Project description:This study demonstrated the role of the glycolytic enzyme alpha-enolase (ENO1) on glycolysis and stemness in gastric cancer (GC). High ENO1 expression was associated with poor prognosis and promoted malignant phenotypes and stem-like characteristics in GC. Mechanistically, ENO1 directly stimulated lactate and ATP production by regulating glycolysis, affecting lactate homeostasis and intracellular ATP pools, and co-regulating the AMPK/mTOR and PI3K/AKT signaling pathways. This ultimately drove GC stemness, epithelial-mesenchymal transition (EMT)-related markers, self-renewal, migration, and invasion.
Project description:Longstanding evidence implicates glioma stem cells (GSCs) as the major driver for glioma propagation and recurrence. GSCs have a distinctive metabolic landscape characterized by elevated glycolysis. Lactate accumulation resulting from enhanced glycolytic activity can drive lysine lactylation to regulate protein functions, suggesting that elucidating the lactylation landscape in GSCs could provide insights into glioma biology. Herein, we demonstrated that global lactylation was significantly elevated in GSCs compared to differentiated glioma cells (DGCs). PTBP1, a central regulator of RNA processing, was hyperlactylated in GSCs, and SIRT1 induced PTBP1 delactylation. PTBP1-K436 lactylation supported glioma progression and GSC maintenance. Mechanistically, K436 lactylation inhibited PTBP1 proteasomal degradation by attenuating the interaction with TRIM21. Moreover, PTBP1 lactylation enhanced its RNA-binding capacity and facilitated PFKFB4 mRNA stabilization, which further increased glycolysis. Together, these findings uncovered a lactylation-mediated mechanism in GSCs driven by metabolic reprogramming that induces aberrant epigenetic modifications to further stimulate glycolysis, resulting in a vicious cycle to exacerbate tumorigenesis.
Project description:We have identified a new histone modification, which is derived from glycolysis end product, lactate. By SILAC-MS/MS based quantification, and U-13C6 glucose labeling experiments, we demonstrate that histone Kla is regulated by cellular glycolysis pathway
Project description:Neuroinflammation is a pathological hallmark of several chronic neurological diseases, including multiple sclerosis (MS), and this process is driven by the sustained activation of myeloid cells. However, the pathogenic myeloid cells subset(s) and their regulation in MS remain unclear. Here, we identify a multiple sclerosis-associated microglia and macrophage (MSMM) subset defined as CD38+CD93+ that drives MS pathogenesis. MSMM exhibits pro-inflammatory and neurotoxic characteristics accompanied by aberrant activation of glycolysis. Mechanistically, we found that aberrant activation of glycolysis results in excessive lactate production and elevation of histone lactylation in MSMM. Histone lactylation (H3K18la and H4K12la) in turn activates the transcriptional modules of genes governing neuroinflammation and glycolysis, thereby promotes the formation of MSMM. Blockade of MSMM with anti-CD38 plus anti-CD93 neutralizing antibodies ameliorates neuroinflammation and MS-like pathologies in an experimental autoimmune encephalomyelitis (EAE) mouse model of MS. Inhibition of glycolysis through Ldha knock out or LDHA inhibitor decreases the number of MSMM and attenuates EAE severity. Together, these findings reveal a MS-associated pathogenic cell subset and provide potential therapeutic approaches for MS.
Project description:Age-related macular degeneration (AMD) is a leading cause of blindness among the elderly. Using clinical samples and knockout mice, we reported that the m1A eraser ALKBH3 reshaped retinal metabolism to promote AMD. In retinal pigment epithelium (RPE), the dm1ACRISPR system demonstrated that ALKBH3 demethylated the glycolytic enzyme HK2 to activate anaerobic glycolysis, producing excessive lactate. The lactate promoted histone lactylation at H3K18, which in turn bound to ALKBH3 to amplify its transcription, establishing a positive feedback loop. The ALKBH3 inhibitor HUHS015 disrupted this loop, effectively mitigating RPE degeneration. Furthermore, ALKBH3 directly targeted the pro-angiogenic factor VEGFA to modulate the metabolic cross-talk between RPE and choroidal capillaries, thus promoting choroidal neovascularization (CNV). HUHS015 inhibited CNV synergistically with the anti-VEGF drug Aflibercept. Our study provides critical insights into the molecular mechanisms and metabolic events facilitating the progression from RPE degeneration to CNV in AMD, laying the groundwork for new treatments of AMD.
