bims-camemi 2023-10-29 papers

bims-camemi

Biomed News

on Mitochondrial metabolism in cancer

Issue of 2023–10–29
fifty-one papers selected by
Christian Frezza, Universität zu Köln

Lactate activates the mitochondrial electron transport chain independently of its metabolism.
G6PD Maintains Redox Homeostasis and Biosynthesis in LKB1-Deficient KRAS-Driven Lung Cancer.
Mitochondrial complex I ROS production and redox signaling in hypoxia.
Stable Isotope-Assisted Untargeted Metabolomics Identifies ALDH1A1-Driven Erythronate Accumulation in Lung Cancer Cells.
A genetically encoded tool to increase cellular NADH/NAD+ ratio in living cells.
The mitochondrial fusion protein OPA1 is dispensable in the liver and its absence induces mitohormesis to protect liver from drug-induced injury.
ASCT2 is the primary serine transporter in cancer cells.
High-throughput single-cell analysis reveals progressive mitochondrial DNA mosaicism throughout life.
Selective Mitochondrial Respiratory Complex I Subunit Deficiency Causes Tumor Immunogenicity.
Mitochondrial DNA Release Is Induced by Apoptotic Stress and Drives the SASP.
Refphase: Multi-sample phasing reveals haplotype-specific copy number heterogeneity.
Defective function of α-ketoglutarate dehydrogenase exacerbates mitochondrial ATP deficits during complex I deficiency.
Metabolic regulation of proteome stability via N-terminal acetylation controls male germline stem cell differentiation and reproduction.
Disruption of sugar nucleotide clearance is a therapeutic vulnerability of cancer cells.
GLUT2, glucose and oxygen sensing in CD8+ T cells.
Beyond energy and growth: the role of metabolism in developmental signaling, cell behavior and diapause.
Histone methyltransferase activity affects metabolism in human cells independently of transcriptional regulation.
Call for papers: Dietary interventions for cardiometabolic health.
Lipocalin 2 regulates mitochondrial phospholipidome remodeling, dynamics, and function in brown adipose tissue in male mice.
Mutant p53 sustains serine-glycine synthesis and essential amino acids intake promoting breast cancer growth.
Mitochondrial dysfunction promotes the transition of precursor to terminally exhausted T cells through HIF-1α-mediated glycolytic reprogramming.
Nutrient-regulated control of lysosome function by signaling lipid conversion.
FluxNorm: Toolbox for metabolic flux assay normalization by in situ cell counting.
How protons pave the way to aggressive cancers.
Mitochondrial gene expression is required for platelet function and blood clotting.
Tyrosine catabolism enhances genotoxic chemotherapy by suppressing translesion DNA synthesis in epithelial ovarian cancer.
The role of branched-chain aminotransferase 1 in driving glioblastoma cell proliferation and invasion varies with tumor subtype.
Acetyl-CoA metabolism as a therapeutic target for cancer.
The glucose transporter 2 regulates CD8+ T cell function via environment sensing.
Reducing mitochondrial mysteries.
Mitochondrial control of antigen presentation in cancer cells.
Proline metabolism shapes the tumor microenvironment: from collagen deposition to immune evasion.
Brown adipose tissue-derived metabolites and their role in regulating metabolism.
Copper-mediated novel cell death pathway in tumor cells and implications for innovative cancer therapies.
Direct ionic stress sensing and mitigation by the transcription factor NFAT5.
KEAP1 mutation in lung adenocarcinoma promotes immune evasion and immunotherapy resistance.
The interplay between metabolic stochasticity and cAMP-CRP regulation in single E. coli cells.
Metabolic sinkholes: Histones as methyl repositories.
Regulation of STING activity in DNA sensing by ISG15 modification.
Lactate biosensors for spectrally and spatially multiplexed fluorescence imaging.
Synaptic BMAL1 phosphorylation controls circadian hippocampal plasticity.
Gut microbiome-derived ammonia modulates stress vulnerability in the host.
Oxygen-regulated post-translation modifications as master signalling pathway in cells.
A DRP-like pseudoenzyme coordinates with MICOS to promote cristae architecture.
Manganese regulation of COPII condensation controls circulating lipid homeostasis.
Metabolic plasticity sustains the robustness of Caenorhabditis elegans embryogenesis.
Chlorophyll biosynthesis under the control of arginine metabolism.
Mitochondrial sAC-cAMP-PKA Axis Modulates the ΔΨm-Dependent Control Coefficients of the Respiratory Chain Complexes: Evidence of Respirasome Plasticity.
Methionine-CBS axis promotes intracellular ROS levels by reprogramming serine metabolism.
Toying with reductive stress.
A guide to epigenetics in leukaemia stem cells.

Mol Cell. 2023 Oct 20. pii: S1097-2765(23)00800-6. [Epub ahead of print]

Lactate activates the mitochondrial electron transport chain independently of its metabolism.

Xin Cai, Charles P Ng, Olivia Jones, Tak Shun Fung, Keun Woo Ryu, Dayi Li, Craig B Thompson.

  Lactate has long been considered a cellular waste product. However, we found that as extracellular lactate accumulates, it also enters the mitochondrial matrix and stimulates mitochondrial electron transport chain (ETC) activity. The resulting increase in mitochondrial ATP synthesis suppresses glycolysis and increases the utilization of pyruvate and/or alternative respiratory substrates. The ability of lactate to increase oxidative phosphorylation does not depend on its metabolism. Both L- and D-lactate are effective at enhancing ETC activity and suppressing glycolysis. Furthermore, the selective induction of mitochondrial oxidative phosphorylation by unmetabolized D-lactate reversibly suppressed aerobic glycolysis in both cancer cell lines and proliferating primary cells in an ATP-dependent manner and enabled cell growth on respiratory-dependent bioenergetic substrates. In primary T cells, D-lactate enhanced cell proliferation and effector function. Together, these findings demonstrate that lactate is a critical regulator of the ability of mitochondrial oxidative phosphorylation to suppress glucose fermentation.

Keywords:  TCA cycle; electron transport chain; glycolysis; lactate; mitochondria; oxidative phosphorylation

DOI:  https://doi.org/10.1016/j.molcel.2023.09.034
bioRxiv. 2023 Oct 09. pii: 2023.10.06.561131. [Epub ahead of print]

G6PD Maintains Redox Homeostasis and Biosynthesis in LKB1-Deficient KRAS-Driven Lung Cancer.

Taijin Lan, Sara Arastu, Samuel Wang, Jarrick Lam, Wenping Wang, Vrushank Bhatt, Eduardo Cararo Lopes, Zhixian Hu, Michael Sun, Xuefei Luo, Jonathan M Ghergurovich, Changlong Li, Xiaoyang Su, Joshua D Rabinowitz, Eileen White, Jessie Yanxiang Guo.

Cancer cells depend on nicotinamide adenine dinucleotide phosphate (NADPH) to combat oxidative stress and support reductive biosynthesis. One major NAPDH production route is the oxidative pentose phosphate pathway (committed step: glucose-6-phosphate dehydrogenase, G6PD). Alternatives exist and can compensate in some tumors. Here, using genetically-engineered lung cancer model, we show that ablation of G6PD significantly suppresses Kras G12D/+ ;Lkb1 -/- (KL) but not Kras G12D/+ ;p53 -/- (KP) lung tumorigenesis. In vivo isotope tracing and metabolomics revealed that G6PD ablation significantly impaired NADPH generation, redox balance and de novo lipogenesis in KL but not KP lung tumors. Mechanistically, in KL tumors, G6PD ablation caused p53 activation that suppressed tumor growth. As tumor progressed, G6PD-deficient KL tumors increased an alternative NADPH source, serine-driven one carbon metabolism, rendering associated tumor-derived cell lines sensitive to serine/glycine depletion. Thus, oncogenic driver mutations determine lung cancer dependence on G6PD, whose targeting is a potential therapeutic strategy for tumors harboring KRAS and LKB1 co-mutations.

DOI: https://doi.org/10.1101/2023.10.06.561131
Redox Biol. 2023 Oct 16. pii: S2213-2317(23)00327-0. [Epub ahead of print]67 102926

Mitochondrial complex I ROS production and redox signaling in hypoxia.

Chidozie N Okoye, Shon A Koren, Andrew P Wojtovich.

  Mitochondria are a main source of cellular energy. Oxidative phosphorylation (OXPHOS) is the major process of aerobic respiration. Enzyme complexes of the electron transport chain (ETC) pump protons to generate a protonmotive force (Δp) that drives OXPHOS. Complex I is an electron entry point into the ETC. Complex I oxidizes nicotinamide adenine dinucleotide (NADH) and transfers electrons to ubiquinone in a reaction coupled with proton pumping. Complex I also produces reactive oxygen species (ROS) under various conditions. The enzymatic activities of complex I can be regulated by metabolic conditions and serves as a regulatory node of the ETC. Complex I ROS plays diverse roles in cell metabolism ranging from physiologic to pathologic conditions. Progress in our understanding indicates that ROS release from complex I serves important signaling functions. Increasing evidence suggests that complex I ROS is important in signaling a mismatch in energy production and demand. In this article, we review the role of ROS from complex I in sensing acute hypoxia.

Keywords:  Acute hypoxia; Mitochondrial complex I; Oxygen sensing; ROS signaling

DOI:  https://doi.org/10.1016/j.redox.2023.102926
Biomedicines. 2023 Oct 19. pii: 2842. [Epub ahead of print]11(10):

Stable Isotope-Assisted Untargeted Metabolomics Identifies ALDH1A1-Driven Erythronate Accumulation in Lung Cancer Cells.

