Metabolic Responses to Reductive Stress

Abstract

Significance: Reducing equivalents (NAD(P)H and glutathione [GSH]) are essential for maintaining cellular redox homeostasis and for modulating cellular metabolism. Reductive stress induced by excessive levels of reduced NAD + (NADH), reduced NADP + (NADPH), and GSH is as harmful as oxidative stress and is implicated in many pathological processes. Recent Advances: Reductive stress broadens our view of the importance of cellular redox homeostasis and the influences of an imbalanced redox niche on biological functions, including cell metabolism. Critical Issues: The distribution of cellular NAD(H), NADP(H), and GSH/GSH disulfide is highly compartmentalized. Understanding how cells coordinate different pools of redox couples under unstressed and stressed conditions is critical for a comprehensive view of redox homeostasis and stress. It is also critical to explore the underlying mechanisms of reductive stress and its biological consequences, including effects on energy metabolism. Future Directions: Future studies are needed to investigate how reductive stress affects cell metabolism and how cells adapt their metabolism to reductive stress. Whether or not NADH shuttles and mitochondrial nicotinamide nucleotide transhydrogenase enzyme can regulate hypoxia-induced reductive stress is also a worthy pursuit. Developing strategies (e.g., antireductant approaches) to counteract reductive stress and its related adverse biological consequences also requires extensive future efforts. Antioxid. Redox Signal. 32, 1330-1347.

Low Molecular Weight Dextran Sulfate (ILB®) Administration Restores Brain Energy Metabolism Following Severe Traumatic Brain Injury in the Rat

“…The ILB ® -induced increase in availability of NAD + and NADH ensures glycolytic flux (via the NAD + -dependent glyceraldehyde-3-phosphate dehydrogenase reaction), PDH complex activity (via the NAD + -dependent acetyl-CoA formation), TCA cycle functioning (via the NAD + -dependent isocitrate dehydrogenase, α-ketoglutarate dehydrogenase, and malate dehydrogenase reactions), and enhanced electron flow through the ETC [51,52]. In addition, the increased availability of NADP + and NADPH allows the tissue to efficiently perform pentose phosphate pathway and biosynthetic reactions (fatty acid biosynthesis for myelin regeneration), and also to catalyze important reductive reactions involved in cell mechanisms of defense (NADPH-dependent GSH-reductase reaction) [53,54]. This last important link was evidenced by the higher values of cerebral GSH measured in ILB ® -treated animals, compared to those found in untreated sTBI rats.…”

Increased glycolysis is an early outcome of palmitate-mediated lipotoxicity

“…Furthermore, under basal conditions, NAD(P)H content is lower in palmitate versus BSA treated cells ( Fig 4A). We should note, however, that this assay cannot separate the different cell compartments, as mitochondrial modulation will also change NAD(P)H redox state in the cytosol, since the pools are connected by the reversible malateaspartate shuttle (Xiao and Loscalzo, 2019). However, our result conclusively indicates that palmitate leads to redox balance changes in PLC cells.…”

Three cytosolic NAD-malate dehydrogenase isoforms of Arabidopsis thaliana: on the crossroad between energy fluxes and redox signaling

“…As the cellular redox-state is not only reflected in cysteine modifications, but even more immediate through the redox-couples NAD + /NADH and NADP + /NADPH, directly connected with the activity of oxidoreductases, both oxidative and reductive stress are sensed at the metabolic level and transferred to a signal-transduction chain [64]. By acting as small molecules affecting protein modifications directly by NAD + -consuming enzymes [21], or indirectly by their effect upon binding to modification sites on enzymes [7] or on transcription factors [65], these coenzymes can fine-tune energy fluxes as required [5].…”