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 by catalyzing its conversion to dioxygen and hydrogen peroxide. Using Saccharomyces cerevisiae and mammalian cells, we discovered that a major new aspect of the antioxidant function of Sod1 is to integrate oxygen availability to promote NADPH production. The mechanism involves Sod1-derived peroxide 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 oxygen via peroxide 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 superoxide 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. Altogether, Sod1-derived peroxide is important for antioxidant defense and a master regulator of metabolism and the thiol redoxome.

Meiotic resetting of the cellular Sod1 pool is driven by protein aggregation, degradation, and transient LUTI-mediated repression

“…Given the high degree of respiration required for meiosis, downregulation of Sod1 protein levels during this process may seem counterintuitive, but recent work argues that although it is best known for its antioxidant role, only a small fraction of this abundant enzyme is needed to protect cells from superoxide (Montllor-Albalate et al, 2019). This discrepancy was puzzling until Sod1 was found to play additional roles, including nutrient sensing and redox homeostasis (Reddi and Culotta, 2013;Montllor-Albalate et al, 2022). Identifying the specific roles that underlie its importance for meiosis is an interesting future area of research.…”

Microbial cell factory optimisation using genome-wide host-pathway interaction screens

“…PPP in response to oxidative stress. This study was found that under oxidative stress, conversion of superoxide into H 2 O 2 by Sod1 directly inhibits the TDH3-encoded glycolytic enzyme Gapdh which redirects carbon flux into the oxidative PPP(Montllor-Albalate et al, 2022). Conversely, loss of Sod1 (or its chaperone Ccs1) should derepress TDH3 regardless of the redox state, inhibiting the oxidative PPP.…”

“…(Montllor-Albalate et al, 2022;Ralser et al, 2007). Hence, decreased NADPH consumption in mutants unable to assimilate sulphur should inhibit the oxidative PPP and improve E4P availability.…”