Skip to main content
SpringerLink
Log in

The Aging Process and Coenzyme Q: Clk-1 Mouse Models

  • Chapter
  • First Online:
Coenzyme Q in Aging

  • 303 Accesses

Abstract

Mitochondria are causally linked to lifespan regulation and the aging process. Coenzyme Q (CoQ), an electron transporter in the mitochondrial respiratory chain, is a key molecule in the regulation of mitochondrial function. Loss of function of the clk-1 gene, which encodes a biosynthetic enzyme of CoQ, results in lifespan extension and slowed biological rhythms in Caenorhabditis elegans. The structure and function of the clk-1 gene are evolutionarily conserved from yeast to humans, however, clk-1−/− mice that lack CoQ are embryonic lethal. Clk-1 mutant nematodes with no dietary supply of CoQ also exhibit developmental arrest and larval death. Taken together, these results indicate that CoQ is critical for survival in the early development of both nematodes and mice, and play an important role for lifespan extension in nematodes. This review provides an overview of the role of clk-1 and CoQ in the regulation of lifespan and biological rhythms of mice.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

References

  • Andersson SG, Zomorodipour A, Andersson JO, Sicheritz-Ponten T, Alsmark UC, Podowski RM, Naslund AK, Eriksson AS, Winkler HH, Kurland CG (1998) The genome sequence of Rickettsia prowazekii and the origin of mitochondria. Nature 396(6707):133–140

    Article  CAS  PubMed  Google Scholar 

  • Asaumi S, Kuroyanagi H, Seki N, Shirasawa T (1999) Orthologues of the Caenorhabditis elegans longevity gene clk-1 in mouse and human. Genomics 58(3):293–301

    Article  CAS  PubMed  Google Scholar 

  • Asencio C, Rodriguez-Aguilera JC, Ruiz-Ferrer M, Vela J, Navas P (2003) Silencing of ubiquinone biosynthesis genes extends life span in Caenorhabditis elegans. FASEB J 17(9):1135–1137. https://doi.org/10.1096/fj.02-1022fje

    Article  CAS  PubMed  Google Scholar 

  • Chin RM, Fu X, Pai MY, Vergnes L, Hwang H, Deng G, Diep S, Lomenick B, Meli VS, Monsalve GC, Hu E, Whelan SA, Wang JX, Jung G, Solis GM, Fazlollahi F, Kaweeteerawat C, Quach A, Nili M, Krall AS, Godwin HA, Chang HR, Faull KF, Guo F, Jiang M, Trauger SA, Saghatelian A, Braas D, Christofk HR, Clarke CF, Teitell MA, Petrascheck M, Reue K, Jung ME, Frand AR, Huang J (2014) The metabolite alpha-ketoglutarate extends lifespan by inhibiting ATP synthase and TOR. Nature 510(7505):397–401. https://doi.org/10.1038/nature13264

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Copeland JM, Cho J, Lo T Jr, Hur JH, Bahadorani S, Arabyan T, Rabie J, Soh J, Walker DW (2009) Extension of Drosophila life span by RNAi of the mitochondrial respiratory chain. Curr Bio 19(19):1591–1598. https://doi.org/10.1016/j.cub.2009.08.016

    Article  CAS  Google Scholar 

  • Dell’agnello C, Leo S, Agostino A, Szabadkai G, Tiveron C, Zulian A, Prelle A, Roubertoux P, Rizzuto R, Zeviani M (2007) Increased longevity and refractoriness to Ca(2+)-dependent neurodegeneration in Surf1 knockout mice. Hum Mol Genet 16(4):431–444. https://doi.org/10.1093/hmg/ddl477

    Article  CAS  PubMed  Google Scholar 

  • Dillin A, Hsu AL, Arantes-Oliveira N, Lehrer-Graiwer J, Hsin H, Fraser AG, Kamath RS, Ahringer J, Kenyon C (2002) Rates of behavior and aging specified by mitochondrial function during development. Science 298(5602):2398–2401. https://doi.org/10.1126/science.1077780

