. In 1986, Folkers got prestigious Priestly Medal for his research in CoQ₁₀ by the American Chemical Society. In a similar context, a British biochemist Peter Dennis Mitchell had been awarded the Nobel Prize in chemistry for his discovery of the chemiosmotic mechanism of ATP synthesis at Glynn Research Centre.

Coenzyme Q₁₀ in Adjuvant Therapy: The level of CoQ₁₀ in the body decreases with age, stress and mutation in genes that cause CoQ₁₀ deficiency, which results in heterogeneous disorders such as encephalomyopathy, nephropathy and cerebral ataxia ¹⁰. Tissue concentration of ubiquinone may be below in patients with a heart problem, cancer, neuronal disorder, and diabetes, while the adequate concentration of coenzyme Q₁₀ is vital for energy production in the body. Isopentenyl pyrophosphate is an intermediary precursor of CoQ₁₀ and cholesterol synthesis both follow the same biosynthetic pathway.

Statins (Lovastatin, simvastatin, pravastatin) are the most frequently prescribed blood cholesterol-lowering drugs (HMG-CoA reductase inhibitor), inhibit the mevalonate pathway which leads to obstruction of CoQ₁₀ biosynthesis, can result in reducing muscle or serum levels of CoQ₁₀ ¹¹. So, many other drugs such as Nitrogen-Bisphosphonates (risedronate and zoledronate) widely used in the bone fragility disorders ¹², antihypertensive and β1 blockers (propranolol, metoprolol) drugs has been shown to diminish an intermediary precursor of CoQ₁₀ biosynthesis, therefore the patient is not capable of producing adequate CoQ₁₀. ^{13, 14}

Coenzyme Q₁₀ is being used as adjuvant therapy in the treatment of various illnesses such as heart health, blood sugar level, bronchi health, gum health, oxidative stress, vision, cancer anti-inflammatory and mental health.

Review of Literatures: Serebruany VL et al., demonstrated that dietary supplementation of Coenzyme Q₁₀ (ubiquinone) has shown a cardioprotective role in several clinical studies. He examined the effect of CoQ₁₀ on surface antigens and platelet size in human volunteers and measured receptor expression with the help of flow cytometry. Observed the inhibition of platelet vitronectin receptor expression, along with a reduction in platelet size and discussed a link between CoQ₁₀ and platelet vitronectin receptor expression, therefore concluded, dilatory supplementation with CoQ₁₀ perceived clinical benefits in the treatment of cardiovascular disease ¹⁵. Khan NA et al. even found that the cardioprotective effect of CoQ₁₀ by regulation of Bcl-2 gene expression and revealed a protective effect on apoptotic rat heart ¹⁶. Yang X et al., discussed about the interconnection between presenilin1 (PS1) protein (encoded by PSEN1 gene) and Alzheimer disease (AD). Inferred that mutation in the PSEN1 gene increases Aβ42 relative to Aβ40 in cultured cells and brains of transgenic mice bearing L286V PS1. These mutations manifest notably higher intracellular amyloid-beta (Aβ) and lead to neurodegeneration without the formation of extracellular plaques, again in-vitro studies displayed that oxidative stress corresponds with amyloid-beta overproduction. Transgenic mice were fed with CoQ₁₀, and demonstrated the reduction in the level of Aβ42 by 23% in the cortex of transgenic mice in the treatment group. Drawing the conclusion from the above data suggested that CoQ₁₀ would be a useful perspective drug for the therapy of Alzheimer's disease ¹⁷.

Brea-Calvo G et al., scrutinized clinically heterogeneous autosomal recessive disorder that is caused by mutations in several genes involved in CoQ₁₀ biosynthesis. At least ten enzymes participate in CoQ₁₀ biosynthesis, which is located in mitochondria and reported CoQ₄ play a structural role in establishing a multi-heteromeric complex that contains most of the CoQ₁₀ biosynthetic enzymes. They included many volunteers in his study, these are two unrelated individuals present with severe hypotonia, bradycardia, respiratory insufficiency and heart failure, two sisters showed antenatal cerebellar hypoplasia, neonatal respiratory distress syndrome, and fifth subjects was an early onset but slowly progressive. All affected subjects showed that a reduced amount of Q₁₀ and often displayed a decrease in Q₁₀ dependent ETC complex activity. They concluded, a mutation in CoQ₄ may lead to heterogeneous disorder ¹⁸.

