Sod1 Integrates Oxygen Availability to Redox Regulate NADPH Production and the Thiol Redoxome

Abstract

Cu/Zn superoxide dismutase (Sod1) is a highly conserved and abundant antioxidant enzyme that detoxifies superoxide (O2 −) by catalyzing its conversion to dioxygen (O2) and hydrogen peroxide (H2O2). Using Saccharomyces cerevisiae and mammalian cells, we discovered that a major new aspect of the antioxidant function of Sod1 is to integrate O2 availability to promote NADPH production. The mechanism involves Sod1-derived H2O2 oxidatively inactivating the glycolytic enzyme, glyceraldehyde phosphate dehydrogenase (GAPDH), which in turn re-routes carbohydrate flux to the oxidative phase of the pentose phosphate pathway (oxPPP) to generate NADPH. The aerobic oxidation of GAPDH is exclusively dependent on and rate-limited by Sod1. Thus, Sod1 senses O2 via O2 − to balance glycolytic and oxPPP flux, through control of GAPDH activity, for adaptation to life in air. Importantly, this new mechanism for Sod1 antioxidant activity requires the bulk of cellular Sod1, unlike for its role in protection against O2 − toxicity, which only requires < 1% of total Sod1. Using mass spectrometry, we identified proteome-wide targets of Sod1-dependent redox signaling, including numerous metabolic enzymes.