bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2023–04–09
39 papers selected by
Christian Frezza, Universität zu Köln
  1. Metaboverse enables automated discovery and visualization of diverse metabolic regulatory patterns.
  2. GAPDH redox redux-rewiring pentose phosphate flux.
  3. Stearoyl coenzyme A desaturase-1: multitasker in cancer, metabolism, and ferroptosis.
  4. The GAPDH redox switch safeguards reductive capacity and enables survival of stressed tumour cells.
  5. Global determination of reaction rates and lipid turnover kinetics in Mus musculus.
  6. NAD+ repletion with niacin counteracts cancer cachexia.
  7. Formate overflow drives toxic folate trapping in MTHFD1 inhibited cancer cells.
  8. Macrotubule associated protein MAP1LC3C regulates lysosomal exocytosis and induces zinc reprogramming in renal cancer cells.
  9. Metabolic set points of mammalian neurodevelopment.
  10. Oxylipin-PPARγ-initiated adipocyte senescence propagates secondary senescence in the bone marrow.
  11. Pancreatic Cancer Is Dependent on De Novo Ornithine Synthesis from Glutamine.
  12. Bub1 and Bub3 regulate metabolic adaptation via macrolipophagy in Drosophila.
  13. Monocyte depletion enhances neutrophil influx and proneural to mesenchymal transition in glioblastoma.
  14. PCK1 dysregulation in cancer: Metabolic reprogramming, oncogenic activation, and therapeutic opportunities.
  15. Mitochondria in Health, Disease, and Ageing.
  16. Targeting glutamine metabolism as a therapeutic strategy for cancer.
  17. Nanozyme-Based Regulation of Cellular Metabolism and their Applications.
  18. Mitochondrial fumarate implicated in inflammation.
  19. TOM complex-independent transport pathway of myoglobin into mitochondria in C2C12 myotubes.
  20. Transcriptional programing of T cell metabolism by STAT family transcription factors.
  21. Spleen fibroblastic reticular cell-derived acetylcholine promotes lipid metabolism to drive autoreactive B cell responses.
  22. Evolution of cisplatin resistance through coordinated metabolic reprogramming of the cellular reductive state.
  23. XOR risk variants drive diabetic kidney disease.
  24. An OMA1 redox site controls mitochondrial homeostasis, sarcoma growth, and immunogenicity.
  25. Generalized Tree Structure to Annotate Untargeted Metabolomics and Stable Isotope Tracing Data.
  26. The moonlighting function of glycolytic enzyme enolase-1 promotes choline phospholipid metabolism and tumor cell proliferation.
  27. Kinase signaling in distinct neuronal populations in the mouse brain controls sleep homeostasis and the circadian clock.
  28. Neurons require glucose uptake and glycolysis in vivo.
  29. Glucocerebrosidase is imported into mitochondria and preserves complex I integrity and energy metabolism.
  30. Repurposing degradation pathways for modular metabolite biosynthesis in nematodes.
  31. The DNA Damage Response and Inflammation in Cancer.
  32. Mapping out mitochondria.
  33. Mitochondrial dynamics as a pathobiological mediator of clonal myeloid disorders.
  34. Triglyceride cycling enables modification of stored fatty acids.
  35. Structural and functional properties of mSWI/SNF chromatin remodeling complexes revealed through single-cell perturbation screens.
  36. An epigenetic switch controls an alternative NR2F2 isoform that unleashes a metastatic program in melanoma.
  37. Dynamic antagonism between key repressive pathways maintains the placental epigenome.
  38. Spatial probabilistic mapping of metabolite ensembles in mass spectrometry imaging.
  39. Reciprocal intra- and extra-cellular polarity enables deep mechanosensing through layered matrices.
  1. Nat Cell Biol. 2023 Apr 03.
    Metaboverse enables automated discovery and visualization of diverse metabolic regulatory patterns.
    Jordan A Berg, Youjia Zhou, Yeyun Ouyang, Ahmad A Cluntun, T Cameron Waller, Megan E Conway, Sara M Nowinski, Tyler Van Ry, Ian George, James E Cox, Bei Wang, Jared Rutter.
      Metabolism is intertwined with various cellular processes, including controlling cell fate, influencing tumorigenesis, participating in stress responses and more. Metabolism is a complex, interdependent network, and local perturbations can have indirect effects that are pervasive across the metabolic network. Current analytical and technical limitations have long created a bottleneck in metabolic data interpretation. To address these shortcomings, we developed Metaboverse, a user-friendly tool to facilitate data exploration and hypothesis generation. Here we introduce algorithms that leverage the metabolic network to extract complex reaction patterns from data. To minimize the impact of missing measurements within the network, we introduce methods that enable pattern recognition across multiple reactions. Using Metaboverse, we identify a previously undescribed metabolite signature that correlated with survival outcomes in early stage lung adenocarcinoma patients. Using a yeast model, we identify metabolic responses suggesting an adaptive role of citrate homeostasis during mitochondrial dysfunction facilitated by the citrate transporter, Ctp1. We demonstrate that Metaboverse augments the user's ability to extract meaningful patterns from multi-omics datasets to develop actionable hypotheses.
    DOI:  https://doi.org/10.1038/s41556-023-01117-9
  2. Nat Metab. 2023 Apr 06.
    GAPDH redox redux-rewiring pentose phosphate flux.
    Laura Torrente, Gina M DeNicola.
      
    DOI:  https://doi.org/10.1038/s42255-021-00523-3
  3. Trends Cancer. 2023 Apr 05. pii: S2405-8033(23)00032-8. [Epub ahead of print]
    Stearoyl coenzyme A desaturase-1: multitasker in cancer, metabolism, and ferroptosis.
    Utsav Sen, Charles Coleman, Triparna Sen.
      Cancer progression is a highly balanced process and is maintained by a sequence of finely tuned metabolic pathways. Stearoyl coenzyme A desaturase-1 (SCD1), the fatty enzyme that converts saturated fatty acids into monounsaturated fatty acids, is a critical modulator of the fatty acid metabolic pathway. SCD1 expression is associated with poor prognosis in several cancer types. SCD1 triggers an iron-dependent cell death called ferroptosis and elevated levels of SCD1 protect cancer cells against ferroptosis. Pharmacological inhibition of SCD1 as monotherapy and in combination with chemotherapeutic agents shows promising antitumor potential in preclinical models. In this review, we summarize the role of SCD in cancer cell progression, survival, and ferroptosis and discuss potential strategies to exploit SCD1 inhibition in future clinical trials.
    Keywords:  NSCLC; SCD1; cancer therapy; fatty acid metabolism; ferroptosis; immunotherapy
    DOI:  https://doi.org/10.1016/j.trecan.2023.03.003
  4. Nat Metab. 2023 Apr 06.
    The GAPDH redox switch safeguards reductive capacity and enables survival of stressed tumour cells.
    Deepti Talwar, Colin G Miller, Justus Grossmann, Lukasz Szyrwiel, Torsten Schwecke, Vadim Demichev, Ana-Matea Mikecin Drazic, Anand Mayakonda, Pavlo Lutsik, Carmen Veith, Michael D Milsom, Karin Müller-Decker, Michael Mülleder, Markus Ralser, Tobias P Dick.
      Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) is known to contain an active-site cysteine residue undergoing oxidation in response to hydrogen peroxide, leading to rapid inactivation of the enzyme. Here we show that human and mouse cells expressing a GAPDH mutant lacking this redox switch retain catalytic activity but are unable to stimulate the oxidative pentose phosphate pathway and enhance their reductive capacity. Specifically, we find that anchorage-independent growth of cells and spheroids is limited by an elevation of endogenous peroxide levels and is largely dependent on a functional GAPDH redox switch. Likewise, tumour growth in vivo is limited by peroxide stress and suppressed when the GAPDH redox switch is disabled in tumour cells. The induction of additional intratumoural oxidative stress by chemo- or radiotherapy synergized with the deactivation of the GAPDH redox switch. Mice lacking the GAPDH redox switch exhibit altered fatty acid metabolism in kidney and heart, apparently in compensation for the lack of the redox switch. Together, our findings demonstrate the physiological and pathophysiological relevance of oxidative GAPDH inactivation in mammals.
    DOI:  https://doi.org/10.1038/s42255-023-00781-3
  5. Cell Metab. 2023 Apr 04. pii: S1550-4131(23)00085-2. [Epub ahead of print]35(4): 711-721.e4
    Global determination of reaction rates and lipid turnover kinetics in Mus musculus.
    Qishan Chen, Hu Li, He Tian, Sin Man Lam, Yilie Liao, Ziyin Zhang, Manyuan Dong, Shaoru Chen, Yuxiao Yao, Jiemiao Meng, Yong Zhang, Lemin Zheng, Zhuo-Xian Meng, Weiping Han, Guanghou Shui, Dahai Zhu, Suneng Fu.
      Metabolism is fundamental to life, but measuring metabolic reaction rates remains challenging. Here, we applied C13 fluxomics to monitor the metabolism of dietary glucose carbon in 12 tissues, 9 brain compartments, and over 1,000 metabolite isotopologues over a 4-day period. The rates of 85 reactions surrounding central carbon metabolism are determined with elementary metabolite unit (EMU) modeling. Lactate oxidation, not glycolysis, occurs at a comparable pace with the tricarboxylic acid cycle (TCA), supporting lactate as the primary fuel. We expand the EMU framework to track and quantify metabolite flows across tissues. Specifically, multi-organ EMU simulation of uridine metabolism shows that tissue-blood exchange, not synthesis, controls nucleotide homeostasis. In contrast, isotopologue fingerprinting and kinetic analyses reveal the brown adipose tissue (BAT) having the highest palmitate synthesis activity but no apparent contribution to circulation, suggesting a tissue-autonomous synthesis-to-burn mechanism. Together, this study demonstrates the utility of dietary fluxomics for kinetic mapping in vivo and provides a rich resource for elucidating inter-organ metabolic cross talk.
    Keywords:  dietary fluxomics; elementary metabolite units; inter-organ metabolite flow; multi-organ EMU modeling
    DOI:  https://doi.org/10.1016/j.cmet.2023.03.007
  6. Nat Commun. 2023 Apr 03. 14(1): 1849
    NAD+ repletion with niacin counteracts cancer cachexia.
    Marc Beltrà, Noora Pöllänen, Claudia Fornelli, Kialiina Tonttila, Myriam Y Hsu, Sandra Zampieri, Lucia Moletta, Samantha Corrà, Paolo E Porporato, Riikka Kivelä, Carlo Viscomi, Marco Sandri, Juha J Hulmi, Roberta Sartori, Eija Pirinen, Fabio Penna.
      Cachexia is a debilitating wasting syndrome and highly prevalent comorbidity in cancer patients. It manifests especially with energy and mitochondrial metabolism aberrations that promote tissue wasting. We recently identified nicotinamide adenine dinucleotide (NAD+) loss to associate with muscle mitochondrial dysfunction in cancer hosts. In this study we confirm that depletion of NAD+ and downregulation of Nrk2, an NAD+ biosynthetic enzyme, are common features of severe cachexia in different mouse models. Testing NAD+ repletion therapy in cachectic mice reveals that NAD+ precursor, vitamin B3 niacin, efficiently corrects tissue NAD+ levels, improves mitochondrial metabolism and ameliorates cancer- and chemotherapy-induced cachexia. In a clinical setting, we show that muscle NRK2 is downregulated in cancer patients. The low expression of NRK2 correlates with metabolic abnormalities underscoring the significance of NAD+ in the pathophysiology of human cancer cachexia. Overall, our results propose NAD+ metabolism as a therapy target for cachectic cancer patients.
    DOI:  https://doi.org/10.1038/s41467-023-37595-6
  7. Nat Metab. 2023 Apr 03.
    Formate overflow drives toxic folate trapping in MTHFD1 inhibited cancer cells.
    Alanna C Green, Petra Marttila, Nicole Kiweler, Christina Chalkiadaki, Elisée Wiita, Victoria Cookson, Antoine Lesur, Kim Eiden, François Bernardin, Karl S A Vallin, Sanjay Borhade, Maeve Long, Elahe Kamali Ghahe, Julio J Jiménez-Alonso, Ann-Sofie Jemth, Olga Loseva, Oliver Mortusewicz, Marianne Meyers, Elodie Viry, Annika I Johansson, Ondřej Hodek, Evert Homan, Nadilly Bonagas, Louise Ramos, Lars Sandberg, Morten Frödin, Etienne Moussay, Ana Slipicevic, Elisabeth Letellier, Jérôme Paggetti, Claus Storgaard Sørensen, Thomas Helleday, Martin Henriksson, Johannes Meiser.
      Cancer cells fuel their increased need for nucleotide supply by upregulating one-carbon (1C) metabolism, including the enzymes methylenetetrahydrofolate dehydrogenase-cyclohydrolase 1 and 2 (MTHFD1 and MTHFD2). TH9619 is a potent inhibitor of dehydrogenase and cyclohydrolase activities in both MTHFD1 and MTHFD2, and selectively kills cancer cells. Here, we reveal that, in cells, TH9619 targets nuclear MTHFD2 but does not inhibit mitochondrial MTHFD2. Hence, overflow of formate from mitochondria continues in the presence of TH9619. TH9619 inhibits the activity of MTHFD1 occurring downstream of mitochondrial formate release, leading to the accumulation of 10-formyl-tetrahydrofolate, which we term a 'folate trap'. This results in thymidylate depletion and death of MTHFD2-expressing cancer cells. This previously uncharacterized folate trapping mechanism is exacerbated by physiological hypoxanthine levels that block the de novo purine synthesis pathway, and additionally prevent 10-formyl-tetrahydrofolate consumption for purine synthesis. The folate trapping mechanism described here for TH9619 differs from other MTHFD1/2 inhibitors and antifolates. Thus, our findings uncover an approach to attack cancer and reveal a regulatory mechanism in 1C metabolism.
    DOI:  https://doi.org/10.1038/s42255-023-00771-5
  8. J Biol Chem. 2023 Mar 30. pii: S0021-9258(23)00305-8. [Epub ahead of print] 104663
    Macrotubule associated protein MAP1LC3C regulates lysosomal exocytosis and induces zinc reprogramming in renal cancer cells.
    Rita Verma, Parul Aggarwal, Megan E Bischoff, James Reigle, Dina Secic, Collin Wetzel, Katherine VandenHeuvel, Jacek Biesiada, Birgit Ehmer, Julio A Landero Figueroa, David R Plas, Mario Medvedovic, Jarek Meller, Maria F Czyzyk-Krzeska.
