Border between natural product and drug: Comparison of the related benzoquinones idebenone and coenzyme Q10

Gueven, Nuri; Woolley, Krystel L.; Smith, Jason A.

doi:10.1016/j.redox.2015.01.009

Cited by 93 publications

(64 citation statements)

References 43 publications

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“…Coenzyme Q10 is rather lipophilic and has poor pharmacokinetic properties, which is the reason why idebenone is preferred in therapeutic studies. 24 We directly examined the effects of idebenone on TMEM16A in patch clamp recordings. tBHP activated large Cl 2 -selective whole-cell currents in TMEM16A-expressing HEK293 cells but not in mock transfected cells ( Figure 6, A and B).…”

Section: Oxidative Stress Induces Growth and Expansion Of Mdck Cystsmentioning

confidence: 99%

Lipid Peroxidation Drives Renal Cyst Growth In Vitro through Activation of TMEM16A

Schreiber

Buchholz

Kraus

et al. 2019

JASN

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Background Transepithelial chloride 2 secretion, through the chloride channels cystic fibrosis transmembrane conductance regulator (CFTR) and TMEM16A (anoctamin 1), drives cyst enlargement in polycystic kidney disease (PKD). Polycystic kidneys are hypoxic, and oxidative stress activates TMEM16A. However, mechanisms for channel activation in PKD remain obscure.Methods Using tissue samples from patients with autosomal dominant PKD, embryonic kidney cultures, and an MDCK in vitro cyst model, we assessed peroxidation of plasma membrane phospholipids in human and mouse polycystic kidneys. We also used electrophysiologic Ussing chamber and patch clamp experiments to analyze activation of TMEM16A and growth of renal cysts.Results Peroxidation of phospholipids in human and mouse kidneys as well as MDCK cysts in vitro is probably due to enhanced levels of reactive oxygen species. Lipid peroxidation correlated with increased cyst volume as shown in renal cultures and MDCK cysts in three-dimensional cultures. Reactive oxygen species and lipid peroxidation strongly activated TMEM16A, leading to depletion of calcium ion stores and store-operated calcium influx. Activation of TMEM16A-and CFTR-dependent chloride secretion strongly augmented cyst growth. Exposure to scavengers of reactive oxygen species, such as glutathione, coenzyme Q10, or idebenone (a synthetic coenzyme Q10 homolog), as well as inhibition of oxidative lipid damage by ferrostatin-1 largely reduced activation of TMEM16A. Inhibition of TMEM16A reduced proliferation and fluid secretion in vitro. ConclusionsThese findings indicate that activation of TMEM16A by lipid peroxidation drives growth of renal cysts. We propose direct inhibition of TMEM16A or inhibition of lipid peroxidation as potentially powerful therapeutic approaches to delay cyst development in PKD.

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Section: Oxidative Stress Induces Growth and Expansion Of Mdck Cystsmentioning

confidence: 99%

Lipid Peroxidation Drives Renal Cyst Growth In Vitro through Activation of TMEM16A

Schreiber

Buchholz

Kraus

et al. 2019

JASN

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“…Due to the indispensable function in the processes of oxidative phosphorylation, Coenzyme Q-10 (CoQ-10) and its derivatives are the most prominent members in the family of Q/HQ [4][5][6][7]. Although the number of studies related to the chemical and redox features of CoQ family members has increased tremendously in the last three decades [8][9][10][11][12][13][14][15][16][17][18], many key features are still not well understood. In our last two publications we have shown that Coenzyme Q-1 (CoQ-1) and CoQ-10 undergo structural changes in strong alkaline environment or in the presence of Cytochrome P450 enzymes [19,20].…”

Section: Introductionmentioning

confidence: 99%

New insights into the chemistry of Coenzyme Q-0: A voltammetric and spectroscopic study

Gulaboski

Bogeski

Kokoškarova

et al. 2016

Bioelectrochemistry

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Coenzyme Q-0 (CoQ-0) is the only Coenzyme Q lacking an isoprenoid group on the quinoid ring, a feature important for its physico-chemical properties. Here, the redox behavior of CoQ-0 in buffered and non-buffered aqueous media was examined. In buffered aqueous media CoQ-0 redox chemistry can be described by a 2-electron-2-proton redox scheme, characteristic for all benzoquinones. In non-buffered media the number of electrons involved in the electrode reaction of CoQ-0 is still 2; however, the number of protons involved varies between 0 and 2. This results in two additional voltammetric signals, attributed to 2-electrons-1H + and 2-electrons-0H + redox processes, in which mono-and di-anionic compounds of CoQ-0 are formed. In addition, CoQ-0 exhibits a complex chemistry in strong alkaline environment. The reaction of CoQ-0 and OH − anions generates several hydroxyl derivatives as products. Their structures were identified with HPLC/MS. The prevailing radical reaction mechanism was analyzed by electron paramagnetic resonance spectroscopy. The hydroxyl derivatives of CoQ-0 have a strong antioxidative potential and form stable complexes with Ca 2+ ions. In summary, our results allow mechanistic insights into the redox properties of CoQ-0 and its hydroxylated derivatives and provide hints on possible applications.

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“…Idebenone is a synthetic short-chain benzoquinone that, like coenzyme Q10, carries energy equivalents within the electron transport chain. Unlike coenzyme Q10, however, idebenone also shuttles energy equivalents from the cytosol to the electron transport chain [40]. Thus, the facilitation of metabolic pathways is the rationale for its potential effect in DMD.…”

Section: Other Mechanismsmentioning

confidence: 99%

Emerging Strategies in the Treatment of Duchenne Muscular Dystrophy

Shieh

2018

Neurotherapeutics

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Duchenne muscular dystrophy (DMD) is a progressive X-linked degenerative muscle disease due to mutations in the DMD gene. Genetic confirmation has become standard in recent years. Improvements in the standard of care for DMD have led to improved survival. Novel treatments for DMD have focused on reducing the dystrophic mechanism of the muscle disease, modulating utrophin protein expression, and restoring dystrophin protein expression. Among the strategies to reduce the dystrophic mechanisms are 1) inhibiting inflammation, 2) promoting muscle growth and regeneration, 3) reducing fibrosis, and 4) facilitating mitochondrial function. The agents under investigation include a novel steroid, myostatin inhibitors, idebenone, an anti-CTGF antibody, a histone deacetylase inhibitor, and cardiosphere-derived cells. For utrophin modulation, AAV-mediated gene therapy with GALGT2 is currently being investigated to upregulate utrophin expression. Finally, the strategies for dystrophin protein restoration include 1) nonsense readthrough, 2) synthetic antisense oligonucleotides for exon skipping, and 3) AAV-mediated micro/minidystrophin gene delivery. With newer agents, we are witnessing the use of more advanced biotechnological methods. Although these potential breakthroughs provide significant promise, they may also raise new questions regarding treatment effect and safety.

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Border between natural product and drug: Comparison of the related benzoquinones idebenone and coenzyme Q10

Cited by 93 publications

References 43 publications

Lipid Peroxidation Drives Renal Cyst Growth In Vitro through Activation of TMEM16A

Lipid Peroxidation Drives Renal Cyst Growth In Vitro through Activation of TMEM16A

New insights into the chemistry of Coenzyme Q-0: A voltammetric and spectroscopic study

Emerging Strategies in the Treatment of Duchenne Muscular Dystrophy

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