bims-mignad 2025-03-16 papers

Issue of 2025–03–16
two papers selected by
Melisa Emel Ermert, Amsterdam UMC

Heliyon. 2025 Feb 28. 11(4): e42735

Enhancing NADPH to restore redox homeostasis and lysosomal function in G6PD-deficient microglia.

Abir Mondal, Soumyadeep Mukherjee, Prince Upadhyay, Isha Saxena, Soumya Pati, Shailja Singh.

Microglia, the immune cells of the central nervous system (CNS), play key roles in neurogenesis, myelination, synaptic transmission, immune surveillance, and neuroinflammation. Inflammatory responses in microglia can lead to oxidative stress and neurodegeneration, contributing to diseases like Parkinson's and Alzheimer's. The enzyme glucose-6-phosphate dehydrogenase (G6PD) is essential for producing nicotinamide adenine dinucleotide phosphate hydrogen (NADPH), which neutralizes oxidative stress. G6PD deficiency has been linked to several disorders, including neurological conditions. Our study shows that G6PD deficiency in microglia reduces NADPH levels, disrupting redox balance and lysosomal function. To address this, we explored alternative metabolic pathways by targeting enzymes like isocitrate dehydrogenase 1 (IDH1) and malic enzyme 1 (ME1), both crucial for NADPH production. Supplementing metabolites such as citric and malic acid improved NADPH levels, while small molecules like dieckol and resveratrol enhanced IDH1 and ME1 expression. The combination of these approaches restored redox homeostasis and lysosomal function, offering potential therapeutic strategies for G6PD deficiency.

Keywords: G6PD deficiency; Metabolites; Oxidative stress; Phytochemicals; Therapeutics

DOI: https://doi.org/10.1016/j.heliyon.2025.e42735

bioRxiv. 2025 Mar 01. pii: 2025.02.26.640389. [Epub ahead of print]

Succinate dehydrogenase activity supports de novo purine synthesis.

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

The de novo purine synthesis pathway is fundamental for nucleic acid production and cellular energetics, yet the role of mitochondrial metabolism in modulating this process remains underexplored. In many cancers, metabolic reprogramming supports rapid proliferation and survival, but the specific contributions of the tricarboxylic acid (TCA) cycle enzymes to nucleotide biosynthesis are not fully understood. Here, we demonstrate that the TCA cycle enzyme succinate dehydrogenase (SDH) is essential for maintaining optimal de novo purine synthesis in normal and cancer cells. Genetic or pharmacological inhibition of SDH markedly attenuates purine synthesis, leading to a significant reduction in cell proliferation. Mechanistically, SDH inhibition causes an accumulation of succinate, which directly impairs the purine biosynthetic pathway. In response, cancer cells compensate by upregulating the purine salvage pathway, a metabolic adaptation that represents a potential therapeutic vulnerability. Notably, co-inhibition of SDH and the purine salvage pathway induces pronounced antiproliferative and antitumoral effects in preclinical models. These findings not only reveal a signaling role for mitochondrial succinate in regulating nucleotide metabolism but also provide a promising therapeutic strategy for targeting metabolic dependencies in cancer.

DOI: https://doi.org/10.1101/2025.02.26.640389