      Microtubule Associated Protein 1 Light Chain 3 Gamma (MAP1LC3C or LC3C) is a member of the microtubule associated family of proteins that are essential in the formation of autophagosomes and lysosomal degradation of cargo. LC3C has tumor suppressing activity and its expression is dependent on kidney cancer tumor suppressors, such as von Hippel-Lindau protein (VHL) and folliculin (FLCN). Recently We demonstrated that LC3C autophagy is regulated by noncanonical upstream regulatory complexes and targets for degradation postdivision midbody rings associated with cancer cells stemness. Here we show that loss of LC3C leads to peripheral positioning of the lysosomes and lysosomal exocytosis (LE). This process is independent of the autophagic activity of LC3C. Analysis of isogenic cells with low and high LE shows substantial transcriptomic reprogramming with altered expression of Zn-related genes and activity of Polycomb Repressor Complex 2 (PRC2), accompanied by a robust decrease in intracellular Zn. Additionally, metabolomic analysis revealed alterations in amino acid steady-state levels. Cells with augmented LE show increased tumor initiation properties and form aggressive tumors in xenograft models. Immunocytochemistry identified high levels of Lysosomal Associated Membrane Protein 1 (LAMP1) on the plasma membrane of cancer cells in human clear cell renal cell carcinoma (ccRCC) and reduced levels of Zn, suggesting that LE occurs in ccRCC, potentially contributing to the loss of Zn. These data indicate that the reprogramming of lysosomal localization and Zn metabolism with implication for epigenetic remodeling in a subpopulation of tumor propagating cancer cells is an important aspect of tumor suppressing activity of LC3C.
    Keywords:  LC3C; exocytosis; lysosome; renal cancer; zinc
    DOI:  https://doi.org/10.1016/j.jbc.2023.104663
  9. Cell Metab. 2023 Apr 04. pii: S1550-4131(23)00090-6. [Epub ahead of print]35(4): 553-554
    Metabolic set points of mammalian neurodevelopment.
    Fumi Suomi, Anna Rappe, Thomas G McWilliams.
      The human nervous system matures over a protracted developmental time frame relative to other species. What sets the pace of maturation has remained a mystery. In a recent publication in Science, Iwata et al. unearth critical contributions of mitochondrial metabolism in setting the pace of species-specific corticogenesis.
    DOI:  https://doi.org/10.1016/j.cmet.2023.03.012
  10. Cell Metab. 2023 Apr 04. pii: S1550-4131(23)00083-9. [Epub ahead of print]35(4): 667-684.e6
    Oxylipin-PPARγ-initiated adipocyte senescence propagates secondary senescence in the bone marrow.
    Xiaonan Liu, Yiru Gu, Surendra Kumar, Sahran Amin, Qiaoyue Guo, Jiekang Wang, Ching-Lien Fang, Xu Cao, Mei Wan.
      The chronic use of glucocorticoids decreases bone mass and quality and increases bone-marrow adiposity, but the underlying mechanisms remain unclear. Here, we show that bone-marrow adipocyte (BMAd) lineage cells in adult mice undergo rapid cellular senescence upon glucocorticoid treatment. The senescent BMAds acquire a senescence-associated secretory phenotype, which spreads senescence in bone and bone marrow. Mechanistically, glucocorticoids increase the synthesis of oxylipins, such as 15d-PGJ2, for peroxisome proliferator-activated receptor gamma (PPARγ) activation. PPARγ stimulates the expression of key senescence genes and also promotes oxylipin synthesis in BMAds, forming a positive feedback loop. Transplanting senescent BMAds into the bone marrow of healthy mice is sufficient to induce the secondary spread of senescent cells and bone-loss phenotypes, whereas transplanting BMAds harboring a p16INK4a deletion did not show such effects. Thus, glucocorticoid treatment induces a lipid metabolic circuit that robustly triggers the senescence of BMAd lineage cells that, in turn, act as the mediators of glucocorticoid-induced bone deterioration.
    Keywords:  INK-family proteins; PPARγ; bone marrow adipocytes; bone marrow adiposity; cellular senescence; glucocorticoids; osteoporosis; oxylipins; prostaglandins; senescence-associated secretory phenotype
    DOI:  https://doi.org/10.1016/j.cmet.2023.03.005
  11. Cancer Discov. 2023 Apr 07. OF1
    Pancreatic Cancer Is Dependent on De Novo Ornithine Synthesis from Glutamine.
      Polyamine synthesis in pancreatic cancer cells is dependent on de novo ornithine synthesis from glutamine.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2023-053
  12. Cell Rep. 2023 Apr 05. pii: S2211-1247(23)00354-6. [Epub ahead of print]42(4): 112343
    Bub1 and Bub3 regulate metabolic adaptation via macrolipophagy in Drosophila.
    Qiaoqiao Zhang, Hui Zheng, Shengye Yang, Tong Feng, Minwen Jie, Haiyang Chen, Hao Jiang.
      Lipophagy, the process of selective catabolism of lipid droplets (LDs) by autophagy, maintains lipid homeostasis and provides cellular energy under metabolic adaptation, yet its underlying mechanism remains largely ambiguous. Here, we show that the Bub1-Bub3 complex, the crucial regulator involved in the whole process of chromosome alignment and separation during mitosis, controls the fasting-induced lipid catabolism in the fat body (FB) of Drosophila. Bidirectional deviations of the Bub1 or Bub3 level affect the consumption of triacylglycerol (TAG) of fat bodies and the survival rate of adult flies under starving. Moreover, Bub1 and Bub3 work together to attenuate lipid degradation via macrolipophagy upon fasting. Thus, we uncover physiological roles of the Bub1-Bub3 complex on metabolic adaptation and lipid metabolism beyond their canonical mitotic functions, providing insights into the in vivo functions and molecular mechanisms of macrolipophagy during nutrient deprivation.
    Keywords:  CP: Metabolism
    DOI:  https://doi.org/10.1016/j.celrep.2023.112343
  13. Nat Commun. 2023 Apr 03. 14(1): 1839
    Monocyte depletion enhances neutrophil influx and proneural to mesenchymal transition in glioblastoma.
    Zhihong Chen, Nishant Soni, Gonzalo Pinero, Bruno Giotti, Devon J Eddins, Katherine E Lindblad, James L Ross, Montserrat Puigdelloses Vallcorba, Tanvi Joshi, Angelo Angione, Wes Thomason, Aislinn Keane, Nadejda M Tsankova, David H Gutmann, Sergio A Lira, Amaia Lujambio, Eliver E B Ghosn, Alexander M Tsankov, Dolores Hambardzumyan.
      Myeloid cells comprise the majority of immune cells in tumors, contributing to tumor growth and therapeutic resistance. Incomplete understanding of myeloid cells response to tumor driver mutation and therapeutic intervention impedes effective therapeutic design. Here, by leveraging CRISPR/Cas9-based genome editing, we generate a mouse model that is deficient of all monocyte chemoattractant proteins. Using this strain, we effectively abolish monocyte infiltration in genetically engineered murine models of de novo glioblastoma (GBM) and hepatocellular carcinoma (HCC), which show differential enrichment patterns for monocytes and neutrophils. Eliminating monocyte chemoattraction in monocyte enriched PDGFB-driven GBM invokes a compensatory neutrophil influx, while having no effect on Nf1-silenced GBM model. Single-cell RNA sequencing reveals that intratumoral neutrophils promote proneural-to-mesenchymal transition and increase hypoxia in PDGFB-driven GBM. We further demonstrate neutrophil-derived TNF-a directly drives mesenchymal transition in PDGFB-driven primary GBM cells. Genetic or pharmacological inhibiting neutrophils in HCC or monocyte-deficient PDGFB-driven and Nf1-silenced GBM models extend the survival of tumor-bearing mice. Our findings demonstrate tumor-type and genotype dependent infiltration and function of monocytes and neutrophils and highlight the importance of targeting them simultaneously for cancer treatments.
