Coenzyme Q10 in Mitochondria and Lysosomal Disorders

A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Immunology".

Deadline for manuscript submissions: closed (31 December 2020) | Viewed by 21229

Special Issue Editor

Special Issue Information

Dear Colleagues,

Coenzyme Q10 (CoQ10) is a lipophilic molecule that serves as an essential electron carrier within the mitochondrial respiratory chain (MRC) and acts as a potent and soluble lipid antioxidant. In view of the essential role that CoQ10 plays within the MRC, it is perhaps not surprising that a deficit in CoQ10 status has been associated with a number of mitochondrial disorders. However, whether the CoQ10 deficiency is the primary cause or a secondary consequence of the disease pathophysiology has yet to be established in the majority of these disorders. The underlying CoQ10 deficiency may explain the therapeutic efficacy demonstrated by CoQ10 in the treatment of some patients with mitochondrial disorders. However, this is not a universal phenomenon, and clinical trials have so far provided equivocal results on the clinical utility of CoQ10 in the treatment of mitochondrial disease. In recent years, there has been a growing interest in the role that CoQ10 plays in lysosomal function, as, together with the mitochondria, lysosomes are also a major site of CoQ10 localisation within the cell.  Interestingly, reports are now emerging of a CoQ10 deficiency in association with certain lysosomal disorders, including mucopolysaccharidosis type III (MPS III), although the cause of the CoQ10 deficiency has yet to be elucidated.

The purpose of this Special Issue will, therefore, be to highlight the evidence available on the causes and consequences of a CoQ10 deficiency in mitochondrial and lysosomal disorders and to discuss the appropriateness and utility of the use of CoQ10 in the treatment of these disorders.

Dr. Iain P. Hargreaves
Guest Editor

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Keywords

  • Coenzyme Q10
  • mitochondria
  • oxidative stress
  • respiratory chain
  • lysosome
  • treatment
  • disease pathophysiology

Published Papers (5 papers)

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Editorial

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2 pages, 158 KiB  
Editorial
Coenzyme Q10 in Mitochondrial and Lysosomal Disorders
by Iain P. Hargreaves
J. Clin. Med. 2021, 10(9), 1970; https://doi.org/10.3390/jcm10091970 - 4 May 2021
Cited by 5 | Viewed by 1544
Abstract
Within the mitochondrial respiratory chain (MRC), coenzyme Q10 (CoQ10) plays a key role as an electron carrier transporting electron derived from complex I (NADH: Ubiquinone reductase) and complex II (succinate: Ubiquinone oxidoreductase) to complex III (ubiquinol: Cytochrome c reductase) [...] Full article
(This article belongs to the Special Issue Coenzyme Q10 in Mitochondria and Lysosomal Disorders)

