Abstract

Nitric oxide, generated in β-cells in response to cytokines, induces DNA damage that activates DNA damage response (DDR) and eventually leads to apoptosis if damage is too extensive. We have shown that nitric oxide, while inducing double-strand DNA breaks (DSBs), also inhibits DDR signaling and protects β-cells from DNA damage-induced apoptosis.The ability of nitric oxide to inhibit the DDR signaling is selective to β-cells and correlates with a loss in ATP levels, while non-β-cells are able to maintain both ATP levels and DDR signaling when treated with nitric oxide. However, the mechanism that regulates this cell type selectiveness is not known. β-cell metabolism is characterized by the coupling of glycolysis to mitochondrial oxidative metabolism, where 90% of the carbons of glucose are oxidized to CO2 in a concentration-dependent manner. Nitric oxide is known to inhibit mitochondrial oxidative metabolism (e.g. aconitase in the TCA cycle and complex IV of electron transport chain (ETC)). In response to nitric oxide, β-cells are not able to compensate the inhibition of mitochondrial oxidation by increasing glycolytic metabolism. In contrast, non-β-cells compensate for the mitochondrial inhibition by increasing glycolytic metabolism to maintain their ATP pool. Consistent with the action of nitric oxide, we showed that rotenone, an inhibitor of complex I of ETC, also inhibit DDR signaling and decrease ATP levels in β-cells but not in non-β-cells. Importantly, when non-β-cells are forced to generate ATP via mitochondrial oxidation, nitric oxide inhibits DDR signaling, decrease ATP levels, and protects cells from DNA damage-induced apoptosis. These findings suggest that the coupling of glycolysis to mitochondrial oxidative metabolism in β-cells allows nitric oxide to decrease ATP levels and subsequently inhibit DDR signaling and protect β-cells from DNA damage-induced apoptosis.

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