bims-meprid 2024-09-29 papers

Mol Metab. 2024 Sep 19. pii: S2212-8778(24)00162-5. [Epub ahead of print]89 102031

Acetate drives ovarian cancer quiescence via ACSS2-mediated acetyl-CoA production.

Allison C Sharrow, Emily Megill, Amanda J Chen, Afifa Farooqi, Naveen Kumar Tangudu, Apoorva Uboveja, Stacy McGonigal, Nadine Hempel, Nathaniel W Snyder, Ronald J Buckanovich, Katherine M Aird.

Quiescence is a reversible cell cycle exit traditionally thought to be associated with a metabolically inactive state. Recent work in muscle cells indicates that metabolic reprogramming is associated with quiescence. Whether metabolic changes occur in cancer to drive quiescence is unclear. Using a multi-omics approach, we found that the metabolic enzyme ACSS2, which converts acetate into acetyl-CoA, is both highly upregulated in quiescent ovarian cancer cells and required for their survival. Indeed, quiescent ovarian cancer cells have increased levels of acetate-derived acetyl-CoA, confirming increased ACSS2 activity in these cells. Furthermore, either inducing ACSS2 expression or supplementing cells with acetate was sufficient to induce a reversible quiescent cell cycle exit. RNA-Seq of acetate treated cells confirmed negative enrichment in multiple cell cycle pathways as well as enrichment of genes in a published G0 gene signature. Finally, analysis of patient data showed that ACSS2 expression is upregulated in tumor cells from ascites, which are thought to be more quiescent, compared to matched primary tumors. Additionally, high ACSS2 expression is associated with platinum resistance and worse outcomes. Together, this study points to a previously unrecognized ACSS2-mediated metabolic reprogramming that drives quiescence in ovarian cancer. As chemotherapies to treat ovarian cancer, such as platinum, have increased efficacy in highly proliferative cells, our data give rise to the intriguing question that metabolically-driven quiescence may affect therapeutic response.

Keywords: ACSS2; Cell cycle; G0 phase; Metabolism

DOI: https://doi.org/10.1016/j.molmet.2024.102031

Mol Metab. 2024 Sep 19. pii: S2212-8778(24)00163-7. [Epub ahead of print] 102032

Linking metabolism and histone acetylation dynamics by integrated metabolic flux analysis of Acetyl-CoA and histone acetylation sites.

Anna-Sophia Egger, Eva Rauch, Suraj Sharma, Tobias Kipura, Madlen Hotze, Thomas Mair, Alina Hohenegg, Philipp Kobler, Ines Heiland, Marcel Kwiatkowski.

Histone acetylation is an important epigenetic modification that regulates various biological processes and cell homeostasis. Acetyl-CoA, a hub molecule of metabolism, is the substrate for histone acetylation, thus linking metabolism with epigenetic regulation. However, still relatively little is known about the dynamics of histone acetylation and its dependence on metabolic processes, due to the lack of integrated methods that can capture site-specific histone acetylation and deacetylation reactions together with the dynamics of acetyl-CoA synthesis. In this study, we present a novel proteo-metabo-flux approach that combines mass spectrometry-based metabolic flux analysis of acetyl-CoA and histone acetylation with computational modelling. We developed a mathematical model to describe metabolic label incorporation into acetyl-CoA and histone acetylation based on experimentally measured relative abundances. We demonstrate that our approach is able to determine acetyl-CoA synthesis dynamics and site-specific histone acetylation and deacetylation reaction rate constants, and that consideration of the metabolically labelled acetyl-CoA fraction is essential for accurate determination of histone acetylation dynamics. Furthermore, we show that without correction, changes in metabolic fluxes would be misinterpreted as changes in histone acetylation dynamics, whereas our proteo-metabo-flux approach allows to distinguish between the two processes.

Keywords: Computational modelling; Epigenetics; Histone modifications; LC-MS; Metabolic flux analysis; Metabolism

DOI: https://doi.org/10.1016/j.molmet.2024.102032

bioRxiv. 2024 Sep 13. pii: 2024.08.19.608538. [Epub ahead of print]

Microbial metabolite-guided CAR T cell engineering enhances anti-tumor immunity via epigenetic-metabolic crosstalk.

Emerging data have highlighted a correlation between microbiome composition and cancer immunotherapy outcome. While commensal bacteria and their metabolites are known to modulate the host environment, contradictory effects and a lack of mechanistic understanding impede the translation of microbiome-based therapies into the clinic. In this study, we demonstrate that abundance of the commensal metabolite pentanoate is predictive for survival of chimeric antigen receptor (CAR) T cell patients in two independent cohorts. Its implementation in the CAR T cell manufacturing workflow overcomes solid tumor microenvironments in immunocompetent cancer models by hijacking the epigenetic-metabolic crosstalk, reducing exhaustion and promoting naive-like differentiation. While synergy of clinically relevant drugs mimicked the phenotype of pentanoate-engineered CAR T cells in vitro, in vivo challenge showed inferior tumor control. Metabolic tracing of 13C-pentanoate revealed citrate generation in the TCA cycle via the acetyl- and succinyl-CoA entry points as a unique feature of the C5 aliphatic chain. Inhibition of the ATP-citrate lyase, which links metabolic output and histone acetylation, led to accumulation of pentanoate-derived citrate from the succinyl-CoA route and decreased functionality of SCFA-engineered CAR T cells. Our data demonstrate that microbial metabolites are incorporated as epigenetic imprints and implementation into CAR T cell production might serve as embodiment of the microbiome-host axis benefits for clinical applications.

