Current Research     |      Representative Publications    |    Lab Group    |    Lab Photos

Introduction
Ubiquinone (coenzyme Q or Q) functions in cells as a redox-active coenzyme of mitochondrial and plasma membrane electron transport, as well as an essential lipid soluble antioxidant. Human dietary supplementation with Q appears to have beneficial effects in slowing the progression of neuro- and muscle-degenerative diseases. However, at least in lower animal species, such as the nematode Caenorhabditis elegans, dietary Q can also contribute to a shortened lifespan. These apparently disparate effects may reflect the potential of Q to contribute to the generation of reactive oxygen species. Cells are capable of synthesizing Q, but much remains to be learned about the sites of its synthesis, mechanisms of inter- and intra-cellular transport, and the regulation and enzymology of its biosynthesis. The goals of my research are to characterize the Coq polypeptides responsible for production of Q and to determine how their activity can be modulated for optimal health.

Research Overview
My research focuses on understanding the physiological roles of Q at the molecular level. Our studies have centered on elucidating the gene-enzyme relationships of Q biosynthesis, characterizing the polypeptide components responsible for the production of Q, and investigating the in vivo functions of Q/QH₂. 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.

Elucidating Q biosynthesis
Our research takes advantage of the availability of respiratory defective coq mutants of the yeast Saccharomyces cerevisiae auxotrophic for Q. The yeast coq mutants provide for the isolation and characterization of the COQ genes and their products from both yeast and animals. Yeast is an ideal organism for these studies because mutants completely lacking Q can remain viable through their ability to grow by fermentation. Synthetic analogs of Q intermediates provide reagents that serve both as standards in the isolation and characterization of Q intermediates, and as substrates for in vitro assays of enzyme activities. Thus, the experimental approach employs a combination of molecular genetics, chemistry and biochemistry to delineate the eukaryotic biosynthetic steps responsible for the production of Q, as well as to investigate the function of Q/QH₂ as an antioxidant. We now have isolated ten yeast COQ genes that complement the corresponding coq respiratory defective mutants. We have thus defined a minimal cohort of the potential polypeptide components in Q biosynthesis. My laboratory has contributed a large part of this information. Nine of the Coq polypeptides are matrix proteins peripherally associated with the mitochondrial inner membrane. A growing body of genetic evidence indicates that certain of these Coq polypeptides, together with Q and/or Q intermediates, interact to form a mitochondrial Q biosynthetic complex.

Q and aging
Mutations in the C. elegans clk-1 gene result in an extended life span, slowed development and sluggish behavior. Homology of nematode clk-1 and yeast COQ7 genes 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. Our studies show that the rescue by dietary Q₈ depends upon the uptake and transport of dietary Q₈ to mitochondria within the nematode. Our recent work shows that the rescue is mediated by Q₈, Q₉ or Q₁₀ isoforms

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 current studies are aimed towards defining the metabolic alterations resulting from dietary Q, and should help determine how diet/environment and genotype interact to change longevity. Based on the strong conservation of Q biosynthesis and function, our findings should be very relevant to aging in other organisms.

Dr. Beth Noelle Marbois

Research Associate

Ph.D., University of California, Los Angeles
B.S., Florida State University
M.S.P.H., UCLA School of Public Health

Dr. Susan Morvaridi

B.S. & Ph.D., Lund University

Chris Allan

B.S., University of California, Los Angeles

Yuchen Shi

B.S., University of California, Los Angeles

Updates? We'd like to know! E-mail cathy@mbi.ucla.edu