Aug 2026· Frontiers in Immunology· Vol 17, pp.
1883095
· 0 citations· 59 references
Medicine
TL;DR
SIRT1–GAPDH signaling represents a post-translational axis linking sirtuin activity directly to glycolytic enzyme function, distinct from SIRT1's traditional transcriptional roles and serving as a viable molecular checkpoint in microglial immunometabolism.
Abstract
Introduction
Microglial activation drives neuroinflammation through a metabolic switch from oxidative phosphorylation to aerobic glycolysis; however, the molecular mechanisms governing this transition remain poorly defined. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH), sirtuin 1 (SIRT1), lipopolysaccharide (LPS), and interferon-gamma (IFN-γ) are central to this study; GAPDH plays plays a key regulatory role in this switch, and its activity is modulated by reversible acetylation at lysine 254 (K254). It remains unclear whether sirtuin deacetylases regulate this modification in microglia.
Methods
Here, we demonstrate that SIRT1 physically associates with GAPDH in murine microglia and deacetylates K254 under basal conditions. Inflammatory activation using LPS/IFN-γ reduced SIRT1 protein levels and deacetylase activity by approximately 50%, leading to a 2.5-fold increase in K254 acetylation. Pharmacological activation of SIRT1 (SRT1720) reversed this modification and enhanced glycolytic output, mimicking the effects of the deacetylation-mimetic K254R mutant. To isolate the causal role of K254, we replaced endogenous GAPDH with K254R or acetylation-mimetic (K254Q) mutant proteins.
Results
K254R microglia exhibited approximately 35% higher GAPDH enzymatic activity, 40% greater glycolytic flux, and 1.6- to 2.2-fold higher secretion of TNF-α, IL-1β, IL-6, and IL-12p70 than K254Q cells. Glycolytic inhibition with 2-deoxyglucose reduced most of the excess cytokines, confirming enhanced flux as the causal factor in K254-driven inflammatory amplification.
Discussion
Thus, SIRT1-GAPDH signaling represents a post-translational axis linking sirtuin activity directly to glycolytic enzyme function, distinct from SIRT1's traditional transcriptional roles and serving as a viable molecular checkpoint in microglial immunometabolism.
Microglia are central regulators of neuroinflammation in Alzheimer’s disease (AD), yet how metabolic states modulate function remains unclear. Here we show that microglia from the APPNL-G-F mouse model revealed upregulation of glycolytic enzymes coinciding with onset of microglial activation. Surprisingly, this glycolytic shift occurred alongside reduced expression of glucose transporters, suggesting that extracellular glucose may not be the primary fuel source, implicating glycogenolysis as the potential metabolic driver. Consistent with this, significant microglial glycogen accumulation was noted in late disease, when cells exhibited features of metabolic exhaustion and functional impairment. Pharmacological inhibition of glycogenolysis blunted microglia responses to Abeta aggregates and markedly reduced Abeta uptake, confirming a functional role for glycogen metabolism in shaping microglial states. Together, these findings identify glycogen as a central regulator of microglial metabolic health and function, highlighting glycogen homeostasis as a potential therapeutic target for promoting Abeta clearance and preserving protective microglial functions in AD.
Hannah McAlister, Heather Merchant, Verity F. T. Mitchener et al.· bioRxiv· 0 citations
It is reported that Dox induces isoform-specific deacetylation and nuclear accumulation of γ2, triggering nucleolar stress and p53-mediated apoptosis and suggested a promising cardio-oncology strategy that combines HDAC inhibitors with Dox to mitigate DIC.
Canrong Li, Tiantian Yi, Yuting Cui et al.· bioRxiv· 0 citations
The modulatory role of Sirtuins in FOXP3 expression and Treg differentiation is reviewed, providing insight into their contribution to tumor immunosuppression and integrating network-based analysis identified miR-34a as a central regulator and validated the miRNA-Transcription Factor-Sirtuin axis as a viable framework for cancer therapeutic targeting.
Aishwarya Saha, Sriparna De, Sreya Chattopadhyay et al.· Molecular Biology Reports· 0 citations
Sirtuins (SIRT1–SIRT7) are nicotinamide adenine dinucleotide (NAD+) dependent deacylases that serves as metabolic sensors, coupling cellular energy status to chromatin structure, mitochondrial function, and stress responses. Dysregulated SIRT activity has been extensively studied in aging, metabolic syndrome, cardiovascular disease, neurodegeneration, cancer, and immune disorders. However, robust human evidence and SIRT‐targeted therapies are lacking. Transgenic mouse models serve as key platforms to study gene function and guide therapeutic development. This review synthesizes evidence from Sirt1–7 transgenic mouse models regarding the core cellular processes governed by SIRTs: metabolism, genome integrity, stress resistance, immunity, and autophagy, and illustrates their operation across different organ systems. By comparing global, tissue‐specific, and inducible knockout (KO) and overexpression (OE) models of cardiovascular, respiratory, digestive, nervous, endocrine, urogenital, musculoskeletal, malignant, and immune diseases, we identified central regulatory SIRTs (SIRT1, SIRT3, and SIRT6), context‐dependent modifiers (SIRT2, SIRT4, SIRT5, and SIRT7), and their organ‐ and cell type‐specific functions. We also summarize representative small‐molecule SIRT activators, inhibitors, and degraders, covering both clinical and preclinical studies, and highlight where contradictions and knowledge gaps remain. Together, these analyses help clarify which aspects of SIRT modulation are most promising and under what isoform, tissue, and disease contexts they should be pursued for the development of SIRT‑targeted therapies in human disease.
Investigating how opioid receptor agonists influence lipopolysaccharide-induced senescence in microglia suggests that opioids may support cell survival, attenuate LPS-associated senescence markers, and be accompanied by changes consistent with increased autophagy-related activity.
Akash S. Mali, Debanjan Das, Denise Greco et al.· Biocell (Mendoza)· 0 citations
A CCR5-driven immune-metabolic-transcriptional axis in microglia that underlies synaptic deficits in depressive-like behaviors is indicated, offering potential targets for therapeutic intervention.
Ying-Ying Jiao, Zhu Zhu, Rui-An Wang et al.· Cell Reports· 0 citations
Related blog posts
MIT News · Artificial Intelligence· news.mit.eduAug 27, 2026
A new machine-learning framework aims to improve the success rate of computational protein design while moving away from results that reproduce sequences found in nature.
