Silencing of ubiquinone biosynthesis genes extends life span in<i>Caenorhabditis elegans</i>

Asencio, Claudio; Rodríguez-Aguilera, Juan Carlos; Ruiz-Ferrer, Macarena; Vela, Jordana; Navas, Plácido

doi:10.1096/fj.02-1022fje

Cited by 69 publications

(50 citation statements)

References 41 publications

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“…Homozygous coq-1 mutants appear Unc as L3 larvae. Degeneration of GABA neurons is initially observed in young adults ( We tested deletion mutants for coq-2 and coq-3 to ask whether genetic ablation of other CoQ biosynthetic genes phenocopies coq-1 knockdown (24). GABA neurons of coq-2(ok1066) and coq-3(ok506) animals also show the swollen morphology ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Coenzyme Q protects Caenorhabditis elegans GABA neurons from calcium-dependent degeneration

Earls

Hacker²,

Watson³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Mitochondria are key regulators of cell viability and provide essential functions that protect against neurodegenerative disease. To develop a model for mitochondrial-dependent neurodegeneration in Caenorhabditis elegans, we used RNA interference (RNAi) and genetic ablation to knock down expression of enzymes in the Coenzyme Q (CoQ) biosynthetic pathway. CoQ is a required component of the ATP-producing electron transport chain in mitochondria. We found that reduced levels of CoQ result in a progressive uncoordinated (Unc) phenotype that is correlated with the appearance of degenerating GABA neurons. Both the Unc and degenerative phenotypes emerge during late larval development and progress in adults. Neuron classes in motor and sensory circuits that use other neurotransmitters (dopamine, acetylcholine, glutamate, serotonin) and body muscle cells were less sensitive to CoQ depletion. Our results indicate that the mechanism of GABA neuron degeneration is calcium-dependent and requires activation of the apoptotic gene, ced-4 (Apaf-1). A molecular cascade involving mitochondrial-initiated cell death is also consistent with our finding that GABA neuron degeneration requires the mitochondrial fission gene, drp-1. We conclude that the cell selectivity and developmental progression of CoQ deficiency in C. elegans indicate that this model may be useful for delineating the role of mitochondrial dysfunction in neurodegenerative disease.cell death | disease | mitochondria | neurodegeneration | necrosis

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Section: Resultsmentioning

confidence: 99%

Coenzyme Q protects Caenorhabditis elegans GABA neurons from calcium-dependent degeneration

Earls

Hacker²,

Watson³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…Recently, RNA interference (RNAi) on the genes for the respiratory complex (Dillin et al, 2002) as well as the genes involved in CoQ synthesis (Asencio et al, 2003) such as clk-1 extend lifespan in C. elegans. These data indicate that the extension of animal lifespan might be attributed to the depressed activities of mitochondrial enzymes (Dillin et al, 2002), or alternatively to the suppressed generation of superoxide caused by depressed CoQ (Asencio et al, 2003). Contrary to the latter hypothesis, Braeckman et al (2002) reported that the generation of ROS in clk-1 (e2519) was slightly elevated when measured using lucigenin luminescence.…”

Section: Discussionmentioning

confidence: 99%

coq7/clk‐1 regulates mitochondrial respiration and the generation of reactive oxygen species via coenzyme Q

et al. 2004

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Summary coq7/clk-1 was isolated from a long-lived mutant ofCaenorhabditis elegans , and shows sluggish behaviours and an extended lifespan. In C. elegans and Saccharomyces cerevisiae , coq7/clk-1 is required for the biosynthesis of coenzyme Q (CoQ), an essential co-factor in mitochondrial respiration. The clk-1 mutant contains dietary CoQ 8 from Escherichia coli and demethoxyubiquinone 9 (DMQ9) instead of CoQ 9 . In a previous study, we generated COQ7-deficient mice by targeted disruption of the coq7 gene and reported that mouse coq7/clk-1 is also essential for CoQ synthesis, maintenance of mitochondrial integrity and neurogenesis. In the present study, we rescued COQ7-deficient mice from embryonic lethality and established a mouse model with decreased CoQ level by transgene expression of COQ7/CLK-1. A biochemical analysis showed a concomitant decrease in CoQ 9 , mitochondrial respiratory enzyme activity and the generation of reactive oxygen species (ROS) in the mitochondria of CoQ-insufficient mice. This implied that the depressed activity of respiratory enzymes and the depressed production of ROS may play a physiological role in the control of lifespan in mammalian species and of C. elegans .

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“…Results of studies in other species are, however, quite contradictory and species-specific. For instance, different groups have reported that life span of the worm, C. elegans, is prolonged by CoQ 10 supplementation (Asencio et al, 2003), or, paradoxically, by a deficiency of CoQ in the diet (Larsen and Clarke, 2002) or even by the inability of a mutant strain to synthesize the normal CoQ homologue (Branicky et al, 2002). One explanation of these contradictory findings may be the unusual life history and the mode of adaptation of C. elegans to stress.…”

Section: Coq Intake Mitochondrial Function and Life Span In Micementioning

confidence: 99%

Coenzyme Q, oxidative stress and aging

2007

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Coenzyme Q (CoQ) has three well-characterized functions in mitochondria, namely (i) transfer of reducing equivalents in the electron transport chain, (ii) generation of superoxide anion radical (O 2˙̄) , and (iii) quenching of free radicals. The main purpose of this review is to discuss the effects of CoQ 10 intake for relatively prolonged periods on mitochondrial respiratory capacity, indicators of oxidative stress, and life span of animals, in context of the broader issue of whether or not the overall progression of the aging process can be modified by CoQ 10 administration. Comparative studies on different mammalian species have indicated that the rate of mitochondrial superoxide anion radical generation is directly correlated with mitochondrial CoQ 9 content and inversely related to amounts of CoQ 10 , particularly the CoQ 10 bound to mitochondrial membrane proteins. Contrary to the historical view, dietary supplementation of mice and rats with CoQ 10 has been demonstrated to augment the endogenous CoQ content (CoQ 9 + CoQ 10) in mitochondria and homogenates of various tissues, albeit to varying extent. Ingestion of CoQ 10 results in the elevation of endogenous CoQ 9 , the predominant homologue in mice and rats. In our studies, there was no indication of a discernable effect of CoQ 10 intake reflecting enhancement of mitochondrial respiratory activity, antioxidant capacity and pro-oxidant potentiation or prolongation of life span. The possibility that CoQ 10 intake affects certain other biological functions by as yet unelucidated mechanisms cannot be ruled out as CoQ has been shown to broadly alter gene expression in mice.

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Silencing of ubiquinone biosynthesis genes extends life span inCaenorhabditis elegans

Cited by 69 publications

References 41 publications

Coenzyme Q protects Caenorhabditis elegans GABA neurons from calcium-dependent degeneration

Coenzyme Q protects Caenorhabditis elegans GABA neurons from calcium-dependent degeneration

coq7/clk‐1 regulates mitochondrial respiration and the generation of reactive oxygen species via coenzyme Q

Coenzyme Q, oxidative stress and aging

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