bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2024–04–28
sixty papers selected by
Christian Frezza, Universität zu Köln
  1. BCAA-nitrogen flux in brown fat controls metabolic health independent of thermogenesis.
  2. Extracellular domains of CARs reprogramme T cell metabolism without antigen stimulation.
  3. Microbiota metabolism of intestinal amino acids impacts host nutrient homeostasis and physiology.
  4. OMA1-Mediated Mitochondrial Dynamics Balance Organellar Homeostasis Upstream of Cellular Stress Responses.
  5. Epstein-Barr-Virus-Driven Cardiolipin Synthesis Sustains Metabolic Remodeling During B-cell Lymphomagenesis.
  6. Mitochondrial sites of contact with the nucleus.
  7. Sedentary behavior in mice induces metabolic inflexibility by suppressing skeletal muscle pyruvate metabolism.
  8. Single-cell analysis reveals context-dependent, cell-level selection of mtDNA.
  9. Warburg Effect Reshapes Tumor Immunogenicity.
  10. Wild-type IDH2 is a therapeutic target for triple-negative breast cancer.
  11. PGC-1α drives small cell neuroendocrine cancer progression towards an ASCL1-expressing subtype with increased mitochondrial capacity.
  12. Cancer cell metabolism and antitumour immunity.
  13. Food perception promotes phosphorylation of MFFS131 and mitochondrial fragmentation in liver.
  14. SUCLG1 restricts POLRMT succinylation to enhance mitochondrial biogenesis and leukemia progression.
  15. Porphyrin overdrive rewires cancer cell metabolism.
  16. Mitochondria inside acute myeloid leukemia cells hydrolyze ATP to resist chemotherapy.
  17. Regulation of mitochondrial fission by fatty acyl-coenzyme A.
  18. Inflammation and mitophagy are mitochondrial checkpoints to aging.
  19. LPCAT1-mediated membrane phospholipid remodelling promotes ferroptosis evasion and tumour growth.
  20. Functional synergy of a human-specific and an ape-specific metabolic regulator in human neocortex development.
  21. DrugMap: A quantitative pan-cancer analysis of cysteine ligandability.
  22. Revisiting liver metabolism through acetyl-CoA carboxylase inhibition.
  23. Metabolite accumulation from oral NMN supplementation drives aging-specific kidney inflammation.
  24. The beauty of brevity.
  25. Exploratory physiological experiments are not clinical trials.
  26. MAPK-mediated PHGDH induction is essential for melanoma formation and represents an actionable vulnerability.
  27. A glycolytic metabolite that drives BRCA2 haploinsufficiency.
  28. Kidney collecting duct cell type composition is regulated by Notch signaling via modulation of mTORC1.
  29. The Glycolytic Metabolite Methylglyoxal Covalently Inactivates the NLRP3 Inflammasome.
  30. STING promotes homeostatic maintenance of tissues and confers longevity with aging.
  31. Integrative spatial analysis reveals a multi-layered organization of glioblastoma.
  32. Transmissible cancers, the genomes that don't melt down.
  33. Presenting metabolomics analyses: what is in a number?
  34. High clonal diversity and spatial genetic admixture in early prostate cancer and surrounding normal tissue.
  35. Organelle-targeted Laurdans measure heterogeneity in subcellular membranes and their responses to saturated lipid stress.
  36. Tumours form without genetic mutations.
  37. Environmental purines decrease Pseudomonas aeruginosa biofilm formation by disrupting c-di-GMP metabolism.
  38. Disordered clock protein interactions and charge blocks turn an hourglass into a persistent circadian oscillator.
  39. Transient loss of Polycomb components induces an epigenetic cancer fate.
  40. Psychobiological regulation of plasma and saliva GDF15 dynamics in health and mitochondrial diseases.
  41. Educate, not kill: treating cancer without triggering its defenses.
  42. SLC17 transporters mediate renal excretion of Lac-Phe in mice and humans.
  43. PGE2 inhibits TIL expansion by disrupting IL-2 signalling and mitochondrial function.
  44. TNF-α signals through ITK-Akt-mTOR to drive CD4+ T cell metabolic reprogramming, which is dysregulated in rheumatoid arthritis.
  45. Fatty acid binding protein 5 suppression attenuates obesity-induced hepatocellular carcinoma by promoting ferroptosis and intratumoral immune rewiring.
  46. Alanyl-tRNA synthetase, AARS1, is a lactate sensor and lactyltransferase that lactylates p53 and contributes to tumorigenesis.
  47. The G1/S transition in mammalian stem cells in vivo is autonomously regulated by cell size.
  48. Maximum entropy determination of mammalian proteome dynamics.
  49. Mitochondrial Physiology of Cellular Redox Regulations.
  50. Redox Regulation of Mitochondrial Potassium Channels Activity.
  51. Iron biology.
  52. SPTLC3 Is Essential for Complex I Activity and Contributes to Ischemic Cardiomyopathy.
  53. Matrix-assisted laser desorption/ionization mass spectrometry imaging for quorum sensing.
  54. PGE2 limits effector expansion of tumour-infiltrating stem-like CD8+ T cells.
  55. Mitofusin-mediated contacts between mitochondria and peroxisomes regulate mitochondrial fusion.
  56. The γ-glutamyl cycle serves as an amino acids supply system in colorectal cancer organoids under chronic hypoxia.
  57. Classification and functional characterization of regulators of intracellular STING trafficking identified by genome-wide optical pooled screening.
  58. Ergothioneine boosts mitochondrial respiration and exercise performance via direct activation of MPST.
  59. Mitochondrial-dependent oxidative phosphorylation is key for postnatal metabolic adaptation of alveolar macrophages in the lung.
  60. Threonine dehydrogenase regulates neutrophil homeostasis but not H3K4me3 levels in zebrafish.
  1. Cell. 2024 Apr 17. pii: S0092-8674(24)00346-5. [Epub ahead of print]
    BCAA-nitrogen flux in brown fat controls metabolic health independent of thermogenesis.
    Anthony R P Verkerke, Dandan Wang, Naofumi Yoshida, Zachary H Taxin, Xu Shi, Shuning Zheng, Yuka Li, Christopher Auger, Satoshi Oikawa, Jin-Seon Yook, Melia Granath-Panelo, Wentao He, Guo-Fang Zhang, Mami Matsushita, Masayuki Saito, Robert E Gerszten, Evanna L Mills, Alexander S Banks, Yasushi Ishihama, Phillip J White, Robert W McGarrah, Takeshi Yoneshiro, Shingo Kajimura.
      Brown adipose tissue (BAT) is best known for thermogenesis. Rodent studies demonstrated that enhanced BAT thermogenesis is tightly associated with increased energy expenditure, reduced body weight, and improved glucose homeostasis. However, human BAT is protective against type 2 diabetes, independent of body weight. The mechanism underlying this dissociation remains unclear. Here, we report that impaired mitochondrial catabolism of branched-chain amino acids (BCAAs) in BAT, by deleting mitochondrial BCAA carriers (MBCs), caused systemic insulin resistance without affecting energy expenditure and body weight. Brown adipocytes catabolized BCAA in the mitochondria as nitrogen donors for the biosynthesis of non-essential amino acids and glutathione. Impaired mitochondrial BCAA-nitrogen flux in BAT resulted in increased oxidative stress, decreased hepatic insulin signaling, and decreased circulating BCAA-derived metabolites. A high-fat diet attenuated BCAA-nitrogen flux and metabolite synthesis in BAT, whereas cold-activated BAT enhanced the synthesis. This work uncovers a metabolite-mediated pathway through which BAT controls metabolic health beyond thermogenesis.
    Keywords:  amino acid metabolism; bioenergetics; brown adipose tissue; diabetes; glucose homeostasis; insulin resistance; inter-organ communication; mitochondria; thermogenesis
    DOI:  https://doi.org/10.1016/j.cell.2024.03.030
  2. Nat Metab. 2024 Apr 24.
    Extracellular domains of CARs reprogramme T cell metabolism without antigen stimulation.
    Aliya Lakhani, Ximin Chen, Laurence C Chen, Mihe Hong, Mobina Khericha, Yu Chen, Yvonne Y Chen, Junyoung O Park.
      Metabolism is an indispensable part of T cell proliferation, activation and exhaustion, yet the metabolism of chimeric antigen receptor (CAR)-T cells remains incompletely understood. CARs are composed of extracellular domains-often single-chain variable fragments (scFvs)-that determine ligand specificity and intracellular domains that trigger signalling following antigen binding. Here, we show that CARs differing only in the scFv variously reprogramme T cell metabolism. Even without exposure to antigens, some CARs increase proliferation and nutrient uptake in T cells. Using stable isotope tracers and mass spectrometry, we observed basal metabolic fluxes through glycolysis doubling and amino acid uptake overtaking anaplerosis in CAR-T cells harbouring a rituximab scFv, unlike other similar anti-CD20 scFvs. Disparate rituximab and 14G2a-based anti-GD2 CAR-T cells are similarly hypermetabolic and channel excess nutrients to nitrogen overflow metabolism. Modest overflow metabolism of CAR-T cells and metabolic compatibility between cancer cells and CAR-T cells are identified as features of efficacious CAR-T cell therapy.
    DOI:  https://doi.org/10.1038/s42255-024-01034-7
  3. Cell Host Microbe. 2024 Apr 22. pii: S1931-3128(24)00121-5. [Epub ahead of print]
    Microbiota metabolism of intestinal amino acids impacts host nutrient homeostasis and physiology.
    JRI Live Cell Bank Consortium
      The intestine and liver are thought to metabolize dietary nutrients and regulate host nutrient homeostasis. Here, we find that the gut microbiota also reshapes the host amino acid (aa) landscape via efficiently metabolizing intestinal aa. To identify the responsible microbes/genes, we developed a metabolomics-based assay to screen 104 commensals and identified candidates that efficiently utilize aa. Using genetics, we identified multiple responsible metabolic genes in phylogenetically diverse microbes. By colonizing germ-free mice with the wild-type strain and their isogenic mutant deficient in individual aa-metabolizing genes, we found that these genes regulate the availability of gut and circulatory aa. Notably, microbiota genes for branched-chain amino acids (BCAAs) and tryptophan metabolism indirectly affect host glucose homeostasis via peripheral serotonin. Collectively, at single-gene level, this work characterizes a microbiota-encoded metabolic activity that affects host nutrient homeostasis and provides a roadmap to interrogate microbiota-dependent activity to improve human health.
    Keywords:  amino acid metabolism; glucose tolerance; gut microbiota and metabolic genes; human microbiota
    DOI:  https://doi.org/10.1016/j.chom.2024.04.004
  4. Int J Mol Sci. 2024 Apr 22. pii: 4566. [Epub ahead of print]25(8):
    OMA1-Mediated Mitochondrial Dynamics Balance Organellar Homeostasis Upstream of Cellular Stress Responses.
    Robert Gilkerson, Harpreet Kaur, Omar Carrillo, Isaiah Ramos.
      In response to cellular metabolic and signaling cues, the mitochondrial network employs distinct sets of membrane-shaping factors to dynamically modulate organellar structures through a balance of fission and fusion. While these organellar dynamics mediate mitochondrial structure/function homeostasis, they also directly impact critical cell-wide signaling pathways such as apoptosis, autophagy, and the integrated stress response (ISR). Mitochondrial fission is driven by the recruitment of the cytosolic dynamin-related protein-1 (DRP1), while fusion is carried out by mitofusins 1 and 2 (in the outer membrane) and optic atrophy-1 (OPA1) in the inner membrane. This dynamic balance is highly sensitive to cellular stress; when the transmembrane potential across the inner membrane (Δψm) is lost, fusion-active OPA1 is cleaved by the overlapping activity with m-AAA protease-1 (OMA1 metalloprotease, disrupting mitochondrial fusion and leaving dynamin-related protein-1 (DRP1)-mediated fission unopposed, thus causing the collapse of the mitochondrial network to a fragmented state. OMA1 is a unique regulator of stress-sensitive homeostatic mitochondrial balance, acting as a key upstream sensor capable of priming the cell for apoptosis, autophagy, or ISR signaling cascades. Recent evidence indicates that higher-order macromolecular associations within the mitochondrial inner membrane allow these specialized domains to mediate crucial organellar functionalities.
