• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of embojLink to Publisher's site
EMBO J. Apr 1, 1999; 18(7): 1783–1792.
PMCID: PMC1171264

CLK-1 controls respiration, behavior and aging in the nematode Caenorhabditis elegans.

Abstract

Mutations in the clk-1 gene of the nematode Caenorhabditis elegans result in an average slowing of a variety of developmental and physiological processes, including the cell cycle, embryogenesis, post-embryonic growth, rhythmic behaviors and aging. In yeast, a CLK-1 homologue is absolutely required for ubiquinone biosynthesis and thus respiration. Here we show that CLK-1 is fully active when fused to green fluorescent protein and is found in the mitochondria of all somatic cells. The activity of mutant mitochondria, however, is only very slightly impaired, as measured in vivo by a dye-uptake assay, and in vitro by the activity of succinate cytochrome c reductase. Overexpression of CLK-1 activity in wild-type worms can increase mitochondrial activity, accelerate behavioral rates during aging and shorten life span, indicating that clk-1 regulates and controls these processes. These observations also provide strong genetic evidence that mitochondria are causally involved in aging. Furthermore, the reduced respiration of the long-lived clk-1 mutants suggests that longevity is promoted by the age-dependent decrease in mitochondrial function that is observed in most species.

Full Text

The Full Text of this article is available as a PDF (282K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Andersson SG, Zomorodipour A, Andersson JO, Sicheritz-Pontén T, Alsmark UC, Podowski RM, Näslund AK, Eriksson AS, Winkler HH, Kurland CG. The genome sequence of Rickettsia prowazekii and the origin of mitochondria. Nature. 1998 Nov 12;396(6707):133–140. [PubMed]
  • Avery L. The genetics of feeding in Caenorhabditis elegans. Genetics. 1993 Apr;133(4):897–917. [PMC free article] [PubMed]
  • Bolanowski MA, Russell RL, Jacobson LA. Quantitative measures of aging in the nematode Caenorhabditis elegans. I. Population and longitudinal studies of two behavioral parameters. Mech Ageing Dev. 1981 Mar;15(3):279–295. [PubMed]
  • Brown GG, Beattie DS. Role of coenzyme Q in the mitochondrial respiratory chain. Reconstitution of activity in coenzyme Q deficient mutants of yeast. Biochemistry. 1977 Oct 4;16(20):4449–4454. [PubMed]
  • Croll NA, Smith JM, Zuckerman BM. The aging process of the nematode Caenorhabditis elegans in bacterial and axenic culture. Exp Aging Res. 1977 May;3(3):175–189. [PubMed]
  • Ewbank JJ, Barnes TM, Lakowski B, Lussier M, Bussey H, Hekimi S. Structural and functional conservation of the Caenorhabditis elegans timing gene clk-1. Science. 1997 Feb 14;275(5302):980–983. [PubMed]
  • Felton J, Michaelis S, Wright A. Mutations in two unlinked genes are required to produce asparagine auxotrophy in Escherichia coli. J Bacteriol. 1980 Apr;142(1):221–228. [PMC free article] [PubMed]
  • Fire A, Xu S, Montgomery MK, Kostas SA, Driver SE, Mello CC. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature. 1998 Feb 19;391(6669):806–811. [PubMed]
  • Hagen TM, Yowe DL, Bartholomew JC, Wehr CM, Do KL, Park JY, Ames BN. Mitochondrial decay in hepatocytes from old rats: membrane potential declines, heterogeneity and oxidants increase. Proc Natl Acad Sci U S A. 1997 Apr 1;94(7):3064–3069. [PMC free article] [PubMed]