Jie Zhang, Mark A Keibler, Wentao Dong, Jenny Ghelfi, Thekla Cordes, Tamara Kanashova, Arnaud Pailot, Carole L Linster, Gunnar Dittmar, Christian M Metallo, Tim Lautenschlaeger, Karsten Hiller, Gregory Stephanopoulos.

  Using an untargeted stable isotope-assisted metabolomics approach, we identify erythronate as a metabolite that accumulates in several human cancer cell lines. Erythronate has been reported to be a detoxification product derived from off-target glycolytic metabolism. We use chemical inhibitors and genetic silencing to define the pentose phosphate pathway intermediate erythrose 4-phosphate (E4P) as the starting substrate for erythronate production. However, following enzyme assay-coupled protein fractionation and subsequent proteomics analysis, we identify aldehyde dehydrogenase 1A1 (ALDH1A1) as the predominant contributor to erythrose oxidation to erythronate in cell extracts. Through modulating ALDH1A1 expression in cancer cell lines, we provide additional support. We hence describe a possible alternative route to erythronate production involving the dephosphorylation of E4P to form erythrose, followed by its oxidation by ALDH1A1. Finally, we measure increased erythronate concentrations in tumors relative to adjacent normal tissues from lung cancer patients. These findings suggest the accumulation of erythronate to be an example of metabolic reprogramming in cancer cells, raising the possibility that elevated levels of erythronate may serve as a biomarker of certain types of cancer.

Keywords:  aldehyde dehydrogenase 1A1 (ALDH1A1); cancer metabolism; erythronate; pentose phosphate pathway; untargeted metabolomics

DOI:  https://doi.org/10.3390/biomedicines11102842
Nat Chem Biol. 2023 Oct 26.

A genetically encoded tool to increase cellular NADH/NAD+ ratio in living cells.

Xingxiu Pan, Mina L Heacock, Evana N Abdulaziz, Sara Violante, Austin L Zuckerman, Nirajan Shrestha, Canglin Yao, Russell P Goodman, Justin R Cross, Valentin Cracan.

Impaired redox metabolism is a key contributor to the etiology of many diseases, including primary mitochondrial disorders, cancer, neurodegeneration and aging. However, mechanistic studies of redox imbalance remain challenging due to limited strategies that can perturb redox metabolism in various cellular or organismal backgrounds. Most studies involving impaired redox metabolism have focused on oxidative stress; consequently, less is known about the settings where there is an overabundance of NADH reducing equivalents, termed reductive stress. Here we introduce a soluble transhydrogenase from Escherichia coli (EcSTH) as a novel genetically encoded tool to promote reductive stress in living cells. When expressed in mammalian cells, EcSTH, and a mitochondrially targeted version (mitoEcSTH), robustly elevated the NADH/NAD+ ratio in a compartment-specific manner. Using this tool, we determined that metabolic and transcriptomic signatures of the NADH reductive stress are cellular background specific. Collectively, our novel genetically encoded tool represents an orthogonal strategy to promote reductive stress.

DOI: https://doi.org/10.1038/s41589-023-01460-w
Nat Commun. 2023 Oct 23. 14(1): 6721

The mitochondrial fusion protein OPA1 is dispensable in the liver and its absence induces mitohormesis to protect liver from drug-induced injury.

Hakjoo Lee, Tae Jin Lee, Chad A Galloway, Wenbo Zhi, Wei Xiao, Karen L de Mesy Bentley, Ashok Sharma, Yong Teng, Hiromi Sesaki, Yisang Yoon.

Mitochondria are critical for metabolic homeostasis of the liver, and their dysfunction is a major cause of liver diseases. Optic atrophy 1 (OPA1) is a mitochondrial fusion protein with a role in cristae shaping. Disruption of OPA1 causes mitochondrial dysfunction. However, the role of OPA1 in liver function is poorly understood. In this study, we delete OPA1 in the fully developed liver of male mice. Unexpectedly, OPA1 liver knockout (LKO) mice are healthy with unaffected mitochondrial respiration, despite disrupted cristae morphology. OPA1 LKO induces a stress response that establishes a new homeostatic state for sustained liver function. Our data show that OPA1 is required for proper complex V assembly and that OPA1 LKO protects the liver from drug toxicity. Mechanistically, OPA1 LKO decreases toxic drug metabolism and confers resistance to the mitochondrial permeability transition. This study demonstrates that OPA1 is dispensable in the liver, and that the mitohormesis induced by OPA1 LKO prevents liver injury and contributes to liver resiliency.

DOI: https://doi.org/10.1038/s41467-023-42564-0
bioRxiv. 2023 Oct 11. pii: 2023.10.09.561530. [Epub ahead of print]

ASCT2 is the primary serine transporter in cancer cells.

Kelly O Conger, Christopher Chidley, Mete Emir Ozgurses, Huiping Zhao, Yumi Kim, Svetlana E Semina, Philippa Burns, Vipin Rawat, Ryan Sheldon, Issam Ben-Sahra, Jonna Frasor, Peter K Sorger, Gina M DeNicola, Jonathan L Coloff.

The non-essential amino acid serine is a critical nutrient for cancer cells due to its diverse biosynthetic functions. While some tumors can synthesize serine de novo , others are auxotrophic for serine and therefore reliant on the uptake of exogenous serine. Importantly, however, the transporter(s) that mediate serine uptake in cancer cells are not known. Here, we characterize the amino acid transporter ASCT2 (coded for by the gene SLC1A5 ) as the primary serine transporter in cancer cells. ASCT2 is well-known as a glutamine transporter in cancer, and our work demonstrates that serine and glutamine compete for uptake through ASCT2. We further show that ASCT2-mediated serine uptake is essential for purine nucleotide biosynthesis and that ERα promotes serine uptake by directly activating SLC1A5 transcription. Together, our work defines an additional important role for ASCT2 as a serine transporter in cancer and evaluates ASCT2 as a potential therapeutic target in serine metabolism.

DOI: https://doi.org/10.1101/2023.10.09.561530
Sci Adv. 2023 Oct 27. 9(43): eadi4038

High-throughput single-cell analysis reveals progressive mitochondrial DNA mosaicism throughout life.

Angelos Glynos, Lyuba V Bozhilova, Michele Frison, Stephen Burr, James B Stewart, Patrick F Chinnery.

Heteroplasmic mitochondrial DNA (mtDNA) mutations are a major cause of inherited disease and contribute to common late-onset human disorders. The late onset and clinical progression of mtDNA-associated disease is thought to be due to changing heteroplasmy levels, but it is not known how and when this occurs. Performing high-throughput single-cell genotyping in two mouse models of human mtDNA disease, we saw unanticipated cell-to-cell differences in mtDNA heteroplasmy levels that emerged prenatally and progressively increased throughout life. Proliferating spleen cells and nondividing brain cells had a similar single-cell heteroplasmy variance, implicating mtDNA or organelle turnover as the major force determining cell heteroplasmy levels. The two different mtDNA mutations segregated at different rates with no evidence of selection, consistent with different rates of random genetic drift in vivo, leading to the accumulation of cells with a very high mutation burden at different rates. This provides an explanation for differences in severity seen in human diseases caused by similar mtDNA mutations.

DOI: https://doi.org/10.1126/sciadv.adi4038
bioRxiv. 2023 Oct 03. pii: 2023.10.02.560316. [Epub ahead of print]

Selective Mitochondrial Respiratory Complex I Subunit Deficiency Causes Tumor Immunogenicity.

Jiaxin Liang, Tevis Vitale, Xixi Zhang, Thomas D Jackson, Deyang Yu, Mark Jedrychowski, Steve P Gygi, Hans R Widlund, Kai W Wucherpfennig, Pere Puigserver.

Targeting of specific metabolic pathways in tumor cells has the potential to sensitize them to immune-mediated attack. Here we provide evidence for a specific means of mitochondrial respiratory Complex I (CI) inhibition that improves tumor immunogenicity and sensitivity to immune checkpoint blockade (ICB). Targeted genetic deletion of the CI subunits Ndufs4 and Ndufs6 , but not other subunits, induces an immune-dependent tumor growth attenuation in mouse melanoma models. We show that deletion of Ndufs4 induces expression of the transcription factor Nlrc5 and genes in the MHC class I antigen presentation and processing pathway. This induction of MHC-related genes is driven by an accumulation of pyruvate dehydrogenase-dependent mitochondrial acetyl-CoA downstream of CI subunit deletion. This work provides a novel functional modality by which selective CI inhibition restricts tumor growth, suggesting that specific targeting of Ndufs4 , or related CI subunits, increases T-cell mediated immunity and sensitivity to ICB.

DOI: https://doi.org/10.1101/2023.10.02.560316
Cancer Discov. 2023 Oct 27. OF1

Mitochondrial DNA Release Is Induced by Apoptotic Stress and Drives the SASP.

Minority mitochondrial outer membrane permeabilization (miMOMP) during senescence drives the SASP.

DOI: https://doi.org/10.1158/2159-8290.CD-RW2023-169
PLoS Comput Biol. 2023 Oct 23. 19(10): e1011379

Refphase: Multi-sample phasing reveals haplotype-specific copy number heterogeneity.

Thomas B K Watkins, Emma C Colliver, Matthew R Huska, Tom L Kaufmann, Emilia L Lim, Cody B Duncan, Kerstin Haase, Peter Van Loo, Charles Swanton, Nicholas McGranahan, Roland F Schwarz.