    Keywords:  DRP1; OMA1; OPA1; apoptosis; autophagy; bioenergetics; cristae; fission; fusion; integrated stress response; mitochondria; transmembrane potential
    DOI:  https://doi.org/10.3390/ijms25084566
  5. Res Sq. 2024 Apr 08. pii: rs.3.rs-4013392. [Epub ahead of print]
    Epstein-Barr-Virus-Driven Cardiolipin Synthesis Sustains Metabolic Remodeling During B-cell Lymphomagenesis.
    Haixi You, Larissa Havey, Zhixuan Li, John Asara, Rui Guo.
      Epstein-Barr Virus (EBV) is associated with a range of B-cell malignancies, including Burkitt, Hodgkin, post-transplant, and AIDS-related lymphomas. Studies highlight EBV's transformative capability to induce oncometabolism in B-cells to support energy, biosynthetic precursors, and redox equivalents necessary for transition from quiescent to proliferation. Mitochondrial dysfunction presents an intrinsic barrier to EBV B-cell immortalization. Yet, how EBV maintains B-cell mitochondrial function and metabolic fluxes remains unclear. Here we show that EBV boosts cardiolipin(CL) biosynthesis, essential for mitochondrial cristae biogenesis, via EBNA2-induced CL enzyme transactivation. Pharmaceutical and CRISPR genetic analyses underscore the essentiality of CL biosynthesis in EBV-transformed B-cells. Metabolomic and isotopic tracing highlight CL's role in sustaining respiration, one-carbon metabolism, and aspartate synthesis, all vital for EBV-transformed B-cells. Targeting CL biosynthesis destabilizes mitochondrial one-carbon enzymes, causing synthetic lethality when coupled with a SHMT1/2 inhibitor. We demonstrate EBV-induced CL metabolism as a therapeutic target, offering new strategies against EBV-associated B-cell malignancies.
    DOI:  https://doi.org/10.21203/rs.3.rs-4013392/v1
  6. J Cell Biol. 2024 Jun 03. pii: e202305010. [Epub ahead of print]223(6):
    Mitochondrial sites of contact with the nucleus.
    Michelangelo Campanella, Brindha Kannan.
      Membrane contact sites (MCS) between mitochondria and the nucleus have been recently described. Termed nucleus associated mitochondria (NAM), they prime the expression of genes required for cellular resistance to stressors, thus offering a tethering mechanism for homeostatic communication. Here, we discuss the composition of NAM and their physiological and pathological significance.
    DOI:  https://doi.org/10.1083/jcb.202305010
  7. J Clin Invest. 2024 Apr 23. pii: e167371. [Epub ahead of print]
    Sedentary behavior in mice induces metabolic inflexibility by suppressing skeletal muscle pyruvate metabolism.
    Piyarat Siripoksup, Guoshen Cao, Ahmad A Cluntun, J Alan Maschek, Quentinn Pearce, Marisa J Lang, Mi-Young Jeong, Hiroaki Eshima, Patrick J Ferrara, Precious C Opurum, Ziad S Mahmassani, Alek D Peterlin, Shinya Watanabe, Maureen A Walsh, Eric B Taylor, James E Cox, Micah J Drummond, Jared Rutter, Katsuhiko Funai.
      Carbohydrates and lipids provide the majority of substrates to fuel mitochondrial oxidative phosphorylation (OXPHOS). Metabolic inflexibility, defined as an impaired ability to switch between these fuels, is implicated in a number of metabolic diseases. Here we explore the mechanism by which physical inactivity promotes metabolic inflexibility in skeletal muscle. We developed a mouse model of sedentariness, small mouse cage (SMC) that, unlike other classic models of disuse in mice, faithfully recapitulated metabolic responses that occur in humans. Bioenergetic phenotyping of skeletal muscle mitochondria displayed metabolic inflexibility induced by physical inactivity, demonstrated by a reduction in pyruvate-stimulated respiration (JO2) in absence of a change in palmitate-stimulated JO2. Pyruvate resistance in these mitochondria was likely driven by a decrease in phosphatidylethanolamine (PE) abundance in the mitochondrial membrane. Reduction in mitochondrial PE by heterozygous deletion of phosphatidylserine decarboxylase (PSD) was sufficient to induce metabolic inflexibility measured at the whole-body level, as well as at the level of skeletal muscle mitochondria. Low mitochondrial PE in C2C12 myotubes was sufficient to increase glucose flux towards lactate. We further implicate that resistance to pyruvate metabolism is due to attenuated mitochondrial entry via mitochondrial pyruvate carrier (MPC). These findings suggest a mechanism by which mitochondrial PE directly regulates MPC activity to modulate metabolic flexibility in mice.
    Keywords:  Metabolism; Mitochondria; Skeletal muscle
    DOI:  https://doi.org/10.1172/JCI167371
  8. Nature. 2024 Apr 24.
    Single-cell analysis reveals context-dependent, cell-level selection of mtDNA.
    Anna V Kotrys, Timothy J Durham, Xiaoyan A Guo, Venkata R Vantaku, Sareh Parangi, Vamsi K Mootha.
      Heteroplasmy occurs when wild-type and mutant mitochondrial DNA (mtDNA) molecules co-exist in single cells1. Heteroplasmy levels change dynamically in development, disease and ageing2,3, but it is unclear whether these shifts are caused by selection or drift, and whether they occur at the level of cells or intracellularly. Here we investigate heteroplasmy dynamics in dividing cells by combining precise mtDNA base editing (DdCBE)4 with a new method, SCI-LITE (single-cell combinatorial indexing leveraged to interrogate targeted expression), which tracks single-cell heteroplasmy with ultra-high throughput. We engineered cells to have synonymous or nonsynonymous complex I mtDNA mutations and found that cell populations in standard culture conditions purge nonsynonymous mtDNA variants, whereas synonymous variants are maintained. This suggests that selection dominates over simple drift in shaping population heteroplasmy. We simultaneously tracked single-cell mtDNA heteroplasmy and ancestry, and found that, although the population heteroplasmy shifts, the heteroplasmy of individual cell lineages remains stable, arguing that selection acts at the level of cell fitness in dividing cells. Using these insights, we show that we can force cells to accumulate high levels of truncating complex I mtDNA heteroplasmy by placing them in environments where loss of biochemical complex I activity has been reported to benefit cell fitness. We conclude that in dividing cells, a given nonsynonymous mtDNA heteroplasmy can be harmful, neutral or even beneficial to cell fitness, but that the 'sign' of the effect is wholly dependent on the environment.
    DOI:  https://doi.org/10.1038/s41586-024-07332-0
  9. Cancer Res. 2024 Apr 24.
    Warburg Effect Reshapes Tumor Immunogenicity.
    Jose A Enríquez, María Mittelbrunn.
      Tumor cells rewire their metabolism to fulfill the demands of highly proliferative cells. This changes cellular metabolism to adapt to fuel and oxygen availability for energy production and to increase the synthesis capacity of building blocks for cell division and growth. In addition, the metabolic shift also modulates the immunogenicity of the tumor cells. Recently, Mahmood and colleagues reported a connection between mitochondrial DNA mutations in cancer cells and their response to immunotherapy in a mouse model of melanoma.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-1304
  10. Nat Commun. 2024 Apr 24. 15(1): 3445
    Wild-type IDH2 is a therapeutic target for triple-negative breast cancer.
    Jiang-Jiang Li, Tiantian Yu, Peiting Zeng, Jingyu Tian, Panpan Liu, Shuang Qiao, Shijun Wen, Yumin Hu, Qiao Liu, Wenhua Lu, Hui Zhang, Peng Huang.
      Mutations in isocitrate dehydrogenases (IDH) are oncogenic events due to the generation of oncogenic metabolite 2-hydroxyglutarate. However, the role of wild-type IDH in cancer development remains elusive. Here we show that wild-type IDH2 is highly expressed in triple negative breast cancer (TNBC) cells and promotes their proliferation in vitro and tumor growth in vivo. Genetic silencing or pharmacological inhibition of wt-IDH2 causes a significant increase in α-ketoglutarate (α-KG), indicating a suppression of reductive tricarboxylic acid (TCA) cycle. The aberrant accumulation of α-KG due to IDH2 abrogation inhibits mitochondrial ATP synthesis and promotes HIF-1α degradation, leading to suppression of glycolysis. Such metabolic double-hit results in ATP depletion and suppression of tumor growth, and renders TNBC cells more sensitive to doxorubicin treatment. Our study reveals a metabolic property of TNBC cells with active utilization of glutamine via reductive TCA metabolism, and suggests that wild-type IDH2 plays an important role in this metabolic process and could be a potential therapeutic target for TNBC.
    DOI:  https://doi.org/10.1038/s41467-024-47536-6
  11. bioRxiv. 2024 Apr 13. pii: 2024.04.09.588489. [Epub ahead of print]
    PGC-1α drives small cell neuroendocrine cancer progression towards an ASCL1-expressing subtype with increased mitochondrial capacity.
    Grigor Varuzhanyan, Chia-Chun Chen, Jack Freeland, Tian He, Wendy Tran, Kai Song, Liang Wang, Donghui Cheng, Shili Xu, Gabriella A Dibernardo, Favour N Esedebe, Evan R Abt, Jung Wook Park, Sanaz Memarzadeh, Thomas Graeber, Orian Shirihai, Owen Witte.
      Adenocarcinomas from multiple tissues can converge to treatment-resistant small cell neuroendocrine (SCN) cancers comprised of ASCL1, POU2F3, NEUROD1, and YAP1 subtypes. We investigated how mitochondrial metabolism influences SCN cancer (SCNC) progression. Extensive bioinformatics analyses encompassing thousands of patient tumors and human cancer cell lines uncovered enhanced expression of PGC-1α, a potent regulator of mitochondrial oxidative phosphorylation (OXPHOS), across several SCNC types. PGC-1α correlated tightly with increased expression of the lineage marker ASCL1 through a positive feedback mechanism. Analyses using a human prostate tissue-based SCN transformation system showed that the ASCL1 subtype has heightened PGC-1α expression and OXPHOS activity. PGC-1α inhibition diminished OXPHOS, reduced SCNC cell proliferation, and blocked SCN prostate tumor formation. PGC-1α overexpression enhanced OXPHOS, tripled the SCN prostate tumor formation rate, and promoted commitment to the ASCL1 lineage. These findings reveal the metabolic heterogeneity among SCNC subtypes and identify PGC-1α-induced OXPHOS as a regulator of SCNC lineage plasticity.
    DOI:  https://doi.org/10.1101/2024.04.09.588489
  12. Nat Rev Immunol. 2024 Apr 22.
    Cancer cell metabolism and antitumour immunity.
    Mara De Martino, Jeffrey C Rathmell, Lorenzo Galluzzi, Claire Vanpouille-Box.
      Accumulating evidence suggests that metabolic rewiring in malignant cells supports tumour progression not only by providing cancer cells with increased proliferative potential and an improved ability to adapt to adverse microenvironmental conditions but also by favouring the evasion of natural and therapy-driven antitumour immune responses. Here, we review cancer cell-intrinsic and cancer cell-extrinsic mechanisms through which alterations of metabolism in malignant cells interfere with innate and adaptive immune functions in support of accelerated disease progression. Further, we discuss the potential of targeting such alterations to enhance anticancer immunity for therapeutic purposes.
    DOI:  https://doi.org/10.1038/s41577-024-01026-4
  13. Science. 2024 Apr 26. 384(6694): 438-446
    Food perception promotes phosphorylation of MFFS131 and mitochondrial fragmentation in liver.
    Sinika Henschke, Hendrik Nolte, Judith Magoley, Tatjana Kleele, Claus Brandt, A Christine Hausen, Claudia M Wunderlich, Corinna A Bauder, Philipp Aschauer, Suliana Manley, Thomas Langer, F Thomas Wunderlich, Jens C Brüning.
      Liver mitochondria play a central role in metabolic adaptations to changing nutritional states, yet their dynamic regulation upon anticipated changes in nutrient availability has remained unaddressed. Here, we found that sensory food perception rapidly induced mitochondrial fragmentation in the liver through protein kinase B/AKT (AKT)-dependent phosphorylation of serine 131 of the mitochondrial fission factor (MFFS131). This response was mediated by activation of hypothalamic pro-opiomelanocortin (POMC)-expressing neurons. A nonphosphorylatable MFFS131G knock-in mutation abrogated AKT-induced mitochondrial fragmentation in vitro. In vivo, MFFS131G knock-in mice displayed altered liver mitochondrial dynamics and impaired insulin-stimulated suppression of hepatic glucose production. Thus, rapid activation of a hypothalamus-liver axis can adapt mitochondrial function to anticipated changes of nutritional state in control of hepatic glucose metabolism.
