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 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, GAPDH, which in turn reroutes carbohydrate flux to the oxidative phase of the pentose phosphate pathway (oxPPP) to generate NADPH. The aerobic oxidation of GAPDH is 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 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. Altogether, Sod1-derived H2O2 is important for antioxidant defense and a master regulator of metabolism and the thiol redoxome.

Tissue-Characteristic Expression of Mouse Proteome

“…Vanin-1, the predominant isoform of pantetheinase ( 38 ), is reported to be upregulated under oxidative stress ( 39 ). Glutathione reductase and Cu/Zn superoxide dismutase are well-studied antioxidant enzymes for maintaining cellular redox homeostasis ( 40 , 41 ). Hypoxia-inducible gene domain family member 1A is reported to lower cellular reactive oxygen species levels ( 42 ).…”

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.…”

Subcellular Redox Responses Reveal Different Cu-dependent Antioxidant Defenses between Mitochondria and Cytosol

“…The delivery of Cu to mitochondria is obligatory for cell survival due to the essential role of Cu for cytochrome c oxidase activity [32,[43][44][45][46]. SOD1, localized to the intermembrane space (IMS), is the front-line antioxidant enzyme that catalyzes the disproportionation of superoxide radicals and integrates oxygen availability to redox regulate NADPH production [47]. We reason the observed decreased mitochondrial SOD1 abundance to the lack of apo-SOD1 polypeptide source under Cu-stressed conditions since only the very immature form of the SOD1 polypeptide that is apo for both Cu and Zn can efficiently enter mitochondria [48].…”