Altered quinone biosynthesis in the long-lived clk-1 mutants of Caenorhabditis elegans.
Mutations in the clk-1 gene of Caenorhabditis elegans result in an extended life span and an average slowing down of developmental and behavioral rates. However, it has not been possible to identify biochemical changes that might underlie the extension of life span observed in clk-1 mutants, and therefore the function of CLK-1 in C. elegans remains unknown. In this report, we analyzed the effect of clk-1 mutation on ubiquinone (UQ(9)) biosynthesis and show that clk-1 mutants mitochondria do not contain detectable levels of UQ(9). Instead, the UQ(9) biosynthesis intermediate, demethoxyubiquinone (DMQ(9)), is present at high levels. This result demonstrates that CLK-1 is absolutely required for the biosynthesis of UQ(9) in C. elegans. Interestingly, the activity levels of NADH-cytochrome c reductase and succinate-cytochrome c reductase in mutant mitochondria are very similar to those in the wild-type, suggesting that DMQ(9) can function as an electron carrier in the respiratory chain. To test this possibility, the short side chain derivative DMQ(2) was chemically synthesized. We find that DMQ(2) can act as an electron acceptor for both complex I and complex II in clk-1 mutant mitochondria, while another ubiquinone biosynthesis precursor, 3-hydroxy-UQ(2), cannot. The accumulation of DMQ(9) and its use in mutant mitochondria indicate, for the first time in any organism, a link between the alteration in the quinone species used in respiration and life span.
Miyadera
H
H
Department of Biomedical Chemistry, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
Amino
H
H
Hiraishi
A
A
Taka
H
H
Murayama
K
K
Miyoshi
H
H
Sakamoto
K
K
Ishii
N
N
Hekimi
S
S
Kita
K
K
D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins; D004579:Electron Transport; D015801:Helminth Proteins / Q000502:physiology*; D008928:Mitochondria / Q000378:metabolism; D009154:Mutation; D014451:Ubiquinone / Q000096:biosynthesis*
C104339:CLK-1 protein, C elegans; D029742:Caenorhabditis elegans Proteins; D015801:Helminth Proteins; D014451:Ubiquinone