Ubiquinone Is Necessary for Mouse Embryonic Development but Is Not Essential for Mitochondrial Respiration

Levavasseur, Françoise; Miyadera, Haruo; Sirois, Jacinthe; Tremblay, Michel L.; Kita, Kiyoshi; Shoubridge, Eric A.; Hekimi, Siegfried

doi:10.1074/jbc.m108980200

Cited by 121 publications

(148 citation statements)

References 24 publications

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“…Mclk1 +/− mice lack one copy of an enzyme that is necessary for the synthesis of the antioxidant and redox co-factor ubiquinone [47]. This leads to numerous metabolic changes but in particular to an increase in mitochondrial oxidative stress [48], which is deleterious under some experimental conditions [49].…”

Section: Ros Signaling Affects Aging and Lifespanmentioning

confidence: 99%

Taking a “good” look at free radicals in the aging process

Hekimi

Lapointe

Yang

2011

Trends in Cell Biology

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511

373

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The mitochondrial free radical theory of aging (MFRTA) proposes that aging is caused by damage to macromolecules from mitochondrial reactive oxygen species (ROS). This is based on the observed association of the rate of aging and the aged phenotype with the generation of ROS and with oxidative damage. The theory has led to the strong conviction in the general public that the consumption of antioxidants is crucial to health and beneficial to lifespan. However, a variety of recent findings convincingly demonstrate that ROS generation and oxidative damage cannot be the cause of aging. Here we propose that ROS play a role in mediating a stress response to agedependent damage, which could generate the observed correlation between aging and ROS without implying that ROS cause aging. Redefining our understanding of the relationship between ROS and agingMitochondria are a major source of reactive oxygen species (ROS), a type of molecule that includes free radicals such as superoxide. ROS spontaneously oxidize and damage macromolecules such as proteins, lipids and nucleic acids. Cells and organisms are said to be sustaining oxidative stress when an imbalance between ROS generation and detoxification or repair leads to an increase in the level of ROS-dependent damage. The mitochondrial free radical theory of aging (MFRTA) has provided an attractive framework that integrates numerous observations about the generation, the toxicity and the detoxification of ROS, as well as about how these parameters change with the physiological state of cells and organisms and with chronological age. The theory proposes that aging is actually caused by the toxicity of ROS through a vicious cycle in which ROS damage to the constituents of mitochondria leads to the generation of more ROS. The theory is based on numerous observations, including (1) that there is a strong correlation between chronological age and the level of ROS generation and oxidative damage, (2) that mitochondrial function is gradually lost during aging, (3) that inhibition of mitochondrial function can enhance ROS production, and (4) that several age-dependent diseases are associated with severe increases in oxidative stress.The strength of the MFRTA is that it provides a framework for many observations while also stating a plausible causal theory of aging. Furthermore, it provided a clear research program by proposing a theory to be tested as well as by suggesting that decreasing the generation of ROS will result in health benefits. In fact the MFRTA is often taught in textbooks and in *

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Section: Ros Signaling Affects Aging and Lifespanmentioning

confidence: 99%

Taking a “good” look at free radicals in the aging process

Hekimi

Lapointe

Yang

2011

Trends in Cell Biology

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511

373

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“…In the absence of CLK-1, worms and mice are defective in Q biosynthesis (4 -6) and accumulate the Q precursor, demethoxyubiquinone (DMQ 9 ) (5, 6). Yet, mitochondrial respiration is not strongly affected in clk-1 mutants, indicating that DMQ can substitute for some, but not all, of the Q functions in vivo (5)(6)(7)(8)(9).…”

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confidence: 99%

Molecular Mechanism of Maternal Rescue in the clk-1 Mutants of Caenorhabditis elegans

Burgess

Hihi

Bénard

et al. 2003

Journal of Biological Chemistry

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The clk-1 mutants of Caenorhabditis elegans display an average slowing down of physiological rates, including those of development, various behaviors, and aging. clk-1 encodes a hydroxylase involved in the biosynthesis of the redox-active lipid ubiquinone (co-enzyme Q), and in clk-1 mutants, ubiquinone is replaced by its biosynthetic precursor demethoxyubiquinone. Surprisingly, homozygous clk-1 mutants display a wild-type phenotype when issued from a heterozygous mother. Here, we show that this maternal effect is the result of the persistence of small amounts of maternally derived CLK-1 protein and that maternal CLK-1 is sufficient for the synthesis of considerable amounts of ubiquinone during development. However, gradual depletion of CLK-1 and ubiquinone, and expression of the mutant phenotype, can be produced experimentally by developmental arrest. We also show that the very long lifespan observed in daf-2 clk-1 double mutants is not abolished by the maternal effect. This suggests that, like developmental arrest, the increased lifespan conferred by daf-2 allows for depletion of maternal CLK-1, resulting in the expression of the synergism between clk-1 and daf-2. Thus, increased adult longevity can be uncoupled from the early mutant phenotypes, indicating that it is possible to obtain an increased adult lifespan from the late inactivation of processes required for normal development and reproduction.The clk-1 gene of Caenorhabditis elegans encodes a 187-amino acid protein that is orthologous to yeast Coq7p as well as to rodent and human sequences (1). CLK-1 is necessary for ubiquinone (coenzyme Q, or Q) 1 biosynthesis. Q n is a prenylated benzoquinone (the numerical subscript denotes the number of isoprene repeats, which is a species-specific trait) that is primarily involved in numerous redox reactions in the cell, including those in the mitochondrial electron transport chain. In its reduced form, Q is an antioxidant, preventing lipid peroxidation in biological membranes (2, 3). In the absence of CLK-1, worms and mice are defective in Q biosynthesis (4 -6) and accumulate the Q precursor, demethoxyubiquinone (DMQ 9 ) (5, 6). Yet, mitochondrial respiration is not strongly affected in clk-1 mutants, indicating that DMQ can substitute for some, but not all, of the Q functions in vivo (5-9).Despite the presence of DMQ, clk-1 mutants require Q from their bacterial food source to proceed through development and become fertile adults (4, 10). Indeed, when clk-1 mutants are transferred onto a Q 8 -deficient E. coli strain before the early larval stages, they arrest development at the second larval stage, and when the animals are transferred onto Q 8 -deficient bacteria later in development, they become sterile adults. This fact strongly suggests that DMQ 9 cannot functionally replace Q 9 for all of its cellular roles, and that at least some Q is required, which can be provided as Q 8 in the diet. Thus, the viability and overall good health of the clk-1 mutants seems to rely on a combination of endogenously produced DM...

