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Regulation of nuclear superoxide production in mouse liver

Redox‐regulated signal transduction requires spatially controlled production of reactive oxygen species in subcellular compartments. The nucleus has long been known to produce superoxide (O2•−); however, the mechanisms that control this function remain largely unknown. We have characterized molecular features of a nuclear superoxide‐producing system in mouse liver. Using electron paramagnetic resonance, we investigated whether several NADPH oxidases and known activators of NOX contribute to nuclear O2•− production in isolated hepatic nuclei. We showed that NOX4 most significantly contributes to nuclear O2•− production that utilizes NADPH as an electron donor. Although NOX4 protein immunolocalized to both nuclear membranes and intranuclear inclusions, fluorescent detection of NADPH‐dependent nuclear O2•− predominantly localized to the perinuclear space. NADP+ and G6P also induced nuclear O2•− production, suggesting that intranuclear glucose 6‐phosphate dehydrogenase (G6PD) controls NOX4 activity through nuclear NADPH production. Using G6PD‐mutant mice and G6PD shRNA, we confirmed that reductions in nuclear G6PD decrease the ability of hepatic nuclei to generate O2•− in response to NADP+ and G6P. NOX4 and G6PD partly co‐localize within the nucleus. These findings provide new insights on the metabolic pathways for substrate regulation of nuclear O2•− production by NOX4.