A Drosophila Model for Primary Coenzyme Q Deficiency and Dietary Rescue in the Developing Nervous System

Dis Model Mech. Nov-Dec 2010;3(11-12):799-806. doi: 10.1242/dmm.005579. Epub 2010 Oct 1.

Abstract

Coenzyme Q (CoQ) or ubiquinone is a lipid component of the electron transport chain required for ATP generation in mitochondria. Mutations in CoQ biosynthetic genes are associated with rare but severe infantile multisystemic diseases. CoQ itself is a popular over-the-counter dietary supplement that some clinical and rodent studies suggest might be beneficial for neurodegenerative diseases. Here, we identify mutations in the Drosophila qless gene, which encodes an orthologue of the human PDSS1 prenyl transferase that synthesizes the isoprenoid side chain of CoQ. We show that neurons lacking qless activity upregulate markers of mitochondrial stress and undergo caspase-dependent apoptosis. Surprisingly, even though experimental inhibition of caspase activity did not prevent mitochondrial disruption, it was sufficient to rescue the size of neural progenitor clones. This demonstrates that, within the developing larval CNS, qless activity is required primarily for cell survival rather than for cell growth and proliferation. Full rescue of the qless neural phenotype was achieved by dietary supplementation with CoQ4, CoQ9 or CoQ10, indicating that a side chain as short as four isoprenoid units can provide in vivo activity. Together, these findings show that Drosophila qless provides a useful model for studying the neural effects of CoQ deficiency and dietary supplementation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkyl and Aryl Transferases / metabolism
  • Amino Acid Sequence
  • Animals
  • Caspases / metabolism
  • Cell Proliferation
  • Cell Survival
  • Conserved Sequence / genetics
  • Cytoprotection
  • Dietary Supplements*
  • Disease Models, Animal*
  • Drosophila Proteins / chemistry
  • Drosophila Proteins / metabolism
  • Drosophila melanogaster / metabolism*
  • Enzyme Activation
  • Humans
  • Mitochondria / pathology
  • Molecular Sequence Data
  • Nervous System / growth & development*
  • Nervous System / metabolism
  • Nervous System / pathology*
  • Neurons / enzymology
  • Neurons / pathology
  • Stress, Physiological
  • Ubiquinone / deficiency*
  • Ubiquinone / metabolism

Substances

  • Drosophila Proteins
  • Ubiquinone
  • Alkyl and Aryl Transferases
  • prenyldiphosphate synthase, subunit 1, human
  • Caspases