Sci. Aging Knowl. Environ., 5 December 2001
Vol. 2001, Issue 10, p. nw38
[DOI: 10.1126/sageke.2001.10.nw38]

NOTEWORTHY ARTICLES

Clocked Out: Mice missing clk-1 die young (Mitochondrial respiration)

R. John Davenport

http://sageke.sciencemag.org/cgi/content/abstract/sageke;2001/10/nw38

Key Words: clk-1 • ubiquinone • coenzyme Q • mitochondria • oxidative damage

Abstract: Ubiquinone plays a key role in the production of useable cellular energy, but the lipid can also cause trouble: It helps manufacture reactive oxygen species (ROS), which likely contribute to aging (see "The Two Faces of Oxygen"). Previously, scientists identified a nematode gene, clk-1, that generates ubiquinone and limits life-span. New work suggests that mice lacking the corresponding gene display similar abnormalities as do worms: For example, they make unusually small amounts of ubiquinone and consume less oxygen than normal, although an effect on life-span has yet to be observed. The work opens up new avenues for studying the role of ubiquinone in mammals and might lead to insights into how ROS production influences aging.

Mutations in clk-1 lengthen life-span in Caenorhabditis elegans and also slow embryonic development. The gene encodes an enzyme that enacts a crucial step in the production of chemical energy: It transforms demethoxyubiquinone (DMQ) into ubiquinone (also known as coenzyme Q). Ubiquinone transfers electrons within the mitochondrial respiratory chain, a series of protein stations that convert food energy into adenosine triphosphate (ATP). The exact mechanism by which clk-1 affects life-span is unclear: A dearth of ubiquinone in worms might slow the process--commonly called respiration--enough to reduce the amount of ROS, but that hypothesis has yet to be confirmed. In addition, ubiquinone assists in numerous chemical reactions unrelated to respiration, any of which could affect longevity: For instance, it helps create sulfur bridges within proteins and prevents oxidative damage to cell membranes.

To further investigate how clk-1 affects respiration and whether it extends life-span in mammals, two independent research teams created clk-1-deficient mice. Animals that bear only one copy of the gene function normally, but mice that lack both copies die after about 10 days of embryonic development. Embryos with no clk-1 don't produce detectable amounts of ubiquinone and instead carry unusually high concentrations of DMQ. Similar results were previously observed in C. elegans: clk-1 mutant worms survive embryonic development only when fed ubiquinone; they also accumulate DMQ.

But the mechanism by which a lack of clk-1 fouls up embryos is unclear. If respiration ground to a halt in the absence of ubiquinone, cells wouldn't generate enough ATP to support normal development. Electron microscope analysis of mouse embryos missing clk-1 is consistent with that idea: Nakai and colleagues observed misshapen brain cells with enlarged mitochondria that resemble those carried by animals with known defects in the respiratory chain. However, the respiratory chain might not be responsible for the developmental problems in clk-1 mice. Levavasseur and colleagues cultured mouse embryonic stem cells in which clk-1 had been deleted and assessed the function of respiratory enzymes that need ubiquinone to work efficiently. Succinate cytochrome c reductase and NADH-cytochrome c reductase productivity dropped 85% and 35%, respectively, compared to that in normal cells. The cells' oxygen consumption dove 35%. These results suggest that a lack of ubiquinone reduces flow through the respiratory chain but doesn't completely shut it off; the researchers speculate that DMQ might partially substitute for ubiquinone--an idea that is bolstered by the same researchers' other studies in worm mitochondria. Perhaps ubiquinone influences development through one of its functions outside the respiratory chain, they propose.

The developmental arrest and large amounts of DMQ in mice without clk-1 indicate that clk-1 exerts some of the same effects in mammals as it does in worms. Whether clk-1 affects longevity in mice remains unclear: The answer might be revealed in future experiments in which researchers knock the gene out of commission only after embryonic development is completed. The new mutant mice offer an additional tool with which to tease apart the functions of ubiquinone and learn how they affect aging.

--R. John Davenport; suggested by Chang-Su Lim

D. Nakai et al., Mouse homologue of coq7/clk-1, longevity gene in Caenorhabditis elegans, is essential for coenzyme Q synthesis, maintenance of mitochondrial integrity, and neurogenesis. Biochem. Biophys. Res. Commun. 289, 463-471 (2001). [Abstract] [Full Text]

F. Levavasseur, H. Miyadera, J. Sirois, M. L. Tremblay, K. Kita, E. Shoubridge, S. Hekimi, Ubiquinone is necessary for mouse embryonic development but is not essential for mitochondrial respiration. J. Biol. Chem. 276, 46160-46164 (2001). [Abstract] [Full Text]

Citation: R. J. Davenport, Clocked Out: Mice missing clk-1 die young (Mitochondrial respiration). Science's SAGE KE (5 December 2001), http://sageke.sciencemag.org/cgi/content/abstract/sageke;2001/10/nw38








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