bims-mignad 2025-11-02 papers

Issue of 2025–11–02
four papers selected by
Melisa Emel Ermert, Amsterdam UMC

Mol Med. 2025 Oct 31. 31(1): 323

From Bench to Clinic: The 2024 FASEB Scientific Research Conference on NAD Metabolism and Signaling.

Shin-Ichiro Imai, Eija Pirinen, Michael N Sack, Jonas T Treebak, Charalampos Tzoulis, Santina Bruzzone, Andreas H Guse, Michael O Hottiger, Xiaolu A Cambronne.

The 2024 FASEB Scientific Research Conference on NAD Metabolism and Signaling was held in Lisbon, Portugal and served to (1) unite researchers, clinicians, and trainees, (2) create opportunities for early-stage investigators by showcasing their work on an international stage and promote collaborations, (3) train the next generation of scientists in the field, and (4) improve human health by furthering our understanding of NAD+ metabolism and signaling. With the burgeoning potential of NAD+ as a therapeutic agent for multiple health conditions, as well as many remaining scientific questions about the NAD+ metabolome, an expert panel discussion titled "NAD+ Health Outcomes Forum: A Call to Action" was hosted on Thursday, August 29, 2024. The main objectives were to discuss and translate what is known about NAD+ biology into tangible actions and to identify what remains unknown into a research call to action. Given the broad and reaching impact of NAD+ on health, there is significant interest in NAD+ pathway modulation, including through precursors such as nicotinic acid, nicotinamide (NAM), nicotinamide riboside (NR), and nicotinamide mononucleotide (NMN). There is also growing research regarding the heterogeneity among individuals, as well as differences and similarities among the NAD+ precursors, specifically in relation to dosing, timing, and their impact on various health conditions.

DOI: https://doi.org/10.1186/s10020-025-01394-0

Mol Cell. 2025 Oct 28. pii: S1097-2765(25)00819-6. [Epub ahead of print]

Accumulation of succinate suppresses de novo purine synthesis through succinylation-mediated control of the mitochondrial folate cycle.

Mushtaq A Nengroo, Austin T Klein, Heather S Carr, Olivia Vidal-Cruchez, Umakant Sahu, Daniel J McGrail, Nidhi Sahni, Niklas B Thompson, Peter A Faull, Peng Gao, John M Asara, Hardik Shah, Marc L Mendillo, Issam Ben-Sahra.

The de novo purine synthesis pathway is fundamental for nucleotide production, yet the role of mitochondrial metabolism in modulating this process remains underexplored. Here, we identify that succinate dehydrogenase (SDH) is essential for maintaining de novo purine synthesis. Genetic or pharmacological inhibition of SDH suppresses purine synthesis, contributing to a decrease in cell proliferation. Mechanistically, SDH inhibition elevates succinate, which in turn promotes the succinylation of serine hydroxymethyltransferase 2 (SHMT2) within the mitochondrial tetrahydrofolate (THF) cycle. This post-translational modification lowers formate output, depriving cells of one-carbon units needed for purine assembly. In turn, cancer cells activate the purine salvage pathway, a metabolic compensatory adaptation that represents a therapeutic vulnerability. Notably, co-inhibition of SDH and purine salvage induces pronounced antiproliferative and antitumoral effects in preclinical models. These findings reveal a signaling role for mitochondrial succinate in tuning nucleotide metabolism and highlight a dual-targeted strategy to exploit metabolic dependencies in cancer.

Keywords: TCA cycle; cancer; formate; mitochondrial metabolism; nucleotide metabolism; succinate

DOI: https://doi.org/10.1016/j.molcel.2025.10.002

Cureus. 2025 Sep;17(9): e93331

The Warburg Effect Redefined: A Kinetic and Regulatory Perspective.

Amal Bhanu Vayakkattil, Aiswarya S Pazhanchery, Shibu Andrews, Udayabhanu Vayakkattil.

The Warburg effect, characterized by the preferential conversion of glucose to lactate despite adequate oxygen availability, constitutes a regulated metabolic adaptation rather than a mere dysfunctional response to hypoxia. This metabolic shift arises because lactate dehydrogenase (LDH) exhibits a significantly higher catalytic capacity compared to pyruvate dehydrogenase (PDH), resulting in a substantial reduction of pyruvate to lactate once PDH becomes saturated. In cancer cells, this kinetic preference is further amplified by the upregulation of glucose and monocarboxylate transporters (GLUT1, MCT1, and MCT4) and alterations to the plasma membrane, which enhance transport efficiency. These adaptations maintain a high glycolytic flux, facilitate continuous lactate efflux, and circumvent traditional feedback inhibition. The accumulation of glycolytic intermediates supports the biosynthesis of nucleotides, lipids, and proteins, thereby promoting tumorigenesis. Over time, metabolite-induced DNA methylation and chromatin remodeling reinforce this metabolic state, stabilizing the oxygen-independent proliferative phenotype. Consequently, the Warburg effect is best conceptualized as a primary metabolic strategy initiated by membrane remodeling, sustained by kinetic flux imbalances, and perpetuated by epigenetic feedback, collectively enabling tumor growth and survival in adverse microenvironments.

Keywords: atp; cancer; cell proliferation; epigenetic; glucose transporter; glycolysis; lactate; lactate dehydrogenase; monocarboxylate transporters; warburg effect

DOI: https://doi.org/10.7759/cureus.93331