SOD2, the principal scavenger of mitochondrial superoxide, is dispensable for embryogenesis and imaginal tissue development but essential for adult survival.

Definitive evidence on the impact of MnSOD/SOD2-deficiency and the consequent effects of high flux of mitochondrial reactive oxygen species (ROS) on pre-natal/pre-adult development has yet to be reported for either Drosophila or mice. Here we report that oocytes lacking maternal SOD2 protein develop into adults just like normal SOD2-containing oocytes suggesting that maternal SOD2-mediated protection against mitochondrial ROS is not essential for oocyte viability. However, the capacity of SOD2-null larvae to undergo successful metamorphosis into adults is negatively influenced in the absence of SOD2. We therefore determined the impact of a high superoxide environment on cell size, progression through the cell cycle, cell differentiation, and cell death and found no difference between SOD2-null and SOD2+ larva and pupa. Thus loss of SOD2 activity clearly has no effect on pre-adult imaginal tissues. Instead, we found that the high mitochondrial superoxide environment arising from the absence of SOD2 leads to the induction of autophagy. Such autophagic response may underpin the resistance of pre-adult tissues to unscavenged ROS. Finally, while our data establish that SOD2 activity is less essential for normal development, the mortality of Sod2-/- neonates of both Drosophila and mice suggests that SOD2 activity is indeed essential for the viability of adults. We therefore asked if the early mortality of SOD2-null young adults could be rescued by activation of SOD2 expression. The results support the conclusion that the early mortality of SOD2-null adults is largely attributable to the absence of SOD2 activity in the adult per se. This finding somewhat contradicts the widely held notion that failure to scavenge the high volume of superoxide emanating from the oxidative demands of development would be highly detrimental to developing tissues.

Mitochondrial superoxide radicals differentially affect muscle activity and neural function.

Cellular superoxide radicals (O(2)(-)) are mostly generated during mitochondrial oxygen metabolism. O(2)(-) serves as the raw material for many reactive oxygen species (ROS) members like H(2)O(2) and OH(.-) radicals following its catalysis by superoxide dismutase (SOD) enzymes and also by autocatalysis (autodismutation) reactions. Mitochondrial ROS generation could have serious implications on degenerative diseases. In model systems overproduction of mitochondrial O(2)(-) resulting from the loss of SOD2 function leads to movement disorders and drastic reduction in life span in vertebrates and invertebrates alike. With the help of a mitochondrial SOD2 loss-of-function mutant, Sod2(n283), we measured the sensitivity of muscles and neurons to ROS attack. Neural outputs from flight motor neurons and sensory neurons were unchanged in Sod2(n283) and the entire neural circuitry between the giant fiber (GF) and the dorsal longitudinal muscles (DLM) showed no overt defect due to elevated ROS. Such insensitivity of neurons to mitochondrial superoxides was further established through neuronal expression of SOD2, which failed to improve survival or locomotive ability of Sod2(n283). On the other hand, ultrastructural analysis of Sod2(n283) muscles revealed fewer mitochondria and reduced muscle ATP production. By targeting the SOD2 expression to the muscle we demonstrate that the early mortality phenotype of Sod2(n283) can be ameliorated along with signs of improved mobility. In summary, muscles appear to be more sensitive to superoxide attack relative to the neurons and such overt phenotypes observed in SOD2-deficient animals can be directly attributed to the muscle.