DOI: https://doi.org/10.1101/2024.08.19.608538

Glia. 2024 Sep 25.

The role of ATP citrate lyase in myelin formation and maintenance.

Andrew Schneider, Seongsik Won, Eric A Armstrong, Aaron J Cooper, Amulya Suresh, Rachell Rivera, Gregory Barrett-Wilt, John M Denu, Judith A Simcox, John Svaren.

Formation of myelin by Schwann cells is tightly coupled to peripheral nervous system development and is important for neuronal function and long-term maintenance. Perturbation of myelin causes a number of specific disorders that are among the most prevalent diseases affecting the nervous system. Schwann cells synthesize myelin lipids de novo rather than relying on uptake of circulating lipids, yet one unresolved matter is how acetyl CoA, a central metabolite in lipid formation is generated during myelin formation and maintenance. Recent studies have shown that glucose-derived acetyl CoA itself is not required for myelination. However, the importance of mitochondrially-derived acetyl CoA has never been tested for myelination in vivo. Therefore, we have developed a Schwann cell-specific knockout of the ATP citrate lyase (Acly) gene to determine the importance of mitochondrial metabolism to supply acetyl CoA in nerve development. Intriguingly, the ACLY pathway is important for myelin maintenance rather than myelin formation. In addition, ACLY is required to maintain expression of a myelin-associated gene program and to inhibit activation of the latent Schwann cell injury program.

Keywords: Schwann; acetyl CoA; lipid; lipidomic; myelin

DOI: https://doi.org/10.1002/glia.24620

Heliyon. 2024 Sep 30. 10(18): e36296

The role of nonhistone lactylation in disease.

Hao Yu, Tingting Zhu, Dongwen Ma, Xiaohan Cheng, Shengjia Wang, Yongzhong Yao.

In 2019, a novel post-translational modification termed lactylation was identified, which established a connection among lactate, transcriptional regulation and epigenetics. Lactate, which is traditionally viewed as a metabolic byproduct, is now recognized for its significant functional role, including modulating the tumor microenvironment, engaging in signaling and interfering in immune regulation. While research on lactylation (KLA) is advancing, the focus has primarily been on histone lactylation. This paper aims to explore the less-studied area of nonhistone lactylation, highlighting its involvement in certain diseases and physiological processes. Additionally, the clinical relevance and potential implications of nonhistone lactylation will be discussed.

Keywords: Cancer; Inflammation; Lactate; Lactylation; Nonhistone

DOI: https://doi.org/10.1016/j.heliyon.2024.e36296

Nature. 2024 Sep 25.

AARS1 and AARS2 sense L-lactate to regulate cGAS as global lysine lactyltransferases.

Heyu Li, Chao Liu, Ran Li, Lili Zhou, Yu Ran, Qiqing Yang, Huizhe Huang, Huasong Lu, Hai Song, Bing Yang, Heng Ru, Shixian Lin, Long Zhang.

L-lactate modifies proteins through lactylation1, but how this process occurs is unclear. Here we identify the alanyl-tRNA synthetases AARS1 and AARS2 (AARS1/2) as intracellular L-lactate sensors required for L-lactate to stimulate the lysine lactylome in cells. AARS1/2 and the evolutionarily conserved Escherichia coli orthologue AlaRS bind to L-lactate with micromolar affinity and they directly catalyse L-lactate for ATP-dependent lactylation on the lysine acceptor end. In response to L-lactate, AARS2 associates with cyclic GMP-AMP synthase (cGAS) and mediates its lactylation and inactivation in cells and in mice. By establishing a genetic code expansion orthogonal system for lactyl-lysine incorporation, we demonstrate that the presence of a lactyl moiety at a specific cGAS amino-terminal site abolishes cGAS liquid-like phase separation and DNA sensing in vitro and in vivo. A lactyl mimetic knock-in inhibits cGAS, whereas a lactyl-resistant knock-in protects mice against innate immune evasion induced through high levels of L-lactate. MCT1 blockade inhibits cGAS lactylation in stressed mice and restores innate immune surveillance, which in turn antagonizes viral replication. Thus, AARS1/2 are conserved intracellular L-lactate sensors and have an essential role as lactyltransferases. Moreover, a chemical reaction process of lactylation targets and inactivates cGAS.

DOI: https://doi.org/10.1038/s41586-024-07992-y