    Article  CAS  PubMed  Google Scholar 

  • Ewbank JJ, Barnes TM, Lakowski B, Lussier M, Bussey H, Hekimi S (1997) Structural and functional conservation of the Caenorhabditis elegans timing gene clk-1. Science 275(5302):980–983

    Article  CAS  PubMed  Google Scholar 

  • Gems D, Doonan R (2009) Antioxidant defense and aging in C. elegans: is the oxidative damage theory of aging wrong? Cell Cycle 8(11):1681–1687. https://doi.org/10.4161/cc.8.11.8595

    Article  CAS  PubMed  Google Scholar 

  • Harman D (1956) Aging: a theory based on free radical and radiation chemistry. J Gerontol 11(3):298–300

    Article  CAS  PubMed  Google Scholar 

  • Harman D (1972) The biologic clock: the mitochondria? J Am Geriatr Soc 20(4):145–147

    Article  CAS  PubMed  Google Scholar 

  • Isomura A, Kageyama R (2014) Ultradian oscillations and pulses: coordinating cellular responses and cell fate decisions. Development 141(19):3627–3636. https://doi.org/10.1242/dev.104497

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Johnson TE, Lithgow GJ (1992) The search for the genetic basis of aging: the identification of gerontogenes in the nematode Caenorhabditis elegans. J Am Geriatr Soc 40(9):936–945

    Article  CAS  PubMed  Google Scholar 

  • Jonassen T, Larsen PL, Clarke CF (2001) A dietary source of coenzyme Q is essential for growth of long-lived Caenorhabditis elegans clk-1 mutants. Proc Natl Acad Sci U S A 98(2):421–426

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jonassen T, Marbois BN, Kim L, Chin A, Xia YR, Lusis AJ, Clarke CF (1996) Isolation and sequencing of the rat Coq7 gene and the mapping of mouse Coq7 to chromosome 7. Arch Biochem Biophys 330(2):285–289

    Article  CAS  PubMed  Google Scholar 

  • Jonassen T, Proft M, Randez-Gil F, Schultz JR, Marbois BN, Entian KD, Clarke CF (1998) Yeast Clk-1 homologue (Coq7/Cat5) is a mitochondrial protein in coenzyme Q synthesis. J Biol Chem 273(6):3351–3357

    Article  CAS  PubMed  Google Scholar 

  • Kang Li YL, Shelton JM, Richardson JA, Spencer E, Chen ZJ, Wang X, Williams RS (2000) Cytochrome c deficiency causes embryonic lethality and attenuates stress-induced apoptosis. Cell 101:389–399

    Article  Google Scholar 

  • Kaufman MH (1991) Histochemical identification of primordial germ cells and differentiation of the gonads in homozygous tetraploid mouse embryos. J Anat 179:169–181

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kaufman MH, Navaratnam V (1981) Early differentiation of the heart in mouse embryos. J Anat 133:235–246

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kawamukai M (2009) Biosynthesis and bioproduction of coenzyme Q10 by yeasts and other organisms. Biotechnol Appl Biochem 53(Pt 4):217–226. https://doi.org/10.1042/BA20090035

    Article  CAS  PubMed  Google Scholar 

  • Kayser EB, Sedensky MM, Morgan PG, Hoppel CL (2004) Mitochondrial oxidative phosphorylation is defective in the long-lived mutant clk-1. J Biol Chem 279(52):54479–54486

    Article  CAS  PubMed  Google Scholar 

  • Lapointe J, Hekimi S (2008) Early mitochondrial dysfunction in long-lived Mclk1+/− mice. J Biol Chem 283(38):26217–26227

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lapointe J, Wang Y, Bigras E, Hekimi S (2012) The submitochondrial distribution of ubiquinone affects respiration in long-lived Mclk1+/− mice. J Cell Biol 199(2):215–224. https://doi.org/10.1083/jcb.201203090

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Larsson NG, Wang J, Wilhelmsson H, Oldfors A, Rustin P, Lewandoski M, Barsh GS, Clayton DA (1998) Mitochondrial transcription factor A is necessary for mtDNA maintenance and embryogenesis in mice. Nat Genet 18(3):231–236