Most computational methods that infer somatic copy number alterations (SCNAs) from bulk sequencing of DNA analyse tumour samples individually. However, the sequencing of multiple tumour samples from a patient's disease is an increasingly common practice. We introduce Refphase, an algorithm that leverages this multi-sampling approach to infer haplotype-specific copy numbers through multi-sample phasing. We demonstrate Refphase's ability to infer haplotype-specific SCNAs and characterise their intra-tumour heterogeneity, to uncover previously undetected allelic imbalance in low purity samples, and to identify parallel evolution in the context of whole genome doubling in a pan-cancer cohort of 336 samples from 99 tumours.

DOI: https://doi.org/10.1371/journal.pcbi.1011379
Redox Biol. 2023 Oct 17. pii: S2213-2317(23)00333-6. [Epub ahead of print]67 102932

Defective function of α-ketoglutarate dehydrogenase exacerbates mitochondrial ATP deficits during complex I deficiency.

Gerardo G Piroli, Allison M Manuel, Richard S McCain, Holland H Smith, Oliver Ozohanics, Sara Mellid, J Hunter Cox, William E Cotham, Michael D Walla, Alberto Cascón, Attila Ambrus, Norma Frizzell.

  The NDUFS4 knockout (KO) mouse phenotype resembles the human Complex I deficiency Leigh Syndrome. The irreversible succination of protein thiols by fumarate is increased in select regions of the NDUFS4 KO brain affected by neurodegeneration. We report that dihydrolipoyllysine-residue succinyltransferase (DLST), a component of the α-ketoglutarate dehydrogenase complex (KGDHC) of the tricarboxylic acid (TCA) cycle, is succinated in the affected regions of the NDUFS4 KO brain. Succination of DLST reduced KGDHC activity in the brainstem (BS) and olfactory bulb (OB) of KO mice. The defective production of KGDHC derived succinyl-CoA resulted in decreased mitochondrial substrate level phosphorylation (SLP), further aggravating the existing oxidative phosphorylation (OXPHOS) ATP deficit. Protein succinylation, an acylation modification that requires succinyl-CoA, was reduced in the KO mice. Modeling succination of a cysteine in the spatial vicinity of the DLST active site or introduction of succinomimetic mutations recapitulates these metabolic deficits. Our data demonstrate that the biochemical deficit extends beyond impaired Complex I assembly and OXPHOS deficiency, functionally impairing select components of the TCA cycle to drive metabolic perturbations in affected neurons.

Keywords:  Alpha-ketoglutarate dehydrogenase; Complex I; Fumarate; Leigh syndrome; Protein succination; Substrate level phosphorylation

DOI:  https://doi.org/10.1016/j.redox.2023.102932
Nat Commun. 2023 Oct 23. 14(1): 6737

Metabolic regulation of proteome stability via N-terminal acetylation controls male germline stem cell differentiation and reproduction.

Charlotte M François, Thomas Pihl, Marion Dunoyer de Segonzac, Chloé Hérault, Bruno Hudry.

The molecular mechanisms connecting cellular metabolism with differentiation remain poorly understood. Here, we find that metabolic signals contribute to stem cell differentiation and germline homeostasis during Drosophila melanogaster spermatogenesis. We discovered that external citrate, originating outside the gonad, fuels the production of Acetyl-coenzyme A by germline ATP-citrate lyase (dACLY). We show that this pathway is essential during the final spermatogenic stages, where a high Acetyl-coenzyme A level promotes NatB-dependent N-terminal protein acetylation. Using genetic and biochemical experiments, we establish that N-terminal acetylation shields key target proteins, essential for spermatid differentiation, from proteasomal degradation by the ubiquitin ligase dUBR1. Our work uncovers crosstalk between metabolism and proteome stability that is mediated via protein post-translational modification. We propose that this system coordinates the metabolic state of the organism with gamete production. More broadly, modulation of proteome turnover by circulating metabolites may be a conserved regulatory mechanism to control cell functions.

DOI: https://doi.org/10.1038/s41467-023-42496-9
Nature. 2023 Oct 25.

Disruption of sugar nucleotide clearance is a therapeutic vulnerability of cancer cells.

Mihir B Doshi, Namgyu Lee, Tenzin Tseyang, Olga Ponomarova, Hira Lal Goel, Meghan Spears, Rui Li, Lihua Julie Zhu, Christopher Ashwood, Karl Simin, Cholsoon Jang, Arthur M Mercurio, Albertha J M Walhout, Jessica B Spinelli, Dohoon Kim.

Identifying metabolic steps that are specifically required for the survival of cancer cells but are dispensable in normal cells remains a challenge1. Here we report a therapeutic vulnerability in a sugar nucleotide biosynthetic pathway that can be exploited in cancer cells with only a limited impact on normal cells. A systematic examination of conditionally essential metabolic enzymes revealed that UXS1, a Golgi enzyme that converts one sugar nucleotide (UDP-glucuronic acid, UDPGA) to another (UDP-xylose), is essential only in cells that express high levels of the enzyme immediately upstream of it, UGDH. This conditional relationship exists because UXS1 is required to prevent excess accumulation of UDPGA, which is produced by UGDH. UXS1 not only clears away UDPGA but also limits its production through negative feedback on UGDH. Excess UDPGA disrupts Golgi morphology and function, which impedes the trafficking of surface receptors such as EGFR to the plasma membrane and diminishes the signalling capacity of cells. UGDH expression is elevated in several cancers, including lung adenocarcinoma, and is further enhanced during chemoresistant selection. As a result, these cancer cells are selectively dependent on UXS1 for UDPGA detoxification, revealing a potential weakness in tumours with high levels of UGDH.

DOI: https://doi.org/10.1038/s41586-023-06676-3
Nat Metab. 2023 Oct 26.

GLUT2, glucose and oxygen sensing in CD8+ T cells.

Xuemei Tong.

DOI: https://doi.org/10.1038/s42255-023-00914-8
Development. 2023 Oct 15. pii: dev201610. [Epub ahead of print]150(20):

Beyond energy and growth: the role of metabolism in developmental signaling, cell behavior and diapause.

Trevor S Tippetts, Matthew H Sieber, Ashley Solmonson.

  Metabolism is crucial for development through supporting cell growth, energy production, establishing cell identity, developmental signaling and pattern formation. In many model systems, development occurs alongside metabolic transitions as cells differentiate and specialize in metabolism that supports new functions. Some cells exhibit metabolic flexibility to circumvent mutations or aberrant signaling, whereas other cell types require specific nutrients for developmental progress. Metabolic gradients and protein modifications enable pattern formation and cell communication. On an organism level, inadequate nutrients or stress can limit germ cell maturation, implantation and maturity through diapause, which slows metabolic activities until embryonic activation under improved environmental conditions.

Keywords:  Diapause; Embryogenesis; Metabolism; Signaling

DOI:  https://doi.org/10.1242/dev.201610
PLoS Biol. 2023 Oct;21(10): e3002354

Histone methyltransferase activity affects metabolism in human cells independently of transcriptional regulation.

Marcos Francisco Perez, Peter Sarkies.

The N-terminal tails of eukaryotic histones are frequently posttranslationally modified. The role of these modifications in transcriptional regulation is well-documented. However, the extent to which the enzymatic processes of histone posttranslational modification might affect metabolic regulation is less clear. Here, we investigated how histone methylation might affect metabolism using metabolomics, proteomics, and RNA-seq data from cancer cell lines, primary tumour samples and healthy tissue samples. In cancer, the expression of histone methyltransferases (HMTs) was inversely correlated to the activity of NNMT, an enzyme previously characterised as a methyl sink that disposes of excess methyl groups carried by the universal methyl donor S-adenosyl methionine (SAM or AdoMet). In healthy tissues, histone methylation was inversely correlated to the levels of an alternative methyl sink, PEMT. These associations affected the levels of multiple histone marks on chromatin genome-wide but had no detectable impact on transcriptional regulation. We show that HMTs with a variety of different associations to transcription are co-regulated by the Retinoblastoma (Rb) tumour suppressor in human cells. Rb-mutant cancers show increased total HMT activity and down-regulation of NNMT. Together, our results suggest that the total activity of HMTs affects SAM metabolism, independent of transcriptional regulation.

DOI: https://doi.org/10.1371/journal.pbio.3002354
Nat Metab. 2023 Oct 26.

Call for papers: Dietary interventions for cardiometabolic health.

DOI: https://doi.org/10.1038/s42255-023-00918-4
Nat Commun. 2023 Oct 23. 14(1): 6729

Lipocalin 2 regulates mitochondrial phospholipidome remodeling, dynamics, and function in brown adipose tissue in male mice.

Hongming Su, Hong Guo, Xiaoxue Qiu, Te-Yueh Lin, Chao Qin, Gail Celio, Peter Yong, Mark Senders, Xianlin Han, David A Bernlohr, Xiaoli Chen.

