bims-meprid 2025-01-19 papers

ACS Pharmacol Transl Sci. 2025 Jan 10. 8(1): 36-46

Molecular Targets and Small Molecules Modulating Acetyl Coenzyme A in Physiology and Diseases.

Heba Ewida, Harrison Benson, Syed Tareq, Mahmoud Salama Ahmed.

Acetyl coenzyme A (acetyl-CoA), a pivotal regulatory metabolite, is a product of numerous catabolic reactions and a substrate for various anabolic responses. Its role extends to crucial physiological processes, such as glucose homeostasis and free fatty acid utilization. Moreover, acetyl-CoA plays a significant part in reshaping the metabolic microenvironment and influencing the progression of several diseases and conditions, including cancer, insulin resistance, diabetes, heart failure, fear, and neuropathic pain. This Review delves into the role of acetyl-CoA in both physiological and pathological conditions, shedding light on the key players in its formation within the cytosol. We specifically focus on the physiological impact of malonyl-CoA decarboxylase (MCD), acetyl-CoA synthetase2 (ACSS2), and ATP-citrate lyase (ACLY) on metabolism, glucose homeostasis, free fatty acid utilization, and post-translational modification cellular processes. Additionally, we present the pathological implications of MCD, ACSS2, and ACLY in various clinical manifestations. This Review also explores the potential and limitations of targeting MCD, ACSS2, and ACLY using small molecules in different clinical settings.

DOI: https://doi.org/10.1021/acsptsci.4c00476

Cell Rep. 2025 Jan 11. pii: S2211-1247(24)01550-X. [Epub ahead of print]44(1): 115199

IL-7 promotes integrated glucose and amino acid sensing during homeostatic CD4+ T cell proliferation.

Seema Bachoo, Nancy Gudgeon, Rebecca Mann, Victoria Stavrou, Emma L Bishop, Audrey Kelly, Alejandro Huerta Uribe, Jordan Loeliger, Corina Frick, Oliver D K Maddocks, Paul Lavender, Christoph Hess, Sarah Dimeloe.

Interleukin (IL)-7 promotes T cell expansion during lymphopenia. We studied the metabolic basis in CD4+ T cells, observing increased glucose usage for nucleotide synthesis and oxidation in the tricarboxylic acid (TCA) cycle. Unlike other TCA metabolites, glucose-derived citrate does not accumulate upon IL-7 exposure, indicating diversion into other processes. In agreement, IL-7 promotes glucose-dependent histone acetylation and chromatin accessibility, notable at the loci of the amino acid-sensing Ragulator complex. Consistently, the expression of its subunit late endosomal/lysosomal adaptor, MAPK and mTOR activator 5 (LAMTOR5) is promoted by IL-7 in a glucose-dependent manner, and glucose availability determines amino acid-dependent mechanistic target of rapamycin (mTOR) activation, confirming integrated nutrient sensing. LAMTOR5 deletion impairs IL-7-mediated T cell expansion, establishing that glycolysis in the absence of Ragulator activation is insufficient to support this. Clinically, CD4+ T cells from stem cell transplant recipients demonstrate coordinated upregulation of glycolytic and TCA cycle enzymes, amino acid-sensing machinery, and mTOR targets, highlighting the potential to therapeutically target this pathway to fine-tune lymphopenia-induced T cell proliferation.

Keywords: IL-7; Immunology; Metabolism; T cell; T lymphocyte; mTOR; metabolism; nutrient sensing; proliferation

DOI: https://doi.org/10.1016/j.celrep.2024.115199

bioRxiv. 2025 Jan 03. pii: 2025.01.02.631150. [Epub ahead of print]

Lactylation fuels nucleotide biosynthesis and facilitates deuterium metabolic imaging of tumor proliferation in H3K27M-mutant gliomas.

Georgios Batsios, Céline Taglang, Suresh Udutha, Anne Marie Gillespie, Simon P Robinson, Timothy Phoenix, Sabine Mueller, Sriram Venneti, Carl Koschmann, Pavithra Viswanath.

Oncogenes hyperactive lactate production, but the mechanisms by which lactate facilitates tumor growth are unclear. Here, we demonstrate that lactate is essential for nucleotide biosynthesis in pediatric diffuse midline gliomas (DMGs). The oncogenic histone H3K27M mutation upregulates phosphoglycerate kinase 1 (PGK1) and drives lactate production from [U- 13 C]-glucose in DMGs. Lactate activates the nucleoside diphosphate kinase NME1 via lactylation and promotes the synthesis of nucleoside triphosphates essential for tumor proliferation. Importantly, we show that this mechanistic link between glycolysis and nucleotide biosynthesis provides a unique opportunity for deuterium metabolic imaging of DMGs. Spatially mapping 2 H-lactate production from [6,6- 2 H]-glucose allows visualization of the metabolically active tumor lesion and provides an early readout of response to standard-of-care radiation and targeted therapy that precedes extended survival and reflects pharmacodynamic alterations at the tissue level in preclinical DMG models in vivo at clinical field strength (3T). In essence, we have identified an H3K27M-lactate-NME1 axis that promotes DMG proliferation and facilitates non-invasive metabolic imaging of DMGs.
STATEMENT OF SIGNIFICANCE: This study establishes a role for lactate in driving nucleotide biosynthesis in DMGs. Importantly, imaging lactate production from glucose using DMI provides a readout of tumor proliferation and early response to therapy in clinically relevant DMG models. Our studies lay the foundation for precision metabolic imaging of DMG patients.

DOI: https://doi.org/10.1101/2025.01.02.631150