Catherine Freitag Clarke, Ph.D.

Laboratory Address:
Young Hall 2107, 5073

Work Address:
Young Hall 5072B

Affiliations
Affiliations
Professor, Chemistry and Biochemistry, Biochemistry, Molecular Biology
Member, Graduate Program in Biochemistry, Molecular and Structural Biology, Molecular Biology Institute, themes
Researcher, Biochemistry, Chemical Biology, Proteomics and Bioinformatics
Research Interests
Coenzyme Q (also known as ubiquinone or Q) is a lipid component of cellular membranes that functions in cells as a redox-active coenzyme of both mitochondria and plasma membrane electron transport, as an essential lipid soluble antioxidant, and plays a role in apoptosis. We study the biosynthesis, regulation and function of Q in the yeast Saccharomyces cerevisiae. Our research takes advantage of a class of respiratory defective yeast mutants deficient in Q. We are characterizing the defects in these mutants by isolating and elucidating the structures of the Q biosynthetic intermediates and are characterizing both yeast and mammalian polypeptides required for Q biosynthesis. Our results suggest that yeast and higher eukaryotes share the same Q biosynthetic pathway, and that a large multi-subunit complex within the mitochondrial matrix is required for Q biosynthesis. Recently we have turned to the nematode Caenorhabditis elegans as an excellent model for genetic studies of the aging process. Gene mutations that increase life span have been identified in C. elegans that have homologs in vertebrates and appear to act by highly conserved mechanisms, and in pathways that parallel those present in humans. Mutations in the C. elegans clk-1 gene result in an extended life span, slowed development and sluggish behavior. Homology of clk-1 and COQ7 suggested that the long-lived C. elegans clk-1 mutants are defective in Q biosynthesis. Normally nematodes are provided a diet of Q-replete E. coli. In the absence of dietary Q, the clk-1 mutants display their true phenotype – growth arrest in early development and sterility when emerging from the dauer stage. These results suggest that clk-1 is essential for Q biosynthesis, and that the aging and developmental phenotypes previously described may be attributed to Q levels. Our recent studies indicate that both mean and maximum life span of wild-type nematodes fed Q-less diets is extended 60%. This life span extension is quite robust and is observed in all Age mutants tested so far, when transferred to the Q-less diet as adults. Our studies will define the metabolic alterations resulting from dietary Q, and will help determine how diet/environment and genotype interact to change longevity. Based on the strong conservation of Q function, our findings should be very relevant to aging in other organisms.
Biography

Professor Clarke has been a faculty member in the Department of Chemistry and Biochemistry since 1993. Dr. Clarke completed her undergraduate and graduate studies at UCLA. Her Ph.D. studies focused on the regulation of cholesterol metabolism. She was a post-doctoral fellow at Princeton University. She returned to UCLA in the Department of Medicine and studied polyisoprene and non-sterol metabolism, and then initiated studies on coenzyme Q biosynthesis using the yeast model. In 1993 she joined the Department of Chemistry and Biochemistry and the Molecular Biology Institute. She was promoted to full professor in 2002, and has served as General Chemistry Advisor and Biochemistry Graduate Student Advisor. The focus of her current research is determining how cells synthesize coenzyme Q, and utilizing yeast and nematode models to understand mechanisms of its inter- and intra-cellular transport, and elucidating functional roles.

Publications

A selected list of publications:

Gomez Fernando, Saiki Ryoichi, Chin Randall, Srinivasan Chandra, Clarke Catherine F   Restoring de novo coenzyme Q biosynthesis in Caenorhabditis elegans coq-3 mutants yields profound rescue compared to exogenous coenzyme Q supplementation Gene, 2012; 506(1): 106-16.
Nguyen Theresa P T, Clarke Catherine F   Folate status of gut microbiome affects Caenorhabditis elegans lifespan BMC Biology, 2012; 10(4): 66.
