bims-mignad 2025-10-26 papers

Issue of 2025–10–26
four papers selected by
Melisa Emel Ermert, Amsterdam UMC

Neurochem Res. 2025 Oct 25. 50(6): 337

Oxidative Stress Induces the Phosphorylation of NAD+ to NADP+ by NAD Kinase in Cultured Primary Rat Astrocytes.

Johanna Elisabeth Willker, Patrick Watermann, Ralf Dringen.

Astrocytes have important functions in the metabolism and antioxidative defence of the brain. Three redox pairs and the ratio of the reduced and oxidized partners in each pair are essential for astrocytic redox metabolism, GSx (glutathione (GSH) plus glutathione disulfide (GSSG)), NADx (NADH plus NAD+) and NADPx (NADPH plus NADP+). In order to elucidate the interactions between the three redox pairs in astrocytes, we first analysed the basal levels of the six redox co-substrates for cultured primary rat astrocytes by using sensitive and specific enzymatic cycling assays. In untreated cultures, the basal specific contents of GSx, NADPx and NADx were 44.7 ± 8.2 nmol/mg protein, 0.64 ± 0.09 nmol/mg protein and 2.91 ± 0.40 nmol/mg protein, with the reduced co-substrates accounting for 97 ± 3%, 37 ± 14% and 28 ± 10% of the total amounts, respectively. Exposure of cultured astrocytes to oxidative stress (100 µM H2O2 in the presence of the pentose-phosphate pathway inhibitor G6PDi-1) caused a rapid and severe but transient oxidation of GSH to GSSG. This increase was accompanied by a doubling of the total pool of NADPx on the expense of the cellular NADx pool, suggesting that NAD+ was phosphorylated to NADP+ under these conditions. Testing for NAD kinase (NADK) activity in lysates of cultured astrocytes revealed that the enzyme is present with a specific vmax activity of around 1 nmol/(min x mg protein) and has KM-values of 1.30 ± 0.19 mM for NAD+ and 2.71 ± 0.18 mM for ATP. Preincubation of astrocytes with thionicotinamide, the precursor for the cellular synthesis of the NADK inhibitor thio-NADP, prevented the transient oxidative stress-induced phosphorylation of NAD+ to NADP+. These data demonstrate that the NADPx pool can be increased in cultured astrocytes during oxidative stress by NADK-mediated phosphorylation of NAD+, providing experimental evidence for an additional interaction of the main astrocytic redox pairs during oxidative stress.

Keywords: Astrocytes; Glutathione; NAD kinase; Nicotinamide coenzymes; Oxidative stress

DOI: https://doi.org/10.1007/s11064-025-04588-4

Fluids Barriers CNS. 2025 Oct 23. 22(1): 105

Reply to Comment by Quistorff: ATP is not consumed solely by hydrolytic reactions.

Gerald A Dienel, Martin Lauritzen.

A Comment to our recent paper that described a budget for brain metabolic water production claimed that all ATP produced by oxidation of glucose is consumed by hydrolysis, and that the net calculated production of metabolic water is equal to that obtained by combustion of glucose. However, ATP is synthesized and consumed by enzymatic reactions that do not involve water in the mechanism. Not all ATP consumed is hydrolyzed.

DOI: https://doi.org/10.1186/s12987-025-00711-3

Rev Endocr Metab Disord. 2025 Oct 23.

Metabolic reprogramming in diabetes and other endocrine and metabolic disorders: exploring the Warburg effect, ketones, and SGLT2 inhibitors.

Pedro Carrera-Bastos, Marcel H A Muskiet, Fernando Mata-Ordoñez, Leo Pruimboom, Alejandro Lucia, Raul M Luque, Frits A J Muskiet.

The "Warburg effect", a metabolic adaptation observed in dividing cells, involves a shift from mitochondrial oxidative phosphorylation to cytoplasmic glucose metabolism. This metabolic process is characterized by increased cellular uptake of glucose and glutamine, elevated intracellular pH and sodium levels, enhanced protection against oxidative stress, altered autophagy, and increased lactate production. Initially identified by Otto Warburg in cancer cells, the Warburg effect is now recognized as a common feature of all dividing cells, prioritizing biomass production for cell proliferation over energy generation for specialized cellular functions. Indeed, the Warburg effect is emerging as an important feature not only in cancer but also in a range of metabolic, endocrine, and neurological chronic disorders, including type 2 diabetes, heart and kidney failure, therapy-refractory epilepsy, Alzheimer's and Parkinson's diseases, chronic fatigue syndrome, and post-viral syndromes. The prevailing notion that "dysfunctional mitochondria" are the primary cause of the "energy deficit" observed in these conditions may be misleading. Instead, this "energy deficit" can result from cells reprogramming their metabolism to support cell division. Additionally, in these disorders, senescent cells are abundant, exhibiting a Warburg-like metabolism with cell cycle arrest and enhanced anabolic activity. This review explores the multifaceted role of the Warburg effect in type 2 diabetes and other metabolic and endocrine chronic disorders and examines the therapeutic potential of different interventions such as intermittent fasting, ketogenic diets, ketone supplements, and sodium/glucose co-transporter 2 inhibitors. Through a comprehensive analysis of existing literature, we aim to shed light on the mechanisms underlying these interventions and their potential impact on disease progression and patient outcomes.

Keywords: Diabetes; Heart failure; Ketones; Senescent cells; Sodium/glucose cotransporter; Warburg effect

DOI: https://doi.org/10.1007/s11154-025-09996-z

Brain. 2025 Oct 22. pii: awaf398. [Epub ahead of print]

Iron on trial: recasting the role of iron in neurodegeneration.

Scott Ayton, Caroline Moreau, David Devos, Ashley I Bush.

Iron is critical for numerous neurophysiological functions, while its dysregulation is potentially hazardous for neurodegeneration through oxidative stress and ferroptosis. For decades, elevated brain iron levels observed in neurodegenerative diseases such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis was presumed to drive disease progression; a hypothesis that propelled clinical trials of strong iron chelators like deferiprone. Results from these trials, however, have challenged this paradigm, with deferiprone markedly worsening outcomes in Alzheimer's and, in certain contexts, Parkinson's patients. These findings underscore the vital role of iron for brain health and suggest functional compensatory mechanisms that could become deleterious at the extremes of iron distribution (both low and high levels). Here, we outline an evolving understanding of iron's role in neurodegeneration, and we explore pathways for therapeutic development strategies that mitigate potential iron-mediated damage, while preserving its essential functions in the brain.

Keywords: Alzheimer’s disease; Parkinson’s disease; chelation; clinical trials; iron

DOI: https://doi.org/10.1093/brain/awaf398