Mitochondrial function is vital for energy metabolism in thermogenic adipocytes. Impaired mitochondrial bioenergetics in brown adipocytes are linked to disrupted thermogenesis and energy balance in obesity and aging. Phospholipid cardiolipin (CL) and phosphatidic acid (PA) jointly regulate mitochondrial membrane architecture and dynamics, with mitochondria-associated endoplasmic reticulum membranes (MAMs) serving as the platform for phospholipid biosynthesis and metabolism. However, little is known about the regulators of MAM phospholipid metabolism and their connection to mitochondrial function. We discover that LCN2 is a PA binding protein recruited to the MAM during inflammation and metabolic stimulation. Lcn2 deficiency disrupts mitochondrial fusion-fission balance and alters the acyl-chain composition of mitochondrial phospholipids in brown adipose tissue (BAT) of male mice. Lcn2 KO male mice exhibit an increase in the levels of CLs containing long-chain polyunsaturated fatty acids (LC-PUFA), a decrease in CLs containing monounsaturated fatty acids, resulting in mitochondrial dysfunction. This dysfunction triggers compensatory activation of peroxisomal function and the biosynthesis of LC-PUFA-containing plasmalogens in BAT. Additionally, Lcn2 deficiency alters PA production, correlating with changes in PA-regulated phospholipid-metabolizing enzymes and the mTOR signaling pathway. In conclusion, LCN2 plays a critical role in the acyl-chain remodeling of phospholipids and mitochondrial bioenergetics by regulating PA production and its function in activating signaling pathways.

DOI: https://doi.org/10.1038/s41467-023-42473-2
Nat Commun. 2023 Oct 25. 14(1): 6777

Mutant p53 sustains serine-glycine synthesis and essential amino acids intake promoting breast cancer growth.

Camilla Tombari, Alessandro Zannini, Rebecca Bertolio, Silvia Pedretti, Matteo Audano, Luca Triboli, Valeria Cancila, Davide Vacca, Manuel Caputo, Sara Donzelli, Ilaria Segatto, Simone Vodret, Silvano Piazza, Alessandra Rustighi, Fiamma Mantovani, Barbara Belletti, Gustavo Baldassarre, Giovanni Blandino, Claudio Tripodo, Silvio Bicciato, Nico Mitro, Giannino Del Sal.

Reprogramming of amino acid metabolism, sustained by oncogenic signaling, is crucial for cancer cell survival under nutrient limitation. Here we discovered that missense mutant p53 oncoproteins stimulate de novo serine/glycine synthesis and essential amino acids intake, promoting breast cancer growth. Mechanistically, mutant p53, unlike the wild-type counterpart, induces the expression of serine-synthesis-pathway enzymes and L-type amino acid transporter 1 (LAT1)/CD98 heavy chain heterodimer. This effect is exacerbated by amino acid shortage, representing a mutant p53-dependent metabolic adaptive response. When cells suffer amino acids scarcity, mutant p53 protein is stabilized and induces metabolic alterations and an amino acid transcriptional program that sustain cancer cell proliferation. In patient-derived tumor organoids, pharmacological targeting of either serine-synthesis-pathway and LAT1-mediated transport synergizes with amino acid shortage in blunting mutant p53-dependent growth. These findings reveal vulnerabilities potentially exploitable for tackling breast tumors bearing missense TP53 mutations.

DOI: https://doi.org/10.1038/s41467-023-42458-1
Nat Commun. 2023 Oct 27. 14(1): 6858

Mitochondrial dysfunction promotes the transition of precursor to terminally exhausted T cells through HIF-1α-mediated glycolytic reprogramming.

Hao Wu, Xiufeng Zhao, Sophia M Hochrein, Miriam Eckstein, Gabriela F Gubert, Konrad Knöpper, Ana Maria Mansilla, Arman Öner, Remi Doucet-Ladevèze, Werner Schmitz, Bart Ghesquière, Sebastian Theurich, Jan Dudek, Georg Gasteiger, Alma Zernecke, Sebastian Kobold, Wolfgang Kastenmüller, Martin Vaeth.

T cell exhaustion is a hallmark of cancer and persistent infections, marked by inhibitory receptor upregulation, diminished cytokine secretion, and impaired cytolytic activity. Terminally exhausted T cells are steadily replenished by a precursor population (Tpex), but the metabolic principles governing Tpex maintenance and the regulatory circuits that control their exhaustion remain incompletely understood. Using a combination of gene-deficient mice, single-cell transcriptomics, and metabolomic analyses, we show that mitochondrial insufficiency is a cell-intrinsic trigger that initiates the functional exhaustion of T cells. At the molecular level, we find that mitochondrial dysfunction causes redox stress, which inhibits the proteasomal degradation of hypoxia-inducible factor 1α (HIF-1α) and promotes the transcriptional and metabolic reprogramming of Tpex cells into terminally exhausted T cells. Our findings also bear clinical significance, as metabolic engineering of chimeric antigen receptor (CAR) T cells is a promising strategy to enhance the stemness and functionality of Tpex cells for cancer immunotherapy.

DOI: https://doi.org/10.1038/s41467-023-42634-3
Cell. 2023 Oct 18. pii: S0092-8674(23)01081-4. [Epub ahead of print]

Nutrient-regulated control of lysosome function by signaling lipid conversion.

Michael Ebner, Dmytro Puchkov, Orestes López-Ortega, Pathma Muthukottiappan, Yanwei Su, Christopher Schmied, Silke Zillmann, Iryna Nikonenko, Jochen Koddebusch, Gillian L Dornan, Max T Lucht, Vonda Koka, Wonyul Jang, Philipp Alexander Koch, Alexander Wallroth, Martin Lehmann, Britta Brügger, Mario Pende, Dominic Winter, Volker Haucke.

  Lysosomes serve dual antagonistic functions in cells by mediating anabolic growth signaling and the catabolic turnover of macromolecules. How these janus-faced activities are regulated in response to cellular nutrient status is poorly understood. We show here that lysosome morphology and function are reversibly controlled by a nutrient-regulated signaling lipid switch that triggers the conversion between peripheral motile mTOR complex 1 (mTORC1) signaling-active and static mTORC1-inactive degradative lysosomes clustered at the cell center. Starvation-triggered relocalization of phosphatidylinositol 4-phosphate (PI(4)P)-metabolizing enzymes reshapes the lysosomal surface proteome to facilitate lysosomal proteolysis and to repress mTORC1 signaling. Concomitantly, lysosomal phosphatidylinositol 3-phosphate (PI(3)P), which marks motile signaling-active lysosomes in the cell periphery, is erased. Interference with this PI(3)P/PI(4)P lipid switch module impairs the adaptive response of cells to altering nutrient supply. Our data unravel a key function for lysosomal phosphoinositide metabolism in rewiring organellar membrane dynamics in response to cellular nutrient status.

Keywords:  catabolism; functional proteomics; live correlative light and electron microscopy; lysosomes; mTOR; myotubularin; nutrient signaling; nutrients; phosphoinositides

DOI:  https://doi.org/10.1016/j.cell.2023.09.027
bioRxiv. 2023 Oct 14. pii: 2023.10.13.562314. [Epub ahead of print]

FluxNorm: Toolbox for metabolic flux assay normalization by in situ cell counting.

Nathalie A Djaja, Teva Bracha, Seungyoon B Yu, Haoming Wang, Natasha M Carlson, Gulcin Pekkurnaz.

Plate-based quantitative metabolic flux analysis has emerged as the central technology to examine cellular metabolism and mitochondrial bioenergetics. However, accurate interpretation of metabolic activity between different experimental conditions in multi-well microplates requires data normalization based on in situ cell counts. Here, we describe FluxNorm, a platform-independent semi-automated computational workflow, validated for three different cell types, to normalize cell density for accurate assessment of cellular bioenergetics.

DOI: https://doi.org/10.1101/2023.10.13.562314
Nat Rev Cancer. 2023 Oct 26.

How protons pave the way to aggressive cancers.

Pawel Swietach, Ebbe Boedtkjer, Stine Falsig Pedersen.

Cancers undergo sequential changes to proton (H+) concentration and sensing that are consequences of the disease and facilitate its further progression. The impact of protonation state on protein activity can arise from alterations to amino acids or their titration. Indeed, many cancer-initiating mutations influence pH balance, regulation or sensing in a manner that enables growth and invasion outside normal constraints as part of oncogenic transformation. These cancer-supporting effects become more prominent when tumours develop an acidic microenvironment owing to metabolic reprogramming and disordered perfusion. The ensuing intracellular and extracellular pH disturbances affect multiple aspects of tumour biology, ranging from proliferation to immune surveillance, and can even facilitate further mutagenesis. As a selection pressure, extracellular acidosis accelerates disease progression by favouring acid-resistant cancer cells, which are typically associated with aggressive phenotypes. Although acid-base disturbances in tumours often occur alongside hypoxia and lactate accumulation, there is now ample evidence for a distinct role of H+-operated responses in key events underpinning cancer. The breadth of these actions presents therapeutic opportunities to change the trajectory of disease.

DOI: https://doi.org/10.1038/s41568-023-00628-9
Cell Rep. 2023 Oct 25. pii: S2211-1247(23)01324-4. [Epub ahead of print]42(11): 113312

Mitochondrial gene expression is required for platelet function and blood clotting.

Tara R Richman, Judith A Ermer, Jessica Baker, Stefan J Siira, Benjamin T Kile, Matthew D Linden, Oliver Rackham, Aleksandra Filipovska.

  Platelets are anucleate blood cells that contain mitochondria and regulate blood clotting in response to injury. Mitochondria contain their own gene expression machinery that relies on nuclear-encoded factors for the biogenesis of the oxidative phosphorylation system to produce energy required for thrombosis. The autonomy of the mitochondrial gene expression machinery from the nucleus is unclear, and platelets provide a valuable model to understand its importance in anucleate cells. Here, we conditionally delete Elac2, Ptcd1, or Mtif3 in platelets, which are essential for mitochondrial gene expression at the level of RNA processing, stability, or translation, respectively. Loss of ELAC2, PTCD1, or MTIF3 leads to increased megakaryocyte ploidy, elevated circulating levels of reticulated platelets, thrombocytopenia, and consequent extended bleeding time. Impaired mitochondrial gene expression reduces agonist-induced platelet activation. Transcriptomic and proteomic analyses show that mitochondrial gene expression is required for fibrinolysis, hemostasis, and blood coagulation in response to injury.