Hill Shauna, Lamberson Connor R, Xu Libin, To Randy, Tsui Hui S, Shmanai Vadim V, Bekish Andrei V, Awad Agape M, Marbois Beth N, Cantor Charles R, Porter Ned A, Clarke Catherine F, Shchepinov Mikhail S   Small amounts of isotope-reinforced polyunsaturated fatty acids suppress lipid autoxidation Free Radical Biology & Medicine, 2012; 53(4): 893-906.
Xie Letian X, Ozeir Mohammad, Tang Jeniffer Y, Chen Jia Y, Jaquinod Sylvie-Kieffer, Fontecave Marc, Clarke Catherine F, Pierrel Fabien   Overexpression of the Coq8 kinase in Saccharomyces cerevisiae coq null mutants allows for accumulation of diagnostic intermediates of the coenzyme Q6 biosynthetic pathway The Journal of Biological Chemistry, 2012; 287(28): 23571-81.
Rahman Shamima, Clarke Catherine F, Hirano Michio   176th ENMC International Workshop: diagnosis and treatment of coenzyme Q deficiency Neuromuscular Disorders, 2012; 22(1): 76-86.
Pfeiffer Matthew, Kayzer Ernst-Bernhard, Yang Xianmei, Abramson Ellen, Kenaston M Alexander, Lago Cory U, Lo Herng-Hsiang, Sedensky Margaret M, Lunceford Adam, Clarke Catherine F, Wu Sarah J, McLeod Chris, Finkel Toren, Morgan Philip G, Mills Edward M   Caenorhabditis elegans UCP4 protein controls complex II-mediated oxidative phosphorylation through succinate transport The Journal of Biological Chemistry, 2011; 286(43): 37712-20.
Clarke Catherine F   Coq6 hydroxylase: unmasked and bypassed Chemistry & Biology, 2011; 18(9): 1069-70.
Falk Marni J, Polyak Erzsebet, Zhang Zhe, Peng Min, King Rhonda, Maltzman Jonathan S, Okwuego Ezinne, Horyn Oksana, Nakamaru-Ogiso Eiko, Ostrovsky Julian, Xie Letian X, Chen Jia Yan, Marbois Beth, Nissim Itzhak, Clarke Catherine F, Gasser David L   Probucol ameliorates renal and metabolic sequelae of primary CoQ deficiency in Pdss2 mutant mice EMBO Molecular Medicine, 2011; 3(7): 410-27.
Heeringa Saskia F, Chernin Gil, Chaki Moumita, Zhou Weibin, Sloan Alexis J, Ji Ziming, Xie Letian X, Salviati Leonardo, Hurd Toby W, Vega-Warner Virginia, Killen Paul D, Raphael Yehoash, Ashraf Shazia, Ovunc Bugsu, Schoeb Dominik S, McLaughlin Heather M, Airik Rannar, Vlangos Christopher N, Gbadegesin Rasheed, Hinkes Bernward, Saisawat Pawaree, Trevisson Eva, Doimo Mara, Casarin Alberto, Pertegato Vanessa, Giorgi Gianpietro, Prokisch Holger, Roetig Agnes, Nürnberg Gudrun, Becker Christian, Wang Su, Ozaltin Fatih, Topaloglu Rezan, Bakkaloglu Aysin, Bakkaloglu Sevcan A, Mueller Dominik, Beissert Antje, Mir Sevgi, Berdeli Afig, Varpizen Seza, Zenker Martin, Matejas Verena, Santos-Ocaña Carlos, Navas Placido, Kusakabe Takehiro, Kispert Andreas, Akman Sema, Soliman Neveen A, Krick Stefanie, Mundel Peter, Reiser Jochen, Nurnberg Peter, Clarke Catherine F, Wiggins Roger C, Faul Christian, Hildebrandt Friedhelm   COQ6 mutations in human patients produce nephrotic syndrome with sensorineural deafness The Journal of Clinical Investigation, 2011; 121(5): 2013-24.
