bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2024–03–31
fifty-nine papers selected by
Christian Frezza, Universität zu Köln
  1. Tumour immunogenicity goes with the (mitochondrial electron) flow.
  2. Embracing cancer complexity: Hallmarks of systemic disease.
  3. Pyrimidines maintain mitochondrial pyruvate oxidation to support de novo lipogenesis.
  4. Glutamine antagonist DRP-104 suppresses tumor growth and enhances response to checkpoint blockade in KEAP1 mutant lung cancer.
  5. Rab4A-directed endosome traffic shapes pro-inflammatory mitochondrial metabolism in T cells via mitophagy, CD98 expression, and kynurenine-sensitive mTOR activation.
  6. Naked mole-rats have distinctive cardiometabolic and genetic adaptations to their underground low-oxygen lifestyles.
  7. Acod1 expression in cancer cells promotes immune evasion through the generation of inhibitory peptides.
  8. Tumor-secreted FGF21 acts as an immune suppressor by rewiring cholesterol metabolism of CD8+T cells.
  9. Mitochondrial H2O2 release does not directly cause damage to chromosomal DNA.
  10. Complex I activity in hypoxia: implications for oncometabolism.
  11. Stress-induced microautophagy is coordinated with lysosome biogenesis and regulated by PIKfyve.
  12. Dynamics of Mitochondrial Proteome and Acetylome in Glioblastoma Cells with Contrasting Metabolic Phenotypes.
  13. Blood glucose concentration measurement without finger pricking.
  14. Targeting DCAF5 suppresses SMARCB1-mutant cancer by stabilizing SWI/SNF.
  15. BCAA metabolism in pancreatic cancer affects lipid balance by regulating fatty acid import into mitochondria.
  16. Targeting STING elicits GSDMD-dependent pyroptosis and boosts anti-tumor immunity in renal cell carcinoma.
  17. A stagewise response to mitochondrial dysfunction in mitochondrial DNA maintenance disorders.
  18. How to make an old immune system young again.
  19. Dysregulated cellular metabolism in atherosclerosis: mediators and therapeutic opportunities.
  20. NADP+/NADPH in Metabolism and its Relation to Cardiovascular Pathologies.
  21. Diverse functions of cytochrome c in cell death and disease.
  22. Germline proliferation trades off with lipid metabolism in Drosophila.
  23. Nucleolar stress caused by arginine-rich peptides triggers a ribosomopathy and accelerates aging in mice.
  24. A defined diet for pre-adult Drosophila melanogaster.
  25. One Carbon to Rule Them All: Formaldehyde is a One-Carbon Signal Connecting One-Carbon Metabolism and Epigenetic Methylation.
  26. A mitotic stopwatch determines cell fate.
  27. The pleiotropic functions of reactive oxygen species in cancer.
  28. Glucosylceramide accumulation in microglia triggers STING-dependent neuroinflammation and neurodegeneration in mice.
  29. Emerging mechanisms in the redox regulation of mitochondrial cytochrome c oxidase assembly and function.
  30. Trans-omic analysis reveals opposite metabolic dysregulation between feeding and fasting in liver associated with obesity.
  31. Distinct types of intramitochondrial protein aggregates protect mitochondria against proteotoxic stress.
  32. Cancer cell genetics shaping of the tumor microenvironment reveals myeloid cell-centric exploitable vulnerabilities in hepatocellular carcinoma.
  33. The one-carbon metabolic enzyme MTHFD2 promotes resection and homologous recombination after ionizing radiation.
  34. Peripheral peroxisomal β-oxidation engages neuronal serotonin signaling to drive stress-induced aversive memory in C. elegans.
  35. Primitive purine biosynthesis connects ancient geochemistry to modern metabolism.
  36. Thioredoxin is a metabolic rheostat controlling regulatory B cells.
  37. Extra centrosomes delay DNA damage-driven tumorigenesis.
  38. Glutamine antagonists may KEAP lung cancer in check.
  39. Ion channel-mediated mitochondrial volume regulation and its relationship with mitochondrial dynamics.
  40. TNF receptor-2 signals clear-cell renal carcinoma proliferation via phosphorylated-4EBP1 and mitochondrial gene translation.
  41. Mechanisms generating network switches and their role in circadian clocks.
  42. Precision mitochondrial medicine.
  43. Trans-Atlantic twists and turns.
  44. Systemic and strict regulation of the glutathione redox state in mitochondria and cytosol is needed for zebrafish ontogeny.
  45. A single-cell atlas enables mapping of homeostatic cellular shifts in the adult human breast.
  46. Pregnancy advances your 'biological' age - but giving birth turns it back.
  47. Spatially Segregated Macrophage Populations Predict Distinct Outcomes In Colon Cancer.
  48. The constitutively active form of a key cholesterol synthesis enzyme is lipid droplet-localized and upregulated in endometrial cancer tissues.
  49. A semi-automatic method for extracting mitochondrial cristae characteristics from 3D focused ion beam scanning electron microscopy data.
  50. BRCA1-mediated dual regulation of ferroptosis exposes a vulnerability to GPX4 and PARP co-inhibition in BRCA1-deficient cancers.
  51. OMA1 protease eliminates arrested protein import intermediates upon mitochondrial depolarization.
  52. A novel machine learning algorithm selects proteome signature to specifically identify cancer exosomes.
  53. Fructose-1,6-bisphosphatase 1 dephosphorylates and inhibits TERT for tumor suppression.
  54. Molecular determinants and signaling effects of PKA RIα phase separation.
  55. KEAP1-Mutant Lung Cancers Weaken Anti-Tumor Immunity and Promote an M2-like Macrophage Phenotype.
  56. ATF4-SLC7A11-GSH axis mediates the acquisition of immunosuppressive properties by activated CD4+ T cells in low arginine condition.
  57. Poised epigenetic states dictate metastatic fitness.
  58. Membrane contact sites regulate vacuolar fission via sphingolipid metabolism.
  59. Cell consciousness: a dissenting opinion : The cellular basis of consciousness theory lacks empirical evidence for its claims that all cells have consciousness.
  1. Mol Oncol. 2024 Mar 22.
    Tumour immunogenicity goes with the (mitochondrial electron) flow.
    Asma Ahmed, Stephen W G Tait.
      Mitochondrial metabolism and electron transport chain (ETC) function are essential for tumour proliferation and metastasis. However, the impact of ETC function on cancer immunogenicity is not well understood. In a recent study, Mangalhara et al. found that inhibition of complex II leads to enhanced tumour immunogenicity, T-cell-mediated cytotoxicity and inhibition of tumour growth. Surprisingly, this antitumour effect is mediated by succinate accumulation affecting histone methylation. Histone methylation promotes the transcriptional upregulation of major histocompatibility complex-antigen processing and presentation (MHC-APP) genes in a manner independent of interferon signalling. Modulating mitochondrial electron flow to enhance tumour immunogenicity provides an exciting new therapeutic avenue and may be particularly attractive for tumours with reduced expression of MHC-APP genes or dampened interferon signalling.
    Keywords:  complex II; electron transport chain; major histocompatibility complex class I; succinate
    DOI:  https://doi.org/10.1002/1878-0261.13627
  2. Cell. 2024 Mar 28. pii: S0092-8674(24)00175-2. [Epub ahead of print]187(7): 1589-1616
    Embracing cancer complexity: Hallmarks of systemic disease.
    Charles Swanton, Elsa Bernard, Chris Abbosh, Fabrice André, Johan Auwerx, Allan Balmain, Dafna Bar-Sagi, René Bernards, Susan Bullman, James DeGregori, Catherine Elliott, Ayelet Erez, Gerard Evan, Mark A Febbraio, Andrés Hidalgo, Mariam Jamal-Hanjani, Johanna A Joyce, Matthew Kaiser, Katja Lamia, Jason W Locasale, Sherene Loi, Ilaria Malanchi, Miriam Merad, Kathryn Musgrave, Ketan J Patel, Sergio Quezada, Jennifer A Wargo, Ashani Weeraratna, Eileen White, Frank Winkler, John N Wood, Karen H Vousden, Douglas Hanahan.
