Article Review: The importance of plasma membrane coenzyme Q in aging and stress response
Article Review: The importance of plasma membrane coenzyme Q in aging and stress response
Placido Navas, Jose Manuel Villalba and Rafael de Cabo
Elsevier B.V. and Mitochondria Research Society
February 3, 2007
The article is a review of different studies that focus on the importance of coenzyme Q in cell aging and stress response. Coenzyme Q is the only lipid antioxidant in the mammalian cell characterized by its ability to exchange two electrons simultaneously or sequentially in a redox cycle between its oxidized and reduced forms. It also acts as a cofactor for uncoupling proteins and enhances the survival of cells subjected to chemotherapy. In the mitochondrial respiratory chain complexes, CoQ acts as an electron carrier.
Together, CoQ and its reductases constitute an antioxidant system spanning the plasma membrane and are responsible for its stabilization, regeneration of antioxidants and regulation of the apoptosis pathway.
However, the regulation of CoQ biosynthesis pathway remains largely unknown. What is known is that, its biosynthesis is completed in the mitochondrion (in the case of yeast), and is driven to the plasma membrane by the brefeldin A-sensitive endomembrane pathway. It has also been posited that the biosynthesis of this compound involves the participation of about nine gene products, making the delineation of its metabolic pathway a challenge.
In order to fully understand the issue, the researchers reviewed various scientific studies about coenzyme Q focusing on its functions in the plasma membrane along with its reductases; its regulation under aging and stress conditions; and its role in the regulation of stress-induced apoptosis.
Review Highlights
Antioxidant System is CoQ Dependent
The antioxidant system of the plasma membrane shelters the cell from various environmental stress. The antioxidant ascorbate protects the hydrophilic cell surface while both CoQ and α-tocopherol protect the hydrophobic phospholipid bilayer.
It has been reported that the oxidized and reduced forms of CoQ in the plasma membrane as well as its free radicals can be detected. This is because CoQ interchanges electrons with other redox compounds as well as superoxides. These exchanges lead to the regeneration of CoQH2, a reduced form that recycles other antioxidants. Among the four CoQ reductases, only NADH-cytochrome b5 reductase and NQO1 were demonstrated to act at the plasma membrane. The former displays maximal activity with CoQ0, while the latter catalyzes the reduction of CoQ to CoQH2 and maintains its reduced state. These two enzymes contribute to the trans-plasma membrane redox system providing the electrons that are required to maintain CoQ’s antioxidant properties.
Based on these findings, the authors developed a scheme of a plasma membrane with a trans-membrane electron transport system that drives electron either from NADH-ascorbate free radical reductase, NQO1, or both, to CoQ which follows a cycle to CoQH2, through the semiquinone radical. This compound is then able to recycle other antioxidants such as ascorbate and α-tocopherol. CoQH2 and α-tocopherol both prevent the oxidative degradation of lipids.
Antioxidant System is Oxidative Stress Modulated
The reviewers pointed out that the actual mechanisms involved in regulating the changes in CoQ concentration in the plasma membrane and the accumulation of its reductases still remain elusive but, evidences are pointing to the activation of a stress signaling pathway.
Scientists found out that the eukaryotic cell has developed an adaptation which can be considered as a general response to impaired mitochondrial function in order to regulate NAD+/NADH levels. This impairment induces an increase of CoQ levels at the plasma membrane resulting in enhanced trans-membrane redox activity. These responses are likely evoked by cells for protection against oxidative stress. The more the oxidative stress, the more biosynthesis of CoQ and its reductases are observed. This increase in biosynthesis is not actually stress-related but an adaptive response to prevent cell death.
In the same manner, oxidative stress can be provoked by feeding on diet deficient with Vitamin E and Selenium, as findings on rat experiment show. This in turn results in increased CoQ biosysynthesis.
Generally, the enhanced amount of CoQ in the plasma membrane may be attributed to the enhanced biosynthesis, translocation of CoQ to the plasma membrane from the ER or mitochondria, or nutrient deficiency. These results support the authors’ findings in their own laboratory that the plasma membrane redox system is at least in part, responsible for the maintenance of the anti-oxidant capacity during oxidative stress induced by diet and aging.
Antioxidant System is Related with Age
Findings from various studies show that the level of antioxidant decreases with age. In the same way, oxidative damage to plasma membrane increases with age. However, this can be retarded by caloric restriction.
In rats, it was observed that aging is associated with increased level of lipid peroxidation, decreased fluidity of the plasma membrane and decreased ratio between good and bad fatty acids. It was also found out that those fed with polyunsaturated fatty acids and supplemented with CoQ10 had longer life span than those without CoQ10 supplements.
CoQ and Apoptosis
A plasma membrane that is supplemented with CoQ demonstrates an increased cell growth. With the increased CoQ concentration, its reductases likewise increase. This makes the plasma membrane more resistant to serum removal oxidative stress mediated apoptosis and accumulates lower levels of ceramide, a chemical signal that regulates programmed cell death and apoptosis.
When growth factors are withdrawn, the neutral sphingomyelinase (n-SMase) is activated in the plasma membrane. The activation of this compound is one of the signals for apoptosis to take place resulting in ceramide production which will eventually activate caspases, the general executioners of apoptosis.
However, CoQ10 can directly inhibit the n-SMase through a non-competitive mechanism at the initiation phase of apoptosis. This was proven in the experiment of pig liver. By preventing the activation of n-SMase in the plasma membrane, the activation of caspase is inhibited, thus the apoptosis pathway is shut down.
My Take
If the introduction of CoQ among rats resulted in longer life span, is it possible that it could also be introduced to humans and produce the same results? What foods are rich in CoQ? What role will CoQ play in the development of carcinomas?