Xie Letian X, Hsieh Edward J, Watanabe Shota, Allan Christopher M, Chen Jia Y, Tran Uyenphuong C, Clarke Catherine F   Expression of the human atypical kinase ADCK3 rescues coenzyme Q biosynthesis and phosphorylation of Coq polypeptides in yeast coq8 mutants Biochimica et Biophysica Acta, 2011; May;1811(5): 348-60.
Devarajan Asokan, Bourquard Noam, Hama Susan, Navab Mohamad, Grijalva Victor R, Morvardi Susan, Clarke Catherine F, Vergnes Laurent, Reue Karen, Teiber John F, Reddy Srinivasa T   Paraoxonase 2 deficiency alters mitochondrial function and exacerbates the development of atherosclerosis Antioxidants & Redox Signaling, 2011; 14(3): 341-51.
Hill Shauna, Hirano Kathleen, Shmanai Vadim V, Marbois Beth N, Vidovic Dragoslav, Bekish Andrei V, Kay Bradley, Tse Vincent, Fine Jonathan, Clarke Catherine F, Shchepinov Mikhail S   Isotope-reinforced polyunsaturated fatty acids protect yeast cells from oxidative stress Free Radical Biology & Medicine, 2011; 50(1): 130-8.
Marbois Beth, Xie Letian X, Choi Samuel, Hirano Kathleen, Hyman Kyle, Clarke Catherine F   Para-aminobenzoic acid is a precursor in coenzyme Q6 biosynthesis in Saccharomyces cerevisiae The Journal of Biological Chemistry, 2010; 285: 27827-27838.
Brajcich Brian C, Iarocci Andrew L, Johnstone Lindsey A G, Morgan Rory K, Lonjers Zachary T, Hotchko Matthew J, Muhs Jordan D, Kieffer Amanda, Reynolds Bree J, Mandel Sarah M, Marbois Beth N, Clarke Catherine F, Shepherd Jennifer N   Evidence that ubiquinone is a required intermediate for rhodoquinone biosynthesis in Rhodospirillum rubrum Journal of Bacteriology, 2010; 192(2): 436-45.
Lomenick Brett, Hao Rui, Jonai Nao, Chin Randall M, Aghajan Mariam, Warburton Sarah, Wang Jianing, Wu Raymond P, Gomez Fernando, Loo Joseph A, Wohlschlegel James A, Vondriska Thomas M, Pelletier Jerry, Herschman Harvey R, Clardy Jon, Clarke Catherine F, Huang Jing   Target identification using drug affinity responsive target stability (DARTS) Proceedings of the National Academy of Sciences of the United States of America, 2009; 106(51): 21984-9.
Padilla-López Sergio, Jiménez-Hidalgo María, Martín-Montalvo Alejandro, Clarke Catherine F, Navas Plácido, Santos-Ocaña Carlos   Genetic evidence for the requirement of the endocytic pathway in the uptake of coenzyme Q(6) in Saccharomyces cerevisiae Biochimica et biophysica acta, 2009; 1788(6): 1238-48.
Cristina David, Cary Michael, Lunceford Adam, Clarke Catherine, Kenyon Cynthia   A regulated response to impaired respiration slows behavioral rates and increases lifespan in Caenorhabditis elegans PLoS Genetics, 2009; 5(4): e1000450.
Padilla S, Tran U C, Jiménez-Hidalgo M, López-Martín J M, Martín-Montalvo A, Clarke C F, Navas P, Santos-Ocaña C   Hydroxylation of demethoxy-Q6 constitutes a control point in yeast coenzyme Q6 biosynthesis Cellular and Molecular Life Sciences : CMLS, 2009; 66(1): 173-86.
Marbois Beth, Gin Peter, Gulmezian Melissa, Clarke Catherine F   The yeast Coq4 polypeptide organizes a mitochondrial protein complex essential for coenzyme Q biosynthesis Biochimica et biophysica acta, 2009; 1791(1): 69-75.
