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Mol Cell Biol. 2019 Aug 27;39(18). pii: e00153-19. doi: 10.1128/MCB.00153-19. Print 2019 Sep 15.

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

Author information

1
Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
2
Department of Biophysics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
3
Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
4
Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, USA jcorbett@mcw.edu.

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; beta cell; insulin; metabolism; mitochondria; nitric oxide; oxidation

PMID:
31235477
PMCID:
PMC6712938
[Available on 2020-02-27]
DOI:
10.1128/MCB.00153-19

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