Keywords:  CP: Immunology; megakaryocytes; mitochondria; mitochondrial gene expression; platelets; translation

DOI:  https://doi.org/10.1016/j.celrep.2023.113312
Cell Metab. 2023 Oct 19. pii: S1550-4131(23)00371-6. [Epub ahead of print]

Tyrosine catabolism enhances genotoxic chemotherapy by suppressing translesion DNA synthesis in epithelial ovarian cancer.

Jie Li, Cuimiao Zheng, Qiuwen Mai, Xi Huang, Wenfeng Pan, Jingyi Lu, Zhengfan Chen, Suman Zhang, Chunyu Zhang, Hua Huang, Yangyang Chen, Hongbo Guo, Zhenyin Wu, Chunnuan Deng, Yiting Jiang, Bo Li, Junxiu Liu, Shuzhong Yao, Chaoyun Pan.

  Amino acid metabolism has been actively investigated as a potential target for antitumor therapy, but how it may alter the response to genotoxic chemotherapy remains largely unknown. Here, we report that the depletion of fumarylacetoacetate hydrolase (FAH), an enzyme that catalyzes the final step of tyrosine catabolism, reduced chemosensitivity in epithelial ovarian cancer (EOC). The expression level of FAH correlated significantly with chemotherapy efficacy in patients with EOC. Mechanistically, under genotoxic chemotherapy, FAH is oxidized at Met308 and translocates to the nucleus, where FAH-mediated tyrosine catabolism predominantly supplies fumarate. FAH-produced fumarate binds directly to REV1, resulting in the suppression of translesion DNA synthesis (TLS) and improved chemosensitivity. Furthermore, in vivo tyrosine supplementation improves sensitivity to genotoxic chemotherapeutics and reduces the occurrence of therapy resistance. Our findings reveal a unique role for tyrosine-derived fumarate in the regulation of TLS and may be exploited to improve genotoxic chemotherapy through dietary tyrosine supplementation.

Keywords:  cancer metabolism; chemotherapy; ovarian cancer

DOI:  https://doi.org/10.1016/j.cmet.2023.10.002
Neurooncol Adv. 2023 Jan-Dec;5(1):5(1): vdad120

The role of branched-chain aminotransferase 1 in driving glioblastoma cell proliferation and invasion varies with tumor subtype.

Maria Fala, Susana Ros, Ashley Sawle, Jyotsna U Rao, Anastasia Tsyben, Laura Tronci, Christian Frezza, Richard Mair, Kevin M Brindle.

   Background: Branched-chain aminotransferase 1 (BCAT1) has been proposed to drive proliferation and invasion of isocitrate dehydrogenase (IDH) wild-type glioblastoma cells. However, the Cancer Genome Atlas (TCGA) dataset shows considerable variation in the expression of this enzyme in glioblastoma. The aim of this study was to determine the role of BCAT1 in driving the proliferation and invasion of glioblastoma cells and xenografts that have widely differing levels of BCAT1 expression and the mechanism responsible.
Methods: The activity of BCAT1 was modulated in IDH wild-type patient-derived glioblastoma cell lines, and in orthotopically implanted tumors derived from these cells, to examine the effects of BCAT1 expression on tumor phenotype.
Results: In cells with constitutively high BCAT1 expression and a glycolytic metabolic phenotype, inducible shRNA knockdown of the enzyme resulted in reduced proliferation and invasion by increasing the concentration of α-ketoglutarate, leading to reduced DNA methylation, HIF-1α destabilization, and reduced expression of the transcription factor Forkhead box protein M1 (FOXM1). Conversely, overexpression of the enzyme increased HIF-1α expression and promoted proliferation and invasion. However, in cells with an oxidative phenotype and very low constitutive expression of BCAT1 increased expression of the enzyme had no effect on invasion and reduced cell proliferation. This occurred despite an increase in HIF-1α levels and could be explained by decreased TCA cycle flux.
Conclusions: There is a wide variation in BCAT1 expression in glioblastoma and its role in proliferation and invasion is dependent on tumor subtype.

Keywords:  alpha-ketoglutarate; branched-chain aminotransferase; glioblastoma; hypoxia-inducible factor; proliferation

DOI:  https://doi.org/10.1093/noajnl/vdad120
Biomed Pharmacother. 2023 Oct 19. pii: S0753-3322(23)01539-1. [Epub ahead of print]168 115741

Acetyl-CoA metabolism as a therapeutic target for cancer.

Guo Chen, Banghe Bao, Yang Cheng, Minxiu Tian, Jiyu Song, Liduan Zheng, Qiangsong Tong.

  Acetyl-coenzyme A (acetyl-CoA), an essential metabolite, not only takes part in numerous intracellular metabolic processes, powers the tricarboxylic acid cycle, serves as a key hub for the biosynthesis of fatty acids and isoprenoids, but also serves as a signaling substrate for acetylation reactions in post-translational modification of proteins, which is crucial for the epigenetic inheritance of cells. Acetyl-CoA links lipid metabolism with histone acetylation to create a more intricate regulatory system that affects the growth, aggressiveness, and drug resistance of malignancies such as glioblastoma, breast cancer, and hepatocellular carcinoma. These fascinating advances in the knowledge of acetyl-CoA metabolism during carcinogenesis and normal physiology have raised interest regarding its modulation in malignancies. In this review, we provide an overview of the regulation and cancer relevance of main metabolic pathways in which acetyl-CoA participates. We also summarize the role of acetyl-CoA in the metabolic reprogramming and stress regulation of cancer cells, as well as medical application of inhibitors targeting its dysregulation in therapeutic intervention of cancers.

Keywords:  Acetyl-coenzyme A metabolism; Cancer progression; Cancer therapy; Metabolic reprogramming; Protein acetylation

DOI:  https://doi.org/10.1016/j.biopha.2023.115741
Nat Metab. 2023 Oct 26.

The glucose transporter 2 regulates CD8+ T cell function via environment sensing.

Hongmei Fu, Juho Vuononvirta, Silvia Fanti, Fabrizia Bonacina, Antonio D'Amati, Guosu Wang, Thanushiyan Poobalasingam, Maria Fankhaenel, Davide Lucchesi, Rachel Coleby, David Tarussio, Bernard Thorens, Robert J Hearnden, M Paula Longhi, Paul Grevitt, Madeeha H Sheikh, Egle Solito, Susana A Godinho, Michele Bombardieri, David M Smith, Dianne Cooper, Asif J Iqbal, Jeffrey C Rathmell, Samuel Schaefer, Valle Morales, Katiuscia Bianchi, Giuseppe Danilo Norata, Federica M Marelli-Berg.

T cell activation is associated with a profound and rapid metabolic response to meet increased energy demands for cell division, differentiation and development of effector function. Glucose uptake and engagement of the glycolytic pathway are major checkpoints for this event. Here we show that the low-affinity, concentration-dependent glucose transporter 2 (Glut2) regulates the development of CD8+ T cell effector responses in mice by promoting glucose uptake, glycolysis and glucose storage. Expression of Glut2 is modulated by environmental factors including glucose and oxygen availability and extracellular acidification. Glut2 is highly expressed by circulating, recently primed T cells, allowing efficient glucose uptake and storage. In glucose-deprived inflammatory environments, Glut2 becomes downregulated, thus preventing passive loss of intracellular glucose. Mechanistically, Glut2 expression is regulated by a combination of molecular interactions involving hypoxia-inducible factor-1 alpha, galectin-9 and stomatin. Finally, we show that human T cells also rely on this glucose transporter, thus providing a potential target for therapeutic immunomodulation.

DOI: https://doi.org/10.1038/s42255-023-00913-9
Nat Chem Biol. 2023 Oct 26.

Reducing mitochondrial mysteries.

Rachel M Guerra, David J Pagliarini.

DOI: https://doi.org/10.1038/s41589-023-01435-x
Cancer Cell. 2023 Oct 19. pii: S1535-6108(23)00357-4. [Epub ahead of print]

Mitochondrial control of antigen presentation in cancer cells.

Ruth Soler-Agesta, Alberto Anel, Lorenzo Galluzzi.

Cytotoxic T lymphocytes recognize and kill cancer cells when the latter present antigenic epitopes complexed with MHC class I molecules on their surface. In a recent Science paper, Mangalhara et al. show that alterations of the mitochondrial electron flow upregulate multiple factors involved in antigen presentation via a succinate-dependent epigenetic mechanism.

DOI: https://doi.org/10.1016/j.ccell.2023.10.001
Curr Opin Biotechnol. 2023 Oct 19. pii: S0958-1669(23)00121-0. [Epub ahead of print]84 103011

Proline metabolism shapes the tumor microenvironment: from collagen deposition to immune evasion.

Emily J Kay, Sara Zanivan, Alessandro Rufini.

Proline is a nonessential amino acid, and its metabolism has been implicated in numerous malignancies. Together with a direct role in regulating cancer cells' proliferation and survival, proline metabolism plays active roles in shaping the tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs) display high rates of proline biosynthesis to support the production of collagen for the extracellular matrix (ECM). Indeed, impaired proline metabolism in CAFs results in reduced collagen deposition and compromises the growth and metastatic spread of cancer. Moreover, the rate of proline metabolism regulates intracellular reactive oxygen species (ROS) levels, which influence the production and release of cytokines from cancer cells, contributing toward an immune-permissive TME. Hence, targeting proline metabolism is a promising anticancer strategy that could improve patients' outcome and response to immunotherapy.

