Cooperative action of antioxidant defense systems in Drosophila

Molecular oxygen is key to aerobic life but is also converted into cytotoxi c byproducts referred to as reactive oxygen species (ROS) [1]. Intracellula r defense systems that protect cells from ROS-induced damage include glutat hione reductase (GR), thioredoxin reductase (TrxR), superoxide dismutase (S od), and catalase (Cat) [2]. Sod and Cat constitute an evolutionary conserv ed ROS defense system against superoxide; Sod converts superoxide anions to H2O2, and Cat prevents free hydroxyl radical formation by breaking down H2 O2 into oxygen and water [2]. As a consequence, they are important effector s in the life span determination of the fly Drosophila [3-7]. ROS defense b y TrxR and GR is more indirect. They transfer reducing equivalents from NAD PH to thioredoxin (Trx) and glutathione disulfide (GSSG), respectively, res ulting in Trx(SH)2 and glutathione (GSH), which act as effective intracellu lar antioxidants [2, 8]. TrxR and GR were found to be molecularly conserved [9]. However, the single GR homolog of Drosophila [10, 11] specifies TrxR activity [12], which compensates for the absence of a true GR system for re cycling GSH [12]. We show that TrxR null mutations reduce the capacity to a dequately protect cells from cytotoxic damage, resulting in larval death, w hereas mutations causing reduced TrxR activity affect pupal eclosion and ca use a severe reduction of the adult life span. We also provide genetic evid ence for a functional interaction between TrxR, Sod1, and Cat, indicating t hat the burden of ROS metabolism in Drosophila is shared by the two defense systems.