Oxidative pentose phosphate pathway and glucose anaplerosis support maintenance of mitochondrial
            NADPH
            pool under mitochondrial oxidative stress

In vitro studies suggested that glucose metabolism through the oxidative pentose phosphate pathway (oxPPP) can paradoxically feed superoxide-generating enzymes in failing hearts. We therefore tested the hypothesis that acute inhibition of the oxPPP reduces oxidative stress and enhances function and metabolism of the failing heart, in vivo. In 10 chronically instrumented dogs, congestive heart failure (HF) was induced by high-frequency cardiac pacing. Myocardial glucose consumption was enhanced by raising arterial glycemia to levels mimicking postprandial peaks, before and after intravenous administration of the oxPPP inhibitor 6-aminonicotinamide (80 mg/kg). Myocardial energy substrate metabolism was measured with radiolabeled glucose and oleic acid, and cardiac 8-isoprostane output was used as an index of oxidative stress. A group of five chronically instrumented, normal dogs served as control. In HF, raising glycemic levels from ∼80 to ∼170 mg/dL increased cardiac isoprostane output by approximately twofold, whereas oxPPP inhibition normalized oxidative stress and enhanced cardiac oxygen consumption, glucose oxidation, and stroke work. In normal hearts glucose infusion did not induce significant changes in cardiac oxidative stress. Myocardial tissue concentration of 6P-gluconate, an intermediate metabolite of the oxPPP, was significantly reduced by ∼50% in treated versus nontreated failing hearts, supporting the inhibitory effect of 6-aminonicotinamide. Our study indicates an important contribution of the oxPPP activity to cardiac oxidative stress in HF, which is particularly pronounced during common physiological changes such as postprandial glycemic peaks.

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Acute Activation of Oxidative Pentose Phosphate Pathway as First-Line Response to Oxidative Stress in Human Skin Cells

Molecular Cell ◽

10.1016/j.molcel.2015.06.017 ◽

2015 ◽

Vol 59 (3) ◽

pp. 359-371 ◽

Cited By ~ 144

Author(s):

Andreas Kuehne ◽

Hila Emmert ◽

Joern Soehle ◽

Marc Winnefeld ◽

Frank Fischer ◽

...

Keyword(s):

Oxidative Stress ◽

Human Skin ◽

Pentose Phosphate Pathway ◽

Pentose Phosphate ◽

Oxidative Pentose Phosphate Pathway ◽

First Line ◽

Skin Cells ◽

Human Skin Cells

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Systematic Identification of Regulators of Oxidative Stress Reveals Non-canonical Roles for Peroxisomal Import and the Pentose Phosphate Pathway

Cell Reports ◽

10.1016/j.celrep.2020.01.013 ◽

2020 ◽

Vol 30 (5) ◽

pp. 1417-1433.e7 ◽

Cited By ~ 7

Author(s):

Michael M. Dubreuil ◽

David W. Morgens ◽

Kanji Okumoto ◽

Masanori Honsho ◽

Kévin Contrepois ◽

...

Keyword(s):

Oxidative Stress ◽

Pentose Phosphate Pathway ◽

Pentose Phosphate ◽

Systematic Identification

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Targeting oxidative pentose phosphate pathway prevents recurrence in mutant Kras colorectal carcinomas

PLoS Biology ◽

10.1371/journal.pbio.3000425 ◽

2019 ◽

Vol 17 (8) ◽

pp. e3000425 ◽

Cited By ~ 1

Author(s):

WenChao Gao ◽

YuTing Xu ◽

Tao Chen ◽

ZunGuo Du ◽

XiuJuan Liu ◽

...

Keyword(s):

Pentose Phosphate Pathway ◽

Pentose Phosphate ◽

Oxidative Pentose Phosphate Pathway ◽

Colorectal Carcinomas

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TIGAR regulates glycolysis in ischemic kidney proximal tubules

AJP Renal Physiology ◽

10.1152/ajprenal.00459.2014 ◽

2015 ◽

Vol 308 (4) ◽

pp. F298-F308 ◽

Cited By ~ 25

Author(s):

Jinu Kim ◽

Kishor Devalaraja-Narashimha ◽

Babu J. Padanilam

Keyword(s):

Oxidative Stress ◽

Reperfusion Injury ◽

Pentose Phosphate Pathway ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Pentose Phosphate ◽

Atp Depletion ◽

G6pd Activity ◽

Histological Damage ◽

Severe Ischemia

Tp53-induced glycolysis and apoptosis regulator (TIGAR) activation blocks glycolytic ATP synthesis by inhibiting phosphofructokinase-1 activity. Our data indicate that TIGAR is selectively induced and activated in renal outermedullary proximal straight tubules (PSTs) after ischemia-reperfusion injury in a p53-dependent manner. Under severe ischemic conditions, TIGAR expression persisted through 48 h postinjury and induced loss of renal function and histological damage. Furthermore, TIGAR upregulation inhibited phosphofructokinase-1 activity, glucose 6-phosphate dehydrogenase (G6PD) activity, and induced ATP depletion, oxidative stress, autophagy, and apoptosis. Small interfering RNA-mediated TIGAR inhibition prevented the aforementioned malevolent effects and protected the kidneys from functional and histological damage. After mild ischemia, but not severe ischemia, G6PD activity and NADPH levels were restored, suggesting that TIGAR activation may redirect the glycolytic pathway into gluconeogenesis or the pentose phosphate pathway to produce NADPH. The increased level of NADPH maintained the level of GSH to scavenge ROS, resulting in a lower sensitivity of PST cells to injury. Under severe ischemia, G6PD activity and NADPH levels were reduced during reperfusion; however, blockade of TIGAR enhanced their levels and reduced oxidative stress and apoptosis. Collectively, these results demonstrate that inhibition of TIGAR may protect PST cells from energy depletion and apoptotic cell death in the setting of severe ischemia-reperfusion injury. However, under low ischemic burden, TIGAR activation induces the pentose phosphate pathway and autophagy as a protective mechanism.

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