Project description:Mutations of the β-glucuronidase protein α-Klotho have been associated with premature aging, and altered cognitive function. Although highly expressed in specific areas of the brain, Klotho functions in the central nervous system remain unknow. Here, we show that cultured hippocampal neurons respond to insulin and glutamate stimulation by elevating Klotho protein levels. Conversely, AMPA and NMDA antagonism suppress neuronal Klotho expression. We also provide evidence that soluble Klotho enhances astrocytic aerobic glycolysis by hindering pyruvate metabolism through the mitochondria, and stimulating its processing by lactate dehydrogenase. Pharmacological inhibition of FGFR1, Erk phosphorylation, and monocarboxylic acid transporters prevents Klotho-induced lactate release from astrocytes. Taken together these data suggest Klotho is a potential new player in the metabolic coupling between neurons and astrocytes. Neuronal glutamatergic activity and insulin modulation elicit Klotho release, which in turn stimulates astrocytic lactate formation and release. Lactate can then be used by neurons as a metabolic substrate contributing to fulfill their elevated energy requirements.
Project description:Embryonic stem cells (ESCs) favor glycolysis over oxidative phosphorylation for energy production, and glycolytic metabolism is critical for pluripotency establishment, maintenance and exit. However, how glycolysis regulates the self-renewal and differentiation of ESCs remains elusive. Here, we demonstrated that protein lactylation, regulated by intracellular lactate, contributes to the self-renewal of ESCs. Next, the lactylome profiles of ESCs with and without a lactate dehydrogenase (Ldh) inhibitor, which suppresses the conversion of pyruvate to lactate, were depicted. It was notable that many lactylated proteins are involved in the self-renewal and differentiation of ESCs. We further showed that Esrrb, an orphan nuclear receptor involved in pluripotency maintenance and extraembryonic endoderm stem cell (XEN) differentiation, is lactylated on K228 and K232. Lactylation of Esrrb enhances its activity in promoting ESC self-renewal in the absence of LIF and XEN differentiation of ESCs, through increasing its binding at target genes. Our studies reveal the importance of protein lactation in the self-renewal and XEN differentiation of ESCs, and the underlying mechanism for glycolytic metabolism regulating cell fate choice.
Project description:Aerobic glycolysis (the Warburg effect) has been demonstrated to facilitate tumor progression by producing lactate, which has important roles as a proinflammatory and immunosuppressive mediator. However, how aerobic glycolysis is directly regulated is largely unknown. Here, we show that ectopic Zeb1 directly increases the transcriptional expression of HK2, PFKP and PKM2, which are glycolytic rate-determining enzymes, thus promoting the Warburg effect and breast cancer proliferation, migration, and chemoresistance in vitro and in vivo. In addition, Zeb1 exerts its biological effects to induce glycolytic activity in response to hypoxia via the PI3K/Akt/HIF-1α signaling axis, which contributes to fostering an immunosuppressive tumor microenvironment (TME). Mechanistically, breast cancer cells with ectopic Zeb1 expression produce lactate in the acidic tumor milieu to induce the alternatively activated macrophage M2-like phenotype through stimulation of the PKA/CREB signaling pathway. Clinically, the expression of Zeb1 is positively correlated with dysregulation of aerobic glycolysis, accumulation of M2-like tumor-associated macrophages (TAMs) and a poor prognosis in patients with breast cancer. In conclusion, these findings identify a Zeb1-dependent mechanism as a driver of breast cancer progression that acts by stimulating tumor-macrophage interplay, which could be a viable therapeutic target for the treatment of advanced human cancers.
Project description:Myelin injury, a hallmark of several neurological diseases, is highly sensitive to glucose metabolism disruptions. Here, we reveal that oligodendrocytes (OLs) within demyelinating lesions exhibit reduced glycolytic efficiency and lactate production, in contrast to the mature OLs. Administration of lactate, the product of glycolysis, or specific overexpression of Lactate Dehydrogenase A (LDHA), the enzyme in lactate production, in Olig1+ OLs, significantly enhances remyelination. In contrast, conditional knockout of LDHA in the Olig1+ lineage or CNPase+ premyelinating OLs leads to severe neuropathy with dysmyelination in a development-dependent and cell-specific manner. Mechanistic insights show that oligodendrocytes within demyelinating lesions undergo lactylation silencing, a lactate-induced epigenetic modification that impedes myelin restoration. Furthermore, lactylation of LDHA and carbonic anhydrase II (CAII) couple glycolysis with oligodendrocyte maturation. Our findings elucidate the metabolic interplay between glycolysis, lactylation, and oligodendrocyte maturation, and provide novel enzymatic therapeutic perspectives for demyelinating disorders for which effective therapies are currently lacking.