    DOI:  https://doi.org/10.1038/s41467-023-37361-8
  14. Genes Dis. 2023 Jan;10(1): 101-112
    PCK1 dysregulation in cancer: Metabolic reprogramming, oncogenic activation, and therapeutic opportunities.
    Jin Xiang, Kai Wang, Ni Tang.
      The last few decades have witnessed an advancement in our understanding of multiple cancer cell pathways related to metabolic reprogramming. One of the most important cancer hallmarks, including aerobic glycolysis (the Warburg effect), the central carbon pathway, and multiple-branch metabolic pathway remodeling, enables tumor growth, progression, and metastasis. Phosphoenolpyruvate carboxykinase 1 (PCK1), a key rate-limiting enzyme in gluconeogenesis, catalyzes the conversion of oxaloacetate to phosphoenolpyruvate. PCK1 expression in gluconeogenic tissues is tightly regulated during fasting. In tumor cells, PCK1 is regulated in a cell-autonomous manner rather than by hormones or nutrients in the extracellular environment. Interestingly, PCK1 has an anti-oncogenic role in gluconeogenic organs (the liver and kidneys), but a tumor-promoting role in cancers arising from non-gluconeogenic organs. Recent studies have revealed that PCK1 has metabolic and non-metabolic roles in multiple signaling networks linking metabolic and oncogenic pathways. Aberrant PCK1 expression results in the activation of oncogenic pathways, accompanied by metabolic reprogramming, to maintain tumorigenesis. In this review, we summarize the mechanisms underlying PCK1 expression and regulation, and clarify the crosstalk between aberrant PCK1 expression, metabolic rewiring, and signaling pathway activation. In addition, we highlight the clinical relevance of PCK1 and its value as a putative cancer therapeutic target.
    Keywords:  Gluconeogenesis; Metabolism; Oncogenesis; PCK1; Tumor
    DOI:  https://doi.org/10.1016/j.gendis.2022.02.010
  15. Physiol Rev. 2023 Apr 06.
    Mitochondria in Health, Disease, and Ageing.
    John S Harrington, Stefan W Ryter, Maria Plataki, David R Price, Augustine M K Choi.
      Mitochondria are well-known as organelles responsible for the maintenance of cellular bioenergetics through the production of ATP. While oxidative phosphorylation may be their most important function, mitochondria are also integral for the synthesis of metabolic precursors, calcium regulation, the production of reactive oxygen species, immune signaling, and apoptosis. Considering the breadth of their responsibilities, mitochondria are fundamental for cellular metabolism and homeostasis. Appreciating this significance, translational medicine has begun to investigate how mitochondrial dysfunction can represent a harbinger of disease. In this review, we provide a detailed overview of mitochondrial metabolism, cellular bioenergetics, mitochondrial dynamics, autophagy, mitochondrial damage-associated molecular patterns, mitochondria-mediated cell-death pathways, and how mitochondrial dysfunction at any of these levels is associated with disease pathogenesis. Mitochondria-dependent pathways may thereby represent an attractive therapeutic target for ameliorating human disease.
    Keywords:  Apoptosis; Inflammation; Mitochondria; Mitochondrial Dysfunction; Mitophagy
    DOI:  https://doi.org/10.1152/physrev.00058.2021
  16. Exp Mol Med. 2023 Apr 03.
    Targeting glutamine metabolism as a therapeutic strategy for cancer.
    Jonghwa Jin, Jun-Kyu Byun, Yeon-Kyung Choi, Keun-Gyu Park.
      Proliferating cancer cells rely largely on glutamine for survival and proliferation. Glutamine serves as a carbon source for the synthesis of lipids and metabolites via the TCA cycle, as well as a source of nitrogen for amino acid and nucleotide synthesis. To date, many studies have explored the role of glutamine metabolism in cancer, thereby providing a scientific rationale for targeting glutamine metabolism for cancer treatment. In this review, we summarize the mechanism(s) involved at each step of glutamine metabolism, from glutamine transporters to redox homeostasis, and highlight areas that can be exploited for clinical cancer treatment. Furthermore, we discuss the mechanisms underlying cancer cell resistance to agents that target glutamine metabolism, as well as strategies for overcoming these mechanisms. Finally, we discuss the effects of glutamine blockade on the tumor microenvironment and explore strategies to maximize the utility of glutamine blockers as a cancer treatment.
    DOI:  https://doi.org/10.1038/s12276-023-00971-9
  17. Adv Mater. 2023 Apr 05. e2301810
    Nanozyme-Based Regulation of Cellular Metabolism and their Applications.
    Yue Wang, Xiaodan Jia, Shangjie An, Wenbo Yin, Jiahao Huang, Xiue Jiang.
      Metabolism is the sum of the enzyme-dependent chemical reactions, which produces energy in catabolic process and synthesizes biomass in anabolic process, exhibiting high similarity in mammalian cell, microbial cell, and plant cell. Consequently, the loss or gain of metabolic enzyme activity will greatly affect cellular metabolism. Nanozymes, as emerging enzyme mimics with diverse functions and adjustable catalytic activities, has shown attractive potential for metabolic regulation. Although the basic metabolic tasks are highly similar for the cells from different species, the concrete metabolic pathway varies with the intracellular structure of different species. In this review, we describe the basic metabolism in living organisms and discuss the similarities and differences in the metabolic pathways among mammalian, microbial and plant cells and the regulation mechanism. We then systematically review the recent progress on regulation of cellular metabolism mainly including nutrients uptake and utilization, energy production and the accompanied redox reactions by different kinds of oxidoreductases and their applications in the field of disease therapy, antimicrobial therapy, and sustainable agriculture. Furthermore, the prospects and challenges of nanozymes in regulating cell metabolism are also discussed, which will broaden their application scenarios. This article is protected by copyright. All rights reserved.
    Keywords:  antimicrobial; cellular metabolism; disease therapy; metabolic regulation; nanozyme; sustainable agriculture
    DOI:  https://doi.org/10.1002/adma.202301810
  18. Nat Rev Rheumatol. 2023 Apr 06.
    Mitochondrial fumarate implicated in inflammation.
    Sarah Onuora.
      
    DOI:  https://doi.org/10.1038/s41584-023-00963-z
  19. Physiol Rep. 2023 Apr;11(7): e15632
    TOM complex-independent transport pathway of myoglobin into mitochondria in C2C12 myotubes.
    Rikuhide Koma, Tsubasa Shibaguchi, Yuhei Araiso, Tatsuya Yamada, Yudai Nonaka, Thomas Jue, Kazumi Masuda.
      Recently, we found that myoglobin (Mb) localizes in both the cytosol and mitochondrial intermembrane space in rodent skeletal muscle. Most proteins of the intermembrane space pass through the outer mitochondrial membrane via the translocase of the outer membrane (TOM) complex. However, whether the TOM complex imports Mb remains unknown. The purpose of this study was to investigate the involvement of the TOM complex in Mb import into the mitochondria. A proteinase K protection assay of mitochondria from C2C12 myotubes confirmed that Mb integrated into the mitochondria. An immunoprecipitation assay verified the interaction of Mb and TOM complex receptors (Tom20, Tom70) in isolated mitochondria. The assay showed a clear interaction of Mb with Tom20 and Tom70. A knockdown experiment using siRNA for TOM complex receptors (Tom20, Tom70) and TOM complex channel (Tom40) did not alter the amount of Mb expression in the mitochondrial fraction. These results suggested that Mb does not necessarily require the TOM complex for mitochondrial import of Mb. Although the physiological role of Mb interactions with TOM complex receptors remains unclear, further studies are needed to clarify how Mb enters the mitochondria independently of the TOM complex.