Placido Navas, Jose Manuel Villalba and Rafael de Cabo
Elsevier B.V. and Mitochondria Research Society
February 3, 2007
The article is a review of different studies that focus on the importance of coenzyme Q in cell aging and stress response. Coenzyme Q is the only lipid antioxidant in the mammalian cell characterized by its ability to exchange two electrons simultaneously or sequentially in a redox cycle between its oxidized and reduced forms. It also acts as a cofactor for uncoupling proteins and enhances the survival of cells subjected to chemotherapy. In the mitochondrial respiratory chain complexes, CoQ acts as an electron carrier.
Together, CoQ and its reductases constitute an antioxidant system spanning the plasma membrane and are responsible for its stabilization, regeneration of antioxidants and regulation of the apoptosis pathway.
However, the regulation of CoQ biosynthesis pathway remains largely unknown. What is known is that, its biosynthesis is completed in the mitochondrion (in the case of yeast), and is driven to the plasma membrane by the brefeldin A-sensitive endomembrane pathway. It has also been posited that the biosynthesis of this compound involves the participation of about nine gene products, making the delineation of its metabolic pathway a challenge.
In order to fully understand the issue, the researchers reviewed various scientific studies about coenzyme Q focusing on its functions in the plasma membrane along with its reductases; its regulation under aging and stress conditions; and its role in the regulation of stress-induced apoptosis.
Review Highlights
Antioxidant System is CoQ Dependent
The antioxidant system of the plasma membrane shelters the cell from various environmental stress. The antioxidant ascorbate protects the hydrophilic cell surface while both CoQ and α-tocopherol protect the hydrophobic phospholipid bilayer.
It has been reported that the oxidized and reduced forms of CoQ in the plasma membrane as well as its free radicals can be detected. This is because CoQ interchanges electrons with other redox compounds as well as superoxides. These exchanges lead to the regeneration of CoQH2, a reduced form that recycles other antioxidants. Among the four CoQ reductases, only NADH-cytochrome b5 reductase and NQO1 were demonstrated to act at the plasma membrane. The former displays maximal activity with CoQ0, while the latter catalyzes the reduction of CoQ to CoQH2 and maintains its reduced state. These two enzymes contribute to the trans-plasma membrane redox system providing the electrons that are required to maintain CoQ’s antioxidant properties.
Based on these findings, the authors developed a scheme of a plasma membrane with a trans-membrane electron transport system that drives electron either from NADH-ascorbate free radical reductase, NQO1, or both, to CoQ which follows a cycle to CoQH2, through the semiquinone radical. This compound is then able to recycle other antioxidants such as ascorbate and α-tocopherol. CoQH2 and α-tocopherol both prevent the oxidative degradation of lipids.
Antioxidant System is Oxidative Stress Modulated
The reviewers pointed out that the actual mechanisms involved in regulating the changes in CoQ concentration in the plasma membrane and the accumulation of its reductases still remain elusive but, evidences are pointing to the activation of a stress signaling pathway.
Scientists found out that the eukaryotic cell has developed an adaptation which can be considered as a general response to impaired mitochondrial function in order to regulate NAD+/NADH levels. This impairment induces an increase of CoQ levels at the plasma membrane resulting in enhanced trans-membrane redox activity. These responses are likely evoked by cells for protection against oxidative stress. The more the oxidative stress, the more biosynthesis of CoQ and its reductases are observed. This increase in biosynthesis is not actually stress-related but an adaptive response to prevent cell death.
In the same manner, oxidative stress can be provoked by feeding on diet deficient with Vitamin E and Selenium, as findings on rat experiment show. This in turn results in increased CoQ biosysynthesis.
Generally, the enhanced amount of CoQ in the plasma membrane may be attributed to the enhanced biosynthesis, translocation of CoQ to the plasma membrane from the ER or mitochondria, or nutrient deficiency. These results support the authors’ findings in their own laboratory that the plasma membrane redox system is at least in part, responsible for the maintenance of the anti-oxidant capacity during oxidative stress induced by diet and aging.
Antioxidant System is Related with Age
Findings from various studies show that the level of antioxidant decreases with age. In the same way, oxidative damage to plasma membrane increases with age. However, this can be retarded by caloric restriction.
In rats, it was observed that aging is associated with increased level of lipid peroxidation, decreased fluidity of the plasma membrane and decreased ratio between good and bad fatty acids. It was also found out that those fed with polyunsaturated fatty acids and supplemented with CoQ10 had longer life span than those without CoQ10 supplements.
CoQ and Apoptosis
A plasma membrane that is supplemented with CoQ demonstrates an increased cell growth. With the increased CoQ concentration, its reductases likewise increase. This makes the plasma membrane more resistant to serum removal oxidative stress mediated apoptosis and accumulates lower levels of ceramide, a chemical signal that regulates programmed cell death and apoptosis.
When growth factors are withdrawn, the neutral sphingomyelinase (n-SMase) is activated in the plasma membrane. The activation of this compound is one of the signals for apoptosis to take place resulting in ceramide production which will eventually activate caspases, the general executioners of apoptosis.
However, CoQ10 can directly inhibit the n-SMase through a non-competitive mechanism at the initiation phase of apoptosis. This was proven in the experiment of pig liver. By preventing the activation of n-SMase in the plasma membrane, the activation of caspase is inhibited, thus the apoptosis pathway is shut down.
My Take
If the introduction of CoQ among rats resulted in longer life span, is it possible that it could also be introduced to humans and produce the same results? What foods are rich in CoQ? What role will CoQ play in the development of carcinomas?
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