Nitrite modulates mitochondrial function through the activation of PKA in normoxia

Nitrite has emerged as a signaling molecule which mediates cytoprotection after ischemia-reperfusion (I/R). Mitochondria have been described as the major target for nitrite's effects. Interestingly, nitrite can still prevent I/R injury when administered 24–72 hours prior to an ischemic episode. This effect is independent of nitrite reduction and involves PKA activation. Thus, we evaluated the mechanism by which nitrite activates PKA and regulates mitochondrial dynamics. We show that nitrite increases cAMP levels to activate PKA by inhibiting mitochondrially localized phosphodiesterase activity. Increases in PKA enhance mitochondrial complex IV activity and the phosphorylation of COXIV at serine 58, resulting in increased respiration. Further, nitrite upregulates the A-kinase anchoring protein, the AKAP121 which localizes PKA to the mitochondrial membrane. In conclusion, our results demonstrate that nitrite can be a versatile signaling molecule, not only by inducing protein nitration and nitrosylation but also through modulating protein expression and phosphorylation. These data contribute to the understanding of the mechanism by which nitrite regulates mitochondrial function and expands the therapeutic potential of nitrite in cardiovascular disease.