    DOI:  https://doi.org/10.1126/science.adk1005
  14. EMBO J. 2024 Apr 22.
    SUCLG1 restricts POLRMT succinylation to enhance mitochondrial biogenesis and leukemia progression.
    Weiwei Yan, Chengmei Xie, Sijun Sun, Quan Zheng, Jingyi Wang, Zihao Wang, Cheuk-Him Man, Haiyan Wang, Yunfan Yang, Tianshi Wang, Leilei Shi, Shengjie Zhang, Chen Huang, Shuangnian Xu, Yi-Ping Wang.
      Mitochondria are cellular powerhouses that generate energy through the electron transport chain (ETC). The mitochondrial genome (mtDNA) encodes essential ETC proteins in a compartmentalized manner, however, the mechanism underlying metabolic regulation of mtDNA function remains unknown. Here, we report that expression of tricarboxylic acid cycle enzyme succinate-CoA ligase SUCLG1 strongly correlates with ETC genes across various TCGA cancer transcriptomes. Mechanistically, SUCLG1 restricts succinyl-CoA levels to suppress the succinylation of mitochondrial RNA polymerase (POLRMT). Lysine 622 succinylation disrupts the interaction of POLRMT with mtDNA and mitochondrial transcription factors. SUCLG1-mediated POLRMT hyposuccinylation maintains mtDNA transcription, mitochondrial biogenesis, and leukemia cell proliferation. Specifically, leukemia-promoting FMS-like tyrosine kinase 3 (FLT3) mutations modulate nuclear transcription and upregulate SUCLG1 expression to reduce succinyl-CoA and POLRMT succinylation, resulting in enhanced mitobiogenesis. In line, genetic depletion of POLRMT or SUCLG1 significantly delays disease progression in mouse and humanized leukemia models. Importantly, succinyl-CoA level and POLRMT succinylation are downregulated in FLT3-mutated clinical leukemia samples, linking enhanced mitobiogenesis to cancer progression. Together, SUCLG1 connects succinyl-CoA with POLRMT succinylation to modulate mitochondrial function and cancer development.
    Keywords:  FMS-like Tyrosine Kinase 3; Lysine Succinylation; Mitochondrial Biogenesis; Mitochondrial RNA Polymerase; Succinate-CoA Ligase
    DOI:  https://doi.org/10.1038/s44318-024-00101-9
  15. Life Sci Alliance. 2024 Jul;pii: e202302547. [Epub ahead of print]7(7):
    Porphyrin overdrive rewires cancer cell metabolism.
    Swamy R Adapa, Gregory A Hunter, Narmin E Amin, Christopher Marinescu, Andrew Borsky, Elizabeth M Sagatys, Said M Sebti, Gary W Reuther, Gloria C Ferreira, Rays Hy Jiang.
      All cancer cells reprogram metabolism to support aberrant growth. Here, we report that cancer cells employ and depend on imbalanced and dynamic heme metabolic pathways, to accumulate heme intermediates, that is, porphyrins. We coined this essential metabolic rewiring "porphyrin overdrive" and determined that it is cancer-essential and cancer-specific. Among the major drivers are genes encoding mid-step enzymes governing the production of heme intermediates. CRISPR/Cas9 editing to engineer leukemia cell lines with impaired heme biosynthetic steps confirmed our whole-genome data analyses that porphyrin overdrive is linked to oncogenic states and cellular differentiation. Although porphyrin overdrive is absent in differentiated cells or somatic stem cells, it is present in patient-derived tumor progenitor cells, demonstrated by single-cell RNAseq, and in early embryogenesis. In conclusion, we identified a dependence of cancer cells on non-homeostatic heme metabolism, and we targeted this cancer metabolic vulnerability with a novel "bait-and-kill" strategy to eradicate malignant cells.
    DOI:  https://doi.org/10.26508/lsa.202302547
  16. bioRxiv. 2024 Apr 15. pii: 2024.04.12.589110. [Epub ahead of print]
    Mitochondria inside acute myeloid leukemia cells hydrolyze ATP to resist chemotherapy.
    James T Hagen, Mclane M Montgomery, Raphael T Aruleba, Brett R Chrest, Thomas D Green, Miki Kassai, Tonya N Zeczycki, Cameron A Schmidt, Debajit Bhowmick, Su-Fern Tan, David J Feith, Charles E Chalfant, Thomas P Loughran, Darla Liles, Mark D Minden, Aaron D Schimmer, Myles C Cabot, Joseph M Mclung, Kelsey H Fisher-Wellman.
      Despite early optimism, therapeutics targeting oxidative phosphorylation (OxPhos) have faced clinical setbacks, stemming from their inability to distinguish healthy from cancerous mitochondria. Herein, we describe an actionable bioenergetic mechanism unique to cancerous mitochondria inside acute myeloid leukemia (AML) cells. Unlike healthy cells which couple respiration to the synthesis of ATP, AML mitochondria were discovered to support inner membrane polarization by consuming ATP. Because matrix ATP consumption allows cells to survive bioenergetic stress, we hypothesized that AML cells may resist cell death induced by OxPhos damaging chemotherapy by reversing the ATP synthase reaction. In support of this, targeted inhibition of BCL-2 with venetoclax abolished OxPhos flux without impacting mitochondrial membrane potential. In surviving AML cells, sustained polarization of the mitochondrial inner membrane was dependent on matrix ATP consumption. Mitochondrial ATP consumption was further enhanced in AML cells made refractory to venetoclax, consequential to downregulations in both the proton-pumping respiratory complexes, as well as the endogenous F 1 -ATPase inhibitor ATP5IF1 . In treatment-naive AML, ATP5IF1 knockdown was sufficient to drive venetoclax resistance, while ATP5IF1 overexpression impaired F 1 -ATPase activity and heightened sensitivity to venetoclax. Collectively, our data identify matrix ATP consumption as a cancer-cell intrinsic bioenergetic vulnerability actionable in the context of mitochondrial damaging chemotherapy.
    DOI:  https://doi.org/10.1101/2024.04.12.589110
  17. Nat Cell Biol. 2024 Apr 23.
    Regulation of mitochondrial fission by fatty acyl-coenzyme A.
      
    DOI:  https://doi.org/10.1038/s41556-024-01406-x
  18. Nat Commun. 2024 Apr 20. 15(1): 3375
    Inflammation and mitophagy are mitochondrial checkpoints to aging.
    Emma Guilbaud, Kristopher A Sarosiek, Lorenzo Galluzzi.
      
    DOI:  https://doi.org/10.1038/s41467-024-47840-1
  19. Nat Cell Biol. 2024 Apr 26.
    LPCAT1-mediated membrane phospholipid remodelling promotes ferroptosis evasion and tumour growth.
    Ziwen Li, Yameng Hu, Haiqing Zheng, Man Li, Yuanji Liu, Rongni Feng, Xincheng Li, Shuxia Zhang, Miaoling Tang, Meisongzhu Yang, Ruyuan Yu, Yingru Xu, Xinyi Liao, Suwen Chen, Wanying Qian, Qiliang Zhang, Daolin Tang, Bo Li, Libing Song, Jun Li.
      The mechanisms underlying the dynamic remodelling of cellular membrane phospholipids to prevent phospholipid peroxidation-induced membrane damage and evade ferroptosis, a non-apoptotic form of cell death driven by iron-dependent lipid peroxidation, remain poorly understood. Here we show that lysophosphatidylcholine acyltransferase 1 (LPCAT1) plays a critical role in ferroptosis resistance by increasing membrane phospholipid saturation via the Lands cycle, thereby reducing membrane levels of polyunsaturated fatty acids, protecting cells from phospholipid peroxidation-induced membrane damage and inhibiting ferroptosis. Furthermore, the enhanced in vivo tumour-forming capability of tumour cells is closely associated with the upregulation of LPCAT1 and emergence of a ferroptosis-resistant state. Combining LPCAT1 inhibition with a ferroptosis inducer synergistically triggers ferroptosis and suppresses tumour growth. Therefore, our results unveil a plausible role for LPCAT1 in evading ferroptosis and suggest it as a promising target for clinical intervention in human cancer.
    DOI:  https://doi.org/10.1038/s41556-024-01405-y
  20. Nat Commun. 2024 Apr 24. 15(1): 3468
    Functional synergy of a human-specific and an ape-specific metabolic regulator in human neocortex development.
    Lei Xing, Vasiliki Gkini, Anni I Nieminen, Hui-Chao Zhou, Matilde Aquilino, Ronald Naumann, Katrin Reppe, Kohichi Tanaka, Peter Carmeliet, Oskari Heikinheimo, Svante Pääbo, Wieland B Huttner, Takashi Namba.
      Metabolism has recently emerged as a major target of genes implicated in the evolutionary expansion of human neocortex. One such gene is the human-specific gene ARHGAP11B. During human neocortex development, ARHGAP11B increases the abundance of basal radial glia, key progenitors for neocortex expansion, by stimulating glutaminolysis (glutamine-to-glutamate-to-alpha-ketoglutarate) in mitochondria. Here we show that the ape-specific protein GLUD2 (glutamate dehydrogenase 2), which also operates in mitochondria and converts glutamate-to-αKG, enhances ARHGAP11B's ability to increase basal radial glia abundance. ARHGAP11B + GLUD2 double-transgenic bRG show increased production of aspartate, a metabolite essential for cell proliferation, from glutamate via alpha-ketoglutarate and the TCA cycle. Hence, during human evolution, a human-specific gene exploited the existence of another gene that emerged during ape evolution, to increase, via concerted changes in metabolism, progenitor abundance and neocortex size.
    DOI:  https://doi.org/10.1038/s41467-024-47437-8
  21. Cell. 2024 Apr 17. pii: S0092-8674(24)00318-0. [Epub ahead of print]
    DrugMap: A quantitative pan-cancer analysis of cysteine ligandability.
    Mariko Takahashi, Harrison B Chong, Siwen Zhang, Tzu-Yi Yang, Matthew J Lazarov, Stefan Harry, Michelle Maynard, Brendan Hilbert, Ryan D White, Heather E Murrey, Chih-Chiang Tsou, Kira Vordermark, Jonathan Assaad, Magdy Gohar, Benedikt R Dürr, Marianne Richter, Himani Patel, Gregory Kryukov, Natasja Brooijmans, Aliyu Sidi Omar Alghali, Karla Rubio, Antonio Villanueva, Junbing Zhang, Maolin Ge, Farah Makram, Hanna Griesshaber, Drew Harrison, Ann-Sophie Koglin, Samuel Ojeda, Barbara Karakyriakou, Alexander Healy, George Popoola, Inbal Rachmin, Neha Khandelwal, Jason R Neil, Pei-Chieh Tien, Nicholas Chen, Tobias Hosp, Sanne van den Ouweland, Toshiro Hara, Lillian Bussema, Rui Dong, Lei Shi, Martin Q Rasmussen, Ana Carolina Domingues, Aleigha Lawless, Jacy Fang, Satoshi Yoda, Linh Phuong Nguyen, Sarah Marie Reeves, Farrah Nicole Wakefield, Adam Acker, Sarah Elizabeth Clark, Taronish Dubash, John Kastanos, Eugene Oh, David E Fisher, Shyamala Maheswaran, Daniel A Haber, Genevieve M Boland, Moshe Sade-Feldman, Russell W Jenkins, Aaron N Hata, Nabeel M Bardeesy, Mario L Suvà, Brent R Martin, Brian B Liau, Christopher J Ott, Miguel N Rivera, Michael S Lawrence, Liron Bar-Peled.
      Cysteine-focused chemical proteomic platforms have accelerated the clinical development of covalent inhibitors for a wide range of targets in cancer. However, how different oncogenic contexts influence cysteine targeting remains unknown. To address this question, we have developed "DrugMap," an atlas of cysteine ligandability compiled across 416 cancer cell lines. We unexpectedly find that cysteine ligandability varies across cancer cell lines, and we attribute this to differences in cellular redox states, protein conformational changes, and genetic mutations. Leveraging these findings, we identify actionable cysteines in NF-κB1 and SOX10 and develop corresponding covalent ligands that block the activity of these transcription factors. We demonstrate that the NF-κB1 probe blocks DNA binding, whereas the SOX10 ligand increases SOX10-SOX10 interactions and disrupts melanoma transcriptional signaling. Our findings reveal heterogeneity in cysteine ligandability across cancers, pinpoint cell-intrinsic features driving cysteine targeting, and illustrate the use of covalent probes to disrupt oncogenic transcription-factor activity.