  • Harman D. The biologic clock: the mitochondria? J Am Geriatr Soc. 1972 Apr;20(4):145–147. [PubMed]
  • Hekimi S, Lakowski B, Barnes TM, Ewbank JJ. Molecular genetics of life span in C. elegans: how much does it teach us? Trends Genet. 1998 Jan;14(1):14–20. [PubMed]
  • Ishii N, Fujii M, Hartman PS, Tsuda M, Yasuda K, Senoo-Matsuda N, Yanase S, Ayusawa D, Suzuki K. A mutation in succinate dehydrogenase cytochrome b causes oxidative stress and ageing in nematodes. Nature. 1998 Aug 13;394(6694):694–697. [PubMed]
  • Johnson LV, Walsh ML, Bockus BJ, Chen LB. Monitoring of relative mitochondrial membrane potential in living cells by fluorescence microscopy. J Cell Biol. 1981 Mar;88(3):526–535. [PMC free article] [PubMed]
  • Jonassen T, Marbois BN, Kim L, Chin A, Xia YR, Lusis AJ, Clarke CF. Isolation and sequencing of the rat Coq7 gene and the mapping of mouse Coq7 to chromosome 7. Arch Biochem Biophys. 1996 Jun 15;330(2):285–289. [PubMed]
  • Jonassen T, Proft M, Randez-Gil F, Schultz JR, Marbois BN, Entian KD, Clarke CF. Yeast Clk-1 homologue (Coq7/Cat5) is a mitochondrial protein in coenzyme Q synthesis. J Biol Chem. 1998 Feb 6;273(6):3351–3357. [PubMed]
  • Labbé JC, Hekimi S, Rokeach LA. The levels of the RoRNP-associated Y RNA are dependent upon the presence of ROP-1, the Caenorhabditis elegans Ro60 protein. Genetics. 1999 Jan;151(1):143–150. [PMC free article] [PubMed]
  • Lakowski B, Hekimi S. Determination of life-span in Caenorhabditis elegans by four clock genes. Science. 1996 May 17;272(5264):1010–1013. [PubMed]
  • Lakowski B, Hekimi S. The genetics of caloric restriction in Caenorhabditis elegans. Proc Natl Acad Sci U S A. 1998 Oct 27;95(22):13091–13096. [PMC free article] [PubMed]
  • Linnane AW, Marzuki S, Ozawa T, Tanaka M. Mitochondrial DNA mutations as an important contributor to ageing and degenerative diseases. Lancet. 1989 Mar 25;1(8639):642–645. [PubMed]
  • Marbois BN, Clarke CF. The COQ7 gene encodes a protein in saccharomyces cerevisiae necessary for ubiquinone biosynthesis. J Biol Chem. 1996 Feb 9;271(6):2995–3004. [PubMed]
  • Mello C, Fire A. DNA transformation. Methods Cell Biol. 1995;48:451–482. [PubMed]
  • Mello CC, Kramer JM, Stinchcomb D, Ambros V. Efficient gene transfer in C.elegans: extrachromosomal maintenance and integration of transforming sequences. EMBO J. 1991 Dec;10(12):3959–3970. [PMC free article] [PubMed]
  • Miquel J. An update on the oxygen stress-mitochondrial mutation theory of aging: genetic and evolutionary implications. Exp Gerontol. 1998 Jan-Mar;33(1-2):113–126. [PubMed]
  • Murfitt RR, Vogel K, Sanadi DR. Characterization of the mitochondria of the free-living nematode, Caenorhabditis elegans. Comp Biochem Physiol B. 1976;53(4):423–430. [PubMed]
  • Poyton RO, McEwen JE. Crosstalk between nuclear and mitochondrial genomes. Annu Rev Biochem. 1996;65:563–607. [PubMed]
  • Shigenaga MK, Hagen TM, Ames BN. Oxidative damage and mitochondrial decay in aging. Proc Natl Acad Sci U S A. 1994 Nov 8;91(23):10771–10778. [PMC free article] [PubMed]
  • Wong A, Boutis P, Hekimi S. Mutations in the clk-1 gene of Caenorhabditis elegans affect developmental and behavioral timing. Genetics. 1995 Mar;139(3):1247–1259. [PMC free article] [PubMed]

Articles from The EMBO Journal are provided here courtesy of The European Molecular Biology Organization

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...