    Keywords:  Tom20; Tom40; Tom70; skeletal muscle
    DOI:  https://doi.org/10.14814/phy2.15632
  20. Eur J Immunol. 2023 Apr 03. e2048825
    Transcriptional programing of T cell metabolism by STAT family transcription factors.
    Alejandro V Villarino.
      T cells adapt their metabolism to meet the energetic and biosynthetic demands imposed by changes in location, behavior and/or differentiation state. Many of these adaptations are controlled by cytokines. Traditionally, research on the metabolic properties of cytokines has focused on downstream signaling via the PI3K-AKT, mTOR, or ERK-MAPK pathways but recent studies indicate that JAK-STAT is also crucial. This review synthesizes current thinking on how JAK-STAT signaling influences T cell metabolism, focusing on adaptations necessary for the naïve, effector, regulatory, memory and resident-memory states. The overarching theme is that JAK-STAT has both direct and indirect effects. Direct regulation involves STATs localizing to and instructing expression of metabolism-related genes. Indirect regulation involves STATs instructing genes encoding upstream or regulatory factors, including cytokine receptors and other transcription factors, as well as non-canonical JAK-STAT activities. Cytokines impact a vast range of metabolic processes. Here, we focus on those that are most prominent in T cells; lipid, amino acid and nucleotide synthesis for anabolic metabolism, glycolysis, glutaminolysis, oxidative phosphorylation and fatty acid oxidation for catabolic metabolism. Ultimately, we advocate the idea that JAK-STAT is a key node in the complex network of signaling inputs and outputs which ensure that T cell metabolism meets lifestyle demands. This article is protected by copyright. All rights reserved.
    Keywords:  Cytokine; JAK-STAT; Metabolism; T cell
    DOI:  https://doi.org/10.1002/eji.202048825
  21. Cell Metab. 2023 Mar 29. pii: S1550-4131(23)00088-8. [Epub ahead of print]
    Spleen fibroblastic reticular cell-derived acetylcholine promotes lipid metabolism to drive autoreactive B cell responses.
    Qin Zeng, Shuyi Wang, Mengyuan Li, Shuang Wang, Chaohuan Guo, Xinyuan Ruan, Ryu Watanabe, Yimei Lai, Yuefang Huang, Xiaoyu Yin, Chuanzhao Zhang, Binfeng Chen, Niansheng Yang, Hui Zhang.
      Autoreactive B cell responses are essential for the development of systemic lupus erythematosus (SLE). Fibroblastic reticular cells (FRCs) are known to construct lymphoid compartments and regulate immune functions. Here, we identify spleen FRC-derived acetylcholine (ACh) as a key factor that controls autoreactive B cell responses in SLE. In SLE, CD36-mediated lipid uptake leads to enhanced mitochondrial oxidative phosphorylation in B cells. Accordingly, the inhibition of fatty acid oxidation results in reduced autoreactive B cell responses and ameliorated diseases in lupus mice. Ablation of CD36 in B cells impairs lipid uptake and differentiation of autoreactive B cells during autoimmune induction. Mechanistically, spleen FRC-derived ACh promotes lipid influx and generation of autoreactive B cells through CD36. Together, our data uncover a novel function of spleen FRCs in lipid metabolism and B cell differentiation, placing spleen FRC-derived ACh in a key position in promoting autoreactive B cells in SLE.
    Keywords:  CD36; acetylcholine; autoreactive B cell responses; choline acetyltransferase; fibroblastic reticular cells; lipid metabolism; mitochondrial respiration; spleen; systemic lupus erythematosus
    DOI:  https://doi.org/10.1016/j.cmet.2023.03.010
  22. Br J Cancer. 2023 Apr 03.
    Evolution of cisplatin resistance through coordinated metabolic reprogramming of the cellular reductive state.
    Wangie Yu, Yunyun Chen, Nagireddy Putluri, Abdullah Osman, Cristian Coarfa, Vasanta Putluri, Abu H M Kamal, Jennifer Kay Asmussen, Panagiotis Katsonis, Jeffrey N Myers, Stephen Y Lai, Wuhao Lu, Clifford C Stephan, Reid T Powell, Faye M Johnson, Heath D Skinner, Jawad Kazi, Kazi Mokim Ahmed, Linghao Hu, Addison Threet, Matthew D Meyer, James A Bankson, Tony Wang, Jack Davis, Kirby R Parker, Madison A Harris, Mokryun L Baek, Gloria V Echeverria, Xiaoli Qi, Jin Wang, Andy I Frederick, Alex J Walsh, Olivier Lichtarge, Mitchell J Frederick, Vlad C Sandulache.
       BACKGROUND: Cisplatin (CDDP) is a mainstay treatment for advanced head and neck squamous cell carcinomas (HNSCC) despite a high frequency of innate and acquired resistance. We hypothesised that tumours acquire CDDP resistance through an enhanced reductive state dependent on metabolic rewiring.
    METHODS: To validate this model and understand how an adaptive metabolic programme might be imprinted, we performed an integrated analysis of CDDP-resistant HNSCC clones from multiple genomic backgrounds by whole-exome sequencing, RNA-seq, mass spectrometry, steady state and flux metabolomics.
    RESULTS: Inactivating KEAP1 mutations or reductions in KEAP1 RNA correlated with Nrf2 activation in CDDP-resistant cells, which functionally contributed to resistance. Proteomics identified elevation of downstream Nrf2 targets and the enrichment of enzymes involved in generation of biomass and reducing equivalents, metabolism of glucose, glutathione, NAD(P), and oxoacids. This was accompanied by biochemical and metabolic evidence of an enhanced reductive state dependent on coordinated glucose and glutamine catabolism, associated with reduced energy production and proliferation, despite normal mitochondrial structure and function.
    CONCLUSIONS: Our analysis identified coordinated metabolic changes associated with CDDP resistance that may provide new therapeutic avenues through targeting of these convergent pathways.
    DOI:  https://doi.org/10.1038/s41416-023-02253-7
  23. Nat Metab. 2023 Apr 06.
    XOR risk variants drive diabetic kidney disease.
    Ke Zhu, Jochen Reiser.
      
    DOI:  https://doi.org/10.1038/s42255-023-00768-0
  24. Life Sci Alliance. 2023 Jun;pii: e202201767. [Epub ahead of print]6(6):
    An OMA1 redox site controls mitochondrial homeostasis, sarcoma growth, and immunogenicity.
    Richard Miallot, Virginie Millet, Yann Groult, Angelika Modelska, Lydie Crescence, Sandrine Roulland, Sandrine Henri, Bernard Malissen, Nicolas Brouilly, Laurence Panicot-Dubois, Renaud Vincentelli, Gerlind Sulzenbacher, Pascal Finetti, Aurélie Dutour, Jean-Yves Blay, François Bertucci, Franck Galland, Philippe Naquet.