    Keywords:  chemical proteomics; covalent inhibitors; cysteine ligandability; transcription factors
    DOI:  https://doi.org/10.1016/j.cell.2024.03.027
  22. Trends Endocrinol Metab. 2024 Apr 24. pii: S1043-2760(24)00093-6. [Epub ahead of print]
    Revisiting liver metabolism through acetyl-CoA carboxylase inhibition.
    Armando Jesús Pérez-Díaz, María Ángeles Núñez-Sánchez, Bruno Ramos-Molina.
      Liver-targeted acetyl-coenzyme A (CoA) carboxylase (ACC) inhibitors in metabolic dysfunction-associated steatotic liver disease (MASLD) trials reveal notable secondary effects: hypertriglyceridemia and altered glucose metabolism, paradoxically with reduced hepatic steatosis. In their study, Deja et al. explored how hepatic ACC influences metabolism using different pharmacological and genetic methods, coupled with targeted metabolomics and stable isotope-based tracing techniques.
    Keywords:  acetyl-CoA carboxylase; autophagy; lipogenesis; liver metabolism; malonyl-CoA
    DOI:  https://doi.org/10.1016/j.tem.2024.04.010
  23. bioRxiv. 2024 Apr 13. pii: 2024.04.09.588624. [Epub ahead of print]
    Metabolite accumulation from oral NMN supplementation drives aging-specific kidney inflammation.
    Tara A Saleh, Jeremy Whitson, Phoebe Keiser, Praveena Prasad, Brenita C Jenkins, Tori Sodeinde, Carolyn N Mann, Peter S Rabinovitch, Melanie R McReynolds, Mariya T Sweetwyne.
      The mitochondrial-rich renal tubule cells are key regulators of blood homeostasis via excretion and reabsorption of metabolic waste. With age, tubules are subject to increasing mitochondrial dysfunction and declining nicotinamide adenine dinucleotide (NAD+) levels, both hampering ATP production efficiency. We tested two mitochondrial interventions in young (6-mo) and aged (26-mo) adult male mice: elamipretide (ELAM), a tetrapeptide in clinical trials that improves mitochondrial structure and function, and nicotinamide mononucleotide (NMN), an NAD+ intermediate and commercially available oral supplement. Kidneys were analyzed from young and aged mice after eight weeks of treatment with ELAM (3 mg/kg/day), NMN (300 mg/kg/day), or from aged mice treated with the two interventions combined (ELAM+NMN). We hypothesized that combining pharmacologic treatments to ameliorate mitochondrial dysfunction and boost NAD+ levels, would more effectively reduce kidney aging than either intervention alone. Unexpectedly, in aged kidneys, NMN increased expression of genetic markers of inflammation (IL-1β and Ccl2) and tubule injury (Kim-1). Metabolomics of endpoint sera showed that NMN-treated aged mice had higher circulating levels of uremic toxins than either aged controls or young NMN-treated mice. ELAM+NMN-treated aged mice accumulated uremic toxins like NMN-only aged mice, but reduced IL-1β and Ccl2 kidney mRNA. This suggests that pre-existing mitochondrial dysfunction in aged kidney underlies susceptibility to inflammatory signaling with NMN supplementation in aged, but not young, mice. These findings demonstrate age and tissue dependent effects on downstream metabolic accumulation from NMN and highlight the need for targeted analysis of aged kidneys to assess the safety of anti-aging supplements in older populations.
    Keywords:  elamipretide; inflammation; kidney; metabolites; nicotinamide mononucleotide
    DOI:  https://doi.org/10.1101/2024.04.09.588624
  24. Nat Metab. 2024 Apr;6(4): 599
    The beauty of brevity.
      
    DOI:  https://doi.org/10.1038/s42255-024-01048-1
  25. Cell Metab. 2024 Apr 16. pii: S1550-4131(24)00125-6. [Epub ahead of print]
    Exploratory physiological experiments are not clinical trials.
    Erik A Richter, David E James, John P Kirwan, Juleen R Zierath.
      
    DOI:  https://doi.org/10.1016/j.cmet.2024.04.005
  26. bioRxiv. 2024 Apr 15. pii: 2024.04.11.589139. [Epub ahead of print]
    MAPK-mediated PHGDH induction is essential for melanoma formation and represents an actionable vulnerability.
    Neel Jasani, Xiaonan Xu, Benjamin Posorske, Yumi Kim, Olga Vera, Kenneth Y Tsai, Gina M DeNicola, Florian A Karreth.
      Overexpression of PHGDH, the rate-limiting enzyme in the serine synthesis pathway, promotes melanomagenesis, melanoma cell proliferation, and survival of metastases in serine-low environments such as the brain. While PHGDH amplification explains PHGDH overexpression in a subset of melanomas, we find that PHGDH levels are universally increased in melanoma cells due to oncogenic BRAF V600E promoting PHGDH transcription through mTORC1-mediated translation of ATF4. Importantly, PHGDH expression was critical for melanomagenesis as depletion of PHGDH in genetic mouse models blocked melanoma formation. Despite BRAF V600E - mediated upregulation, PHGDH was further induced by exogenous serine restriction. Surprisingly, BRAF V600E inhibition diminished serine restriction-mediated PHGDH expression by preventing ATF4 induction, creating a potential vulnerability whereby melanoma cells could be specifically starved of serine by combining BRAF V600E inhibition with exogenous serine restriction. Indeed, we show that this combination promoted cell death in vitro and attenuated melanoma growth in vivo. This study identified a melanoma cell-specific PHGDH-dependent vulnerability.
    DOI:  https://doi.org/10.1101/2024.04.11.589139
  27. Cell. 2024 Apr 25. pii: S0092-8674(24)00319-2. [Epub ahead of print]187(9): 2124-2126
    A glycolytic metabolite that drives BRCA2 haploinsufficiency.
    Peng Jiang.
      Many types of tumor cells alter metabolic pathways to meet their energy and biosynthetic demands for proliferation or stress adaptation. In this issue of Cell, Kong et al. find that the glycolytic metabolite methylglyoxal causes cancer-associated mutant single-base substitution features by inducing BRCA2 proteolysis, leading to functional haploinsufficiency of BRCA2.
    DOI:  https://doi.org/10.1016/j.cell.2024.03.028
  28. bioRxiv. 2024 Apr 09. pii: 2024.04.09.587573. [Epub ahead of print]
    Kidney collecting duct cell type composition is regulated by Notch signaling via modulation of mTORC1.
    Jennifer deRiso, Malini Mukherjee, Madhusudhana Janga, Alicia Simmons, Michael Kareta, Jianning Tao, Indra Chandrasekar, Kameswaran Surendran.
      The plasticity and diversity of cell types with specialized functions likely defines the capacity of multicellular organisms to adapt to physiologic stressors. The kidney collecting ducts contribute to water, electrolyte, and pH homeostasis and are composed of mature intermingled epithelial cell types that are susceptible to transdifferentiate. The conversion of kidney collecting duct principal cells to intercalated cells is actively inhibited by Notch signaling to ensure urine concentrating capability. Here we identify Hes1, a target of Notch signaling, allows for maintenance of functionally distinct epithelial cell types within the same microenvironment by regulating mechanistic target of rapamycin complex 1 (mTORC1) activity. Hes1 directly represses the expression of insulin receptor substrate 1 ( Irs1 ), an upstream component of mTOR pathway and suppresses mTORC1 activity in principal cells. Genetic inactivation of tuberous sclerosis complex 2 ( Tsc2 ) to increase mTORC1 activity in mature principal cells is sufficient to promote acquisition of intercalated cell properties, while inhibition of mTORC1 in adult kidney epithelia suppresses intercalated cell properties. Considering that mTORC1 integrates environmental cues, the linkage of functionally distinct epithelial cell types to mTORC1 activity levels likely allows for cell plasticity to be regulated by physiologic and metabolic signals and the ability to sense/transduce these signals.
    DOI:  https://doi.org/10.1101/2024.04.09.587573
  29. bioRxiv. 2024 Apr 20. pii: 2024.04.19.589802. [Epub ahead of print]
    The Glycolytic Metabolite Methylglyoxal Covalently Inactivates the NLRP3 Inflammasome.
    Caroline Stanton, Chavin Buasakdi, Jie Sun, Ian Levitan, Prerona Bora, Sergei Kutseikin, R Luke Wiseman, Michael J Bollong.
      The NLRP3 inflammasome promotes inflammation in disease, yet the full repertoire of mechanisms regulating its activity are not well delineated. Among established regulatory mechanisms, covalent modification of NLRP3 has emerged as a common route for pharmacological inactivation of this protein. Here, we show that inhibition of the glycolytic enzyme PGK1 results in the accumulation of methylglyoxal, a reactive metabolite whose increased levels decrease NLRP3 assembly and inflammatory signaling in cells. We find that methylglyoxal inactivates NLRP3 via a non-enzymatic, covalent crosslinking-based mechanism, promoting inter- and intra-protein MICA posttranslational linkages within NLRP3. This work establishes NLRP3 as capable of sensing a host of electrophilic chemicals, both exogenous small molecules and endogenous reactive metabolites, and suggests a mechanism by which glycolytic flux can moderate the activation status of a central inflammatory signaling pathway.
    DOI:  https://doi.org/10.1101/2024.04.19.589802
  30. bioRxiv. 2024 Apr 08. pii: 2024.04.04.588107. [Epub ahead of print]
    STING promotes homeostatic maintenance of tissues and confers longevity with aging.
    Jacob W Hopkins, Katherine B Sulka, Machlan Sawden, Kimberly A Carroll, Ronald D Brown, Stephen C Bunnell, Alexander Poltorak, Albert Tai, Eric R Reed, Shruti Sharma.
      Local immune processes within aging tissues are a significant driver of aging associated dysfunction, but tissue-autonomous pathways and cell types that modulate these responses remain poorly characterized. The cytosolic DNA sensing pathway, acting through cyclic GMP-AMP synthase (cGAS) and Stimulator of Interferon Genes (STING), is broadly expressed in tissues, and is poised to regulate local type I interferon (IFN-I)-dependent and independent inflammatory processes within tissues. Recent studies suggest that the cGAS/STING pathway may drive pathology in various in vitro and in vivo models of accelerated aging. To date, however, the role of the cGAS/STING pathway in physiological aging processes, in the absence of genetic drivers, has remained unexplored. This remains a relevant gap, as STING is ubiquitously expressed, implicated in multitudinous disorders, and loss of function polymorphisms of STING are highly prevalent in the human population (>50%). Here we reveal that, during physiological aging, STING-deficiency leads to a significant shortening of murine lifespan, increased pro-inflammatory serum cytokines and tissue infiltrates, as well as salient changes in histological composition and organization. We note that aging hearts, livers, and kidneys express distinct subsets of inflammatory, interferon-stimulated gene (ISG), and senescence genes, collectively comprising an immune fingerprint for each tissue. These distinctive patterns are largely imprinted by tissue-specific stromal and myeloid cells. Using cellular interaction network analyses, immunofluorescence, and histopathology data, we show that these immune fingerprints shape the tissue architecture and the landscape of cell-cell interactions in aging tissues. These age-associated immune fingerprints are grossly dysregulated with STING-deficiency, with key genes that define aging STING- sufficient tissues greatly diminished in the absence of STING. Changes in immune signatures are concomitant with a restructuring of the stromal and myeloid fractions, whereby cell:cell interactions are grossly altered and resulting in disorganization of tissue architecture in STING-deficient organs. This altered homeostasis in aging STING-deficient tissues is associated with a cross-tissue loss of homeostatic tissue-resident macrophage (TRM) populations in these tissues. Ex vivo analyses reveal that basal STING- signaling limits the susceptibility of TRMs to death-inducing stimuli and determines their in situ localization in tissue niches, thereby promoting tissue homeostasis. Collectively, these data upend the paradigm that cGAS/STING signaling is primarily pathological in aging and instead indicate that basal STING signaling sustains tissue function and supports organismal longevity. Critically, our study urges caution in the indiscriminate targeting of these pathways, which may result in unpredictable and pathological consequences for health during aging.
    HIGHLIGHTS: Aging tissues are associated with tissue-autonomous immune fingerprints, primarily driven by interactions of tissue stromal and myeloid populations. STING shapes these immune fingerprints of aging tissues in unexpected ways.Loss of STING alters the location, numbers, and viability of tissue resident macrophages.STING signaling is critical for longer lifespans and maintenance of tissue architecture.
