HAAO-1 INHIBITION ENHANCES C. ELEGANS OXIDATIVE STRESS RESPONSE

Abstract

The kynurenine pathway is the sole de novo biosynthetic pathway that produces nicotinamide adenine dinucleotide (NAD+) from available tryptophan. Previous work in our lab has shown that elevating endogenous levels of the kynurenine pathway metabolite 3-hydroxyanthranilic acid (3HAA) through either inhibition of 3HAA dioxygenase (HAAO) or 3HAA supplementation increases the lifespan of the nematode Caenorhabditis elegans. HAAO metabolizes 3HAA into 2-amino-3-carboxymuconate-6- semialdehyde (ACMSA), a precursor of NAD+. However, the mechanism of lifespan extension through this pathway is still unknown. Here, we investigated the relationship between haao-1 and oxidative stress in C. elegans. Animals with reduced HAAO expression are resistant to multiple forms of oxidative stress. We found that haao-1(tm4627) animals (HAAO KO) have elevated endogenous reactive oxygen species (ROS) and activation of the NRF2/SKN-1 oxidative stress response pathway. Treating haao-1(tm4627) animals with the glutathione precursor N-Acetyl Cysteine (NAC) rescues the increase in ROS, but only partially rescues activation of NRF2/SKN-1 in animals with mutant haao-1 or haao-1 RNAi. This demonstrates that activation of SKN-1 in the haao-1(tm4627) mutant background is partially dependent on ROS, but also there are also likely non-ROS-dependent mechanisms.