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The Role of Metabolic Flexibility in the Regulation of the DNA Damage Response by Nitric Oxide. Mol Cell Biol 2019 09 15;39(18)

Date

06/27/2019

Pubmed ID

31235477

Pubmed Central ID

PMC6712938

DOI

10.1128/MCB.00153-19

Scopus ID

2-s2.0-85071713105   2 Citations

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.

Author List

Oleson BJ, Broniowska KA, Yeo CT, Flancher M, Naatz A, Hogg N, Tarakanova VL, Corbett JA

Authors

John A. Corbett PhD Chair, Professor in the Biochemistry department at Medical College of Wisconsin
Neil Hogg PhD Associate Dean, Professor in the Biophysics department at Medical College of Wisconsin
Vera Tarakanova PhD Associate Professor in the Microbiology and Immunology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Adenosine Triphosphate
Animals
Cell Line
Cell Respiration
Cell Survival
DNA Damage
DNA Repair
Glycolysis
Hep G2 Cells
Humans
Insulin-Secreting Cells
Male
Mice
Mitochondria
NAD
Nitric Oxide
Rats
Rats, Sprague-Dawley
jenkins-FCD Prod-482 91ad8a360b6da540234915ea01ff80e38bfdb40a