Impaired energy metabolism in a Drosophila model of mitochondrial aconitase deficiency

• DOI: 10.1016/j.bbrc.2013.02.040
• Publication Date: 2013-02-21T20:16:02Z
• Authors: Zhang Cheng; Manabu Tsuda; Yoshihito Kishita; Yukiko Sato; Toshiro Aigaki
• Keywords: Aconitate Hydratase; 0303 health sciences; Base Sequence; Cell Death; Citric Acid Cycle; Longevity; Genes, Insect; Lipid Metabolism; Models, Biological; Mitochondria; Gene Knockout Techniques; 03 medical and health sciences; Drosophila melanogaster; Acetyl Coenzyme A; Gene Knockdown Techniques; Metabolome; Animals; Drosophila Proteins; Female; Energy Metabolism; Glycolysis; DNA Primers

Aconitase catalyzes the conversion of citrate to isocitrate in the tricarboxylic acid (TCA) cycle, and its deficiency in humans is associated with an infantile neurodegenerative disorder affecting mainly the cerebellum and retina. Here we investigated the effect of gene knockout and knockdown of the mitochondrial aconitase Acon in Drosophila. Acon-knockout flies were homozygous lethal, indicating that Acon is essential for viability. RNA interference-generated Acon-knockdown flies exhibited a variety of phenotypes, such as reduced locomotor activity, a shortened lifespan, and increased cell death in the developing brain. Metabolomic analysis revealed that acetyl-CoA, citrate/isocitrate, and cis-aconitate were significantly increased, while most metabolites of glycolysis and the TCA cycle were reduced. Reduced triacylglyceride and increased acetyl-CoA suggested that lipids were used as an energy source because of the impaired glycolysis and TCA cycle. The Acon-knockdown model should facilitate further understanding of the pathophysiology of m-aconitase deficiency in humans.