title: Reversal of slow growth and heartbeat through the restoration of mitochondrial function in clk-1-deficient mouse embryos by exogenous administration of coenzyme Q10.
abstract: The longevity gene clk-1/coq7 encodes an enzyme that is essential for the biosynthesis of coenzyme Q (CoQ) in mitochondria and regulates the lifespan and behavioral timing in Caenorhabditis elegans and the chronological lifespan in fission yeast. However, whether the mammalian clk-1/coq7 ortholog (clk-1) regulates these phenotypes in mammals remains to be fully evaluated due to the embryonic lethality of clk-1-deficient (clk-1(-/-)) mice. To investigate whether clk-1 regulates biological functions, such as growth and heartbeat, through CoQ in mouse embryos, we cultivated the cells and hearts of clk-1(-/-) mouse embryos at embryonic day 10.5 (E10.5) for at least 10 days in the presence of fetal bovine serum. In embryonic cells, cardiomyocytes, and hearts, the growth and heart rates were significantly slowed in clk-1(-/-) compared with wild-type or heterozygous mouse tissues. Moreover, frequent apoptosis and a significant reduction in mitochondrial functions, including membrane potential and ATP production, were observed in the clk-1(-/-) cells and hearts. The slowed growth and heart rates and the reduced mitochondrial function of clk-1(-/-) embryonic cells and hearts in culture were almost completely rescued by the administration of exogenous CoQ(10). The results indicate that clk-1 regulates growth and heart rates through CoQ-mediated mitochondrial functions in mouse embryos.
authors.affiliation: Biological Process of Aging, Tokyo Metropolitan Institute of Gerontology, Itabashi-ku, Tokyo 173-0015, Japan. mmtaka@tmig.or.jp
authors.forename: Mayumi
authors.initials: M
authors.lastname: Takahashi
authors.forename: Takahiko
authors.initials: T
authors.lastname: Shimizu
authors.forename: Takuji
authors.initials: T
authors.lastname: Shirasawa
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005318:Fetal Heart / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D009924:Organ Culture Techniques; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000172:deficiency / Q000502:physiology*; D014451:Ubiquinone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D014815:Vitamins / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D014815:Vitamins; D014451:Ubiquinone; D000255:Adenosine Triphosphate; C066780:Clk dual-specificity kinases; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; C024989:coenzyme Q10