Faculty Collaboration Database

β-cell-selective inhibition of DNA damage response signaling by nitric oxide is associated with an attenuation in glucose uptake. J Biol Chem 2023 Mar;299(3):102994

Date

02/12/2023

Pubmed ID

36773802

Pubmed Central ID

PMC10023961

DOI

10.1016/j.jbc.2023.102994

Scopus ID

2-s2.0-85150358100 (requires institutional sign-in at Scopus site)

Abstract

Nitric oxide (NO) plays a dual role in regulating DNA damage response (DDR) signaling in pancreatic β-cells. As a genotoxic agent, NO activates two types of DDR signaling; however, when produced at micromolar levels by the inducible isoform of NO synthase, NO inhibits DDR signaling and DDR-induced apoptosis in a β-cell-selective manner. DDR signaling inhibition by NO correlates with mitochondrial oxidative metabolism inhibition and decreases in ATP and NAD⁺. Unlike most cell types, β-cells do not compensate for impaired mitochondrial oxidation by increasing glycolytic flux, and this metabolic inflexibility leads to a decrease in ATP and NAD⁺. Here, we used multiple analytical approaches to determine changes in intermediary metabolites in β-cells and non-β-cells treated with NO or complex I inhibitor rotenone. In addition to ATP and NAD⁺, glycolytic and tricarboxylic acid cycle intermediates as well as NADPH are significantly decreased in β-cells treated with NO or rotenone. Consistent with glucose-6-phosphate residing at the metabolic branchpoint for glycolysis and the pentose phosphate pathway (NADPH), we show that mitochondrial oxidation inhibitors limit glucose uptake in a β-cell-selective manner. Our findings indicate that the β-cell-selective inhibition of DDR signaling by NO is associated with a decrease in ATP to levels that fall significantly below the K_M for ATP of glucokinase (glucose uptake) and suggest that this action places the β-cell in a state of suspended animation where it is metabolically inert until NO is removed, and metabolic function can be restored.

Author List

Yeo CT, Kropp EM, Hansen PA, Pereckas M, Oleson BJ, Naatz A, Stancill JS, Ross KA, Gundry RL, Corbett JA

Author

John A. Corbett PhD Chair, Professor in the Biochemistry department at Medical College of Wisconsin

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

Adenosine Triphosphate
DNA Damage
Glucose
NAD
NADP
Nitric Oxide
Rotenone