Research

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21 pages, 3586 KiB  
Article
CoQ10 Deficient Endothelial Cell Culture Model for the Investigation of CoQ10 Blood–Brain Barrier Transport
by Luke Wainwright, Iain P. Hargreaves, Ana R. Georgian, Charles Turner, R. Neil Dalton, N. Joan Abbott, Simon J. R. Heales and Jane E. Preston
J. Clin. Med. 2020, 9(10), 3236; https://doi.org/10.3390/jcm9103236 - 10 Oct 2020
Cited by 23 | Viewed by 3560
Abstract
Primary coenzyme Q10 (CoQ10) deficiency is unique among mitochondrial respiratory chain disorders in that it is potentially treatable if high-dose CoQ10 supplements are given in the early stages of the disease. While supplements improve peripheral abnormalities, neurological symptoms are [...] Read more.
Primary coenzyme Q10 (CoQ10) deficiency is unique among mitochondrial respiratory chain disorders in that it is potentially treatable if high-dose CoQ10 supplements are given in the early stages of the disease. While supplements improve peripheral abnormalities, neurological symptoms are only partially or temporarily ameliorated. The reasons for this refractory response to CoQ10 supplementation are unclear, however, a contributory factor may be the poor transfer of CoQ10 across the blood–brain barrier (BBB). The aim of this study was to investigate mechanisms of CoQ10 transport across the BBB, using normal and pathophysiological (CoQ10 deficient) cell culture models. The study identifies lipoprotein-associated CoQ10 transcytosis in both directions across the in vitro BBB. Uptake via SR-B1 (Scavenger Receptor) and RAGE (Receptor for Advanced Glycation Endproducts), is matched by efflux via LDLR (Low Density Lipoprotein Receptor) transporters, resulting in no “net” transport across the BBB. In the CoQ10 deficient model, BBB tight junctions were disrupted and CoQ10 “net” transport to the brain side increased. The addition of anti-oxidants did not improve CoQ10 uptake to the brain side. This study is the first to generate in vitro BBB endothelial cell models of CoQ10 deficiency, and the first to identify lipoprotein-associated uptake and efflux mechanisms regulating CoQ10 distribution across the BBB. The results imply that the uptake of exogenous CoQ10 into the brain might be improved by the administration of LDLR inhibitors, or by interventions to stimulate luminal activity of SR-B1 transporters. Full article
(This article belongs to the Special Issue Coenzyme Q10 in Mitochondria and Lysosomal Disorders)
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14 pages, 2137 KiB  
Article
The Effect of Cellular Coenzyme Q10 Deficiency on Lysosomal Acidification
by Robert A. Heaton, Simon Heales, Khalid Rahman, Darren W. Sexton and Iain Hargreaves
J. Clin. Med. 2020, 9(6), 1923; https://doi.org/10.3390/jcm9061923 - 19 Jun 2020
Cited by 23 | Viewed by 4250
Abstract
Coenzyme Q10 (CoQ10) deficiency currently represents the only treatable mitochondrial disorder, however, little is known about how it may affect other organelles. The lysosome has been found to have a large concentration of CoQ10 localised at its membrane; additionally, [...] Read more.
Coenzyme Q10 (CoQ10) deficiency currently represents the only treatable mitochondrial disorder, however, little is known about how it may affect other organelles. The lysosome has been found to have a large concentration of CoQ10 localised at its membrane; additionally, it has been suggested that it plays a role in the normal acidification of the lysosomal lumen. As a result, in this study we assessed the effect of CoQ10 deficiency on lysosomal acidification. In order to investigate this, a neuronal cell model of CoQ10 deficiency was established via the treatment of SH-SY5Y cells with para-aminobenzoic acid (PABA). This method works through the competitive inhibition of the CoQ10 biosynthetic pathway enzyme, CoQ2. A single 1 mM (5 days) treatment with PABA resulted in a decrease of up to 58% in cellular CoQ10 (p < 0.05). It was found that this resulted in a significant decrease in fluorescence of both the LysoSensor (23%) and LysoTracker (35%) probes used to measure lysosomal pH (p < 0.05). It was found that subsequent treatment with CoQ10 (5 µM, 3 days) was able to restore cellular CoQ10 concentration (p < 0.005), which was associated with an increase in fluorescence from both probes to around 90% of controls (p < 0.05), suggesting a restoration of lysosomal pH. This study provides insights into the association between lysosomal pH and cellular CoQ10 status and the possibility that a deficit in the status of this isoprenoid may result in an impairment of lysosomal acidification. Full article
(This article belongs to the Special Issue Coenzyme Q10 in Mitochondria and Lysosomal Disorders)
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20 pages, 1626 KiB  
Article
Fluorescent Light Energy (FLE) Acts on Mitochondrial Physiology Improving Wound Healing
by Letizia Ferroni, Michela Zago, Simone Patergnani, Shannon E. Campbell, Lise Hébert, Michael Nielsen, Carlotta Scarpa, Franco Bassetto, Paolo Pinton and Barbara Zavan
J. Clin. Med. 2020, 9(2), 559; https://doi.org/10.3390/jcm9020559 - 18 Feb 2020
Cited by 15 | Viewed by 3955
Abstract
Fluorescent light energy (FLE) has been used to treat various injured tissues in a non-pharmacological and non-thermal fashion. It was applied to stimulate cell proliferation, accelerate healing in chronic and acute wounds, and reduce pain and inflammation. FLE has been shown to reduce [...] Read more.
Fluorescent light energy (FLE) has been used to treat various injured tissues in a non-pharmacological and non-thermal fashion. It was applied to stimulate cell proliferation, accelerate healing in chronic and acute wounds, and reduce pain and inflammation. FLE has been shown to reduce pro-inflammatory cytokines while promoting an environment conducive to healing. A possible mechanism of action of FLE is linked to regulation of mitochondrial homeostasis. This work aims to investigate the effect of FLE on mitochondrial homeostasis in an in vitro model of inflammation. Confocal microscopy and gene expression profiling were performed on cultures of inflamed human dermal fibroblasts treated with either direct light from a multi-LED lamp, or FLE from either an amorphous gel or sheet hydrogel matrix. Assessment using confocal microscopy revealed mitochondrial fragmentation in inflamed cells, likely due to exposure to inflammatory cytokines, however, mitochondrial networks were restored to normal 24-h after treatment with FLE. Moreover, gene expression analysis found that treatment with FLE resulted in upregulation of uncoupling protein 1 (UCP1) and carnitine palmitoyltransferase 1B (CPT1B) genes, which encode proteins favoring mitochondrial ATP production through oxidative phosphorylation and lipid β-oxidation, respectively. These observations demonstrate a beneficial effect of FLE on mitochondrial homeostasis in inflamed cells. Full article
(This article belongs to the Special Issue Coenzyme Q10 in Mitochondria and Lysosomal Disorders)
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Review

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22 pages, 2163 KiB  
Review
Mechanisms of Mitochondrial Dysfunction in Lysosomal Storage Disorders: A Review
by Karolina M. Stepien, Federico Roncaroli, Nadia Turton, Christian J. Hendriksz, Mark Roberts, Robert A. Heaton and Iain Hargreaves
J. Clin. Med. 2020, 9(8), 2596; https://doi.org/10.3390/jcm9082596 - 11 Aug 2020
Cited by 54 | Viewed by 6956
Abstract
Mitochondrial dysfunction is emerging as an important contributory factor to the pathophysiology of lysosomal storage disorders (LSDs). The cause of mitochondrial dysfunction in LSDs appears to be multifactorial, although impaired mitophagy and oxidative stress appear to be common inhibitory mechanisms shared amongst these [...] Read more.
Mitochondrial dysfunction is emerging as an important contributory factor to the pathophysiology of lysosomal storage disorders (LSDs). The cause of mitochondrial dysfunction in LSDs appears to be multifactorial, although impaired mitophagy and oxidative stress appear to be common inhibitory mechanisms shared amongst these heterogeneous disorders. Once impaired, dysfunctional mitochondria may impact upon the function of the lysosome by the generation of reactive oxygen species as well as depriving the lysosome of ATP which is required by the V-ATPase proton pump to maintain the acidity of the lumen. Given the reported evidence of mitochondrial dysfunction in LSDs together with the important symbiotic relationship between these two organelles, therapeutic strategies targeting both lysosome and mitochondrial dysfunction may be an important consideration in the treatment of LSDs. In this review we examine the putative mechanisms that may be responsible for mitochondrial dysfunction in reported LSDs which will be supplemented with morphological and clinical information. Full article
(This article belongs to the Special Issue Coenzyme Q10 in Mitochondria and Lysosomal Disorders)
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