    Article  CAS  PubMed  Google Scholar 

  • Lee SJ, Hwang AB, Kenyon C (2010) Inhibition of respiration extends C. elegans life span via reactive oxygen species that increase HIF-1 activity. Curr Biol 20(23):2131–2136. https://doi.org/10.1016/j.cub.2010.10.057

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Levavasseur F, Miyadera H, Sirois J, Tremblay ML, Kita K, Shoubridge E, Hekimi S (2001) Ubiquinone is necessary for mouse embryonic development but is not essential for mitochondrial respiration. J Biol Chem 276(49):46160–46164

    Article  CAS  PubMed  Google Scholar 

  • Levine HJ (1997) Rest heart rate and life expectancy. J Am Coll Cardiol 30(4):1104–1106

    Article  CAS  PubMed  Google Scholar 

  • Lloyd D, Rossi E (1992) Ultradian rhythms in life processes: a fundamental inquiry into chronobiology and psychobiology. Springer, New York, pp 1–406

    Book  Google Scholar 

  • Marbois BN, Clarke CF (1996) The COQ7 gene encodes a protein in saccharomyces cerevisiae necessary for ubiquinone biosynthesis. J Biol Chem 6:2995–3004

    Article  Google Scholar 

  • Miyadera H, Amino H, Hiraishi A, Taka H, Murayama K, Miyoshi H, Sakamoto K, Ishii N, Hekimi S, Kita K (2001) Altered quinone biosynthesis in the long-lived clk-1 mutants of Caenorhabditis elegans. J Biol Chem 276(11):7713–7716

    Article  CAS  PubMed  Google Scholar 

  • Nakai D, Shimizu T, Nojiri H, Uchiyama S, Koike H, Takahashi M, Hirokawa K, Shirasawa T (2004) coq7/clk-1 regulates mitochondrial respiration and the generation of reactive oxygen species via coenzyme Q. Aging Cell 3(5):273–281

    Article  CAS  PubMed  Google Scholar 

  • Nakai D, Yuasa S, Takahashi M, Shimizu T, Asaumi S, Isono K, Takao T, Suzuki Y, Kuroyanagi H, Hirokawa K, Koseki H, Shirasawa T (2001) 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(2):463–471

    Article  CAS  PubMed  Google Scholar 

  • Sanz A, Fernandez-Ayala DJ, Stefanatos RK, Jacobs HT (2010) Mitochondrial ROS production correlates with, but does not directly regulate lifespan in Drosophila. Aging 2(4):200–223

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shepard TH, Muffley LA, Smith LT (1998) Ultrastructural study of mitochondria and their cristae in embryonic rats and primate (N. nemistrina). Anat Rec 252(3):383–392

    Article  CAS  PubMed  Google Scholar 

  • Stenmark P, Grunler J, Mattsson J, Sindelar PJ, Nordlund P, Berthold DA (2001) A new member of the family of di-iron carboxylate proteins. Coq7 (clk-1), a membrane-bound hydroxylase involved in ubiquinone biosynthesis. J Biol Chem 276(36):33297–33300

    Article  CAS  PubMed  Google Scholar 

  • Takahashi K, Noda Y, Ohsawa I, Shirasawa T, Takahashi M (2014) Extended lifespan, reduced body size and leg skeletal muscle mass, and decreased mitochondrial function in clk-1 transgenic mice. Exp Gerontol 58:146–153. https://doi.org/10.1016/j.exger.2014.08.003

    Article  CAS  PubMed  Google Scholar 

  • Takahashi M, Asaumi S, Honda S, Suzuki Y, Nakai D, Kuroyanagi H, Shimizu T, Honda Y, Shirasawa T (2001) Mouse coq7/clk-1 orthologue rescued slowed rhythmic behavior and extended life span of clk-1 longevity mutant in Caenorhabditis elegans. Biochem Biophys Res Commun 286(3):534–540