      Aggressive tumors often display mitochondrial dysfunction. Upon oxidative stress, mitochondria undergo fission through OMA1-mediated cleavage of the fusion effector OPA1. In yeast, a redox-sensing switch participates in OMA1 activation. 3D modeling of OMA1 comforted the notion that cysteine 403 might participate in a similar sensor in mammalian cells. Using prime editing, we developed a mouse sarcoma cell line in which OMA1 cysteine 403 was mutated in alanine. Mutant cells showed impaired mitochondrial responses to stress including ATP production, reduced fission, resistance to apoptosis, and enhanced mitochondrial DNA release. This mutation prevented tumor development in immunocompetent, but not nude or cDC1 dendritic cell-deficient, mice. These cells prime CD8+ lymphocytes that accumulate in mutant tumors, whereas their depletion delays tumor control. Thus, OMA1 inactivation increased the development of anti-tumor immunity. Patients with complex genomic soft tissue sarcoma showed variations in the level of OMA1 and OPA1 transcripts. High expression of OPA1 in primary tumors was associated with shorter metastasis-free survival after surgery, and low expression of OPA1, with anti-tumor immune signatures. Targeting OMA1 activity may enhance sarcoma immunogenicity.
    DOI:  https://doi.org/10.26508/lsa.202201767
  25. Anal Chem. 2023 Apr 05.
    Generalized Tree Structure to Annotate Untargeted Metabolomics and Stable Isotope Tracing Data.
    Shuzhao Li, Shujian Zheng.
      In untargeted metabolomics, multiple ions are often measured for each original metabolite, including isotopic forms and in-source modifications, such as adducts and fragments. Without prior knowledge of the chemical identity or formula, computational organization and interpretation of these ions is challenging, which is the deficit of previous software tools that perform the task using network algorithms. We propose here a generalized tree structure to annotate ions in relationships to the original compound and infer neutral mass. An algorithm is presented to convert mass distance networks to this tree structure with high fidelity. This method is useful for both regular untargeted metabolomics and stable isotope tracing experiments. It is implemented as a Python package (khipu) and provides a JSON format for easy data exchange and software interoperability. By generalized preannotation, khipu makes it feasible to connect metabolomics data with common data science tools and supports flexible experimental designs.
    DOI:  https://doi.org/10.1021/acs.analchem.2c05810
  26. Proc Natl Acad Sci U S A. 2023 Apr 11. 120(15): e2209435120
    The moonlighting function of glycolytic enzyme enolase-1 promotes choline phospholipid metabolism and tumor cell proliferation.
    Qingxia Ma, Hongfei Jiang, Leina Ma, Gaoxiang Zhao, Qianqian Xu, Dong Guo, Ningning He, Hao Liu, Zhaoyuan Meng, Juanjuan Liu, Lei Zhu, Qian Lin, Xiaolin Wu, Min Li, Shudi Luo, Jing Fang, Zhimin Lu.
      Aberrantly upregulated choline phospholipid metabolism is a novel emerging hallmark of cancer, and choline kinase α (CHKα), a key enzyme for phosphatidylcholine production, is overexpressed in many types of human cancer through undefined mechanisms. Here, we demonstrate that the expression levels of the glycolytic enzyme enolase-1 (ENO1) are positively correlated with CHKα expression levels in human glioblastoma specimens and that ENO1 tightly governs CHKα expression via posttranslational regulation. Mechanistically, we reveal that both ENO1 and the ubiquitin E3 ligase TRIM25 are associated with CHKα. Highly expressed ENO1 in tumor cells binds to I199/F200 of CHKα, thereby abrogating the interaction between CHKα and TRIM25. This abrogation leads to the inhibition of TRIM25-mediated polyubiquitylation of CHKα at K195, increased stability of CHKα, enhanced choline metabolism in glioblastoma cells, and accelerated brain tumor growth. In addition, the expression levels of both ENO1 and CHKα are associated with poor prognosis in glioblastoma patients. These findings highlight a critical moonlighting function of ENO1 in choline phospholipid metabolism and provide unprecedented insight into the integrated regulation of cancer metabolism by crosstalk between glycolytic and lipidic enzymes.
    Keywords:  CHKα; TRIM25; enolase
    DOI:  https://doi.org/10.1073/pnas.2209435120
  27. Proc Natl Acad Sci U S A. 2023 Apr 11. 120(15): e2303354120
    Kinase signaling in distinct neuronal populations in the mouse brain controls sleep homeostasis and the circadian clock.
    Yoshitaka Fukada.
      
    DOI:  https://doi.org/10.1073/pnas.2303354120
  28. Cell Rep. 2023 Apr 06. pii: S2211-1247(23)00346-7. [Epub ahead of print]42(4): 112335
    Neurons require glucose uptake and glycolysis in vivo.
    Huihui Li, Caroline Guglielmetti, Yoshitaka J Sei, Misha Zilberter, Lydia M Le Page, Lauren Shields, Joyce Yang, Kevin Nguyen, Brice Tiret, Xiao Gao, Neal Bennett, Iris Lo, Talya L Dayton, Martin Kampmann, Yadong Huang, Jeffrey C Rathmell, Matthew Vander Heiden, Myriam M Chaumeil, Ken Nakamura.
      Neurons require large amounts of energy, but whether they can perform glycolysis or require glycolysis to maintain energy remains unclear. Using metabolomics, we show that human neurons do metabolize glucose through glycolysis and can rely on glycolysis to supply tricarboxylic acid (TCA) cycle metabolites. To investigate the requirement for glycolysis, we generated mice with postnatal deletion of either the dominant neuronal glucose transporter (GLUT3cKO) or the neuronal-enriched pyruvate kinase isoform (PKM1cKO) in CA1 and other hippocampal neurons. GLUT3cKO and PKM1cKO mice show age-dependent learning and memory deficits. Hyperpolarized magnetic resonance spectroscopic (MRS) imaging shows that female PKM1cKO mice have increased pyruvate-to-lactate conversion, whereas female GLUT3cKO mice have decreased conversion, body weight, and brain volume. GLUT3KO neurons also have decreased cytosolic glucose and ATP at nerve terminals, with spatial genomics and metabolomics revealing compensatory changes in mitochondrial bioenergetics and galactose metabolism. Therefore, neurons metabolize glucose through glycolysis in vivo and require glycolysis for normal function.
    Keywords:  CP: Neuroscience; bioenergetics; brain energy; galactose metabolism; glucose transporter; glycolysis; hyperpolarized magnetic resonance spectroscopic imaging; metabolomics; neuronal glucose metabolism; pyruvate kinase
    DOI:  https://doi.org/10.1016/j.celrep.2023.112335
  29. Nat Commun. 2023 Apr 06. 14(1): 1930
    Glucocerebrosidase is imported into mitochondria and preserves complex I integrity and energy metabolism.
    Pascale Baden, Maria Jose Perez, Hariam Raji, Federico Bertoli, Stefanie Kalb, María Illescas, Fokion Spanos, Claudio Giuliano, Alessandra Maria Calogero, Marvin Oldrati, Hannah Hebestreit, Graziella Cappelletti, Kathrin Brockmann, Thomas Gasser, Anthony H V Schapira, Cristina Ugalde, Michela Deleidi.
      Mutations in GBA1, the gene encoding the lysosomal enzyme β-glucocerebrosidase (GCase), which cause Gaucher's disease, are the most frequent genetic risk factor for Parkinson's disease (PD). Here, we employ global proteomic and single-cell genomic approaches in stable cell lines as well as induced pluripotent stem cell (iPSC)-derived neurons and midbrain organoids to dissect the mechanisms underlying GCase-related neurodegeneration. We demonstrate that GCase can be imported from the cytosol into the mitochondria via recognition of internal mitochondrial targeting sequence-like signals. In mitochondria, GCase promotes the maintenance of mitochondrial complex I (CI) integrity and function. Furthermore, GCase interacts with the mitochondrial quality control proteins HSP60 and LONP1. Disease-associated mutations impair CI stability and function and enhance the interaction with the mitochondrial quality control machinery. These findings reveal a mitochondrial role of GCase and suggest that defective CI activity and energy metabolism may drive the pathogenesis of GCase-linked neurodegeneration.