    DOI:  https://doi.org/10.1101/2024.04.04.588107
  31. Cell. 2024 Apr 16. pii: S0092-8674(24)00320-9. [Epub ahead of print]
    Integrative spatial analysis reveals a multi-layered organization of glioblastoma.
    Alissa C Greenwald, Noam Galili Darnell, Rouven Hoefflin, Dor Simkin, Christopher W Mount, L Nicolas Gonzalez Castro, Yotam Harnik, Sydney Dumont, Dana Hirsch, Masashi Nomura, Tom Talpir, Merav Kedmi, Inna Goliand, Gioele Medici, Julie Laffy, Baoguo Li, Vamsi Mangena, Hadas Keren-Shaul, Michael Weller, Yoseph Addadi, Marian C Neidert, Mario L Suvà, Itay Tirosh.
      Glioma contains malignant cells in diverse states. Here, we combine spatial transcriptomics, spatial proteomics, and computational approaches to define glioma cellular states and uncover their organization. We find three prominent modes of organization. First, gliomas are composed of small local environments, each typically enriched with one major cellular state. Second, specific pairs of states preferentially reside in proximity across multiple scales. This pairing of states is consistent across tumors. Third, these pairwise interactions collectively define a global architecture composed of five layers. Hypoxia appears to drive the layers, as it is associated with a long-range organization that includes all cancer cell states. Accordingly, tumor regions distant from any hypoxic/necrotic foci and tumors that lack hypoxia such as low-grade IDH-mutant glioma are less organized. In summary, we provide a conceptual framework for the organization of cellular states in glioma, highlighting hypoxia as a long-range tissue organizer.
    Keywords:  glioblastoma; glioma; hypoxia; intratumor heterogeneity; spatial proteomics; spatial transcriptomics
    DOI:  https://doi.org/10.1016/j.cell.2024.03.029
  32. Evolution. 2024 Apr 24. pii: qpae063. [Epub ahead of print]
    Transmissible cancers, the genomes that don't melt down.
    Georgina Bramwell, James DeGregori, Frédéric Thomas, Beata Ujvari.
      Evolutionary theory predicts that accumulation of deleterious mutations in asexually reproducing organisms should lead to genomic decay. Clonally reproducing cell lines, i.e., transmissible cancers, when cells are transmitted as allografts/xenografts, break these rules, and survive for centuries and millennia. The currently known 11 transmissible cancer lineages occur in dogs (Canine Venereal Tumour Disease, CTVT), in Tasmanian devils (Devil Facial Tumour Diseases, DFT 1 and DFT2) and in bivalves (bivalve transmissible neoplasia, BTN). Despite the mutation loads of these cell lines being much higher than observed in human cancers, they have not been eliminated in space and time. Here we provide potential explanations how these fascinating cell lines may have overcome the fitness decline due to the progressive accumulation of deleterious mutations and propose that the high mutation load may carry an indirect positive fitness outcome. We offer ideas on how these host-pathogen systems could be used to answer outstanding questions in evolutionary biology. The recent studies on the evolution of these clonal pathogens reveal key mechanistic insight into transmissible cancer genomes, information that is essential for future studies investigating how these contagious cancer cell lines can repeatedly evade immune recognition, evolve, and survive in the landscape of highly diverse hosts.
    Keywords:  Muller’s ratchet; coevolution; competition; cooperation; mutation load
    DOI:  https://doi.org/10.1093/evolut/qpae063
  33. EMBO J. 2024 Apr 25.
    Presenting metabolomics analyses: what is in a number?
    Johannes Meiser, Christian Frezza.
      
    DOI:  https://doi.org/10.1038/s44318-024-00098-1
  34. Nat Commun. 2024 Apr 24. 15(1): 3475
    High clonal diversity and spatial genetic admixture in early prostate cancer and surrounding normal tissue.
    Ning Zhang, Luuk Harbers, Michele Simonetti, Constantin Diekmann, Quentin Verron, Enrico Berrino, Sara E Bellomo, Gabriel M C Longo, Michael Ratz, Niklas Schultz, Firas Tarish, Peng Su, Bo Han, Wanzhong Wang, Sofia Onorato, Dora Grassini, Roberto Ballarino, Silvia Giordano, Qifeng Yang, Anna Sapino, Jonas Frisén, Kanar Alkass, Henrik Druid, Vassilis Roukos, Thomas Helleday, Caterina Marchiò, Magda Bienko, Nicola Crosetto.
      Somatic copy number alterations (SCNAs) are pervasive in advanced human cancers, but their prevalence and spatial distribution in early-stage, localized tumors and their surrounding normal tissues are poorly characterized. Here, we perform multi-region, single-cell DNA sequencing to characterize the SCNA landscape across tumor-rich and normal tissue in two male patients with localized prostate cancer. We identify two distinct karyotypes: 'pseudo-diploid' cells harboring few SCNAs and highly aneuploid cells. Pseudo-diploid cells form numerous small-sized subclones ranging from highly spatially localized to broadly spread subclones. In contrast, aneuploid cells do not form subclones and are detected throughout the prostate, including normal tissue regions. Highly localized pseudo-diploid subclones are confined within tumor-rich regions and carry deletions in multiple tumor-suppressor genes. Our study reveals that SCNAs are widespread in normal and tumor regions across the prostate in localized prostate cancer patients and suggests that a subset of pseudo-diploid cells drive tumorigenesis in the aging prostate.
    DOI:  https://doi.org/10.1038/s41467-024-47664-z
  35. bioRxiv. 2024 Apr 20. pii: 2024.04.16.589828. [Epub ahead of print]
    Organelle-targeted Laurdans measure heterogeneity in subcellular membranes and their responses to saturated lipid stress.
    Adrian M Wong, Itay Budin.
      Cell organelles feature characteristic lipid compositions that lead to differences in membrane properties. In living cells, membrane ordering and fluidity are commonly measured using the solvatochromic dye Laurdan, whose fluorescence is sensitive to membrane packing. As a general lipophilic dye, Laurdan stains all hydrophobic environments in cells, so it is challenging to characterize membrane properties in specific organelles or assess their responses to pharmacological treatments in intact cells. Here, we describe the synthesis and application of Laurdan-derived probes that read out membrane packing of individual cellular organelles. The set of Organelle-targeted Laurdans (OTL) localizes to the ER, mitochondria, lysosomes and Golgi compartments with high specificity, while retaining the spectral resolution needed to detect biological changes in membrane packing. We show that ratiometric imaging with OTL can resolve membrane heterogeneity within organelles, as well as changes in membrane packing resulting from inhibition of lipid trafficking or bioenergetic processes. We apply these probes to characterize organelle-specific responses to saturated lipid stress. While ER and lysosomal membrane fluidity is sensitive to exogenous saturated fatty acids, that of mitochondrial membranes is protected. We then use differences in ER membrane fluidity to sort populations of cells based on their fatty acid diet, highlighting the ability of organelle-localized solvatochromic probes to distinguish between cells based on their metabolic state. These results expand the repertoire of targeted membrane probes and demonstrate their application to interrogating lipid dysregulation.
    DOI:  https://doi.org/10.1101/2024.04.16.589828
  36. Nature. 2024 Apr 24.
    Tumours form without genetic mutations.
    Anne-Kathrin Classen.
      
    Keywords:  Cancer; Epigenetics; Molecular biology
    DOI:  https://doi.org/10.1038/d41586-024-01019-2
  37. Cell Rep. 2024 Apr 25. pii: S2211-1247(24)00482-0. [Epub ahead of print]43(5): 114154
    Environmental purines decrease Pseudomonas aeruginosa biofilm formation by disrupting c-di-GMP metabolism.
    Corey Kennelly, Peter Tran, Arthur Prindle.
      Cyclic di-guanosine monophosphate (c-di-GMP) is a bacterial second messenger that governs the lifestyle switch between planktonic and biofilm states. While substantial investigation has focused on the proteins that produce and degrade c-di-GMP, less attention has been paid to the potential for metabolic control of c-di-GMP signaling. Here, we show that micromolar levels of specific environmental purines unexpectedly decrease c-di-GMP and biofilm formation in Pseudomonas aeruginosa. Using a fluorescent genetic reporter, we show that adenosine and inosine decrease c-di-GMP even when competing purines are present. We confirm genetically that purine salvage is required for c-di-GMP decrease. Furthermore, we find that (p)ppGpp prevents xanthosine and guanosine from producing an opposing c-di-GMP increase, reinforcing a salvage hierarchy that favors c-di-GMP decrease even at the expense of growth. We propose that purines can act as a cue for bacteria to shift their lifestyle away from the recalcitrant biofilm state via upstream metabolic control of c-di-GMP signaling.
    Keywords:  CP: Microbiology; Pseudomonas aeruginosa; bacteria; biofilms; c-di-GMP; microbiology; nucleotide signaling; purines
    DOI:  https://doi.org/10.1016/j.celrep.2024.114154
  38. Nat Commun. 2024 Apr 25. 15(1): 3523
    Disordered clock protein interactions and charge blocks turn an hourglass into a persistent circadian oscillator.
    Meaghan S Jankowski, Daniel Griffith, Divya G Shastry, Jacqueline F Pelham, Garrett M Ginell, Joshua Thomas, Pankaj Karande, Alex S Holehouse, Jennifer M Hurley.
      Organismal physiology is widely regulated by the molecular circadian clock, a feedback loop composed of protein complexes whose members are enriched in intrinsically disordered regions. These regions can mediate protein-protein interactions via SLiMs, but the contribution of these disordered regions to clock protein interactions had not been elucidated. To determine the functionality of these disordered regions, we applied a synthetic peptide microarray approach to the disordered clock protein FRQ in Neurospora crassa. We identified residues required for FRQ's interaction with its partner protein FRH, the mutation of which demonstrated FRH is necessary for persistent clock oscillations but not repression of transcriptional activity. Additionally, the microarray demonstrated an enrichment of FRH binding to FRQ peptides with a net positive charge. We found that positively charged residues occurred in significant "blocks" within the amino acid sequence of FRQ and that ablation of one of these blocks affected both core clock timing and physiological clock output. Finally, we found positive charge clusters were a commonly shared molecular feature in repressive circadian clock proteins. Overall, our study suggests a mechanistic purpose for positive charge blocks and yielded insights into repressive arm protein roles in clock function.
    DOI:  https://doi.org/10.1038/s41467-024-47761-z
  39. Nature. 2024 Apr 24.
    Transient loss of Polycomb components induces an epigenetic cancer fate.
    V Parreno, V Loubiere, B Schuettengruber, L Fritsch, C C Rawal, M Erokhin, B Győrffy, D Normanno, M Di Stefano, J Moreaux, N L Butova, I Chiolo, D Chetverina, A-M Martinez, G Cavalli.
      Although cancer initiation and progression are generally associated with the accumulation of somatic mutations1,2, substantial epigenomic alterations underlie many aspects of tumorigenesis and cancer susceptibility3-6, suggesting that genetic mechanisms might not be the only drivers of malignant transformation7. However, whether purely non-genetic mechanisms are sufficient to initiate tumorigenesis irrespective of mutations has been unknown. Here, we show that a transient perturbation of transcriptional silencing mediated by Polycomb group proteins is sufficient to induce an irreversible switch to a cancer cell fate in Drosophila. This is linked to the irreversible derepression of genes that can drive tumorigenesis, including members of the JAK-STAT signalling pathway and zfh1, the fly homologue of the ZEB1 oncogene, whose aberrant activation is required for Polycomb perturbation-induced tumorigenesis. These data show that a reversible depletion of Polycomb proteins can induce cancer in the absence of driver mutations, suggesting that tumours can emerge through epigenetic dysregulation leading to inheritance of altered cell fates.
    DOI:  https://doi.org/10.1038/s41586-024-07328-w
  40. bioRxiv. 2024 Apr 21. pii: 2024.04.19.590241. [Epub ahead of print]
    Psychobiological regulation of plasma and saliva GDF15 dynamics in health and mitochondrial diseases.
    Qiuhan Huang, Caroline Trumpff, Anna S Monzel, Shannon Rausser, Rachel Haahr, Jack Devine, Cynthia C Liu, Catherine Kelly, Elizabeth Thompson, Mangesh Kurade, Jeremy Michelson, Evan D Shaulson, Shufang Li, Kris Engelstad, Kurenai Tanji, Vincenzo Lauriola, Tian Wang, Shuang Wang, Faris M Zuraikat, Marie-Pierre St-Onge, Brett A Kaufman, Richard Sloan, Robert-Paul Juster, Anna L Marsland, Gilles Gouspillou, Michio Hirano, Martin Picard.