      The last 50 years have witnessed extraordinary developments in understanding mechanisms of carcinogenesis, synthesized as the hallmarks of cancer. Despite this logical framework, our understanding of the molecular basis of systemic manifestations and the underlying causes of cancer-related death remains incomplete. Looking forward, elucidating how tumors interact with distant organs and how multifaceted environmental and physiological parameters impinge on tumors and their hosts will be crucial for advances in preventing and more effectively treating human cancers. In this perspective, we discuss complexities of cancer as a systemic disease, including tumor initiation and promotion, tumor micro- and immune macro-environments, aging, metabolism and obesity, cancer cachexia, circadian rhythms, nervous system interactions, tumor-related thrombosis, and the microbiome. Model systems incorporating human genetic variation will be essential to decipher the mechanistic basis of these phenomena and unravel gene-environment interactions, providing a modern synthesis of molecular oncology that is primed to prevent cancers and improve patient quality of life and cancer outcomes.
    DOI:  https://doi.org/10.1016/j.cell.2024.02.009
  3. Science. 2024 Mar 29. 383(6690): 1484-1492
    Pyrimidines maintain mitochondrial pyruvate oxidation to support de novo lipogenesis.
    Umakant Sahu, Elodie Villa, Colleen R Reczek, Zibo Zhao, Brendan P O'Hara, Michael D Torno, Rohan Mishra, William D Shannon, John M Asara, Peng Gao, Ali Shilatifard, Navdeep S Chandel, Issam Ben-Sahra.
      Cellular purines, particularly adenosine 5'-triphosphate (ATP), fuel many metabolic reactions, but less is known about the direct effects of pyrimidines on cellular metabolism. We found that pyrimidines, but not purines, maintain pyruvate oxidation and the tricarboxylic citric acid (TCA) cycle by regulating pyruvate dehydrogenase (PDH) activity. PDH activity requires sufficient substrates and cofactors, including thiamine pyrophosphate (TPP). Depletion of cellular pyrimidines decreased TPP synthesis, a reaction carried out by TPP kinase 1 (TPK1), which reportedly uses ATP to phosphorylate thiamine (vitamin B1). We found that uridine 5'-triphosphate (UTP) acts as the preferred substrate for TPK1, enabling cellular TPP synthesis, PDH activity, TCA-cycle activity, lipogenesis, and adipocyte differentiation. Thus, UTP is required for vitamin B1 utilization to maintain pyruvate oxidation and lipogenesis.
    DOI:  https://doi.org/10.1126/science.adh2771
  4. Sci Adv. 2024 Mar 29. 10(13): eadm9859
    Glutamine antagonist DRP-104 suppresses tumor growth and enhances response to checkpoint blockade in KEAP1 mutant lung cancer.
    Ray Pillai, Sarah E LeBoeuf, Yuan Hao, Connie New, Jenna L E Blum, Ali Rashidfarrokhi, Shih Ming Huang, Christian Bahamon, Warren L Wu, Burcu Karadal-Ferrena, Alberto Herrera, Ellie Ivanova, Michael Cross, Jozef P Bossowski, Hongyu Ding, Makiko Hayashi, Sahith Rajalingam, Triantafyllia Karakousi, Volkan I Sayin, Kamal M Khanna, Kwok-Kin Wong, Robert Wild, Aristotelis Tsirigos, John T Poirier, Charles M Rudin, Shawn M Davidson, Sergei B Koralov, Thales Papagiannakopoulos.
      Loss-of-function mutations in KEAP1 frequently occur in lung cancer and are associated with poor prognosis and resistance to standard of care treatment, highlighting the need for the development of targeted therapies. We previously showed that KEAP1 mutant tumors consume glutamine to support the metabolic rewiring associated with NRF2-dependent antioxidant production. Here, using preclinical patient-derived xenograft models and antigenic orthotopic lung cancer models, we show that the glutamine antagonist prodrug DRP-104 impairs the growth of KEAP1 mutant tumors. We find that DRP-104 suppresses KEAP1 mutant tumors by inhibiting glutamine-dependent nucleotide synthesis and promoting antitumor T cell responses. Using multimodal single-cell sequencing and ex vivo functional assays, we demonstrate that DRP-104 reverses T cell exhaustion, decreases Tregs, and enhances the function of CD4 and CD8 T cells, culminating in an improved response to anti-PD1 therapy. Our preclinical findings provide compelling evidence that DRP-104, currently in clinical trials, offers a promising therapeutic approach for treating patients with KEAP1 mutant lung cancer.
    DOI:  https://doi.org/10.1126/sciadv.adm9859
  5. Nat Commun. 2024 Mar 22. 15(1): 2598
    Rab4A-directed endosome traffic shapes pro-inflammatory mitochondrial metabolism in T cells via mitophagy, CD98 expression, and kynurenine-sensitive mTOR activation.
    Nick Huang, Thomas Winans, Brandon Wyman, Zachary Oaks, Tamas Faludi, Gourav Choudhary, Zhi-Wei Lai, Joshua Lewis, Miguel Beckford, Manuel Duarte, Daniel Krakko, Akshay Patel, Joy Park, Tiffany Caza, Mahsa Sadeghzadeh, Laurence Morel, Mark Haas, Frank Middleton, Katalin Banki, Andras Perl.
      Activation of the mechanistic target of rapamycin (mTOR) is a key metabolic checkpoint of pro-inflammatory T-cell development that contributes to the pathogenesis of autoimmune diseases, such as systemic lupus erythematosus (SLE), however, the underlying mechanisms remain poorly understood. Here, we identify a functional role for Rab4A-directed endosome traffic in CD98 receptor recycling, mTOR activation, and accumulation of mitochondria that connect metabolic pathways with immune cell lineage development and lupus pathogenesis. Based on integrated analyses of gene expression, receptor traffic, and stable isotope tracing of metabolic pathways, constitutively active Rab4AQ72L exerts cell type-specific control over metabolic networks, dominantly impacting CD98-dependent kynurenine production, mTOR activation, mitochondrial electron transport and flux through the tricarboxylic acid cycle and thus expands CD4+ and CD3+CD4-CD8- double-negative T cells over CD8+ T cells, enhancing B cell activation, plasma cell development, antinuclear and antiphospholipid autoantibody production, and glomerulonephritis in lupus-prone mice. Rab4A deletion in T cells and pharmacological mTOR blockade restrain CD98 expression, mitochondrial metabolism and lineage skewing and attenuate glomerulonephritis. This study identifies Rab4A-directed endosome traffic as a multilevel regulator of T cell lineage specification during lupus pathogenesis.
    DOI:  https://doi.org/10.1038/s41467-024-46441-2
  6. Nat Commun. 2024 Mar 27. 15(1): 2204
    Naked mole-rats have distinctive cardiometabolic and genetic adaptations to their underground low-oxygen lifestyles.
    Chris G Faulkes, Thomas R Eykyn, Jan Lj Miljkovic, James D Gilbert, Rebecca L Charles, Hiran A Prag, Nikayla Patel, Daniel W Hart, Michael P Murphy, Nigel C Bennett, Dunja Aksentijevic.
      The naked mole-rat Heterocephalus glaber is a eusocial mammal exhibiting extreme longevity (37-year lifespan), extraordinary resistance to hypoxia and absence of cardiovascular disease. To identify the mechanisms behind these exceptional traits, metabolomics and RNAseq of cardiac tissue from naked mole-rats was compared to other African mole-rat genera (Cape, Cape dune, Common, Natal, Mahali, Highveld and Damaraland mole-rats) and evolutionarily divergent mammals (Hottentot golden mole and C57/BL6 mouse). We identify metabolic and genetic adaptations unique to naked mole-rats including elevated glycogen, thus enabling glycolytic ATP generation during cardiac ischemia. Elevated normoxic expression of HIF-1α is observed while downstream hypoxia responsive-genes are down-regulated, suggesting adaptation to low oxygen environments. Naked mole-rat hearts show reduced succinate levels during ischemia compared to C57/BL6 mouse and negligible tissue damage following ischemia-reperfusion injury. These evolutionary traits reflect adaptation to a unique hypoxic and eusocial lifestyle that collectively may contribute to their longevity and health span.
    DOI:  https://doi.org/10.1038/s41467-024-46470-x
  7. Cell Rep. 2024 Mar 22. pii: S2211-1247(24)00312-7. [Epub ahead of print]43(4): 113984
    Acod1 expression in cancer cells promotes immune evasion through the generation of inhibitory peptides.
