Decrease in cytochrome c oxidase reserve capacity diminishes robustness of Drosophila melanogaster and shortens lifespan.

The phenotypic effects of under- and over-expression of CcO (cytochrome c oxidase) regulatory subunits IV and Vb were examined in Drosophila melanogaster in order to test further the hypothesis that suppression of the activities of mitochondrial ETC (electron-transport chain) oxidoreductases retards the aging process and extends lifespan. Underexpression of both CcO subunits, induced by RNAi, resulted in decreases in the respective mRNA and protein levels, CcO holoenzyme activity, rate of mitochondrial respiration, walking speed and the lifespan of fruitflies. Overexpression of CcO IV or Vb in young fruitflies increased the amount of mRNA, but had no effect on the protein level or CcO catalytic activity. On the other hand, in older fruitflies, overexpression of CcO Vb, but not CcO IV, elevated the mRNA and protein amounts as well as the CcO holoenzyme activity, thereby preventing the typical age-related decline in CcO activity. Nevertheless, lifespans of the fruitflies overexpressing CcO IV or Vb were neither extended nor shortened. Our results demonstrate that: (i) the suppression of CcO function exerts deleterious rather than benign effects on fitness and survival, and (ii) the structure/function of CcO, an ETC oxidoreductase, can be 're-engineered' in vivo.