Akram Nezhadi et al., found that the behavioral recovery and histological outcome after combination treatment of the bone marrow stromal cell (BMSC) graft and Coenzyme Q₁₀ in a rat model of Parkinson's disease. BMSC_s are the most promising candidate in the transplantation of a degenerative nervous system without any immunological problems, it also known for trophic factor expression leads to promising result in axonal regeneration, (an increase neuronal property and functional recovery) combined treatment of CoQ₁₀ and BMSC showed that better recovery in lesion group as compared to individual treatment of CoQ₁₀ and found increased level of tyrosine hydroxylase gene expression. The study reported that combined treatment can be effective in Parkinson’s disease ¹⁹.

Yeung Ck et al., discussed that varying doses of CoQ₁₀ in hemodialysis patients also detailed the safety, tolerability, efficacy and effect of CoQ₁₀ on free radicals. He discussed at high doses (1800 mg/day) CoQ₁₀ supplimation is a safe, well-tolerated and essential cofactor for energy production in the mitochondrial respiratory chain as well as decrease reactive oxygen species in patient during hemodialysis treatment ²⁰. Yakugaku Xasshi et al., also reported that about an alternative medical assessment for neuroprotective therapy. He established coenzyme Q₁₀ is an imperative lipophilic compound of mitochondria to cure Parkinson's disease. In the present scenario, the available pharmacotherapy and surgical approaches can ameliorate the only symptom of PD. Consequently, he explored the neuroprotective activity of CoQ₁₀ in PD. finally he concluded oral CoQ₁₀ administration that prevented the degeneration of dopaminergic neurons in the striatum of brain²¹.

Shazia Ashraf et al., concluded that how to coenzyme Q₁₀ biosynthesis are interfered in steroid-resistant nephrotic syndrome (SRNS) also focused ADCK4 gene involved in coenzyme Q₁₀ biosynthesis pathway and mutation in ADCK4 gene which actively participates in the pathogenesis of  SRNS  as well as disrupt CoQ₁₀ biosynthesis ²². Mohammad Ali Eghbal et al., and other researchers discussed major side effects of statin drugs in isolated rat hepatocytes and found the deficiency of coenzyme Q₁₀ against statin toxicity. He observed different parameters in his in-vitro study such as reactive oxygen species (ROS), formation, cell death, and mitochondrial membrane potential. In-vitro experimental data expressed cell death as well GSSG is decreased by coenzyme Q₁₀. Therefore, CoQ₁₀ may use as an adjuvant therapy along with statins drug which remarkably decreases liver toxicity ²³.

Carrasco J et al., reported that extracorporeal shockwave lithotripsy (ESWL) causes major renal injury as well as mentioned the protective effect of coenzyme Q₁₀ in ESWL on the basis of available data. He noticed an increased glomerular filtration rate in his study along with a reduction in the concentrations of albumin, creatinine, macro-globulin (β2M) in the coenzyme Q₁₀ treated group. Further, he concluded CoQ₁₀ actively involved in maintaining renal function, vasoactive hormonal activities and inflammatory parameters after extracorporeal shockwave lithotripsy ²⁴.

Greenlee et al. reviewed the etiology, evaluation and treatment of doxorubicin-induced cardiotoxicity that is used in breast cancer treatment. Cardiomyopathy changes and congestive heart failure observed in 3 to 20 / of the breast cancer patients because of DRX toxicity. DRX increases the generation of free radicals primarily within mitochondria of heart cells. This study analyzed DRX efficacy had not altered by CoQ₁₀. But it has been considered as cardioprotective in cancer treatment ²⁵. Romero-Moya et al. discussed that mutation in coenzyme Q (CoQ) genes that are (liable for coenzyme Q₁₀ biosynthesis) diminishes CoQ10 biosynthesis. This mutation can outcome in mitochondrial dysfunction mainly in cells of the brain and skeletal muscles because these organs entails high energy for their biological function. He investigated that mutation in CoQ₄ genes may lead to mitochondrial heterogonous disorder ²⁶.