    James H Schofield, Joseph Longo, Ryan D Sheldon, Emma Albano, Abigail E Ellis, Mark A Hawk, Sean Murphy, Loan Duong, Sharif Rahmy, Xin Lu, Russell G Jones, Zachary T Schafer.
      Targeting programmed cell death protein 1 (PD-1) is an important component of many immune checkpoint blockade (ICB) therapeutic approaches. However, ICB is not an efficacious strategy in a variety of cancer types, in part due to immunosuppressive metabolites in the tumor microenvironment. Here, we find that αPD-1-resistant cancer cells produce abundant itaconate (ITA) due to enhanced levels of aconitate decarboxylase (Acod1). Acod1 has an important role in the resistance to αPD-1, as decreasing Acod1 levels in αPD-1-resistant cancer cells can sensitize tumors to αPD-1 therapy. Mechanistically, cancer cells with high Acod1 inhibit the proliferation of naive CD8+ T cells through the secretion of inhibitory factors. Surprisingly, inhibition of CD8+ T cell proliferation is not dependent on the secretion of ITA but is instead a consequence of the release of small inhibitory peptides. Our study suggests that strategies to counter the activity of Acod1 in cancer cells may sensitize tumors to ICB therapy.
    Keywords:  Acod1; CP: Cancer; CP: Immunology; TCA cycle; immune evasion; itaconate
    DOI:  https://doi.org/10.1016/j.celrep.2024.113984
  8. Cell Metab. 2024 Mar 26. pii: S1550-4131(24)00092-5. [Epub ahead of print]
    Tumor-secreted FGF21 acts as an immune suppressor by rewiring cholesterol metabolism of CD8+T cells.
    Cegui Hu, Wen Qiao, Xiang Li, Zhi-Kun Ning, Jiang Liu, Sumiya Dalangood, Hanjun Li, Xiang Yu, Zhen Zong, Zhenke Wen, Jun Gui.
      
    DOI:  https://doi.org/10.1016/j.cmet.2024.03.013
  9. Nat Commun. 2024 Mar 28. 15(1): 2725
    Mitochondrial H2O2 release does not directly cause damage to chromosomal DNA.
    Daan M K van Soest, Paulien E Polderman, Wytze T F den Toom, Janneke P Keijer, Markus J van Roosmalen, Tim M F Leyten, Johannes Lehmann, Susan Zwakenberg, Sasha De Henau, Ruben van Boxtel, Boudewijn M T Burgering, Tobias B Dansen.
      Reactive Oxygen Species (ROS) derived from mitochondrial respiration are frequently cited as a major source of chromosomal DNA mutations that contribute to cancer development and aging. However, experimental evidence showing that ROS released by mitochondria can directly damage nuclear DNA is largely lacking. In this study, we investigated the effects of H2O2 released by mitochondria or produced at the nucleosomes using a titratable chemogenetic approach. This enabled us to precisely investigate to what extent DNA damage occurs downstream of near- and supraphysiological amounts of localized H2O2. Nuclear H2O2 gives rise to DNA damage and mutations and a subsequent p53 dependent cell cycle arrest. Mitochondrial H2O2 release shows none of these effects, even at levels that are orders of magnitude higher than what mitochondria normally produce. We conclude that H2O2 released from mitochondria is unlikely to directly damage nuclear genomic DNA, limiting its contribution to oncogenic transformation and aging.
    DOI:  https://doi.org/10.1038/s41467-024-47008-x
  10. Biochem Soc Trans. 2024 Mar 25. pii: BST20230189. [Epub ahead of print]
    Complex I activity in hypoxia: implications for oncometabolism.
    Christos Chinopoulos.
      Certain cancer cells within solid tumors experience hypoxia, rendering them incapable of oxidative phosphorylation (OXPHOS). Despite this oxygen deficiency, these cells exhibit biochemical pathway activity that relies on NAD+. This mini-review scrutinizes the persistent, residual Complex I activity that oxidizes NADH in the absence of oxygen as the electron acceptor. The resulting NAD+ assumes a pivotal role in fueling the α-ketoglutarate dehydrogenase complex, a critical component in the oxidative decarboxylation branch of glutaminolysis - a hallmark oncometabolic pathway. The proposition is that through glutamine catabolism, high-energy phosphate intermediates are produced via substrate-level phosphorylation in the mitochondrial matrix substantiated by succinyl-CoA ligase, partially compensating for an OXPHOS deficiency. These insights provide a rationale for exploring Complex I inhibitors in cancer treatment, even when OXPHOS functionality is already compromised.
    Keywords:  OXPHOS; cancer; hypoxia; mitochondria; mtSLP
    DOI:  https://doi.org/10.1042/BST20230189
  11. Mol Biol Cell. 2024 Mar 27. mbcE23080332
    Stress-induced microautophagy is coordinated with lysosome biogenesis and regulated by PIKfyve.
    Alison D Klein, Kayla L Petruzzi, Chan Lee, Michael Overholtzer.
      Lysosome turnover and biogenesis are induced in response to treatment of cells with agents that cause membrane rupture, but whether other stress conditions engage similar homeostatic mechanisms is not well understood. Recently we described a form of selective turnover of lysosomes that is induced by metabolic stress or by treatment of cells with ionophores or lysosomotropic agents, involving the formation of intraluminal vesicles within intact organelles through microautophagy. Selective turnover involves non-canonical autophagy and the lipidation of LC3 onto lysosomal membranes, as well as the autophagy gene-dependent formation of intraluminal vesicles. Here we find a form of microautophagy induction that requires activity of the lipid kinase PIKfyve and is associated with the nuclear translocation of TFEB, a known mediator of lysosome biogenesis. We show that LC3 undergoes turnover during this process, and that PIKfyve is required for the formation of intraluminal vesicles and LC3 turnover, but not for LC3 lipidation onto lysosomal membranes, demonstrating that microautophagy is regulated by PIKfyve downstream of non-canonical autophagy. We further show that TFEB activation requires non-canonical autophagy but not PIKfyve, distinguishing the regulation of biogenesis from microautophagy occurring in response to agents that induce lysosomal stress. [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text].
    DOI:  https://doi.org/10.1091/mbc.E23-08-0332
  12. Int J Mol Sci. 2024 Mar 19. pii: 3450. [Epub ahead of print]25(6):
    Dynamics of Mitochondrial Proteome and Acetylome in Glioblastoma Cells with Contrasting Metabolic Phenotypes.
    Diana Lashidua Fernández-Coto, Jeovanis Gil, Guadalupe Ayala, Sergio Encarnación-Guevara.
      Glioblastoma, a type of cancer affecting the central nervous system, is characterized by its poor prognosis and the dynamic alteration of its metabolic phenotype to fuel development and progression. Critical to cellular metabolism, mitochondria play a pivotal role, where the acetylation of lysine residues on mitochondrial enzymes emerges as a crucial regulatory mechanism of protein function. This post-translational modification, which negatively impacts the mitochondrial proteome's functionality, is modulated by the enzyme sirtuin 3 (SIRT3). Aiming to elucidate the regulatory role of SIRT3 in mitochondrial metabolism within glioblastoma, we employed high-resolution mass spectrometry to analyze the proteome and acetylome of two glioblastoma cell lines, each exhibiting distinct metabolic behaviors, following the chemical inhibition of SIRT3. Our findings reveal that the protein synthesis machinery, regulated by lysine acetylation, significantly influences the metabolic phenotype of these cells. Moreover, we have shed light on potential novel SIRT3 targets, thereby unveiling new avenues for future investigations. This research highlights the critical function of SIRT3 in mitochondrial metabolism and its broader implications for cellular energetics. It also provides a comparative analysis of the proteome and acetylome across glioblastoma cell lines with opposing metabolic phenotypes.
    Keywords:  SIRT3; glioblastoma; lysine acetylation; metabolism; mitochondria
    DOI:  https://doi.org/10.3390/ijms25063450
  13. Nat Metab. 2024 Mar 27.
    Blood glucose concentration measurement without finger pricking.
      
    DOI:  https://doi.org/10.1038/s42255-024-01017-8
  14. Nature. 2024 Mar 27.
    Targeting DCAF5 suppresses SMARCB1-mutant cancer by stabilizing SWI/SNF.