      GDF15 (growth differentiation factor 15) is a marker of cellular energetic stress linked to physical-mental illness, aging, and mortality. However, questions remain about its dynamic properties and measurability in human biofluids other than blood. Here, we examine the natural dynamics and psychobiological regulation of plasma and saliva GDF15 in four human studies representing 4,749 samples from 188 individuals. We show that GDF15 protein is detectable in saliva (8% of plasma concentration), likely produced by salivary glands secretory duct cells. Plasma and saliva GDF15 levels are not correlated. Using a brief laboratory socio-evaluative stressor paradigm, we find that psychological stress increases plasma (+3.4-5.3%) and saliva GDF15 (+45%) with distinct kinetics, within minutes. Moreover, saliva GDF15 exhibits a robust awakening response, declining by ∼42-92% within 30-45 minutes from its peak level at the time of waking up. Clinically, individuals with genetic mitochondrial OxPhos diseases show elevated baseline plasma and saliva GDF15, and post-stress GDF15 levels in both biofluids correlate with multi-system disease severity, exercise intolerance, and the subjective experience of fatigue. Taken together, our data establish the dynamic properties of saliva GDF15, reveal it as a stress-sensitive, and as a clinically relevant marker of mitochondrial diseases. These findings point to a shared psychobiological pathway integrating metabolic and mental stress.
    DOI:  https://doi.org/10.1101/2024.04.19.590241
  41. Trends Mol Med. 2024 Apr 23. pii: S1471-4914(24)00091-1. [Epub ahead of print]
    Educate, not kill: treating cancer without triggering its defenses.
    Aneta Škarková, Mariano Bizzarri, Radoslav Janoštiak, Jan Mašek, Daniel Rosel, Jan Brábek.
      Traditionally, anticancer therapies focus on restraining uncontrolled proliferation. However, these cytotoxic therapies expose cancer cells to direct killing, instigating the process of natural selection favoring survival of resistant cells that become the foundation for tumor progression and therapy failure. Recognizing this phenomenon has prompted the development of alternative therapeutic strategies. Here we propose strategies targeting cancer hallmarks beyond proliferation, aiming at re-educating cancer cells towards a less malignant phenotype. These strategies include controlling cell dormancy, transdifferentiation therapy, normalizing the cancer microenvironment, and using migrastatic therapy. Adaptive resistance to these educative strategies does not confer a direct proliferative advantage to resistant cells, as non-resistant cells are not subject to eradication, thereby delaying or preventing the development of therapy-resistant tumors.
    Keywords:  dormancy; metastasis; migrastatics; resistance; transdifferentiation; tumor reversion
    DOI:  https://doi.org/10.1016/j.molmed.2024.04.003
  42. bioRxiv. 2024 Apr 18. pii: 2024.04.18.589815. [Epub ahead of print]
    SLC17 transporters mediate renal excretion of Lac-Phe in mice and humans.
    Veronica L Li, Shuke Xiao, Pascal Schlosser, Nora Scherer, Amanda L Wiggenhorn, Jan Spaas, Alan Sheng-Hwa Tung, Edward D Karoly, Anna Köttgen, Jonathan Z Long.
      N-lactoyl-phenylalanine (Lac-Phe) is a lactate-derived metabolite that suppresses food intake and body weight. Little is known about the mechanisms that mediate Lac-Phe transport across cell membranes. Here we identify SLC17A1 and SLC17A3, two kidney-restricted plasma membrane-localized solute carriers, as physiologic urine Lac-Phe transporters. In cell culture, SLC17A1/3 exhibit high Lac-Phe efflux activity. In humans, levels of Lac-Phe in urine exhibit a strong genetic association with the SLC17A1-4 locus. Urine Lac-Phe levels are also increased following a Wingate sprint test. In mice, genetic ablation of either SLC17A1 or SLC17A3 reduces urine Lac-Phe levels. Despite these differences, both knockout strains have normal blood Lac-Phe and body weights, demonstrating that urine and plasma Lac-Phe pools are functionally and biochemically de-coupled. Together, these data establish SLC17 family members as the physiologic urine transporters for Lac-Phe and uncover a biochemical pathway for the renal excretion of this signaling metabolite.
    DOI:  https://doi.org/10.1101/2024.04.18.589815
  43. Nature. 2024 Apr 24.
    PGE2 inhibits TIL expansion by disrupting IL-2 signalling and mitochondrial function.
    Matteo Morotti, Alizee J Grimm, Helen Carrasco Hope, Marion Arnaud, Mathieu Desbuisson, Nicolas Rayroux, David Barras, Maria Masid, Baptiste Murgues, Bovannak S Chap, Marco Ongaro, Ioanna A Rota, Catherine Ronet, Aspram Minasyan, Johanna Chiffelle, Sebastian B Lacher, Sara Bobisse, Clément Murgues, Eleonora Ghisoni, Khaoula Ouchen, Ribal Bou Mjahed, Fabrizio Benedetti, Naoill Abdellaoui, Riccardo Turrini, Philippe O Gannon, Khalil Zaman, Patrice Mathevet, Loic Lelievre, Isaac Crespo, Marcus Conrad, Gregory Verdeil, Lana E Kandalaft, Julien Dagher, Jesus Corria-Osorio, Marie-Agnes Doucey, Ping-Chih Ho, Alexandre Harari, Nicola Vannini, Jan P Böttcher, Denarda Dangaj Laniti, George Coukos.
      Expansion of antigen-experienced CD8+ T cells is critical for the success of tumour-infiltrating lymphocyte (TIL)-adoptive cell therapy (ACT) in patients with cancer1. Interleukin-2 (IL-2) acts as a key regulator of CD8+ cytotoxic T lymphocyte functions by promoting expansion and cytotoxic capability2,3. Therefore, it is essential to comprehend mechanistic barriers to IL-2 sensing in the tumour microenvironment to implement strategies to reinvigorate IL-2 responsiveness and T cell antitumour responses. Here we report that prostaglandin E2 (PGE2), a known negative regulator of immune response in the tumour microenvironment4,5, is present at high concentrations in tumour tissue from patients and leads to impaired IL-2 sensing in human CD8+ TILs via the PGE2 receptors EP2 and EP4. Mechanistically, PGE2 inhibits IL-2 sensing in TILs by downregulating the IL-2Rγc chain, resulting in defective assembly of IL-2Rβ-IL2Rγc membrane dimers. This results in impaired IL-2-mTOR adaptation and PGC1α transcriptional repression, causing oxidative stress and ferroptotic cell death in tumour-reactive TILs. Inhibition of PGE2 signalling to EP2 and EP4 during TIL expansion for ACT resulted in increased IL-2 sensing, leading to enhanced proliferation of tumour-reactive TILs and enhanced tumour control once the cells were transferred in vivo. Our study reveals fundamental features that underlie impairment of human TILs mediated by PGE2 in the tumour microenvironment. These findings have therapeutic implications for cancer immunotherapy and cell therapy, and enable the development of targeted strategies to enhance IL-2 sensing and amplify the IL-2 response in TILs, thereby promoting the expansion of effector T cells with enhanced therapeutic potential.
    DOI:  https://doi.org/10.1038/s41586-024-07352-w
  44. Sci Signal. 2024 Apr 23. 17(833): eadg5678
    TNF-α signals through ITK-Akt-mTOR to drive CD4+ T cell metabolic reprogramming, which is dysregulated in rheumatoid arthritis.
    Emma L Bishop, Nancy Gudgeon, Taylor Fulton-Ward, Victoria Stavrou, Jennie Roberts, Adam Boufersaoui, Daniel A Tennant, Martin Hewison, Karim Raza, Sarah Dimeloe.
      Upon activation, T cells undergo metabolic reprogramming to meet the bioenergetic demands of clonal expansion and effector function. Because dysregulated T cell cytokine production and metabolic phenotypes coexist in chronic inflammatory disease, including rheumatoid arthritis (RA), we investigated whether inflammatory cytokines released by differentiating T cells amplified their metabolic changes. We found that tumor necrosis factor-α (TNF-α) released by human naïve CD4+ T cells upon activation stimulated the expression of a metabolic transcriptome and increased glycolysis, amino acid uptake, mitochondrial oxidation of glutamine, and mitochondrial biogenesis. The effects of TNF-α were mediated by activation of Akt-mTOR signaling by the kinase ITK and did not require the NF-κB pathway. TNF-α stimulated the differentiation of naïve cells into proinflammatory T helper 1 (TH1) and TH17 cells, but not that of regulatory T cells. CD4+ T cells from patients with RA showed increased TNF-α production and consequent Akt phosphorylation upon activation. These cells also exhibited increased mitochondrial mass, particularly within proinflammatory T cell subsets implicated in disease. Together, these findings suggest that T cell-derived TNF-α drives their metabolic reprogramming by promoting signaling through ITK, Akt, and mTOR, which is dysregulated in autoinflammatory disease.
    DOI:  https://doi.org/10.1126/scisignal.adg5678
  45. Nat Metab. 2024 Apr;6(4): 741-763
    Fatty acid binding protein 5 suppression attenuates obesity-induced hepatocellular carcinoma by promoting ferroptosis and intratumoral immune rewiring.
    Jonathan Sun, Enric Esplugues, Alicia Bort, Magdalena P Cardelo, Inmaculada Ruz-Maldonado, Pablo Fernández-Tussy, Clara Wong, Hehe Wang, Iwao Ojima, Martin Kaczocha, Rachel Perry, Yajaira Suárez, Carlos Fernández-Hernando.
      Due to the rise in overnutrition, the incidence of obesity-induced hepatocellular carcinoma (HCC) will continue to escalate; however, our understanding of the obesity to HCC developmental axis is limited. We constructed a single-cell atlas to interrogate the dynamic transcriptomic changes during hepatocarcinogenesis in mice. Here we identify fatty acid binding protein 5 (FABP5) as a driver of obesity-induced HCC. Analysis of transformed cells reveals that FABP5 inhibition and silencing predispose cancer cells to lipid peroxidation and ferroptosis-induced cell death. Pharmacological inhibition and genetic ablation of FABP5 ameliorates the HCC burden in male mice, corresponding to enhanced ferroptosis in the tumour. Moreover, FABP5 inhibition induces a pro-inflammatory tumour microenvironment characterized by tumour-associated macrophages with increased expression of the co-stimulatory molecules CD80 and CD86 and increased CD8+ T cell activation. Our work unravels the dual functional role of FABP5 in diet-induced HCC, inducing the transformation of hepatocytes and an immunosuppressive phenotype of tumour-associated macrophages and illustrates FABP5 inhibition as a potential therapeutic approach.
    DOI:  https://doi.org/10.1038/s42255-024-01019-6
  46. Cell. 2024 Apr 17. pii: S0092-8674(24)00397-0. [Epub ahead of print]
    Alanyl-tRNA synthetase, AARS1, is a lactate sensor and lactyltransferase that lactylates p53 and contributes to tumorigenesis.
    Zhi Zong, Feng Xie, Shuai Wang, Xiaojin Wu, Zhenyu Zhang, Bing Yang, Fangfang Zhou.
      Lysine lactylation is a post-translational modification that links cellular metabolism to protein function. Here, we find that AARS1 functions as a lactate sensor that mediates global lysine lacylation in tumor cells. AARS1 binds to lactate and catalyzes the formation of lactate-AMP, followed by transfer of lactate to the lysince acceptor residue. Proteomics studies reveal a large number of AARS1 targets, including p53 where lysine 120 and lysine 139 in the DNA binding domain are lactylated. Generation and utilization of p53 variants carrying constitutively lactylated lysine residues revealed that AARS1 lactylation of p53 hinders its liquid-liquid phase separation, DNA binding, and transcriptional activation. AARS1 expression and p53 lacylation correlate with poor prognosis among cancer patients carrying wild type p53. β-alanine disrupts lactate binding to AARS1, reduces p53 lacylation, and mitigates tumorigenesis in animal models. We propose that AARS1 contributes to tumorigenesis by coupling tumor cell metabolism to proteome alteration.
