Clk-1 deficiency induces apoptosis associated with mitochondrial dysfunction in mouse embryos.
Clk-1 gene encodes demethoxyubiquinone hydroxylase that catalyzes the production of coenzyme Q (CoQ) in mitochondria. Clk-1-deficient mice that lack CoQ fail to survive beyond the embryonic day 10.5 (E10.5). However, the relationship between the clk-1-deficiency and embryonic lethality remains unclear. We show in this study that TUNEL-positive cells are frequently observed in whole bodies of clk-1-deficient mouse embryos at E10.5. In addition, dissociated cells from the embryos exhibited characteristic features of apoptosis, such as externalization of phosphatidylserine on the plasma membrane, caspase-3 activation, and the release of cytochrome c from mitochondria into the cytoplasm, as the first sign of mitochondria-mediated apoptosis. In embryonic cells, the mitochondrial functions such as maintenance of the mitochondrial membrane potential and intracellular ATP level were impaired. Since exogenous CoQ10 rescued the mitochondrial dysfunction and suppressed apoptosis in clk-1-deficient cells, we propose that clk-1-deficiency induces apoptosis associated with mitochondrial dysfunction due to a lack of CoQ, which may lead to embryonic lethality in mice around E10.5.
Takahashi
Mayumi
M
Research Team for Molecular Biomarkers, Tokyo Metropolitan Institute of Gerontology, Itabashi-ku, Tokyo 173-0015, Japan.
Shimizu
Takahiko
T
Moriizumi
Eiko
E
Shirasawa
Takuji
T
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D003574:Cytochrome c Group / Q000378:metabolism; D004622:Embryo, Mammalian; D008564:Membrane Potentials / Q000235:genetics; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism* / Q000502:physiology; D024101:Mitochondrial Proteins; D006899:Mixed Function Oxygenases
D003574:Cytochrome c Group; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; C076615:cytochrome c''; D006899:Mixed Function Oxygenases; C434481:Coq7 protein, mouse