    DOI:  https://doi.org/10.1038/s41467-023-37454-4
  30. Nat Chem Biol. 2023 Apr 06.
    Repurposing degradation pathways for modular metabolite biosynthesis in nematodes.
    Chester J J Wrobel, Frank C Schroeder.
      Recent studies have revealed that Caenorhabditis elegans and other nematodes repurpose products from biochemical degradation pathways for the combinatorial assembly of complex modular structures that serve diverse signaling functions. Building blocks from neurotransmitter, amino acid, nucleoside and fatty acid metabolism are attached to scaffolds based on the dideoxyhexose ascarylose or glucose, resulting in hundreds of modular ascarosides and glucosides. Genome-wide association studies have identified carboxylesterases as the key enzymes mediating modular assembly, enabling rapid compound discovery via untargeted metabolomics and suggesting that modular metabolite biosynthesis originates from the 'hijacking' of conserved detoxification mechanisms. Modular metabolites thus represent a distinct biosynthetic strategy for generating structural and functional diversity in nematodes, complementing the primarily polyketide synthase- and nonribosomal peptide synthetase-derived universe of microbial natural products. Although many aspects of modular metabolite biosynthesis and function remain to be elucidated, their identification demonstrates how phenotype-driven compound discovery, untargeted metabolomics and genomic approaches can synergize to facilitate the annotation of metabolic dark matter.
    DOI:  https://doi.org/10.1038/s41589-023-01301-w
  31. Cancer Discov. 2023 Apr 07. OF1-OF25
    The DNA Damage Response and Inflammation in Cancer.
    Vanessa Klapp, Beatriz Álvarez-Abril, Giuseppe Leuzzi, Guido Kroemer, Alberto Ciccia, Lorenzo Galluzzi.
      Genomic stability in normal cells is crucial to avoid oncogenesis. Accordingly, multiple components of the DNA damage response (DDR) operate as bona fide tumor suppressor proteins by preserving genomic stability, eliciting the demise of cells with unrepairable DNA lesions, and engaging cell-extrinsic oncosuppression via immunosurveillance. That said, DDR sig-naling can also favor tumor progression and resistance to therapy. Indeed, DDR signaling in cancer cells has been consistently linked to the inhibition of tumor-targeting immune responses. Here, we discuss the complex interactions between the DDR and inflammation in the context of oncogenesis, tumor progression, and response to therapy.
    SIGNIFICANCE: Accumulating preclinical and clinical evidence indicates that DDR is intimately connected to the emission of immunomodulatory signals by normal and malignant cells, as part of a cell-extrinsic program to preserve organismal homeostasis. DDR-driven inflammation, however, can have diametrically opposed effects on tumor-targeting immunity. Understanding the links between the DDR and inflammation in normal and malignant cells may unlock novel immunotherapeutic paradigms to treat cancer.
    DOI:  https://doi.org/10.1158/2159-8290.CD-22-1220
  32. Nat Rev Cancer. 2023 Apr 03.
    Mapping out mitochondria.
    Anna Dart.
      
    DOI:  https://doi.org/10.1038/s41568-023-00572-8
  33. Cancer Sci. 2023 Apr 07.
    Mitochondrial dynamics as a pathobiological mediator of clonal myeloid disorders.
    Yoshihiro Hayashi, Hironori Harada.
      Myeloid malignancies, including myelodysplastic syndromes and acute myeloid leukemia, are a group of clonal hematopoietic stem cell (HSC) diseases. The incidence increases with global population aging. Genome sequencing uncovered mutational profiles in patients with myeloid malignancies and healthy elderly individuals. However, the molecular and cellular basis of disease development remains unclear. Accumulating evidence shows mitochondrial involvement in the pathogenesis of myeloid malignancies, aging-related HSC phenotypes, and clonal hematopoiesis. Mitochondria are dynamic organelles that continuously undergo fission and fusion processes to maintain their function, integrity, and activity. Mitochondria could be a hub of various biological processes that underlie cellular and systemic homeostasis. Thus, mitochondrial dysfunction could directly lead to the disruption of cellular homeostasis and the development of various disorders, including cancer. Notably, emerging data have revealed that mitochondria dynamics also primarily affect not only mitochondrial function and activity but also cellular homeostasis, the aging process, and tumorigenesis. Here, by focusing on mitochondrial dynamics, we highlight the current understanding of mitochondrial roles as a pathobiological mediator of myeloid malignancies and aging-related clonal hematopoiesis.
    Keywords:  acute myeloid leukemia; aging; clonal hematopoiesis; mitochondrial dynamics; myelodysplastic syndromes
    DOI:  https://doi.org/10.1111/cas.15810
  34. Nat Metab. 2023 Apr 03.
    Triglyceride cycling enables modification of stored fatty acids.
    Klaus Wunderling, Jelena Zurkovic, Fabian Zink, Lars Kuerschner, Christoph Thiele.
      Triglyceride cycling is the process of continuous degradation and re-synthesis of triglyceride in cellular stores. We show in 3T3-L1 adipocytes that triglycerides are subject to rapid turnover and re-arrangement of fatty acids with an estimated half-life of 2-4 h. We develop a tracing technology that can simultaneously and quantitatively follow the metabolism of multiple fatty acids to study the triglyceride futile substrate cycle directly and with molecular species resolution. Our approach is based on alkyne fatty acid tracers and mass spectrometry. The triglyceride cycling is connected to modification of released fatty acids by elongation and desaturation. Through cycling and modification, saturated fatty acids are slowly converted to monounsaturated fatty acids, and linoleic acid to arachidonic acid. We conclude that triglyceride cycling renders stored fatty acids accessible for metabolic alteration. The overall process facilitates cellular adjustments to the stored fatty acid pool to meet changing needs of the cell.
    DOI:  https://doi.org/10.1038/s42255-023-00769-z
  35. Mol Cell. 2023 Apr 01. pii: S1097-2765(23)00203-4. [Epub ahead of print]
    Structural and functional properties of mSWI/SNF chromatin remodeling complexes revealed through single-cell perturbation screens.
    Jordan E Otto, Oana Ursu, Alexander P Wu, Evan B Winter, Michael S Cuoco, Sai Ma, Kristin Qian, Brittany C Michel, Jason D Buenrostro, Bonnie Berger, Aviv Regev, Cigall Kadoch.
      The mammalian SWI/SNF (mSWI/SNF or BAF) family of chromatin remodeling complexes play critical roles in regulating DNA accessibility and gene expression. The three final-form subcomplexes-cBAF, PBAF, and ncBAF-are distinct in biochemical componentry, chromatin targeting, and roles in disease; however, the contributions of their constituent subunits to gene expression remain incompletely defined. Here, we performed Perturb-seq-based CRISPR-Cas9 knockout screens targeting mSWI/SNF subunits individually and in select combinations, followed by single-cell RNA-seq and SHARE-seq. We uncovered complex-, module-, and subunit-specific contributions to distinct regulatory networks and defined paralog subunit relationships and shifted subcomplex functions upon perturbations. Synergistic, intra-complex genetic interactions between subunits reveal functional redundancy and modularity. Importantly, single-cell subunit perturbation signatures mapped across bulk primary human tumor expression profiles both mirror and predict cBAF loss-of-function status in cancer. Our findings highlight the utility of Perturb-seq to dissect disease-relevant gene regulatory impacts of heterogeneous, multi-component master regulatory complexes.