    Keywords:  AARS1; LLPS; alanyl-tRNA synthetase 1; lactate; lactylation; lactyltransferase; liquid-liquid phase separation; p53; tumor progression; β-alanine
    DOI:  https://doi.org/10.1016/j.cell.2024.04.002
  47. bioRxiv. 2024 Apr 11. pii: 2024.04.09.588781. [Epub ahead of print]
    The G1/S transition in mammalian stem cells in vivo is autonomously regulated by cell size.
    Shicong Xie, Shuyuan Zhang, Gustavo de Medeiros, Prisca Liberali, Jan M Skotheim.
      Cell growth and division must be coordinated to maintain a stable cell size, but how this coordination is implemented in multicellular tissues remains unclear. In unicellular eukaryotes, autonomous cell size control mechanisms couple cell growth and division with little extracellular input. However, in multicellular tissues we do not know if autonomous cell size control mechanisms operate the same way or whether cell growth and cell cycle progression are separately controlled by cell-extrinsic signals. Here, we address this question by tracking single epidermal stem cells growing in adult mice. We find that a cell-autonomous size control mechanism, dependent on the RB pathway, sets the timing of S phase entry based on the cell's current size. Cell-extrinsic variations in the cellular microenvironment affect cell growth rates but not this autonomous coupling. Our work reassesses long-standing models of cell cycle regulation within complex metazoan tissues and identifies cell-autonomous size control as a critical mechanism regulating cell divisions in vivo and thereby a major contributor to stem cell heterogeneity.
    DOI:  https://doi.org/10.1101/2024.04.09.588781
  48. Proc Natl Acad Sci U S A. 2024 Apr 30. 121(18): e2313107121
    Maximum entropy determination of mammalian proteome dynamics.
    Alexander J Dear, Gonzalo A Garcia, Georg Meisl, Galen A Collins, Tuomas P J Knowles, Alfred L Goldberg.
      Full understanding of proteostasis and energy utilization in cells will require knowledge of the fraction of cell proteins being degraded with different half-lives and their rates of synthesis. We therefore developed a method to determine such information that combines mathematical analysis of protein degradation kinetics obtained in pulse-chase experiments with Bayesian data fitting using the maximum entropy principle. This approach will enable rapid analyses of whole-cell protein dynamics in different cell types, physiological states, and neurodegenerative disease. Using it, we obtained surprising insights about protein stabilities in cultured cells normally and upon activation of proteolysis by mTOR inhibition and increasing cAMP or cGMP. It revealed that >90% of protein content in dividing mammalian cell lines is long-lived, with half-lives of 24 to 200 h, and therefore comprises much of the proteins in daughter cells. The well-studied short-lived proteins (half-lives < 10 h) together comprise <2% of cell protein mass, but surprisingly account for 10 to 20% of measurable newly synthesized protein mass. Evolution thus appears to have minimized intracellular proteolysis except to rapidly eliminate misfolded and regulatory proteins.
    Keywords:  maximum entropy; protein degradation; protein half-lives; proteome; proteostasis
    DOI:  https://doi.org/10.1073/pnas.2313107121
  49. Physiol Res. 2024 Apr 22.
    Mitochondrial Physiology of Cellular Redox Regulations.
    P Ježek, A Dlasková, H Engstová, J Špačková, J Tauber, P Průchová, E Kloppel, O Mozheitova, M Jabůrek.
      Mitochondria (mt) represent the vital hub of the molecular physiology of the cell, being decision-makers in cell life/death and information signaling, including major redox regulations and redox signaling. Now we review recent advances in understanding mitochondrial redox homeostasis, including superoxide sources and H2O2 consumers, i.e., antioxidant mechanisms, as well as exemplar situations of physiological redox signaling, including the intramitochondrial one and mt-to-cytosol redox signals, which may be classified as acute and long-term signals. This review exemplifies the acute redox signals in hypoxic cell adaptation and upon insulin secretion in pancreatic beta-cells. We also show how metabolic changes under these circumstances are linked to mitochondrial cristae narrowing at higher intensity of ATP synthesis. Also, we will discuss major redox buffers, namely the peroxiredoxin system, which may also promote redox signaling. We will point out that pathological thresholds exist, specific for each cell type, above which the superoxide sources exceed regular antioxidant capacity and the concomitant harmful processes of oxidative stress subsequently initiate etiology of numerous diseases. The redox signaling may be impaired when sunk in such excessive pro-oxidative state.
  50. Antioxidants (Basel). 2024 Apr 03. pii: 434. [Epub ahead of print]13(4):
    Redox Regulation of Mitochondrial Potassium Channels Activity.
    Joanna Lewandowska, Barbara Kalenik, Antoni Wrzosek, Adam Szewczyk.
      Redox reactions exert a profound influence on numerous cellular functions with mitochondria playing a central role in orchestrating these processes. This pivotal involvement arises from three primary factors: (1) the synthesis of reactive oxygen species (ROS) by mitochondria, (2) the presence of a substantial array of redox enzymes such as respiratory chain, and (3) the responsiveness of mitochondria to the cellular redox state. Within the inner mitochondrial membrane, a group of potassium channels, including ATP-regulated, large conductance calcium-activated, and voltage-regulated channels, is present. These channels play a crucial role in conditions such as cytoprotection, ischemia/reperfusion injury, and inflammation. Notably, the activity of mitochondrial potassium channels is intricately governed by redox reactions. Furthermore, the regulatory influence extends to other proteins, such as kinases, which undergo redox modifications. This review aims to offer a comprehensive exploration of the modulation of mitochondrial potassium channels through diverse redox reactions with a specific focus on the involvement of ROS.
    Keywords:  ROS; calcium; ischemia/reperfusion injury; mitochondria; mitochondrial potassium channel; potassium; reactive oxygen species; redox
    DOI:  https://doi.org/10.3390/antiox13040434
  51. Nephrol Dial Transplant. 2024 Apr 24. pii: gfae095. [Epub ahead of print]
    Iron biology.
    Lucia Del Vecchio, Domenico Girelli, Francesca Vinchi, Mario Cozzolino, Steve Elliott, Patrick B Mark, Luca Valenti, Christopher Qian, Qian Guo, Zhong-Ming Qian, Paola Ciceri, Francesco Locatelli.
      Iron is a fundamental element for biological life, starting from bacteria till humans. Iron is essential for cell function and survival, energy production and metabolism, whereas increased levels cause oxidative stress. It is also a constituent of haemoglobin and thus it is necessary for oxygen transportation through the body. Given these multiple functions, the regulation of iron metabolism is complex and tight coupled with oxygen homeostasis at tissue and cellular levels, thanks to the interaction with the hypoxia inducible factor (HIF) system. In patients with chronic kidney disease (CKD), iron deficiency significantly contributes to anaemia development. This frequently overlaps with chronic inflammation, causing iron- restricted erythropoiesis. To add further complexity, metabolic hyperferritinemia may, on one side, increase the risk for CKD and, on the other, overlaps with functional iron deficiency. Excessive intracellular iron in certain cell types during CKD can also mediate cellular death (called ferroptosis), and contribute to the pathogenesis of kidney damage, atherosclerosis and vascular calcifications. This review is aimed at broadening the perspective of iron metabolism in the setting of CKD not just as a contributor to anaemia in CKD patients, but also as an important player with an impact on cell metabolism, renal fibrosis, and the cardiovascular system.
    Keywords:  anaemia; cardiovascular disease; chronic kidney disease; ferroptosis; inflammation; iron; metabolic hyperferritinaemia; vascular calcification
    DOI:  https://doi.org/10.1093/ndt/gfae095
  52. Circulation. 2024 Apr 25.
    SPTLC3 Is Essential for Complex I Activity and Contributes to Ischemic Cardiomyopathy.
    Anna Kovilakath, Adolfo G Mauro, Yolander Valentine, Frank Raucci, Maryam Jamil, Christiane Carter, Jeremy Thompson, Qun Chen, Beutner Gisela, Yang Yue, Jeremy Allegood, Xiaoxin X Wang, Jordan Dail, Teja Devarakonda, Komuraiah Myakala, Jolene J Windle, Mark A Subler, David Montefusco, Belinda Willard, Ali Javaheri, Tytus Bernas, Sushil K Mahata, Moshe Levi, Jinze Liu, George A Porter, Edward J Lesnefsky, Fadi N Salloum, L Ashley Cowart.
       BACKGROUND: Dysregulated metabolism of bioactive sphingolipids, including ceramides and sphingosine-1-phosphate, has been implicated in cardiovascular disease, although the specific species, disease contexts, and cellular roles are not completely understood. Sphingolipids are produced by the serine palmitoyltransferase enzyme, canonically composed of 2 subunits, SPTLC1 (serine palmitoyltransferase long chain base subunit 1) and SPTLC2 (serine palmitoyltransferase long chain base subunit 2). Noncanonical sphingolipids are produced by a more recently described subunit, SPTLC3 (serine palmitoyltransferase long chain base subunit 3).
    METHODS: The noncanonical (d16) and canonical (d18) sphingolipidome profiles in cardiac tissues of patients with end-stage ischemic cardiomyopathy and in mice with ischemic cardiomyopathy were analyzed by targeted lipidomics. Regulation of SPTLC3 by HIF1α under ischemic conditions was determined with chromatin immunoprecipitation. Transcriptomics, lipidomics, metabolomics, echocardiography, mitochondrial electron transport chain, mitochondrial membrane fluidity, and mitochondrial membrane potential were assessed in the cSPTLC3KO transgenic mice we generated. Furthermore, morphological and functional studies were performed on cSPTLC3KO mice subjected to permanent nonreperfused myocardial infarction.
    RESULTS: Herein, we report that SPTLC3 is induced in both human and mouse models of ischemic cardiomyopathy and leads to production of atypical sphingolipids bearing 16-carbon sphingoid bases, resulting in broad changes in cell sphingolipid composition. This induction is in part attributable to transcriptional regulation by HIF1α under ischemic conditions. Furthermore, cardiomyocyte-specific depletion of SPTLC3 in mice attenuates oxidative stress, fibrosis, and hypertrophy in chronic ischemia, and mice demonstrate improved cardiac function and increased survival along with increased ketone and glucose substrate metabolism utilization. Depletion of SPTLC3 mechanistically alters the membrane environment and subunit composition of mitochondrial complex I of the electron transport chain, decreasing its activity.
    CONCLUSIONS: Our findings suggest a novel essential role for SPTLC3 in electron transport chain function and a contribution to ischemic injury by regulating complex I activity.
    Keywords:  cardiomyopathy; electron transport complex I; mitochondria; serine C-palmitoyltransferase; sphingolipids
    DOI:  https://doi.org/10.1161/CIRCULATIONAHA.123.066879
  53. AMB Express. 2024 Apr 25. 14(1): 45
    Matrix-assisted laser desorption/ionization mass spectrometry imaging for quorum sensing.
    Christel Kuik, Sanne W G van Hoogstraten, Jacobus J C Arts, Maarten Honing, Berta Cillero-Pastor.
      Quorum sensing (QS) is a complex communication system in bacteria, directing their response to the environment. QS is also one of the main regulators of bacterial biofilms' formation, maturation and dispersion. Matrix-assisted laser desorption ionization (MALDI) mass spectrometry imaging (MSI) is a molecular imaging technique that allows the mapping of QS molecules in bacterial biofilms. Here, we highlight the latest advances in MALDI-MSI in recent years and how this technology can improve QS understanding at the molecular level.
    Keywords:  Biofilm; Matrix-assisted laser desorption ionization mass spectrometry imaging; Quorum sensing
    DOI:  https://doi.org/10.1186/s13568-024-01703-6
  54. Nature. 2024 Apr 24.
    PGE2 limits effector expansion of tumour-infiltrating stem-like CD8+ T cells.
    Sebastian B Lacher, Janina Dörr, Gustavo P de Almeida, Julian Hönninger, Felix Bayerl, Anna Hirschberger, Anna-Marie Pedde, Philippa Meiser, Lukas Ramsauer, Thomas J Rudolph, Nadine Spranger, Matteo Morotti, Alizee J Grimm, Sebastian Jarosch, Arman Oner, Lisa Gregor, Stefanie Lesch, Stefanos Michaelides, Luisa Fertig, Daria Briukhovetska, Lina Majed, Sophia Stock, Dirk H Busch, Veit R Buchholz, Percy A Knolle, Dietmar Zehn, Denarda Dangaj Laniti, Sebastian Kobold, Jan P Böttcher.