Saiki R, Lunceford A., Shi Y, Marbois B, King R, Pachuski J, Kawamukai M, Gasser DL, Clarke CF   Coenzyme Q10 Supplementation Rescues Renal Disease in Pdss2kd/kd mice with mutations in Prenyldiphosphate synthase subunit 2 American Journal of Physiology. Renal Physiology, 2008; 181(6): .
Do Thai Q, Moshkani Safiehkhatoon, Castillo Patricia, Anunta Suda, Pogosyan Adelina, Cheung Annie, Marbois Beth, Faull Kym F, Ernst William, Chiang Su Ming, Fujii Gary, Clarke Catherine F, Foster Krishna, Porter Edith   Lipids including cholesteryl linoleate and cholesteryl arachidonate contribute to the inherent antibacterial activity of human nasal fluid Journal of Immunology (Baltimore, Md. : 1950), 2008; 181(6): 4177-87.
Kiebish Michael A, Han Xianlin, Cheng Hua, Lunceford Adam, Clarke Catherine F, Moon Hwi, Chuang Jeffrey H, Seyfried Thomas N   Lipidomic analysis and electron transport chain activities in C57BL/6J mouse brain mitochondria J. Neurochem, 2008; 106(1): 299-312.
Saiki Ryoichi, Lunceford Adam L, Bixler Tarra, Dang Peter, Lee Wendy, Furukawa Satoru, Larsen Pamela L, Clarke Catherine F   Altered bacterial metabolism, not coenzyme Q content, is responsible for the lifespan extension in Caenorhabditis elegans fed an Escherichia coli diet lacking coenzyme Q Aging Cell, 2008; 7(3): 291-304.
Peng Min, Falk Marni J, Haase Volker H, King Rhonda, Polyak Erzsebet, Selak Mary, Yudkoff Marc, Hancock Wayne W, Meade Ray, Saiki Ryoichi, Lunceford Adam L, Clarke Catherine F, L Gasser David   Primary coenzyme Q deficiency in Pdss2 mutant mice causes isolated renal disease PLoS Genet, 2008; 4(4): e1000061.
Gulmezian Melissa, Hyman Kyle R, Marbois Beth N, Clarke Catherine F, Javor George T   The role of UbiX in Escherichia coli coenzyme Q biosynthesis Arch. Biochem. Biophys, 2007; 467(2): 144-53.
Hsieh Edward J, Gin Peter, Gulmezian Melissa, Tran UyenPhuong C, Saiki Ryoichi, Marbois Beth N, Clarke Catherine F   Saccharomyces cerevisiae Coq9 polypeptide is a subunit of the mitochondrial coenzyme Q biosynthetic complex Arch. Biochem. Biophys, 2007; 463(1): 19-26.
Tran UyenPhuong C, Clarke Catherine F   Endogenous synthesis of coenzyme Q in eukaryotes Mitochondrion, 2007; 7 Suppl(1): S62-71.
Gulmezian Melissa, Zhang Haitao, Javor George T, Clarke Catherine F   Genetic evidence for an interaction of the UbiG O-methyltransferase with UbiX in Escherichia coli coenzyme Q biosynthesis J. Bacteriol, 2006; 188(17): 6435-9.
Tran UyenPhuong C, Marbois Beth, Gin Peter, Gulmezian Melissa, Jonassen Tanya, Clarke Catherine F   Complementation of Saccharomyces cerevisiae coq7 mutants by mitochondrial targeting of the Escherichia coli UbiF polypeptide: two functions of yeast Coq7 polypeptide in coenzyme Q biosynthesis J. Biol. Chem, 2006; 281(24): 16401-9.
Barros Mario H, Johnson Alisha, Gin Peter, Marbois Beth N, Clarke Catherine F, Tzagoloff Alexander   The Saccharomyces cerevisiae COQ10 gene encodes a START domain protein required for function of coenzyme Q in respiration J. Biol. Chem, 2005; 280(52): 42627-35.
Johnson Alisha, Gin Peter, Marbois Beth N, Hsieh Edward J, Wu Mian, Barros Mario H, Clarke Catherine F, Tzagoloff Alexander   COQ9, a new gene required for the biosynthesis of coenzyme Q in Saccharomyces cerevisiae J. Biol. Chem, 2005; 280(36): 31397-404.