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“…In the mouse, a mutation replacing ubiquinone, UQ, the cofactor of the mitochondrial respiratory chain, by demethoxyubiquinone has been shown to reduce by 35% the mitochondrial oxygen consumption and to induce an arrest of the development of the embryo [65]. Moreover, in cell cultures, targeting a ubiquinone derivative to the mitochondria inhibited lipid peroxidation of the organelle's membrane as well as apoptosis [66], while endogenous ubiquinol also protects both lipids and proteins of beef heart sub-mitochondrial particles against oxidation [46].…”

Section: Ros Formation In the Mitochondria Of Placental And Fetal Tismentioning

confidence: 99%

“…Another radical trapping component, ubiquinone, which is also essential for energy metabolism [65] has also been reported to be essential for gestation outcome or viability of stem cells in the mouse.…”

Section: Defense Against Ros and The Outcome Of Gestationmentioning

confidence: 99%

“…Conflicting observations are obtained on the role of vitamin B1 deficiency in gestation failure: secretion of pituitary hormones or estrogen do not seem to be impaired despite a loss of appetite in gestating rats [57], while this vitamin can be recruited and activated in cells of the pituitary or blood vessel walls scavenging damaged cell components after an episode of ischemia [105] and is also an efficient ROS trapping component [59]. Increased rates of ROS fluxes have been reported in vitamin A, B2, B6, B9 or B12 deficiencies [60,94,[106][107][108] which, together with the ROS trapping ability of these compounds [21,60,61,69,70,109,110], points to some relationship to ROS phenomena, in addition to their effect on the control of gene expression and metabolism [29,65,67,68,[110][111][112].…”

Section: Defense Against Ros and The Outcome Of Gestationmentioning

confidence: 99%

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Gestation linked radical oxygen species fluxes and vitamins and trace mineral deficiencies in the ruminant

2006

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-In mammals, radical oxygen species (ROS) are essential factors of cell replication, differentiation and growth (oxidative signal), notably during gestation, but are also potentially damaging agents. In Women, ROS play a role in remodeling of uterine tissues, implantation of the embryo, settlement of the villi and development of blood vessels characteristic of gestation. The body stores of vitamins and minerals of gestating females are used to keep ROS fluxes at a level corresponding to oxidative signals and to prevent an imbalance between their production and scavenging (oxidative stress), which would be detrimental to the mother and fetus. There is some evidence that, although based on different regulatory mechanisms, most of the effects of ROS reported in humans also occur in pregnant ruminant females, some of which have been actually reported. Many vitamins and trace elements have dual effects in the organism of mammals: (a) they are involved in the control of metabolic pathways or/and gene expression, (b) but most of the time they also display ROS trapping activity or their deficiencies induce high rates of ROS production. Deficiencies induce different disorders of gestation and can be induced by different kinds of stress. An example is given, corresponding to the decreased contents of cobalt of forages, when exposed to sustained heavy rains, so that the supply of vitamins B12 to the organism of the ruminant that grazes them is reduced and failure of gestation is induced. Outdoor exposure of ruminants to adverse climatic conditions by itself can increase the vitamin and trace element requirements. Adaptation of production systems taking into account these interactions between gestation and sources of stress or change of the quality of feeding stuffs as well as further developments of knowledge in that field is necessary to promote sustainable agricultural practices.gestation / ovine / bovine / vitamins / trace elements / antioxidant enzymes / radical oxygen species / radical phenomena

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Ubiquinone Is Necessary for Mouse Embryonic Development but Is Not Essential for Mitochondrial Respiration

Cited by 121 publications

References 24 publications

Taking a “good” look at free radicals in the aging process

Taking a “good” look at free radicals in the aging process

Molecular Mechanism of Maternal Rescue in the clk-1 Mutants of Caenorhabditis elegans

Gestation linked radical oxygen species fluxes and vitamins and trace mineral deficiencies in the ruminant

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