DOI: https://doi.org/10.1016/j.copbio.2023.103011
Metabolism. 2023 Oct 20. pii: S0026-0495(23)00313-X. [Epub ahead of print] 155709

Brown adipose tissue-derived metabolites and their role in regulating metabolism.

Khanyisani Ziqubu, Phiwayinkosi V Dludla, Sihle E Mabhida, Babalwa U Jack, Susanne Keipert, Martin Jastroch, Sithandiwe E Mazibuko-Mbeje.

  The discovery and rejuvenation of metabolically active brown adipose tissue (BAT) in adult humans have offered a new approach to treating obesity and metabolic diseases. Beyond an accomplished role in adaptive thermogenesis, BAT secretes signaling molecules known as "batokines", which are instrumental in regulating whole-body metabolism via autocrine, paracrine, and endocrine action. In addition to the intrinsic BAT metabolite-oxidizing activity, the endocrine functions of these molecules may help to explain the association between BAT activity and a healthy systemic metabolic profile. Herein, we review the evidence that underscores the significance of BAT-derived metabolites, especially highlighting their role in controlling physiological and metabolic processes involving thermogenesis, substrate metabolism, and other essential biological processes. The conversation extends to their capacity to enhance energy expenditure and mitigate features of obesity and its related metabolic complications. Thus, metabolites derived from BAT may provide new avenues for the discovery of metabolic health-promoting drugs with far-reaching impacts. This review aims to dissect the complexities of the secretory role of BAT in modulating local and systemic metabolism in metabolic health and disease.

Keywords:  Batokines; Brown adipose tissue; Metabolic diseases; Metabolism; Metabolites; Obesity; Secretome

DOI:  https://doi.org/10.1016/j.metabol.2023.155709
Biomed Pharmacother. 2023 Oct 19. pii: S0753-3322(23)01528-7. [Epub ahead of print]168 115730

Copper-mediated novel cell death pathway in tumor cells and implications for innovative cancer therapies.

Xiaodan Zhang, Tao Tao, Yishu Qiu, Xiaojun Guo, Xiao Zhu, Xiaorong Zhou.

  Previous investigations have unraveled an array of cellular demise modalities, encompassing apoptosis, necrosis, pyroptosis, iron death, and several others. These diverse pathways of cell death have been harnessed as therapeutic strategies for eradicating tumor cells. Recent scientific inquiries have unveiled a novel mode of cell death, namely copper death, which is contingent upon intracellular copper levels. Diverging from conventional cell death mechanisms, copper death exhibits a heightened reliance on mitochondrial respiration, specifically the tricarboxylic acid (TCA) cycle. Tumor cells exhibit distinctive metabolic profiles and an elevated copper content compared to their normal counterparts. The emergence of copper death presents a tantalizing prospect for targeted therapies in the realm of cancer treatment. Thus, the primary objective of this review is to introduce the proteins and intricate mechanisms underlying copper death, while comprehensively summarizing the extensive body of knowledge concerning its ramifications across diverse tumor types. The insights garnered from this comprehensive synthesis will serve as an invaluable reference for driving the development of tailor-made therapeutic interventions for tumors.

Keywords:  Cellular demise modalities; Copper death; Mitochondrial respiration; Tailored therapeutic interventions; Therapeutic strategies; Tumor cell metabolism

DOI:  https://doi.org/10.1016/j.biopha.2023.115730
bioRxiv. 2023 Sep 24. pii: 2023.09.23.559074. [Epub ahead of print]

Direct ionic stress sensing and mitigation by the transcription factor NFAT5.

Chandni B Khandwala, Parijat Sarkar, H Broder Schmidt, Mengxiao Ma, Maia Kinnebrew, Ganesh V Pusapati, Bhaven B Patel, Desiree Tillo, Andres M Lebensohn, Rajat Rohatgi.

Homeostatic control of intracellular ionic strength is essential for protein, organelle and genome function, yet mechanisms that sense and enable adaptation to ionic stress remain poorly understood in animals. We find that the transcription factor NFAT5 directly senses solution ionic strength using a C-terminal intrinsically disordered region. Both in intact cells and in a purified system, NFAT5 forms dynamic, reversible biomolecular condensates in response to increasing ionic strength. This self-associative property, conserved from insects to mammals, allows NFAT5 to accumulate in the nucleus and activate genes that restore cellular ion content. Mutations that reduce condensation or those that promote aggregation both reduce NFAT5 activity, highlighting the importance of optimally tuned associative interactions. Remarkably, human NFAT5 alone is sufficient to reconstitute a mammalian transcriptional response to ionic or hypertonic stress in yeast. Thus NFAT5 is both the sensor and effector of a cell-autonomous ionic stress response pathway in animal cells.

DOI: https://doi.org/10.1101/2023.09.23.559074
Cell Rep. 2023 Oct 25. pii: S2211-1247(23)01307-4. [Epub ahead of print]42(11): 113295

KEAP1 mutation in lung adenocarcinoma promotes immune evasion and immunotherapy resistance.

Anastasia-Maria Zavitsanou, Ray Pillai, Yuan Hao, Warren L Wu, Eric Bartnicki, Triantafyllia Karakousi, Sahith Rajalingam, Alberto Herrera, Angeliki Karatza, Ali Rashidfarrokhi, Sabrina Solis, Metamia Ciampricotti, Anna H Yeaton, Ellie Ivanova, Corrin A Wohlhieter, Terkild B Buus, Makiko Hayashi, Burcu Karadal-Ferrena, Harvey I Pass, John T Poirier, Charles M Rudin, Kwok-Kin Wong, Andre L Moreira, Kamal M Khanna, Aristotelis Tsirigos, Thales Papagiannakopoulos, Sergei B Koralov.

  Lung cancer treatment has benefited greatly through advancements in immunotherapies. However, immunotherapy often fails in patients with specific mutations like KEAP1, which are frequently found in lung adenocarcinoma. We established an antigenic lung cancer model and used it to explore how Keap1 mutations remodel the tumor immune microenvironment. Using single-cell technology and depletion studies, we demonstrate that Keap1-mutant tumors diminish dendritic cell and T cell responses driving immunotherapy resistance. This observation was corroborated in patient samples. CRISPR-Cas9-mediated gene targeting revealed that hyperactivation of the NRF2 antioxidant pathway is responsible for diminished immune responses in Keap1-mutant tumors. Importantly, we demonstrate that combining glutaminase inhibition with immune checkpoint blockade can reverse immunosuppression, making Keap1-mutant tumors susceptible to immunotherapy. Our study provides new insight into the role of KEAP1 mutations in immune evasion, paving the way for novel immune-based therapeutic strategies for KEAP1-mutant cancers.

Keywords:  CD103 DC; CP: Cancer; CP: Immunology; KEAP1; LUAD; NRF2; NSCLC; T cell; adenocarcinoma; immune surveillance; immunotherapy; lung cancer

DOI:  https://doi.org/10.1016/j.celrep.2023.113295
Cell Rep. 2023 Oct 20. pii: S2211-1247(23)01296-2. [Epub ahead of print]42(10): 113284

The interplay between metabolic stochasticity and cAMP-CRP regulation in single E. coli cells.

Martijn Wehrens, Laurens H J Krah, Benjamin D Towbin, Rutger Hermsen, Sander J Tans.

  The inherent stochasticity of metabolism raises a critical question for understanding homeostasis: are cellular processes regulated in response to internal fluctuations? Here, we show that, in E. coli cells under constant external conditions, catabolic enzyme expression continuously responds to metabolic fluctuations. The underlying regulatory feedback is enabled by the cyclic AMP (cAMP) and cAMP receptor protein (CRP) system, which controls catabolic enzyme expression based on metabolite concentrations. Using single-cell microscopy, genetic constructs in which this feedback is disabled, and mathematical modeling, we show how fluctuations circulate through the metabolic and genetic network at sub-cell-cycle timescales. Modeling identifies four noise propagation modes, including one specific to CRP regulation. Together, these modes correctly predict noise circulation at perturbed cAMP levels. The cAMP-CRP system may thus have evolved to control internal metabolic fluctuations in addition to external growth conditions. We conjecture that second messengers may more broadly function to achieve cellular homeostasis.

Keywords:  CP: Cell biology; CP: Microbiology; CRP; Escherichia coli; cAMP-CRP; gene expression; heterogeneity; noise; regulation; single cell; stochasticity; time lapse microscopy

DOI:  https://doi.org/10.1016/j.celrep.2023.113284
PLoS Biol. 2023 Oct;21(10): e3002371

Metabolic sinkholes: Histones as methyl repositories.

Ansar Karimian, Maria Vogelauer, Siavash K Kurdistani.

Perez and Sarkies uncover histones as methyl group repositories in normal and cancer human cells, shedding light on an intriguing function of histone methylation in optimizing the cellular methylation potential independently of gene regulation.

DOI: https://doi.org/10.1371/journal.pbio.3002371
Cell Rep. 2023 Oct 20. pii: S2211-1247(23)01289-5. [Epub ahead of print]42(11): 113277

Regulation of STING activity in DNA sensing by ISG15 modification.

Chaohui Lin, Edmund Osei Kuffour, Nina V Fuchs, Christoph G W Gertzen, Jesko Kaiser, Maximilian Hirschenberger, Xiao Tang, Haifeng C Xu, Oliver Michel, Ronny Tao, Alexandra Haase, Ulrich Martin, Thomas Kurz, Ingo Drexler, Boris Görg, Philipp A Lang, Tom Luedde, Konstantin M J Sparrer, Holger Gohlke, Renate König, Carsten Münk.

