The Effect of Coenzyme Q10 Therapy in Parkinson Disease Could Be Symptomatic—Reply

Shults, Clifford W.; Haas, Richard; Oakes, David; Kieburtz, Karl; Plumb, Sandra; Shoulson, Ira; Kurlan, Roger; Beal, M. Flint; Juncos, Jorge L.; Watts, Ray L.; Nutt, John G.; Carter, Julie; Kompoliti, Katie; Perlmutter, Joel S.; Reich, Stephen G.; Stern, Menachem; Molho, Eric; Harrison, Madeline; Lew, Mark F.

doi:10.1001/archneur.60.8.1172

Cited by 30 publications

(49 citation statements)

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“…Mitochondria were solubilized with digitonin (2:1, g/g) and the 100,000 ϫ g supernatant obtained from 2 mg of mitochondria was applied to a Superose 6 column. The column eluant was monitored for protein content (A 280 nm ), and fractions were collected and assayed for Coq3 O-methyltransferase activity, Coq polypeptides, and analyzed for the content of Q 6 and DMQ 6 . Coq3 O-methyltransferase activity (Fig.…”

Section: Coq3p and O-methyltransferase Activity Coelute With Coq4p Anmentioning

confidence: 99%

“…The Q Biosynthetic Intermediate DMQ 6 Is Associated with the Coq3-Coq4-Coq6 Complex-The co-migration of Coq3 activity and of Coq3, Coq4, and Coq6 polypeptides in gel filtration fractions provides physical evidence for a high molecular mass Q-biosynthetic complex. Previous work with the yeast coq mutants has implicated Q, or a Q-biosynthetic intermediate, as a lipid component potentially involved in maintaining steady levels of the Coq3, Coq4, and Coq6 polypeptides (25,26).…”

Section: Coq3p and O-methyltransferase Activity Coelute With Coq4p Anmentioning

confidence: 99%

“…and Saccharomyces cerevisiae Q 6 . Within the inner mitochondrial membrane Q functions in respiratory electron transport, where it transfers two electrons from either complex I or complex II to complex III (1).…”

mentioning

confidence: 99%

“…In addition to this role, Q has been found to act as a chain-breaking antioxidant (3) and to be involved in the electron transport chains of plasma and lysosomal membranes (4,5). Q supplementation in humans slows the functional decline in patients with Parkinson disease (6), is useful for treating patients with respiratory chain defects (7), and has promise as a treatment in other neurodegenerative diseases (8).…”

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confidence: 99%

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Coq3 and Coq4 Define a Polypeptide Complex in Yeast Mitochondria for the Biosynthesis of Coenzyme Q

Marbois¹,

Gin²,

Faull

et al. 2005

Journal of Biological Chemistry

120

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Coenzyme Q (Q) is a redox active lipid essential for aerobic respiration in eukaryotes. In Saccharomyces cerevisiae at least eight mitochondrial polypeptides, designated Coq1-Coq8, are required for Q biosynthesis. Here we present physical evidence for a coenzyme Qbiosynthetic polypeptide complex in isolated mitochondria. Separation of digitonin-solubilized mitochondrial extracts in one-and two-dimensional Blue Native PAGE analyses shows that Coq3 and Coq4 polypeptides comigrate as high molecular mass complexes. Similarly, gel filtration chromatography shows that Coq1p, Coq3p, Coq4p, Coq5p, and Coq6p elute in fractions higher than expected for their respective subunit molecular masses. Coq3p, Coq4p, and Coq6p coelute with an apparent molecular mass exceeding 700 kDa. Coq3 O-methyltransferase activity, a surrogate for Q biosynthesis and complex activity, also elutes at this high molecular mass. We have determined the quinone content in lipid extracts of gel filtration fractions by liquid chromatography-tandem mass spectrometry and find that demethoxy-Q 6 is enriched in fractions with Coq3p. Co-precipitation of biotinylated-Coq3 and Coq4 polypeptide from digitoninsolubilized mitochondrial extracts shows their physical association. This study identifies Coq3p and Coq4p as defining members of a Q-biosynthetic Coq polypeptide complex. Coenzyme Q (ubiquinone or Q) 1 is a redox active lipid containing a long polyprenyl tail attached to a fully substituted benzoquinone ring. The number (n) of isoprene units in the polyprenyl tail (Q n ) is distinct in different organisms; humans produce Q 10 , Caenorhabditis elegans Q 9 , Escherichia coli Q 8 , and Saccharomyces cerevisiae Q 6 . Within the inner mitochondrial membrane Q functions in respiratory electron transport, where it transfers two electrons from either complex I or complex II to complex III (1). Q is present in almost all organisms, with the quantity roughly matching the respiratory capability of the tissue from which it is isolated (2). In addition to this role, Q has been found to act as a chain-breaking antioxidant (3) and to be involved in the electron transport chains of plasma and lysosomal membranes (4, 5). Q supplementation in humans slows the functional decline in patients with Parkinson disease (6), is useful for treating patients with respiratory chain defects (7), and has promise as a treatment in other neurodegenerative diseases (8).As observed with other redox active compounds, Q has the potential to act as a source of oxidative stress. In certain species, the amount of reactive oxygen species generated by mitochondria has been related to Q content (9, 10). These described dual roles as antioxidant and prooxidant associate Q with both extended and shortened life spans. C. elegans fed E. coli diets lacking Q 8 , and C. elegans clk-1 mutants with defects in Q biosynthesis show increased life spans, and we have proposed that the decreased levels of Q are associated with a decreased level of the Q semiquinone radical (Q . ) and a decreased propensity to...

