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

• Published in: Molecular and cellular biology Vol. 39; no. 18
• Main Authors: Oleson, Bryndon J., Broniowska, Katarzyna A., Yeo, Chay Teng, Flancher, Michael, Naatz, Aaron, Hogg, Neil, Tarakanova, Vera L., Corbett, John A.
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 01-09-2019; American Society for Microbiology
• Subjects: Adenosine Triphosphate - metabolism; Animals; beta cell; Cell Line; Cell Respiration - drug effects; Cell Survival - drug effects; DDR; DNA Damage; DNA Repair - drug effects; Glycolysis - drug effects; Hep G2 Cells; Humans; insulin; Insulin-Secreting Cells - cytology; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - metabolism; Male; metabolism; Mice; mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; NAD - metabolism; nitric oxide; Nitric Oxide - pharmacology; oxidation; Rats; Rats, Sprague-Dawley; Spotlight; beta cell; nitric oxide; DDR; insulin; mitochondria; oxidation; metabolism
• ISSN: 1098-5549; 0270-7306; 1098-5549
• DOI: 10.1128/MCB.00153-19

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.