      Cancer-specific TCF1+ stem-like CD8+ T cells can drive protective anticancer immunity through expansion and effector cell differentiation1-4; however, this response is dysfunctional in tumours. Current cancer immunotherapies2,5-9 can promote anticancer responses through TCF1+ stem-like CD8+ T cells in some but not all patients. This variation points towards currently ill-defined mechanisms that limit TCF1+CD8+ T cell-mediated anticancer immunity. Here we demonstrate that tumour-derived prostaglandin E2 (PGE2) restricts the proliferative expansion and effector differentiation of TCF1+CD8+ T cells within tumours, which promotes cancer immune escape. PGE2 does not affect the priming of TCF1+CD8+ T cells in draining lymph nodes. PGE2 acts through EP2 and EP4 (EP2/EP4) receptor signalling in CD8+ T cells to limit the intratumoural generation of early and late effector T cell populations that originate from TCF1+ tumour-infiltrating CD8+ T lymphocytes (TILs). Ablation of EP2/EP4 signalling in cancer-specific CD8+ T cells rescues their expansion and effector differentiation within tumours and leads to tumour elimination in multiple mouse cancer models. Mechanistically, suppression of the interleukin-2 (IL-2) signalling pathway underlies the PGE2-mediated inhibition of TCF1+ TIL responses. Altogether, we uncover a key mechanism that restricts the IL-2 responsiveness of TCF1+ TILs and prevents anticancer T cell responses that originate from these cells. This study identifies the PGE2-EP2/EP4 axis as a molecular target to restore IL-2 responsiveness in anticancer TILs to achieve cancer immune control.
    DOI:  https://doi.org/10.1038/s41586-024-07254-x
  55. PLoS Biol. 2024 Apr 26. 22(4): e3002602
    Mitofusin-mediated contacts between mitochondria and peroxisomes regulate mitochondrial fusion.
    Cynthia Alsayyah, Manish K Singh, Maria Angeles Morcillo-Parra, Laetitia Cavellini, Nadav Shai, Christine Schmitt, Maya Schuldiner, Einat Zalckvar, Adeline Mallet, Naïma Belgareh-Touzé, Christophe Zimmer, Mickaël M Cohen.
      Mitofusins are large GTPases that trigger fusion of mitochondrial outer membranes. Similarly to the human mitofusin Mfn2, which also tethers mitochondria to the endoplasmic reticulum (ER), the yeast mitofusin Fzo1 stimulates contacts between Peroxisomes and Mitochondria when overexpressed. Yet, the physiological significance and function of these "PerMit" contacts remain unknown. Here, we demonstrate that Fzo1 naturally localizes to peroxisomes and promotes PerMit contacts in physiological conditions. These contacts are regulated through co-modulation of Fzo1 levels by the ubiquitin-proteasome system (UPS) and by the desaturation status of fatty acids (FAs). Contacts decrease under low FA desaturation but reach a maximum during high FA desaturation. High-throughput genetic screening combined with high-resolution cellular imaging reveal that Fzo1-mediated PerMit contacts favor the transit of peroxisomal citrate into mitochondria. In turn, citrate enters the TCA cycle to stimulate the mitochondrial membrane potential and maintain efficient mitochondrial fusion upon high FA desaturation. These findings thus unravel a mechanism by which inter-organelle contacts safeguard mitochondrial fusion.
    DOI:  https://doi.org/10.1371/journal.pbio.3002602
  56. Biochem Biophys Res Commun. 2024 Apr 22. pii: S0006-291X(24)00513-8. [Epub ahead of print]714 149977
    The γ-glutamyl cycle serves as an amino acids supply system in colorectal cancer organoids under chronic hypoxia.
    Sho Tabata, Hiroko Endo, Hideki Makinoshima, Tomoyoshi Soga, Masahiro Inoue.
      Malignant tumors are characterized by a hypoxic microenvironment, and metabolic reprogramming is necessary to ensure energy production and oxidative stress resistance. Although the microenvironmental properties of tumors vary under acute and chronic hypoxia, studies on chronic hypoxia-induced metabolic changes are limited. In the present study, we performed a comprehensive metabolic analysis in a chronic hypoxia model using colorectal cancer (CRC) organoids, and identified an amino acid supply system through the γ-glutamyl cycle, a glutathione recycling pathway. We analyzed the metabolic changes caused by hypoxia over time and observed that chronic hypoxia resulted in an increase in 5-oxoproline and a decrease in oxidized glutathione (GSSG) compared to acute hypoxia. These findings suggest that chronic hypoxia induces metabolic changes in the γ-glutamyl cycle. Moreover, inhibition of the γ-glutamyl cycle via γ-glutamyl cyclotransferase (GGCT) and γ-glutamyl transferase 1 (GGT1) knockdown significantly reversed chronic hypoxia-induced upregulation of 5-oxoproline and several amino acids. Notably, GGT1 knockdown downregulated the intracellular levels of γ-glutamyl amino acids. Conclusively, these results indicate that the γ-glutamyl cycle serves as an amino acid supply system in CRC under chronic hypoxia, which provides fresh insight into cancer metabolism under chronic hypoxia.
    Keywords:  Amino acid metabolism; CTOS; Colorectal cancer; Organoid; γ-glutamyl amino acids; γ-glutamyl cycle
    DOI:  https://doi.org/10.1016/j.bbrc.2024.149977
  57. bioRxiv. 2024 Apr 09. pii: 2024.04.07.588166. [Epub ahead of print]
    Classification and functional characterization of regulators of intracellular STING trafficking identified by genome-wide optical pooled screening.
    Matteo Gentili, Rebecca J Carlson, Bingxu Liu, Quentin Hellier, Jocelyn Andrews, Yue Qin, Paul C Blainey, Nir Hacohen.
      STING is an innate immune sensor that traffics across many cellular compartments to carry out its function of detecting cyclic di-nucleotides and triggering defense processes. Mutations in factors that regulate this process are often linked to STING-dependent human inflammatory disorders. To systematically identify factors involved in STING trafficking, we performed a genome-wide optical pooled screen and examined the impact of genetic perturbations on intracellular STING localization. Based on subcellular imaging of STING protein and trafficking markers in 45 million cells perturbed with sgRNAs, we defined 464 clusters of gene perturbations with similar cellular phenotypes. A higher-dimensional focused optical pooled screen on 262 perturbed genes which assayed 11 imaging channels identified 73 finer phenotypic clusters. In a cluster containing USE1, a protein that mediates Golgi to ER transport, we found a gene of unknown function, C19orf25. Consistent with the known role of USE1, loss of C19orf25 enhanced STING signaling. Other clusters contained subunits of the HOPS, GARP and RIC1-RGP1 complexes. We show that HOPS deficiency delayed STING degradation and consequently increased signaling. Similarly, GARP/RIC1-RGP1 loss increased STING signaling by delaying STING exit from the Golgi. Our findings demonstrate that genome-wide genotype-phenotype maps based on high-content cell imaging outperform other screening approaches, and provide a community resource for mining for factors that impact STING trafficking as well as other cellular processes observable in our dataset.
    DOI:  https://doi.org/10.1101/2024.04.07.588166
  58. bioRxiv. 2024 Apr 10. pii: 2024.04.10.588849. [Epub ahead of print]
    Ergothioneine boosts mitochondrial respiration and exercise performance via direct activation of MPST.
    Hans-Georg Sprenger, Melanie J Mittenbühler, Yizhi Sun, Jonathan G Van Vranken, Sebastian Schindler, Abhilash Jayaraj, Sumeet A Khetarpal, Ariana Vargas-Castillo, Anna M Puszynska, Jessica B Spinelli, Andrea Armani, Tenzin Kunchok, Birgitta Ryback, Hyuk-Soo Seo, Kijun Song, Luke Sebastian, Coby O'Young, Chelsea Braithwaite, Sirano Dhe-Paganon, Nils Burger, Evanna L Mills, Steven P Gygi, Haribabu Arthanari, Edward T Chouchani, David M Sabatini, Bruce M Spiegelman.
      Ergothioneine (EGT) is a diet-derived, atypical amino acid that accumulates to high levels in human tissues. Reduced EGT levels have been linked to age-related disorders, including neurodegenerative and cardiovascular diseases, while EGT supplementation is protective in a broad range of disease and aging models in mice. Despite these promising data, the direct and physiologically relevant molecular target of EGT has remained elusive. Here we use a systematic approach to identify how mitochondria remodel their metabolome in response to exercise training. From this data, we find that EGT accumulates in muscle mitochondria upon exercise training. Proteome-wide thermal stability studies identify 3-mercaptopyruvate sulfurtransferase (MPST) as a direct molecular target of EGT; EGT binds to and activates MPST, thereby boosting mitochondrial respiration and exercise training performance in mice. Together, these data identify the first physiologically relevant EGT target and establish the EGT-MPST axis as a molecular mechanism for regulating mitochondrial function and exercise performance.
    DOI:  https://doi.org/10.1101/2024.04.10.588849
  59. Int Immunopharmacol. 2024 Apr 23. pii: S1567-5769(24)00530-7. [Epub ahead of print]133 112012
    Mitochondrial-dependent oxidative phosphorylation is key for postnatal metabolic adaptation of alveolar macrophages in the lung.
    Jun Zhang, Yu Peng, Haosen Song, Siqi Liu, Chuanwei Li, Yi Zhang, Xiaowei Shi, Huifang Guo, Yingping Xu.
      Alveolar macrophages (AMs) seed in lung during embryogenesis and become mature in perinatal period. Establishment of acclimatization to environmental challenges is important, whereas the detailed mechanisms that drive metabolic adaptation of AMs remains to be elucidated. Here, we showed that energy metabolism of AMs was transformed from glycolysis prenatally to oxidative phosphorylation (OXPHOS) postnatally accompanied by up-regulated expression of mitochondrial transcription factor A (TFAM). TFAM deficiency disturbed mitochondrial stability and decreased OXPHOS, which finally impaired AM maintenance and function, but not AM embryonic development. Mechanistically, Tfam-deletion resulted in impaired mitochondrial respiration and decreased ATP production, which triggered endoplasmic reticulum (ER) stress to cause B cell lymphoma 2 ovarian killer (BOK) accumulation and abnormal distribution of intracellular Ca2+, eventually led to induce AM apoptotic death. Thus, our data illustrated mitochondrial-dependent OXPHOS played a key role in orchestrating AM postnatal metabolic adaptation.
    Keywords:  Alveolar macrophages; Endoplasmic reticulum stress; Metabolic adaptation; mitochondrial transcription factor A
    DOI:  https://doi.org/10.1016/j.intimp.2024.112012
  60. FEBS J. 2024 Apr 23.
    Threonine dehydrogenase regulates neutrophil homeostasis but not H3K4me3 levels in zebrafish.
    Ning-Zhe Li, Zi-Xuan Wang, Fan Zhang, Chang-Zhou Feng, Yi Chen, Dian-Jia Liu, Shu-Bei Chen, Yi Jin, Yuan-Liang Zhang, Yin-Yin Xie, Qiu-Hua Huang, Lan Wang, Bing Li, Xiao-Jian Sun.
      l-threonine dehydrogenase (Tdh) is an enzyme that links threonine metabolism to epigenetic modifications and mitochondria biogenesis. In vitro studies show that it is critical for the regulation of trimethylation of histone H3 lysine 4 (H3K4me3) levels and cell fate determination of mouse embryonic stem cells (mESCs). However, whether Tdh regulates a developmental process in vivo and, if it does, whether it also primarily regulates H3K4me3 levels in this process as it does in mESCs, remains elusive. Here, we revealed that, in zebrafish hematopoiesis, tdh is preferentially expressed in neutrophils. Knockout of tdh causes a decrease in neutrophil number and slightly suppresses their acute injury-induced migration, but, unlike the mESCs, the level of H3K4me3 is not evidently reduced in neutrophils sorted from the kidney marrow of adult tdh-null zebrafish. These phenotypes are dependent on the enzymatic activity of Tdh. Importantly, a soluble supplement of nutrients that are able to fuel the acetyl-CoA pool, such as pyruvate, glucose and branched-chain amino acids, is sufficient to rescue the reduction in neutrophils caused by tdh deletion. In summary, our study presents evidence for the functional requirement of Tdh-mediated threonine metabolism in a developmental process in vivo. It also provides an animal model for investigating the nutritional regulation of myelopoiesis and immune response, as well as a useful tool for high-throughput drug/nutrition screening.
    Keywords:  neutrophil; threonine dehydrogenase; threonine metabolism; trimethylation of histone H3 lysine 4; zebrafish
    DOI:  https://doi.org/10.1111/febs.17138
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