  Sensing of human immunodeficiency virus type 1 (HIV-1) DNA is mediated by the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling axis. Signal transduction and regulation of this cascade is achieved by post-translational modifications. Here we show that cGAS-STING-dependent HIV-1 sensing requires interferon-stimulated gene 15 (ISG15). ISG15 deficiency inhibits STING-dependent sensing of HIV-1 and STING agonist-induced antiviral response. Upon external stimuli, STING undergoes ISGylation at residues K224, K236, K289, K347, K338, and K370. Inhibition of STING ISGylation at K289 suppresses STING-mediated type Ⅰ interferon induction by inhibiting its oligomerization. Of note, removal of STING ISGylation alleviates gain-of-function phenotype in STING-associated vasculopathy with onset in infancy (SAVI). Molecular modeling suggests that ISGylation of K289 is an important regulator of oligomerization. Taken together, our data demonstrate that ISGylation at K289 is crucial for STING activation and represents an important regulatory step in DNA sensing of viruses and autoimmune responses.

Keywords:  CP: Molecular biology; DNA sensing; HIV sensing; ISG15; ISGylation; SAVI; USP18; innate immunity

DOI:  https://doi.org/10.1016/j.celrep.2023.113277
Nat Commun. 2023 Oct 27. 14(1): 6598

Lactate biosensors for spectrally and spatially multiplexed fluorescence imaging.

Yusuke Nasu, Abhi Aggarwal, Giang N T Le, Camilla Trang Vo, Yuki Kambe, Xinxing Wang, Felix R M Beinlich, Ashley Bomin Lee, Tina R Ram, Fangying Wang, Kelsea A Gorzo, Yuki Kamijo, Marc Boisvert, Suguru Nishinami, Genki Kawamura, Takeaki Ozawa, Hirofumi Toda, Grant R Gordon, Shaoyu Ge, Hajime Hirase, Maiken Nedergaard, Marie-Eve Paquet, Mikhail Drobizhev, Kaspar Podgorski, Robert E Campbell.

L-Lactate is increasingly appreciated as a key metabolite and signaling molecule in mammals. However, investigations of the inter- and intra-cellular dynamics of L-lactate are currently hampered by the limited selection and performance of L-lactate-specific genetically encoded biosensors. Here we now report a spectrally and functionally orthogonal pair of high-performance genetically encoded biosensors: a green fluorescent extracellular L-lactate biosensor, designated eLACCO2.1, and a red fluorescent intracellular L-lactate biosensor, designated R-iLACCO1. eLACCO2.1 exhibits excellent membrane localization and robust fluorescence response. To the best of our knowledge, R-iLACCO1 and its affinity variants exhibit larger fluorescence responses than any previously reported intracellular L-lactate biosensor. We demonstrate spectrally and spatially multiplexed imaging of L-lactate dynamics by coexpression of eLACCO2.1 and R-iLACCO1 in cultured cells, and in vivo imaging of extracellular and intracellular L-lactate dynamics in mice.

DOI: https://doi.org/10.1038/s41467-023-42230-5
Sci Adv. 2023 Oct 27. 9(43): eadj1010

Synaptic BMAL1 phosphorylation controls circadian hippocampal plasticity.

Ilaria Barone, Nicole M Gilette, Hannah Hawks-Mayer, Jonathan Handy, Kevin J Zhang, Fortunate F Chifamba, Engie Mostafa, Erin M Johnson-Venkatesh, Yan Sun, Jennifer M Gibson, Alexander Rotenberg, Hisashi Umemori, Peter T Tsai, Jonathan O Lipton.

The time of day strongly influences adaptive behaviors like long-term memory, but the correlating synaptic and molecular mechanisms remain unclear. The circadian clock comprises a canonical transcription-translation feedback loop (TTFL) strictly dependent on the BMAL1 transcription factor. We report that BMAL1 rhythmically localizes to hippocampal synapses in a manner dependent on its phosphorylation at Ser42 [pBMAL1(S42)]. pBMAL1(S42) regulates the autophosphorylation of synaptic CaMKIIα and circadian rhythms of CaMKIIα-dependent molecular interactions and LTP but not global rest/activity behavior. Therefore, our results suggest a model in which repurposing of the clock protein BMAL1 to synapses locally gates the circadian timing of plasticity.

DOI: https://doi.org/10.1126/sciadv.adj1010
Nat Metab. 2023 Oct 23.

Gut microbiome-derived ammonia modulates stress vulnerability in the host.

Pei Wang, Peng-Fei Wu, Hua-Jie Wang, Fang Liao, Fang Wang, Jian-Guo Chen.

Ammonia has been long recognized as a metabolic waste product with well-known neurotoxic effects. However, little is known about the beneficial function of endogenous ammonia. Here, we show that gut ammonia links microbe nitrogen metabolism to host stress vulnerability by maintaining brain glutamine availability in male mice. Chronic stress decreases blood ammonia levels by altering gut urease-positive microbiota. A representative urease-producing strain, Streptococcus thermophilus, can reverse depression-like behaviours induced by gut microbiota that was altered by stress, whereas pharmacological inhibition of gut ammonia production increases stress vulnerability. Notably, abnormally low blood ammonia levels limit the brain's availability of glutamine, a key metabolite produced by astrocytes that is required for presynaptic γ-aminobutyric acid (GABA) replenishment and confers stress vulnerability through cortical GABAergic dysfunction. Of therapeutic interest, ammonium chloride (NH4Cl), a commonly used expectorant in the clinic, can rescue behavioural abnormalities and GABAergic deficits in mouse models of depression. In sum, ammonia produced by the gut microbiome can help buffer stress in the host, providing a gut-brain signalling basis for emotional behaviour.

DOI: https://doi.org/10.1038/s42255-023-00909-5
EMBO Rep. 2023 Oct 25. e57849

Oxygen-regulated post-translation modifications as master signalling pathway in cells.

Michael Batie, Temitope Fasanya, Niall S Kenneth, Sonia Rocha.

  Oxygen is essential for viability in mammalian organisms. However, cells are often exposed to changes in oxygen availability, due to either increased demand or reduced oxygen supply, herein called hypoxia. To be able to survive and/or adapt to hypoxia, cells activate a variety of signalling cascades resulting in changes to chromatin, gene expression, metabolism and viability. Cellular signalling is often mediated via post-translational modifications (PTMs), and this is no different in response to hypoxia. Many enzymes require oxygen for their activity and oxygen can directly influence several PTMS. Here, we review the direct impact of changes in oxygen availability on PTMs such as proline, asparagine, histidine and lysine hydroxylation, lysine and arginine methylation and cysteine dioxygenation, with a focus on mammalian systems. In addition, indirect hypoxia-dependent effects on phosphorylation, ubiquitination and sumoylation will also be discussed. Direct and indirect oxygen-regulated changes to PTMs are coordinated to achieve the cell's ultimate response to hypoxia. However, specific oxygen sensitivity and the functional relevance of some of the identified PTMs still require significant research.

Keywords:  2-oxoglutarate dioxygenases; PTMs; hydroxylation; hypoxia; methylations

DOI:  https://doi.org/10.15252/embr.202357849
bioRxiv. 2023 Oct 04. pii: 2023.10.03.560745. [Epub ahead of print]

A DRP-like pseudoenzyme coordinates with MICOS to promote cristae architecture.

Abhishek Kumar, Mehmet Oguz Gok, Kailey N Nguyen, Michael L Reese, Jeremy G Wideman, Sergio A Muñoz-Gómez, Jonathan R Friedman.

Mitochondrial cristae architecture is crucial for optimal respiratory function of the organelle. Cristae shape is maintained in part by the mitochondrial inner membrane-localized MICOS complex. While MICOS is required for normal cristae morphology, the precise mechanistic role of each of the seven human MICOS subunits, and how the complex coordinates with other cristae shaping factors, has not been fully determined. Here, we examine the MICOS complex in Schizosaccharomyces pombe , a minimal model whose genome only encodes for four core subunits. Using an unbiased proteomics approach, we identify a poorly characterized inner mitochondrial membrane protein that interacts with MICOS and is required to maintain cristae morphology, which we name Mmc1. We demonstrate that Mmc1 works in concert with MICOS complexes to promote normal mitochondrial morphology and respiratory function. Bioinformatic analyses reveal that Mmc1 is a distant relative of the Dynamin-Related Protein (DRP) family of GTPases, which are well established to shape and remodel membranes. We find that, like DRPs, Mmc1 self-associates and forms high molecular weight assemblies. Interestingly, however, Mmc1 is a pseudoenzyme that lacks key residues required for GTP binding and hydrolysis, suggesting it does not dynamically remodel membranes. These data are consistent with a model in which Mmc1 stabilizes cristae architecture by acting as a scaffold to support cristae ultrastructure on the matrix side of the inner membrane. Our study reveals a new class of proteins that evolved early in fungal phylogeny and is required for the maintenance of cristae architecture. This highlights the possibility that functionally analogous proteins work with MICOS to establish cristae morphology in metazoans.

DOI: https://doi.org/10.1101/2023.10.03.560745
Nat Cell Biol. 2023 Oct 26.

Manganese regulation of COPII condensation controls circulating lipid homeostasis.

Xiao Wang, Runze Huang, Yawei Wang, Wenjing Zhou, Yating Hu, Yuanhang Yao, Kunlun Cheng, Xin Li, Bolin Xu, Jie Zhang, Yaowen Xu, Fanxin Zeng, Yuangang Zhu, Xiao-Wei Chen.