Marbois Beth, Gin Peter, Faull Kym F, Poon Wayne W, Lee Peter T, Strahan Jeff, Shepherd Jennifer N, Clarke Catherine F   Coq3 and Coq4 define a polypeptide complex in yeast mitochondria for the biosynthesis of coenzyme Q J. Biol. Chem, 2005; 280(21): 20231-8.
Gin Peter, Clarke Catherine F   Genetic evidence for a multi-subunit complex in coenzyme Q biosynthesis in yeast and the role of the Coq1 hexaprenyl diphosphate synthase J. Biol. Chem, 2005; 280(4): 2676-81.
Dyall Sabrina D, Yan Weihong, Delgadillo-Correa Maria G, Lunceford Adam, Loo Joseph A, Clarke Catherine F, Johnson Patricia J   Non-mitochondrial complex I proteins in a hydrogenosomal oxidoreductase complex Nature, 2004; 431(7012): 1103-7.
Padilla, S., Jonassen, T., Jimenez-Hidalgo, M. J., Fernandez-Ayala, D. J. M., Lopez-Lluch, G. M., Marbois, B., Navas, P., Clarke, C. F. and Santos-Ocana, C.   Demethoxy-Q, an intermediate of coenzyme Q biosynthesis, fails to support respiration in Saccharomyces cerevisiae and lacks antioxidant activity J. Biol. Chem, 2004; 279(25): 25995-6004.
Hsieh Edward J, Dinoso Jason B, Clarke Catherine F   A tRNA(TRP) gene mediates the suppression of cbs2-223 previously attributed to ABC1/COQ8 Biochem. Biophys. Res. Commun, 2004; 317(2): 648-53.
Esteves Telma C, Echtay Karim S, Jonassen Tanya, Clarke Catherine F, Brand Martin D   Ubiquinone is not required for proton conductance by uncoupling protein 1 in yeast mitochondria The Biochemical Journal, 2004; 379(Pt 2): 309-15.
Baba Suzie W, Belogrudov Grigory I, Lee Justine C, Lee Peter T, Strahan Jeff, Shepherd Jennifer N, Clarke Catherine F   Yeast Coq5 C-methyltransferase is required for stability of other polypeptides involved in coenzyme Q biosynthesis The Journal of biological chemistry, 2004; 279(11): 10052-9.
Jonassen Tanya, Davis Diana E, Larsen Pamela L, Clarke Catherine F   Reproductive fitness and quinone content of Caenorhabditis elegans clk-1 mutants fed coenzyme Q isoforms of varying length The Journal of biological chemistry, 2003; 278(51): 51735-42.
Gin Peter, Hsu Adam Y, Rothman Steven C, Jonassen Tanya, Lee Peter T, Tzagoloff Alexander, Clarke Catherine F   The Saccharomyces cerevisiae COQ6 gene encodes a mitochondrial flavin-dependent monooxygenase required for coenzyme Q biosynthesis The Journal of biological chemistry, 2003; 278(28): 25308-16.
Jonassen Tanya, Marbois Beth N, Faull Kym F, Clarke Catherine F, Larsen Pamela L   Development and fertility in Caenorhabditis elegans clk-1 mutants depend upon transport of dietary coenzyme Q8 to mitochondria The Journal of Biological Chemistry, 2002; 277(47): 45020-7.
Santos-Ocaña Carlos, Do Thai Q, Padilla Sergio, Navas Placido, Clarke Catherine F   Uptake of exogenous coenzyme Q and transport to mitochondria is required for bc1 complex stability in yeast coq mutants The Journal of Biological Chemistry, 2002; 277(13): 10973-81.
Larsen Pamela L, Clarke Catherine F   Extension of life-span in Caenorhabditis elegans by a diet lacking coenzyme Q Science (New York, N.Y.), 2002; 295(5552): 120-3.