    Article  CAS  PubMed  Google Scholar 

  • Takahashi M, Ogawara M, Shimizu T, Shirasawa T (2012a) Restoration of the behavioral rates and lifespan in clk-1 mutant nematodes in response to exogenous coenzyme Q(10). Exp Gerontol 47(3):276–279. https://doi.org/10.1016/j.exger.2011.12.012

    Article  CAS  PubMed  Google Scholar 

  • Takahashi M, Shimizu T, Moriizumi E, Shirasawa T (2008) Clk-1 deficiency induces apoptosis associated with mitochondrial dysfunction in mouse embryos. Mech Ageing Dev 129(5):291–298

    Article  CAS  PubMed  Google Scholar 

  • Takahashi M, Shimizu T, Shirasawa T (2012b) Reversal of slow growth and heartbeat through the restoration of mitochondrial function in clk-1-deficient mouse embryos by exogenous administration of coenzyme Q10. Exp Gerontol 47(6):425–431. https://doi.org/10.1016/j.exger.2012.03.008

    Article  CAS  PubMed  Google Scholar 

  • Turunen M, Olsson J, Dallner G (2004) Metabolism and function of coenzyme Q. Biochim Biophys Acta 1660(1–2):171–199

    Article  CAS  PubMed  Google Scholar 

  • Vajo Z, King LM, Jonassen T, Wilkin DJ, Ho N, Munnich A, Clarke CF, Francomano CA (1999) Conservation of the Caenorhabditis elegans timing gene clk-1 from yeast to human: a gene required for ubiquinone biosynthesis with potential implications for aging. Mamm Genome 10(10):1000–1004

    Article  CAS  PubMed  Google Scholar 

  • Wang Y, Oxer D, Hekimi S (2015) Mitochondrial function and lifespan of mice with controlled ubiquinone biosynthesis. Nat Commun 6:6393. https://doi.org/10.1038/ncomms7393

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Williams GC, Pleitropy N (1957) Selection and the evolution of senescence. Evolution 11:398–411

    Article  Google Scholar 

  • Wong A, Boutis P, Hekimi S (1995) Mutations in the clk-1 gene of Caenorhabditis elegans affect developmental and behavioral timing. Genetics 139(3):1247–1259

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yang W, Hekimi S (2010) A mitochondrial superoxide signal triggers increased longevity in Caenorhabditis elegans. PLoS Biol 8(12):e1000556. https://doi.org/10.1371/journal.pbio.1000556

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yu EA, Weaver DR (2011) Disrupting the circadian clock: gene-specific effects on aging, cancer, and other phenotypes. Aging 3(5):479–493

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zheng H, Lapointe J, Hekimi S (2010) Lifelong protection from global cerebral ischemia and reperfusion in long-lived Mclk1(+/)(−) mutants. Exp Neurol 223(2):557–565. https://doi.org/10.1016/j.expneurol.2010.02.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Biological Process of Aging, Tokyo Metropolitan Institute of Gerontology, Itabashi-ku, Tokyo, Japan

    Mayumi Takahashi & Kazuhide Takahashi

  2. Shirasawa Anti-Aging Medical Institute, Bunkyo-ku, Tokyo, Japan

    Takuji Shirasawa

Authors
  1. Mayumi Takahashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kazuhide Takahashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Takuji Shirasawa
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mayumi Takahashi .

Editor information

Editors and Affiliations

  1. Physiology, Anatomy and Cell Biology Department Andalusian Center of Developmental Biology (CSIC-UPO), CIBERER Carlos III Health Institute, Pablo de Olavide University, Sevilla, Spain

    Guillermo López Lluch

Rights and permissions

Reprints and permissions

Copyright information

© 2020 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Takahashi, M., Takahashi, K., Shirasawa, T. (2020). The Aging Process and Coenzyme Q: Clk-1 Mouse Models. In: López Lluch, G. (eds) Coenzyme Q in Aging. Springer, Cham. https://doi.org/10.1007/978-3-030-45642-9_8

Download citation

Publish with us

Policies and ethics

Search

Navigation