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Section: Coq3p and O-methyltransferase Activity Coelute With Coq4p Anmentioning

confidence: 99%

Section: Coq3p and O-methyltransferase Activity Coelute With Coq4p Anmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Coq3 and Coq4 Define a Polypeptide Complex in Yeast Mitochondria for the Biosynthesis of Coenzyme Q

Marbois¹,

Gin²,

Faull

et al. 2005

Journal of Biological Chemistry

120

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“…(the Q semiquinone radical) generated during respiratory electron transport (9). In humans, Q supplementation has been shown to be effective in treating patients with specific respiratory chain defects (10) and to slow the progression of Parkinson's disease symptoms (11).…”

mentioning

confidence: 99%

The Saccharomyces cerevisiae COQ6 Gene Encodes a Mitochondrial Flavin-dependent Monooxygenase Required for Coenzyme Q Biosynthesis

Gin

Hsu

Rothman

et al. 2003

Journal of Biological Chemistry

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Coenzyme Q (Q) is a lipid that functions as an electron carrier in the mitochondrial respiratory chain in eukaryotes. There are eight complementation groups of Q-deficient Saccharomyces cerevisiae mutants, designated coq1-coq8. Here we have isolated the COQ6 gene by functional complementation and, in contrast to a previous report, find it is not an essential gene. coq6 mutants are unable to grow on nonfermentable carbon sources and do not synthesize Q but instead accumulate the Q biosynthetic intermediate 3-hexaprenyl-4-hydroxybenzoic acid. The Coq6 polypeptide is imported into the mitochondria in a membrane potential-dependent manner. Coq6p is a peripheral membrane protein that localizes to the matrix side of the inner mitochondrial membrane. Based on sequence homology to known proteins, we suggest that COQ6 encodes a flavindependent monooxygenase required for one or more steps in Q biosynthesis.

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Reactive oxygen species, toxicity, oxidative stress, and antioxidants: chronic diseases and aging

Jomova,

Raptova,

Alomar

et al. 2023

Arch Toxicol

271

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A physiological level of oxygen/nitrogen free radicals and non-radical reactive species (collectively known as ROS/RNS) is termed oxidative eustress or “good stress” and is characterized by low to mild levels of oxidants involved in the regulation of various biochemical transformations such as carboxylation, hydroxylation, peroxidation, or modulation of signal transduction pathways such as Nuclear factor-κB (NF-κB), Mitogen-activated protein kinase (MAPK) cascade, phosphoinositide-3-kinase, nuclear factor erythroid 2–related factor 2 (Nrf2) and other processes. Increased levels of ROS/RNS, generated from both endogenous (mitochondria, NADPH oxidases) and/or exogenous sources (radiation, certain drugs, foods, cigarette smoking, pollution) result in a harmful condition termed oxidative stress (“bad stress”). Although it is widely accepted, that many chronic diseases are multifactorial in origin, they share oxidative stress as a common denominator. Here we review the importance of oxidative stress and the mechanisms through which oxidative stress contributes to the pathological states of an organism. Attention is focused on the chemistry of ROS and RNS (e.g. superoxide radical, hydrogen peroxide, hydroxyl radicals, peroxyl radicals, nitric oxide, peroxynitrite), and their role in oxidative damage of DNA, proteins, and membrane lipids. Quantitative and qualitative assessment of oxidative stress biomarkers is also discussed. Oxidative stress contributes to the pathology of cancer, cardiovascular diseases, diabetes, neurological disorders (Alzheimer’s and Parkinson’s diseases, Down syndrome), psychiatric diseases (depression, schizophrenia, bipolar disorder), renal disease, lung disease (chronic pulmonary obstruction, lung cancer), and aging. The concerted action of antioxidants to ameliorate the harmful effect of oxidative stress is achieved by antioxidant enzymes (Superoxide dismutases-SODs, catalase, glutathione peroxidase-GPx), and small molecular weight antioxidants (vitamins C and E, flavonoids, carotenoids, melatonin, ergothioneine, and others). Perhaps one of the most effective low molecular weight antioxidants is vitamin E, the first line of defense against the peroxidation of lipids. A promising approach appears to be the use of certain antioxidants (e.g. flavonoids), showing weak prooxidant properties that may boost cellular antioxidant systems and thus act as preventive anticancer agents. Redox metal-based enzyme mimetic compounds as potential pharmaceutical interventions and sirtuins as promising therapeutic targets for age-related diseases and anti-aging strategies are discussed.

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The Effect of Coenzyme Q10 Therapy in Parkinson Disease Could Be Symptomatic—Reply

Cited by 30 publications

References 0 publications

Coq3 and Coq4 Define a Polypeptide Complex in Yeast Mitochondria for the Biosynthesis of Coenzyme Q

Coq3 and Coq4 Define a Polypeptide Complex in Yeast Mitochondria for the Biosynthesis of Coenzyme Q

The Saccharomyces cerevisiae COQ6 Gene Encodes a Mitochondrial Flavin-dependent Monooxygenase Required for Coenzyme Q Biosynthesis

Reactive oxygen species, toxicity, oxidative stress, and antioxidants: chronic diseases and aging

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