Coenzyme Q₁₀ - Primary and Secondary Deficiency: Ogasahara et al., in 1989, discussed CoQ₁₀ deficiency in patients ²⁷. CoQ₁₀ deficiency in tissue or plasma level may be due to its bioavailability impairment or due to its altered biosynthesis which can lead to a variety of disease states, extremely cardiovascular disease, coronary artery disease, myocardial infarction, reperfusion injury, encephalomyopathy, neurodegenerative disease and cerebral ataxia. Moreover, the deficiency of vitamin B₆ and ascorbic acid can also impair the biosynthesis of coenzyme Q_10, because it is essential nutrition for the biochemical pathway in CoQ₁₀ synthesis.

There are many genetic disorders that may diminish the biosynthesis of coenzyme Q_10, via mutation in genes such as PDSS1, PPSS2, CoQ4, CoQ6, ADCK3, and ADCK4. It has also been reported in several diseases that primarily affect the mitochondrial function of the brain, skeletal muscle and myocardial cells. The deficiency of CoQ₁₀ levels can be either primary or secondary. In many studies has been indicated primary deficiency can result from a gene mutation that is involved in CoQ₁₀ synthesis. Many other neurological abnormalities such as poor muscle tone (hypotonia), seizures, progressive muscle stiffness (spasticity), neurological abnormalities, nephrotic syndrome, cardiomyopathy and cerebral ataxia all come under the primary CoQ₁₀ deficiency ²⁸.

Secondary deficiency has been related to several disorders such as lactic acidosis, stroke-like episode, cardiovascular disease, neurological, mitochondrial disorders and it may be associated with hydroxymethylglutary- coenzyme A reductase inhibitors such as statins (anti-hyper cholesteric drugs) ²⁹.

Biosynthesis of Coenzyme Q₁₀: Human cells synthesize CoQ₁₀ in the mitochondrial inner membrane from amino acids tyrosine or phenylalanine ³⁰. 4- Hydroxybenzoate and polyprenyl chain are not only principal compounds of CoQ₁₀ biosynthesis but also dependents on sufficient levels of vitamins such as folic acid, pyridoxine, riboflavin and niacin ³¹. Human CoQ consists of ten isoprene units in the side chain of isoprenoid. Dimethylallyl pyrophosphate (DMAPP) and its isomer isopentenyl pyrophosphate (IPP) is the precursor of the isoprene unit. Elongation of the isoprene tail is formed by a heterotetrameric protein which is encoded by PDSS1, and PDSS2 genes, after this benzoquinone ring modified in the inner mitochondrial membrane at least 12 protein (CoQ) are involved, which are necessary for the formation of synthome (multiprotein complex). Mevalonate pathway is liable for the biosynthesis of CoQ₁₀, cholesterol, dolichol, heam A and isoprenylated proteins ³². Finally, eight steps are required in the biosynthesis of Coenzyme Q₁₀.

CONCLUSION: Coenzyme Q₁₀ (ubiquinone) is a vitamin-like substance that is being used as an antioxidant, in addition to its role in the mitochondrial electron transport chain (ETC)  as electron carrier from complex I and II to complex III. It is also known as ubiquinone and biosynthesized by a precursor called 1, 4-benzoquinone, where Q refers to the quinine moiety and ten (10) refers to the quantity of isoprenyl subunits. It offers a substantial advantage in dietary supplementation. Coenzyme Q₁₀ is retained in the body better and increases tissue concentrations in the organ-system because of its fat-soluble nature. Besides these properties, it exhibits a range of activity and clinical corollaries which has not been shown by other dietary supplements.

It is evident from the existing literature that coenzyme Q₁₀ has many potential benefits when it was consumed by human recipients. It is also being utilized as an adjuvant drug in order to alleviate certain diseases (ref). Hence, it can be concluded that the drug has a higher significance in pharmacology and therapeutics. It is obvious that coenzyme Q₁₀ exerted effective treatments of many disorders and it is widely recognized as a potential medicine. It manifests a significant role in the health management and treatment of illnesses.

ACKNOWLEDGEMENT: Authors are immensely thankful to GLA University Mathura, Uttar Pradesh, India for providing necessary facilities.

CONFLICTS OF INTEREST: The authors declare no conflict of interest.

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    How to cite this article:

    Gupta JK and Giri S: Coenzyme Q₁₀: a potential breakthrough in physiological dysfunctions. Int J Pharm Sci & Res 2019; 11(2): 599-04. doi: 10.13040/IJPSR.0975-8232.11(2).599-04.

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