Precise control of circulating lipids is instrumental in health and disease. Bulk lipids, carried by specialized lipoproteins, are secreted into the circulation, initially via the coat protein complex II (COPII). How the universal COPII machinery accommodates the abundant yet unconventional lipoproteins remains unclear, let alone its therapeutic translation. Here we report that COPII uses manganese-tuning, self-constrained condensation to selectively drive lipoprotein delivery and set lipid homeostasis in vivo. Serendipitously, adenovirus hijacks the condensation-based transport mechanism, thus enabling the identification of cytosolic manganese as an unexpected control signal. Manganese directly binds the inner COPII coat and enhances its condensation, thereby shifting the assembly-versus-dynamics balance of the transport machinery. Manganese can be mobilized from mitochondria stores to signal COPII, and selectively controls lipoprotein secretion with a distinctive, bell-shaped function. Consequently, dietary titration of manganese enables tailored lipid management that counters pathological dyslipidaemia and atherosclerosis, implicating a condensation-targeting strategy with broad therapeutic potential for cardio-metabolic health.

DOI: https://doi.org/10.1038/s41556-023-01260-3
EMBO Rep. 2023 Oct 27. e57440

Metabolic plasticity sustains the robustness of Caenorhabditis elegans embryogenesis.

Siyu Chen, Xing Su, Jinglin Zhu, Long Xiao, Yulin Cong, Leilei Yang, Zhuo Du, Xun Huang.

  Embryogenesis is highly dependent on maternally loaded materials, particularly those used for energy production. Different environmental conditions and genetic backgrounds shape embryogenesis. The robustness of embryogenesis in response to extrinsic and intrinsic changes remains incompletely understood. By analyzing the levels of two major nutrients, glycogen and neutral lipids, we discovered stage-dependent usage of these two nutrients along with mitochondrial morphology changes during Caenorhabditis elegans embryogenesis. ATGL, the rate-limiting lipase in cellular lipolysis, is expressed and required in the hypodermis to regulate mitochondrial function and support embryogenesis. The embryonic lethality of atgl-1 mutants can be suppressed by reducing sinh-1/age-1-akt signaling, likely through modulating glucose metabolism to maintain sustainable glucose consumption. The embryonic lethality of atgl-1(xd314) is also affected by parental nutrition. Parental glucose and oleic acid supplements promote glycogen storage in atgl-1(xd314) embryos to compensate for the impaired lipolysis. The rescue by parental vitamin B12 supplement is likely through enhancing mitochondrial function in atgl-1 mutants. These findings reveal that metabolic plasticity contributes to the robustness of C. elegans embryogenesis.

Keywords:  ATGL; embryogenesis; lipolysis; metabolic plasticity

DOI:  https://doi.org/10.15252/embr.202357440
Cell Rep. 2023 Oct 20. pii: S2211-1247(23)01277-9. [Epub ahead of print]42(11): 113265

Chlorophyll biosynthesis under the control of arginine metabolism.

Éva Kiss, Jana Talbot, Nathan B P Adams, Stanislav Opekar, Martin Moos, Jan Pilný, Tatjana Kvasov, Emilia Schneider, Peter Koník, Petr Šimek, Roman Sobotka.

  In natural environments, photosynthetic organisms adjust their metabolism to cope with the fluctuating availability of combined nitrogen sources, a growth-limiting factor. For acclimation, the dynamic degradation/synthesis of tetrapyrrolic pigments, as well as of the amino acid arginine, is pivotal; however, there has been no evidence that these processes could be functionally coupled. Using co-immunopurification and spectral shift assays, we found that in the cyanobacterium Synechocystis sp. PCC 6803, the arginine metabolism-related ArgD and CphB enzymes form protein complexes with Gun4, an essential protein for chlorophyll biosynthesis. Gun4 binds ArgD with high affinity, and the Gun4-ArgD complex accumulates in cells supplemented with ornithine, a key intermediate of the arginine pathway. Elevated ornithine levels restricted de novo synthesis of tetrapyrroles, which arrested the recovery from nitrogen deficiency. Our data reveal a direct crosstalk between tetrapyrrole biosynthesis and arginine metabolism that highlights the importance of balancing photosynthetic pigment synthesis with nitrogen homeostasis.

Keywords:  CP: Plants; Synechocystis; arginine metabolism; bilins; chlorophyll; genome-uncoupled-4; nitrogen homeostasis; tetrapyrrole biosynthesis

DOI:  https://doi.org/10.1016/j.celrep.2023.113265
Int J Mol Sci. 2023 Oct 13. pii: 15144. [Epub ahead of print]24(20):

Mitochondrial sAC-cAMP-PKA Axis Modulates the ΔΨm-Dependent Control Coefficients of the Respiratory Chain Complexes: Evidence of Respirasome Plasticity.

Rosella Scrima, Olga Cela, Michela Rosiello, Ari Qadir Nabi, Claudia Piccoli, Giuseppe Capitanio, Francesco Antonio Tucci, Aldo Leone, Giovanni Quarato, Nazzareno Capitanio.

  The current view of the mitochondrial respiratory chain complexes I, III and IV foresees the occurrence of their assembly in supercomplexes, providing additional functional properties when compared with randomly colliding isolated complexes. According to the plasticity model, the two structural states of the respiratory chain may interconvert, influenced by the intracellular prevailing conditions. In previous studies, we suggested the mitochondrial membrane potential as a factor for controlling their dynamic balance. Here, we investigated if and how the cAMP/PKA-mediated signalling influences the aggregation state of the respiratory complexes. An analysis of the inhibitory titration profiles of the endogenous oxygen consumption rates in intact HepG2 cells with specific inhibitors of the respiratory complexes was performed to quantify, in the framework of the metabolic flux theory, the corresponding control coefficients. The attained results, pharmacologically inhibiting either PKA or sAC, indicated that the reversible phosphorylation of the respiratory chain complexes/supercomplexes influenced their assembly state in response to the membrane potential. This conclusion was supported by the scrutiny of the available structure of the CI/CIII2/CIV respirasome, enabling us to map several PKA-targeted serine residues exposed to the matrix side of the complexes I, III and IV at the contact interfaces of the three complexes.

Keywords:  cAMP/PKA signaling pathway; metabolic flux theory; mitochondrial membrane potential; mitochondrial respiratory chain complexes; soluble adenylate cyclase; supercomplexes

DOI:  https://doi.org/10.3390/ijms242015144
FASEB J. 2023 Dec;37(12): e23268

Methionine-CBS axis promotes intracellular ROS levels by reprogramming serine metabolism.

Jingyun Chen, Xiangyan Cui, Ning Fang, Yu Wu, Shujian Yu, Dong Xiao.

  As a non-essential amino acid, cysteine could be obtained through both exogenous uptake and endogenous de novo synthesis pathways. Research has demonstrated that restricting the uptake of cystine could result in a depletion of intracellular cysteine and glutathione, ultimately leading to an increase in intracellular reactive oxygen species (ROS) levels. However, the role of methionine in regulating intracellular ROS levels is currently unclear. Here, we want to explore the role of methionine in regulating intracellular ROS levels. We found that methionine restriction could lead to a decrease in intracellular ROS levels, while supplementation with SAM can restore these levels through flow cytometry. Mechanically, we found that the methionine-SAM axis relies on CBS when regulating intracellular ROS levels. Furthermore, we speculate and prove that the methionine-SAM-CBS axis alters the metabolism of serine, thereby reducing intracellular reductive power, therefore promoting intracellular ROS levels through changing metabolite levels and genetic methods. Finally, our study revealed that high expression of CBS in tumor cells could lead to increased intracellular ROS levels, ultimately resulting in faster proliferation rates. Together, our study confirmed that methionine plays a promoting role in the regulation of intracellular ROS levels.

Keywords:  CBS; ROS; SAM; methionine; serine

DOI:  https://doi.org/10.1096/fj.202300804RRRR
Nat Chem Biol. 2023 Oct 26.

Toying with reductive stress.

Alexandria C Murphy, Melanie R McReynolds.

DOI: https://doi.org/10.1038/s41589-023-01461-9
Mol Oncol. 2023 Oct 23.

A guide to epigenetics in leukaemia stem cells.

Shuchi Agrawal-Singh, Jaana Bagri, Nathalie Sakakini, Brian J P Huntly.

  Leukaemia stem cells (LSCs) are the critical seed for the growth of haematological malignancies, driving the clonal expansion that enables disease initiation, relapse and often resistance. Specifically, they display inherent phenotypic and epigenetic plasticity resulting in complex heterogenic diseases. In this review, we discuss the key principles of deregulation of epigenetic processes that shape this disease evolution. We consider measures to define and quantify clonal heterogeneity, combining information from recent studies assessing mutational, transcriptional and epigenetic landscapes at single cell resolution in Myeloid Neoplasms (MN). We highlight the importance of integrating epigenetic and genetic information to better understand inter- and intra-patient heterogeneity and discuss how this understanding further informs evolution and progression trajectories and subsequent clinical response in MN. Under this topic, we also discuss efforts to identify mechanisms of resistance, by longitudinal analysis of patient samples. Finally, we highlight how we might target these aberrant epigenetic processes for better therapeutic outcomes and to potentially eradicate LSCs.

Keywords:  Leukaemia stem cells; Myeloid neoplasms; epigenetic plasticity; heterogeneity; single cell studies and multiomics; targeting LSC

DOI:  https://doi.org/10.1002/1878-0261.13544