    Sandi Radko-Juettner, Hong Yue, Jacquelyn A Myers, Raymond D Carter, Alexis N Robertson, Priya Mittal, Zhexin Zhu, Baranda S Hansen, Katherine A Donovan, Moritz Hunkeler, Wojciech Rosikiewicz, Zhiping Wu, Meghan G McReynolds, Shourya S Roy Burman, Anna M Schmoker, Nada Mageed, Scott A Brown, Robert J Mobley, Janet F Partridge, Elizabeth A Stewart, Shondra M Pruett-Miller, Behnam Nabet, Junmin Peng, Nathanael S Gray, Eric S Fischer, Charles W M Roberts.
      Whereas oncogenes can potentially be inhibited with small molecules, the loss of tumour suppressors is more common and is problematic because the tumour-suppressor proteins are no longer present to be targeted. Notable examples include SMARCB1-mutant cancers, which are highly lethal malignancies driven by the inactivation of a subunit of SWI/SNF (also known as BAF) chromatin-remodelling complexes. Here, to generate mechanistic insights into the consequences of SMARCB1 mutation and to identify vulnerabilities, we contributed 14 SMARCB1-mutant cell lines to a near genome-wide CRISPR screen as part of the Cancer Dependency Map Project1-3. We report that the little-studied gene DDB1-CUL4-associated factor 5 (DCAF5) is required for the survival of SMARCB1-mutant cancers. We show that DCAF5 has a quality-control function for SWI/SNF complexes and promotes the degradation of incompletely assembled SWI/SNF complexes in the absence of SMARCB1. After depletion of DCAF5, SMARCB1-deficient SWI/SNF complexes reaccumulate, bind to target loci and restore SWI/SNF-mediated gene expression to levels that are sufficient to reverse the cancer state, including in vivo. Consequently, cancer results not from the loss of SMARCB1 function per se, but rather from DCAF5-mediated degradation of SWI/SNF complexes. These data indicate that therapeutic targeting of ubiquitin-mediated quality-control factors may effectively reverse the malignant state of some cancers driven by disruption of tumour suppressor complexes.
    DOI:  https://doi.org/10.1038/s41586-024-07250-1
  15. Cancer Metab. 2024 Mar 26. 12(1): 10
    BCAA metabolism in pancreatic cancer affects lipid balance by regulating fatty acid import into mitochondria.
    Klára Gotvaldová, Jitka Špačková, Jiří Novotný, Kamila Baslarová, Petr Ježek, Lenka Rossmeislová, Jan Gojda, Katarína Smolková.
       BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) has been associated with the host dysmetabolism of branched-chain amino acids (BCAAs), however, the implications for the role of BCAA metabolism in PDAC development or progression are not clear. The mitochondrial catabolism of valine, leucine, and isoleucine is a multistep process leading to the production of short-chain R-CoA species. They can be subsequently exported from mitochondria as short-chain carnitines (SC-CARs), utilized in anabolic pathways, or released from the cells.
    METHODS: We examined the specificities of BCAA catabolism and cellular adaptation strategies to BCAA starvation in PDAC cells in vitro. We used metabolomics and lipidomics to quantify major metabolic changes in response to BCAA withdrawal. Using confocal microscopy and flow cytometry we quantified the fluorescence of BODIPY probe and the level of lipid droplets (LDs). We used BODIPY-conjugated palmitate to evaluate transport of fatty acids (FAs) into mitochondria. Also, we have developed a protocol for quantification of SC-CARs, BCAA-derived metabolites.
    RESULTS: Using metabolic profiling, we found that BCAA starvation leads to massive triglyceride (TG) synthesis and LD accumulation. This was associated with the suppression of activated FA transport into the mitochondrial matrix. The suppression of FA import into mitochondria was rescued with the inhibitor of the acetyl-CoA carboxylase (ACC) and the activator of AMP kinase (AMPK), which both regulate carnitine palmitoyltransferase 1A (CPT1) activation status.
    CONCLUSIONS: Our data suggest that BCAA catabolism is required for the import of long chain carnitines (LC-CARs) into mitochondria, whereas the disruption of this link results in the redirection of activated FAs into TG synthesis and its deposition into LDs. We propose that this mechanism protects cells against mitochondrial overload with LC-CARs and it might be part of the universal reaction to amino acid perturbations during cancer growth, regulating FA handling and storage.
    Keywords:  BCAA metabolism; Fatty acid/Transport; Fluorescence microscopy; Lipid droplets; Lipidomics; Mitochondria; Pancreatic cancer; Triglycerides
    DOI:  https://doi.org/10.1186/s40170-024-00335-5
  16. Oncogene. 2024 Mar 28.
    Targeting STING elicits GSDMD-dependent pyroptosis and boosts anti-tumor immunity in renal cell carcinoma.
    Shengpan Wu, Baojun Wang, Hongzhao Li, Hanfeng Wang, Songliang Du, Xing Huang, Yang Fan, Yu Gao, Liangyou Gu, Qingbo Huang, Jianjun Chen, Xu Zhang, Yan Huang, Xin Ma.
      While Stimulator-of-interferon genes (STING) is an innate immune adapter cruicial for sensing cytosolic DNA and modulating immune microenvironment, its tumor-promoting role in tumor survival and immune evasion remains largely unknown. Here we reported that renal cancer cells are exceptionally dependent on STING for survival and evading immunosurveillance via suppressing ER stress-mediated pyroptosis. We found that STING is significantly amplified and upregulated in clear cell renal cell carcinoma (ccRCC), and its elevated expression is associated with worse clinical outcomes. Mechanically, STING depletion in RCC cells specifically triggers activation of the PERK/eIF2α/ATF4/CHOP pathway and activates cleavage of Caspase-8, thereby inducing GSDMD-mediated pyroptosis, which is independent of the innate immune pathway of STING. Moreover, animal study revealed that STING depletion promoted infiltration of CD4+ and CD8+ T cells, consequently boosting robust antitumor immunity via pyroptosis-induced inflammation. From the perspective of targeted therapy, we found that Compound SP23, a PROTAC STING degrader, demonstrated comparable efficacy to STING depletion both in vitro and in vivo for treatment of ccRCC. These findings collectively unveiled an unforeseen function of STING in regulating GSDMD-dependent pyroptosis, thus regulating immune response in RCC. Consequently, pharmacological degradation of STING by SP23 may become an attractive strategy for treatment of advanced RCC.
    DOI:  https://doi.org/10.1038/s41388-024-03013-4
  17. Biochim Biophys Acta Mol Basis Dis. 2024 Mar 21. pii: S0925-4439(24)00120-0. [Epub ahead of print] 167131
    A stagewise response to mitochondrial dysfunction in mitochondrial DNA maintenance disorders.
    Amy E Vincent, Chun Chen, Tiago Bernardino Gomes, Valeria Di Leo, Tuomas Laalo, Kamil Pabis, Rodrick Capaldi, Michael F Marusich, David McDonald, Andrew Filby, Andrew Fuller, Diana Lehmann Urban, Stephan Zierz, Marcus Deschauer, Doug Turnbull, Amy K Reeve, Conor Lawless.
      Mitochondrial DNA (mtDNA) deletions which clonally expand in skeletal muscle of patients with mtDNA maintenance disorders, impair mitochondrial oxidative phosphorylation dysfunction. Previously we have shown that these mtDNA deletions arise and accumulate in perinuclear mitochondria causing localised mitochondrial dysfunction before spreading through the muscle fibre. We believe that mito-nuclear signalling is a key contributor in the accumulation and spread of mtDNA deletions, and that knowledge of how muscle fibres respond to mitochondrial dysfunction is key to our understanding of disease mechanisms. To understand the contribution of mito-nuclear signalling to the spread of mitochondrial dysfunction, we use imaging mass cytometry. We characterise the levels of mitochondrial Oxidative Phosphorylation proteins alongside a mitochondrial mass marker, in a cohort of patients with mtDNA maintenance disorders. Our expanded panel included protein markers of key signalling pathways, allowing us to investigate cellular responses to different combinations of oxidative phosphorylation dysfunction and ragged red fibres. We find combined Complex I and IV deficiency to be most common. Interestingly, in fibres deficient for one or more complexes, the remaining complexes are often upregulated beyond the increase of mitochondrial mass typically observed in ragged red fibres. We further find that oxidative phosphorylation deficient fibres exhibit an increase in the abundance of proteins involved in proteostasis, e.g. HSP60 and LONP1, and regulation of mitochondrial metabolism (including oxidative phosphorylation and proteolysis, e.g. PHB1). Our analysis suggests that the cellular response to mitochondrial dysfunction changes depending on the combination of deficient oxidative phosphorylation complexes in each fibre.