    Keywords:  ATAC-seq; ATP-dependent chromatin remodeling; BAF complex; Perturb-seq; SHARE-Seq; cancer; chromatin accessibility; gene expression; mammalian SWI/SNF complexes; pediatric cancer; rare diseases
    DOI:  https://doi.org/10.1016/j.molcel.2023.03.013
  36. Nat Commun. 2023 Apr 04. 14(1): 1867
    An epigenetic switch controls an alternative NR2F2 isoform that unleashes a metastatic program in melanoma.
    Veronica Davalos, Claudia D Lovell, Richard Von Itter, Igor Dolgalev, Praveen Agrawal, Gillian Baptiste, David J Kahler, Elena Sokolova, Sebastian Moran, Laia Piqué, Eleazar Vega-Saenz de Miera, Barbara Fontanals-Cirera, Alcida Karz, Aristotelis Tsirigos, Chi Yun, Farbod Darvishian, Heather C Etchevers, Iman Osman, Manel Esteller, Markus Schober, Eva Hernando.
      Metastatic melanoma develops once transformed melanocytic cells begin to de-differentiate into migratory and invasive melanoma cells with neural crest cell (NCC)-like and epithelial-to-mesenchymal transition (EMT)-like features. However, it is still unclear how transformed melanocytes assume a metastatic melanoma cell state. Here, we define DNA methylation changes that accompany metastatic progression in melanoma patients and discover Nuclear Receptor Subfamily 2 Group F, Member 2 - isoform 2 (NR2F2-Iso2) as an epigenetically regulated metastasis driver. NR2F2-Iso2 is transcribed from an alternative transcriptional start site (TSS) and it is truncated at the N-terminal end which encodes the NR2F2 DNA-binding domain. We find that NR2F2-Iso2 expression is turned off by DNA methylation when NCCs differentiate into melanocytes. Conversely, this process is reversed during metastatic melanoma progression, when NR2F2-Iso2 becomes increasingly hypomethylated and re-expressed. Our functional and molecular studies suggest that NR2F2-Iso2 drives metastatic melanoma progression by modulating the activity of full-length NR2F2 (Isoform 1) over EMT- and NCC-associated target genes. Our findings indicate that DNA methylation changes play a crucial role during metastatic melanoma progression, and their control of NR2F2 activity allows transformed melanocytes to acquire NCC-like and EMT-like features. This epigenetically regulated transcriptional plasticity facilitates cell state transitions and metastatic spread.
    DOI:  https://doi.org/10.1038/s41467-023-36967-2
  37. Nat Cell Biol. 2023 Apr 06.
    Dynamic antagonism between key repressive pathways maintains the placental epigenome.
    Raha Weigert, Sara Hetzel, Nina Bailly, Chuck Haggerty, Ibrahim A Ilik, Philip Yuk Kwong Yung, Carmen Navarro, Adriano Bolondi, Abhishek Sampath Kumar, Chiara Anania, Björn Brändl, David Meierhofer, Darío G Lupiáñez, Franz-Josef Müller, Tugce Aktas, Simon J Elsässer, Helene Kretzmer, Zachary D Smith, Alexander Meissner.
      DNA and Histone 3 Lysine 27 methylation typically function as repressive modifications and operate within distinct genomic compartments. In mammals, the majority of the genome is kept in a DNA methylated state, whereas the Polycomb repressive complexes regulate the unmethylated CpG-rich promoters of developmental genes. In contrast to this general framework, the extra-embryonic lineages display non-canonical, globally intermediate DNA methylation levels, including disruption of local Polycomb domains. Here, to better understand this unusual landscape's molecular properties, we genetically and chemically perturbed major epigenetic pathways in mouse trophoblast stem cells. We find that the extra-embryonic epigenome reflects ongoing and dynamic de novo methyltransferase recruitment, which is continuously antagonized by Polycomb to maintain intermediate, locally disordered methylation. Despite its disorganized molecular appearance, our data point to a highly controlled equilibrium between counteracting repressors within extra-embryonic cells, one that can seemingly persist indefinitely without bistable features typically seen for embryonic forms of epigenetic regulation.
    DOI:  https://doi.org/10.1038/s41556-023-01114-y
  38. Nat Commun. 2023 Apr 01. 14(1): 1823
    Spatial probabilistic mapping of metabolite ensembles in mass spectrometry imaging.
    Denis Abu Sammour, James L Cairns, Tobias Boskamp, Christian Marsching, Tobias Kessler, Carina Ramallo Guevara, Verena Panitz, Ahmed Sadik, Jonas Cordes, Stefan Schmidt, Shad A Mohammed, Miriam F Rittel, Mirco Friedrich, Michael Platten, Ivo Wolf, Andreas von Deimling, Christiane A Opitz, Wolfgang Wick, Carsten Hopf.
      Mass spectrometry imaging vows to enable simultaneous spatially resolved investigation of hundreds of metabolites in tissues, but it primarily relies on traditional ion images for non-data-driven metabolite visualization and analysis. The rendering and interpretation of ion images neither considers nonlinearities in the resolving power of mass spectrometers nor does it yet evaluate the statistical significance of differential spatial metabolite abundance. Here, we outline the computational framework moleculaR ( https://github.com/CeMOS-Mannheim/moleculaR ) that is expected to improve signal reliability by data-dependent Gaussian-weighting of ion intensities and that introduces probabilistic molecular mapping of statistically significant nonrandom patterns of relative spatial abundance of metabolites-of-interest in tissue. moleculaR also enables cross-tissue statistical comparisons and collective molecular projections of entire biomolecular ensembles followed by their spatial statistical significance evaluation on a single tissue plane. It thereby fosters the spatially resolved investigation of ion milieus, lipid remodeling pathways, or complex scores like the adenylate energy charge within the same image.
    DOI:  https://doi.org/10.1038/s41467-023-37394-z
  39. Cell Rep. 2023 Apr 05. pii: S2211-1247(23)00373-X. [Epub ahead of print]42(4): 112362
    Reciprocal intra- and extra-cellular polarity enables deep mechanosensing through layered matrices.
    Christopher Walter, Jairaj Mathur, Amit Pathak.
      Adherent cells migrate on layered tissue interfaces to drive morphogenesis, wound healing, and tumor invasion. Although stiffer surfaces are known to enhance cell migration, it remains unclear whether cells sense basal stiff environments buried under softer, fibrous matrix. Using layered collagen-polyacrylamide gel systems, we unveil a migration phenotype driven by cell-matrix polarity. Here, cancer (but not normal) cells with stiff base matrix generate stable protrusions, faster migration, and greater collagen deformation because of "depth mechanosensing" through the top collagen layer. Cancer cell protrusions with front-rear polarity produce polarized collagen stiffening and deformations. Disruption of either extracellular or intracellular polarity via collagen crosslinking, laser ablation, or Arp2/3 inhibition independently abrogates depth-mechanosensitive migration of cancer cells. Our experimental findings, validated by lattice-based energy minimization modeling, present a cell migration mechanism whereby polarized cellular protrusions and contractility are reciprocated by mechanical extracellular polarity, culminating in a cell-type-dependent ability to mechanosense through matrix layers.
    Keywords:  CP: Cell biology; atomic force microscopy; cell migration; cell polarity; collagen; depth sensing; extracellular matrix polarity; laser ablation; layered matrix; mechanobiology; mechanosensing
    DOI:  https://doi.org/10.1016/j.celrep.2023.112362
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