The Role of Metabolic Flexibility in the Regulation of the DNA Damage Response by Nitric Oxide

ABSTRACT

In this report, we show that nitric oxide suppresses DNA damage response (DDR) signaling in the pancreatic β-cell line INS 832/13 and rat islets by inhibiting intermediary metabolism. Nitric oxide is known to inhibit complex IV of the electron transport chain and aconitase of the Krebs cycle. Non-β cells compensate by increasing glycolytic metabolism to maintain ATP levels; however, β cells lack this metabolic flexibility, resulting in a nitric oxide-dependent decrease in ATP and NAD⁺. Like nitric oxide, mitochondrial toxins inhibit DDR signaling in β cells by a mechanism that is associated with a decrease in ATP. Non-β cells compensate for the effects of mitochondrial toxins with an adaptive shift to glycolytic ATP generation that allows for DDR signaling. Forcing non-β cells to derive ATP via mitochondrial respiration (replacing glucose with galactose in the medium) and glucose deprivation sensitizes these cells to nitric oxide-mediated inhibition of DDR signaling. These findings indicate that metabolic flexibility is necessary to maintain DDR signaling under conditions in which mitochondrial oxidative metabolism is inhibited and support the inhibition of oxidative metabolism (decreased ATP) as one protective mechanism by which nitric oxide attenuates DDR-dependent β-cell apoptosis.

KEYWORDS:

• DDR
• mitochondria
• nitric oxide
• beta cell
• insulin
• metabolism
• oxidation

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ACKNOWLEDGMENTS

We thank Polly Hansen and Joshua Stafford (Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI) for helpful discussions related to this project and for proofreading the manuscript.

We declare that we have no conflicts of interest with the contents of this article.

This work was supported by the National Institutes of Health, including National Institute of Diabetes and Digestive and Kidney Diseases grant DK-052194 and National Institute of Allergy and Infectious Diseases grant AI-044458 (to J.A.C.), and a gift from the Forest County Potawatomi Foundation. K.A.B. and B.J.O. were supported by American Heart Association fellowships 13POST16940076 and 14PRE20380585, respectively.