    Keywords:  Cell signalling; Mitochondrial DNA deletion; Mitochondrial disease; Myopathy; OXPHOS
    DOI:  https://doi.org/10.1016/j.bbadis.2024.167131
  18. Nature. 2024 Mar 27.
    How to make an old immune system young again.
    Heidi Ledford.
      
    Keywords:  Ageing; Cancer; Immunology; Medical research
    DOI:  https://doi.org/10.1038/d41586-024-00871-6
  19. Nat Metab. 2024 Mar 26.
    Dysregulated cellular metabolism in atherosclerosis: mediators and therapeutic opportunities.
    Chad Stroope, Felix Sebastian Nettersheim, Brian Coon, Alexandra C Finney, Martin A Schwartz, Klaus Ley, Oren Rom, Arif Yurdagul.
      Accumulating evidence over the past decades has revealed an intricate relationship between dysregulation of cellular metabolism and the progression of atherosclerotic cardiovascular disease. However, an integrated understanding of dysregulated cellular metabolism in atherosclerotic cardiovascular disease and its potential value as a therapeutic target is missing. In this Review, we (1) summarize recent advances concerning the role of metabolic dysregulation during atherosclerosis progression in lesional cells, including endothelial cells, vascular smooth muscle cells, macrophages and T cells; (2) explore the complexity of metabolic cross-talk between these lesional cells; (3) highlight emerging technologies that promise to illuminate unknown aspects of metabolism in atherosclerosis; and (4) suggest strategies for targeting these underexplored metabolic alterations to mitigate atherosclerosis progression and stabilize rupture-prone atheromas with a potential new generation of cardiovascular therapeutics.
    DOI:  https://doi.org/10.1038/s42255-024-01015-w
  20. Curr Med Chem. 2024 Feb 16.
    NADP+/NADPH in Metabolism and its Relation to Cardiovascular Pathologies.
    Yuanyuan Sun, Dan Wu, Qingxun Hu.
      The nicotinamide adenine dinucleotide phosphate (NADP+/NADPH) redox couple serves as a substrate or cofactor for many enzymes to maintain cellular redox homeostasis as well as to regulate biosynthetic metabolism. The deficiency or imbalance of NADP+/NADPH redox couple is strongly associated with cardiovascular-related pathologies. An imbalance in the NADP+/NADPH ratio can lead to either oxidative or reductive stress. Reductive stress complicates the cellular redox environment and provides new insights into the cellular redox state. Newly discovered biosynthetic enzymes and developed genetically encoded biosensors provide technical support for studying how cells maintain a compartmentalized NADP(H) pool. NADP(H) plays an important role in cardiovascular pathologies. However, whether NADP(H) is injurious or protective in these diseases is uncertain, as either deficiency or excess NADP(H) levels can lead to imbalances in cellular redox state and metabolic homeostasis, resulting in energy stress, redox stress, and ultimately disease state. Additional study of the replicative regulatory network of NADP(H) metabolism in different compartments, and the mechanisms by which NADP(H) regulates redox state and metabolism under normal and pathological conditions, will develop the targeted and novel therapies based on NADP(H) metabolism.
    Keywords:  NADP+; NADPH; cardiovascular-related diseases; metabolism; oxidative stress; redox state; reductive stress
    DOI:  https://doi.org/10.2174/0109298673275187231121054541
  21. Cell Death Differ. 2024 Mar 23.
    Diverse functions of cytochrome c in cell death and disease.
    Zhuan Zhou, Tasnim Arroum, Xu Luo, Rui Kang, Yong J Lee, Daolin Tang, Maik Hüttemann, Xinxin Song.
      The redox-active protein cytochrome c is a highly positively charged hemoglobin that regulates cell fate decisions of life and death. Under normal physiological conditions, cytochrome c is localized in the mitochondrial intermembrane space, and its distribution can extend to the cytosol, nucleus, and extracellular space under specific pathological or stress-induced conditions. In the mitochondria, cytochrome c acts as an electron carrier in the electron transport chain, facilitating adenosine triphosphate synthesis, regulating cardiolipin peroxidation, and influencing reactive oxygen species dynamics. Upon cellular stress, it can be released into the cytosol, where it interacts with apoptotic peptidase activator 1 (APAF1) to form the apoptosome, initiating caspase-dependent apoptotic cell death. Additionally, following exposure to pro-apoptotic compounds, cytochrome c contributes to the survival of drug-tolerant persister cells. When translocated to the nucleus, it can induce chromatin condensation and disrupt nucleosome assembly. Upon its release into the extracellular space, cytochrome c may act as an immune mediator during cell death processes, highlighting its multifaceted role in cellular biology. In this review, we explore the diverse structural and functional aspects of cytochrome c in physiological and pathological responses. We summarize how posttranslational modifications of cytochrome c (e.g., phosphorylation, acetylation, tyrosine nitration, and oxidation), binding proteins (e.g., HIGD1A, CHCHD2, ITPR1, and nucleophosmin), and mutations (e.g., G41S, Y48H, and A51V) affect its function. Furthermore, we provide an overview of the latest advanced technologies utilized for detecting cytochrome c, along with potential therapeutic approaches related to this protein. These strategies hold tremendous promise in personalized health care, presenting opportunities for targeted interventions in a wide range of conditions, including neurodegenerative disorders, cardiovascular diseases, and cancer.
    DOI:  https://doi.org/10.1038/s41418-024-01284-8
  22. Evol Lett. 2024 Apr;8(2): 295-310
    Germline proliferation trades off with lipid metabolism in Drosophila.
    Marisa A Rodrigues, Chantal Dauphin-Villemant, Margot Paris, Martin Kapun, Esra Durmaz Mitchell, Envel Kerdaffrec, Thomas Flatt.
      Little is known about the metabolic basis of life-history trade-offs but lipid stores seem to play a pivotal role. During reproduction, an energetically highly costly process, animals mobilize fat reserves. Conversely, reduced or curtailed reproduction promotes lipid storage in many animals. Systemic signals from the gonad seem to be involved: Caenorhabditis elegans lacking germline stem cells display endocrine changes, have increased fat stores and are long-lived. Similarly, germline-ablated Drosophila melanogaster exhibit major somatic physiological changes, but whether and how germline loss affects lipid metabolism remains largely unclear. Here we show that germline-ablated flies have profoundly altered energy metabolism at the transcriptional level and store excess fat as compared to fertile flies. Germline activity thus constrains or represses fat accumulation, and this effect is conserved between flies and worms. More broadly, our findings confirm that lipids represent a major energetic currency in which costs of reproduction are paid.
    Keywords:  cost of reproduction; energy stores; fat reserves; germline; lipid metabolism; trade-offs
    DOI:  https://doi.org/10.1093/evlett/qrad059
  23. Mol Cell. 2024 Mar 11. pii: S1097-2765(24)00173-4. [Epub ahead of print]
    Nucleolar stress caused by arginine-rich peptides triggers a ribosomopathy and accelerates aging in mice.
    Oleksandra Sirozh, Anabel Saez-Mas, Bomi Jung, Laura Sanchez-Burgos, Eduardo Zarzuela, Sara Rodrigo-Perez, Ivan Ventoso, Vanesa Lafarga, Oscar Fernandez-Capetillo.
      Nucleolar stress (NS) has been associated with age-related diseases such as cancer or neurodegeneration. To investigate how NS triggers toxicity, we used (PR)n arginine-rich peptides present in some neurodegenerative diseases as inducers of this perturbation. We here reveal that whereas (PR)n expression leads to a decrease in translation, this occurs concomitant with an accumulation of free ribosomal (r) proteins. Conversely, (PR)n-resistant cells have lower rates of r-protein synthesis, and targeting ribosome biogenesis by mTOR inhibition or MYC depletion alleviates (PR)n toxicity in vitro. In mice, systemic expression of (PR)97 drives widespread NS and accelerated aging, which is alleviated by rapamycin. Notably, the generalized accumulation of orphan r-proteins is a common outcome of chemical or genetic perturbations that induce NS. Together, our study presents a general model to explain how NS induces cellular toxicity and provides in vivo evidence supporting a role for NS as a driver of aging in mammals.
    Keywords:  aging; nucleolar stress; nucleolus; ribosomal proteins; ribosomopathy
    DOI:  https://doi.org/10.1016/j.molcel.2024.02.031
  24. Sci Rep. 2024 03 23. 14(1): 6974
    A defined diet for pre-adult Drosophila melanogaster.
    Felipe Martelli, Annelise Quig, Sarah Mele, Jiayi Lin, Tahlia L Fulton, Mia Wansbrough, Christopher K Barlow, Ralf B Schittenhelm, Travis K Johnson, Matthew D W Piper.
      Drosophila melanogaster is unique among animal models because it has a fully defined synthetic diet available to study nutrient-gene interactions. However, use of this diet is limited to adult studies due to impaired larval development and survival. Here, we provide an adjusted formula that reduces the developmental period, restores fat levels, enhances body mass, and fully rescues survivorship without compromise to adult lifespan. To demonstrate an application of this formula, we explored pre-adult diet compositions of therapeutic potential in a model of an inherited metabolic disorder affecting the metabolism of branched-chain amino acids. We reveal rapid, specific, and predictable nutrient effects on the disease state consistent with observations from mouse and patient studies. Together, our diet provides a powerful means with which to examine the interplay between diet and metabolism across all life stages in an animal model.
    Keywords:  Acetate; Amino acids; Developmental timing; Fruit flies; Holidic diet; Lipids; Nutrigenomics; Precision nutrition
    DOI:  https://doi.org/10.1038/s41598-024-57681-z
  25. ACS Chem Biol. 2024 Mar 26.
    One Carbon to Rule Them All: Formaldehyde is a One-Carbon Signal Connecting One-Carbon Metabolism and Epigenetic Methylation.
    Logan Tenney, Vanha N Pham, Christopher J Chang.
      Formaldehyde is commonly thought of as an environmental toxin or laboratory fixation reagent, but there is a growing appreciation for its broader physiological contributions as a naturally generated one-carbon metabolite across all kingdoms of life. In this In Focus article, we summarize emerging advances in the field that show how formaldehyde plays diverse roles as a one-carbon signal in DNA damage, one-carbon metabolism, and epigenetic regulation.
    DOI:  https://doi.org/10.1021/acschembio.4c00106
  26. Science. 2024 Mar 29. 383(6690): 1414-1415
    A mitotic stopwatch determines cell fate.
    Agustina P Bertolin, Vanesa Gottifredi.
      Surveillance of mitotic timing prevents amplification of damaged cells.
    DOI:  https://doi.org/10.1126/science.ado5703
  27. Nat Cancer. 2024 Mar;5(3): 384-399
    The pleiotropic functions of reactive oxygen species in cancer.
    Katherine Wu, Ahmed Ezat El Zowalaty, Volkan I Sayin, Thales Papagiannakopoulos.
      Cellular redox homeostasis is an essential, dynamic process that ensures the balance between reducing and oxidizing reactions within cells and thus has implications across all areas of biology. Changes in levels of reactive oxygen species can disrupt redox homeostasis, leading to oxidative or reductive stress that contributes to the pathogenesis of many malignancies, including cancer. From transformation and tumor initiation to metastatic dissemination, increasing reactive oxygen species in cancer cells can paradoxically promote or suppress the tumorigenic process, depending on the extent of redox stress, its spatiotemporal characteristics and the tumor microenvironment. Here we review how redox regulation influences tumorigenesis, highlighting therapeutic opportunities enabled by redox-related alterations in cancer cells.
    DOI:  https://doi.org/10.1038/s43018-024-00738-9
  28. Sci Signal. 2024 Mar 26. 17(829): eadk8249
    Glucosylceramide accumulation in microglia triggers STING-dependent neuroinflammation and neurodegeneration in mice.
    Rui Wang, Hongyang Sun, Yifan Cao, Zhixiong Zhang, Yajing Chen, Xiying Wang, Lele Liu, Jin Wu, Hao Xu, Dan Wu, Chenchen Mu, Zongbing Hao, Song Qin, Haigang Ren, Junhai Han, Ming Fang, Guanghui Wang.
      Mutations in the gene encoding the lysosomal enzyme glucocerebrosidase (GCase) are responsible for Gaucher disease (GD) and are considered the strongest genetic risk factor for Parkinson's disease (PD) and Lewy body dementia (LBD). GCase deficiency leads to extensive accumulation of glucosylceramides (GCs) in cells and contributes to the neuropathology of GD, PD, and LBD by triggering chronic neuroinflammation. Here, we investigated the mechanisms by which GC accumulation induces neuroinflammation. We found that GC accumulation within microglia induced by pharmacological inhibition of GCase triggered STING-dependent inflammation, which contributed to neuronal loss both in vitro and in vivo. GC accumulation in microglia induced mitochondrial DNA (mtDNA) leakage to the cytosol to trigger STING-dependent inflammation. Rapamycin, a compound that promotes lysosomal activity, improved mitochondrial function, thereby decreasing STING signaling. Furthermore, lysosomal damage caused by GC accumulation led to defects in the degradation of activated STING, further exacerbating inflammation mediated by microglia. Thus, limiting STING activity may be a strategy to suppress neuroinflammation caused by GCase deficiency.
    DOI:  https://doi.org/10.1126/scisignal.adk8249
  29. Biochem Soc Trans. 2024 Mar 25. pii: BST20231183. [Epub ahead of print]
    Emerging mechanisms in the redox regulation of mitochondrial cytochrome c oxidase assembly and function.
    Suleva Povea-Cabello, Michele Brischigliaro, Erika Fernández-Vizarra.
      In eukaryotic cells, mitochondria perform cellular respiration through a series of redox reactions ultimately reducing molecular oxygen to water. The system responsible for this process is the respiratory chain or electron transport system (ETS) composed of complexes I-IV. Due to its function, the ETS is the main source of reactive oxygen species (ROS), generating them on both sides of the mitochondrial inner membrane, i.e. the intermembrane space (IMS) and the matrix. A correct balance between ROS generation and scavenging is important for keeping the cellular redox homeostasis and other important aspects of cellular physiology. However, ROS generated in the mitochondria are important signaling molecules regulating mitochondrial biogenesis and function. The IMS contains a large number of redox sensing proteins, containing specific Cys-rich domains, that are involved in ETS complex biogenesis. The large majority of these proteins function as cytochrome c oxidase (COX) assembly factors, mainly for the handling of copper ions necessary for the formation of the redox reactive catalytic centers. A particular case of ROS-regulated COX assembly factor is COA8, whose intramitochondrial levels are increased by oxidative stress, promoting COX assembly and/or protecting the enzyme from oxidative damage. In this review, we will discuss the current knowledge concerning the role played by ROS in regulating mitochondrial activity and biogenesis, focusing on the COX enzyme and with a special emphasis on the functional role exerted by the redox sensitive Cys residues contained in the COX assembly factors.
    Keywords:  complex IV; mitochondrial dysfunction; reactive oxygen species; redox signaling; respiratory chain assembly
    DOI:  https://doi.org/10.1042/BST20231183
  30. iScience. 2024 Mar 15. 27(3): 109121
    Trans-omic analysis reveals opposite metabolic dysregulation between feeding and fasting in liver associated with obesity.
    Yunfan Bai, Keigo Morita, Toshiya Kokaji, Atsushi Hatano, Satoshi Ohno, Riku Egami, Yifei Pan, Dongzi Li, Katsuyuki Yugi, Saori Uematsu, Hiroshi Inoue, Yuka Inaba, Yutaka Suzuki, Masaki Matsumoto, Masatomo Takahashi, Yoshihiro Izumi, Takeshi Bamba, Akiyoshi Hirayama, Tomoyoshi Soga, Shinya Kuroda.
      Dysregulation of liver metabolism associated with obesity during feeding and fasting leads to the breakdown of metabolic homeostasis. However, the underlying mechanism remains unknown. Here, we measured multi-omics data in the liver of wild-type and leptin-deficient obese (ob/ob) mice at ad libitum feeding and constructed a differential regulatory trans-omic network of metabolic reactions. We compared the trans-omic network at feeding with that at 16 h fasting constructed in our previous study. Intermediate metabolites in glycolytic and nucleotide metabolism decreased in ob/ob mice at feeding but increased at fasting. Allosteric regulation reversely shifted between feeding and fasting, generally showing activation at feeding while inhibition at fasting in ob/ob mice. Transcriptional regulation was similar between feeding and fasting, generally showing inhibiting transcription factor regulations and activating enzyme protein regulations in ob/ob mice. The opposite metabolic dysregulation between feeding and fasting characterizes breakdown of metabolic homeostasis associated with obesity.
    Keywords:  Biological sciences; Metabolomics; Physiology; Proteomics; Transcriptomics
    DOI:  https://doi.org/10.1016/j.isci.2024.109121
  31. Cell Rep. 2024 Mar 28. pii: S2211-1247(24)00346-2. [Epub ahead of print]43(4): 114018
    Distinct types of intramitochondrial protein aggregates protect mitochondria against proteotoxic stress.
    Lea Bertgen, Jan-Eric Bökenkamp, Tim Schneckmann, Christian Koch, Markus Räschle, Zuzana Storchová, Johannes M Herrmann.
      Mitochondria consist of hundreds of proteins, most of which are inaccessible to the proteasomal quality control system of the cytosol. How cells stabilize the mitochondrial proteome during challenging conditions remains poorly understood. Here, we show that mitochondria form spatially defined protein aggregates as a stress-protecting mechanism. Two different types of intramitochondrial protein aggregates can be distinguished. The mitoribosomal protein Var1 (uS3m) undergoes a stress-induced transition from a soluble, chaperone-stabilized protein that is prevalent under benign conditions to an insoluble, aggregated form upon acute stress. The formation of Var1 bodies stabilizes mitochondrial proteostasis, presumably by sequestration of aggregation-prone proteins. The AAA chaperone Hsp78 is part of a second type of intramitochondrial aggregate that transiently sequesters proteins and promotes their folding or Pim1-mediated degradation. Thus, mitochondrial proteins actively control the formation of distinct types of intramitochondrial protein aggregates, which cooperate to stabilize the mitochondrial proteome during proteotoxic stress conditions.
    Keywords:  CP: Cell biology; CP: Molecular biology; Hsp78; MitoStores; Pim1 protease; Var1 bodies; aggregates; chaperones; mitochondria; mitoribosome; protein folding; protein import
    DOI:  https://doi.org/10.1016/j.celrep.2024.114018
  32. Nat Commun. 2024 Mar 22. 15(1): 2581
    Cancer cell genetics shaping of the tumor microenvironment reveals myeloid cell-centric exploitable vulnerabilities in hepatocellular carcinoma.
    Christel F A Ramirez, Daniel Taranto, Masami Ando-Kuri, Marnix H P de Groot, Efi Tsouri, Zhijie Huang, Daniel de Groot, Roelof J C Kluin, Daan J Kloosterman, Joanne Verheij, Jing Xu, Serena Vegna, Leila Akkari.
      Myeloid cells are abundant and plastic immune cell subsets in the liver, to which pro-tumorigenic, inflammatory and immunosuppressive roles have been assigned in the course of tumorigenesis. Yet several aspects underlying their dynamic alterations in hepatocellular carcinoma (HCC) progression remain elusive, including the impact of distinct genetic mutations in shaping a cancer-permissive tumor microenvironment (TME). Here, in newly generated, clinically-relevant somatic female HCC mouse models, we identify cancer genetics' specific and stage-dependent alterations of the liver TME associated with distinct histopathological and malignant HCC features. Mitogen-activated protein kinase (MAPK)-activated, NrasG12D-driven tumors exhibit a mixed phenotype of prominent inflammation and immunosuppression in a T cell-excluded TME. Mechanistically, we report a NrasG12D cancer cell-driven, MEK-ERK1/2-SP1-dependent GM-CSF secretion enabling the accumulation of immunosuppressive and proinflammatory monocyte-derived Ly6Clow cells. GM-CSF blockade curbs the accumulation of these cells, reduces inflammation, induces cancer cell death and prolongs animal survival. Furthermore, GM-CSF neutralization synergizes with a vascular endothelial growth factor (VEGF) inhibitor to restrain HCC outgrowth. These findings underscore the profound alterations of the myeloid TME consequential to MAPK pathway activation intensity and the potential of GM-CSF inhibition as a myeloid-centric therapy tailored to subsets of HCC patients.
    DOI:  https://doi.org/10.1038/s41467-024-46835-2
  33. Mol Oncol. 2024 Mar 27.
    The one-carbon metabolic enzyme MTHFD2 promotes resection and homologous recombination after ionizing radiation.
    Petra Marttila, Nadilly Bonagas, Christina Chalkiadaki, Hannah Stigsdotter, Korbinian Schelzig, Jianyu Shen, Crystal M Farhat, Amber Hondema, Julian Albers, Elisée Wiita, Azita Rasti, Ulrika Warpman Berglund, Ana Slipicevic, Oliver Mortusewicz, Thomas Helleday.
      The one-carbon metabolism enzyme bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase 2 (MTHFD2) is among the most overexpressed proteins across tumors and is widely recognized as a promising anticancer target. While MTHFD2 is mainly described as a mitochondrial protein, a new nuclear function is emerging. Here, we observe that nuclear MTHFD2 protein levels and association with chromatin increase following ionizing radiation (IR) in an ataxia telangiectasia mutated (ATM)- and DNA-dependent protein kinase (DNA-PK)-dependent manner. Furthermore, repair of IR-induced DNA double-strand breaks (DSBs) is delayed upon MTHFD2 knockdown, suggesting a role for MTHFD2 in DSB repair. In support of this, we observe impaired recruitment of replication protein A (RPA), reduced resection, decreased IR-induced DNA repair protein RAD51 homolog 1 (RAD51) levels and impaired homologous recombination (HR) activity in MTHFD2-depleted cells following IR. In conclusion, we identify a key role for MTHFD2 in HR repair and describe an interdependency between MTHFD2 and HR proficiency that could potentially be exploited for cancer therapy.
    Keywords:  DSB repair; MTHFD2; homologous recombination; ionizing radiation
    DOI:  https://doi.org/10.1002/1878-0261.13645
  34. Cell Rep. 2024 Mar 22. pii: S2211-1247(24)00324-3. [Epub ahead of print]43(4): 113996
    Peripheral peroxisomal β-oxidation engages neuronal serotonin signaling to drive stress-induced aversive memory in C. elegans.
    Shang-Heng Tsai, Yu-Chun Wu, Diana Fajardo Palomino, Frank C Schroeder, Chun-Liang Pan.
      Physiological dysfunction confers negative valence to coincidental sensory cues to induce the formation of aversive associative memory. How peripheral tissue stress engages neuromodulatory mechanisms to form aversive memory is poorly understood. Here, we show that in the nematode C. elegans, mitochondrial disruption induces aversive memory through peroxisomal β-oxidation genes in non-neural tissues, including pmp-4/very-long-chain fatty acid transporter, dhs-28/3-hydroxylacyl-CoA dehydrogenase, and daf-22/3-ketoacyl-CoA thiolase. Upregulation of peroxisomal β-oxidation genes under mitochondrial stress requires the nuclear hormone receptor NHR-49. Importantly, the memory-promoting function of peroxisomal β-oxidation is independent of its canonical role in pheromone production. Peripheral signals derived from the peroxisomes target NSM, a critical neuron for memory formation under stress, to upregulate serotonin synthesis and remodel evoked responses to sensory cues. Our genetic, transcriptomic, and metabolomic approaches establish peroxisomal lipid signaling as a crucial mechanism that connects peripheral mitochondrial stress to central serotonin neuromodulation in aversive memory formation.
    Keywords:  C. elegans; CP: Cell biology; CP: Neuroscience; aversive memory; gut-brain signaling; mitochondria; neural activity; peroxisome; response properties; serotonin; stress; very-long-chain fatty acids
    DOI:  https://doi.org/10.1016/j.celrep.2024.113996
  35. Nat Ecol Evol. 2024 Mar 22.
    Primitive purine biosynthesis connects ancient geochemistry to modern metabolism.
    Joshua E Goldford, Harrison B Smith, Liam M Longo, Boswell A Wing, Shawn Erin McGlynn.
      An unresolved question in the origin and evolution of life is whether a continuous path from geochemical precursors to the majority of molecules in the biosphere can be reconstructed from modern-day biochemistry. Here we identified a feasible path by simulating the evolution of biosphere-scale metabolism, using only known biochemical reactions and models of primitive coenzymes. We find that purine synthesis constitutes a bottleneck for metabolic expansion, which can be alleviated by non-autocatalytic phosphoryl coupling agents. Early phases of the expansion are enriched with enzymes that are metal dependent and structurally symmetric, supporting models of early biochemical evolution. This expansion trajectory suggests distinct hypotheses regarding the tempo, mode and timing of metabolic pathway evolution, including a late appearance of methane metabolisms and oxygenic photosynthesis consistent with the geochemical record. The concordance between biological and geological analyses suggests that this trajectory provides a plausible evolutionary history for the vast majority of core biochemistry.
    DOI:  https://doi.org/10.1038/s41559-024-02361-4
  36. Nat Immunol. 2024 Mar 29.
    Thioredoxin is a metabolic rheostat controlling regulatory B cells.
    Hannah F Bradford, Thomas C R McDonnell, Alexander Stewart, Andrew Skelton, Joseph Ng, Zara Baig, Franca Fraternali, Deborah Dunn-Walters, David A Isenberg, Adnan R Khan, Claudio Mauro, Claudia Mauri.
      Metabolic programming is important for B cell fate, but the bioenergetic requirement for regulatory B (Breg) cell differentiation and function is unknown. Here we show that Breg cell differentiation, unlike non-Breg cells, relies on mitochondrial electron transport and homeostatic levels of reactive oxygen species (ROS). Single-cell RNA sequencing analysis revealed that TXN, encoding the metabolic redox protein thioredoxin (Trx), is highly expressed by Breg cells, unlike Trx inhibitor TXNIP which was downregulated. Pharmacological inhibition or gene silencing of TXN resulted in mitochondrial membrane depolarization and increased ROS levels, selectively suppressing Breg cell differentiation and function while favoring pro-inflammatory B cell differentiation. Patients with systemic lupus erythematosus (SLE), characterized by Breg cell deficiencies, present with B cell mitochondrial membrane depolarization, elevated ROS and fewer Trx+ B cells. Exogenous Trx stimulation restored Breg cells and mitochondrial membrane polarization in SLE B cells to healthy B cell levels, indicating Trx insufficiency underlies Breg cell impairment in patients with SLE.
    DOI:  https://doi.org/10.1038/s41590-024-01798-w
  37. Sci Adv. 2024 Mar 29. 10(13): eadk0564
    Extra centrosomes delay DNA damage-driven tumorigenesis.
    Vincent Z Braun, Gerlinde Karbon, Fabian Schuler, Marina A Schapfl, Johannes G Weiss, Paul Y Petermann, Diana C J Spierings, Andrea E Tijhuis, Floris Foijer, Verena Labi, Andreas Villunger.
      Deregulated centrosome numbers are frequently found in human cancer and can promote malignancies in model organisms. Current research aims to clarify if extra centrosomes are cause or consequence of malignant transformation, and if their biogenesis can be targeted for therapy. Here, we show that oncogene-driven blood cancer is inert to genetic manipulation of centrosome numbers, whereas the formation of DNA damage-induced malignancies is delayed. We provide first evidence that this unexpected phenomenon is connected to extra centrosomes eliciting a pro-death signal engaging the apoptotic machinery. Apoptosis induction requires the PIDDosome multi-protein complex, as it can be abrogated by loss of any of its three components, Caspase-2, Raidd/Cradd, or Pidd1. BCL2 overexpression equally blocks cell death, documenting for the first time induction of mitochondrial apoptosis downstream of extra centrosomes. Our findings demonstrate context-dependent effects of centrosome amplification during transformation and ask to adjust current belief that extra centrosomes are intrinsically pro-tumorigenic.
    DOI:  https://doi.org/10.1126/sciadv.adk0564
  38. Sci Adv. 2024 Mar 29. 10(13): eado7808
    Glutamine antagonists may KEAP lung cancer in check.
    Eliot B Blatt, Ralph J DeBerardinis.
      The glutamine antagonist DRP-104 blocks purine synthesis and combines with checkpoint inhibitors to promote antitumor immunity in KEAP1/NRF2-mutant lung cancers.
    DOI:  https://doi.org/10.1126/sciadv.ado7808
  39. Channels (Austin). 2024 Dec;18(1): 2335467
    Ion channel-mediated mitochondrial volume regulation and its relationship with mitochondrial dynamics.
    Yujia Zhuang, Wenting Jiang, Zhe Zhao, Wencui Li, Zhiqin Deng, Jianquan Liu.
      The mitochondrion, one of the important cellular organelles, has the major function of generating adenosine triphosphate and plays an important role in maintaining cellular homeostasis, governing signal transduction, regulating membrane potential, controlling programmed cell death and modulating cell proliferation. The dynamic balance of mitochondrial volume is an important factor required for maintaining the structural integrity of the organelle and exerting corresponding functions. Changes in the mitochondrial volume are closely reflected in a series of biological functions and pathological changes. The mitochondrial volume is controlled by the osmotic balance between the cytoplasm and the mitochondrial matrix. Thus, any disruption in the influx of the main ion, potassium, into the cells can disturb the osmotic balance between the cytoplasm and the matrix, leading to water movement between these compartments and subsequent alterations in mitochondrial volume. Recent studies have shown that mitochondrial volume homeostasis is closely implicated in a variety of diseases. In this review, we provide an overview of the main influencing factors and research progress in the field of mitochondrial volume homeostasis.
    Keywords:  Ion channels; cell volume regulation; mitochondrial
    DOI:  https://doi.org/10.1080/19336950.2024.2335467
  40. Am J Pathol. 2024 Mar 25. pii: S0002-9440(24)00113-5. [Epub ahead of print]
    TNF receptor-2 signals clear-cell renal carcinoma proliferation via phosphorylated-4EBP1 and mitochondrial gene translation.
    Rafia S Al-Lamki, Aviva M Tolkovsky, Mohammad Alawwami, WanHua Lu, Sarah F Field, Jun Wang, Jordan S Pober, John R Bradley.
      Clear cell renal cell carcinoma (ccRCC), a tubular epithelial malignancy, secretes tumor necrosis factor (TNF) which signals ccRCC cells in an autocrine manner via two cell surface receptors, TNFR1 and TNFR2, to activate shared and distinct signalling pathways. Selective ligation of TNFR2 was shown to drive cell cycle entry of malignant cells via a signalling pathway involving Etk, VEGFR2, PI3K, Akt, pSer727-Stat3 and mTOR. In this study, phosphorylated-4EBP1 serine 65 (pSer65-4EBP1) is identified as a downstream target of this TNFR2 signalling pathway. pSer65-4EBP1 expression is significantly elevated relative to total 4EBP1 in ccRCC tissue compared to normal kidneys, signal intensity increasing with malignant grade. Selective ligation of TNFR2 with the mutein R2TNF increases pSer65-4EBP1 expression in organ cultures that co-localises with internalised TNFR2 in mitochondria and increases expression of mitochondrially-encoded COX (cytochrome c oxidase subunit) Cox1, as well as nuclear-encoded Cox4/5b subunits. Pharmacological inhibition of mTOR reduces both R2TNF-mediated phosphorylation of 4EBP1 and cell cycle activation in tumor cells while increasing cell death. These results signify the importance of pSer65-4EBP1 in mediating TNFR2-driven cell-cycle entry in tumor cells in ccRCC and implicate a novel relationship between the TNFR2/pSer65-4EBP1/COX axis and mitochondrial function.
    DOI:  https://doi.org/10.1016/j.ajpath.2024.02.019
  41. J Biol Chem. 2024 Mar 22. pii: S0021-9258(24)01715-0. [Epub ahead of print] 107220
    Mechanisms generating network switches and their role in circadian clocks.
    Marta Del Olmo, Stefan Legewie, Michael Brunner, Thomas Höfer, Achim Kramer, Nils Blüthgen, Hanspeter Herzel.
      Circadian rhythms are generated by complex interactions among genes and proteins. Self-sustained ∼24 hour oscillations require negative feedback loops and sufficiently strong nonlinearities that are the product of molecular and network switches. Here we review common mechanisms to obtain switch-like behavior, including cooperativity, antagonistic enzymes, multisite phosphorylation, positive feedback, and sequestration. We discuss how network switches play a crucial role as essential components in cellular circadian clocks, serving as integral parts of transcription-translation feedback loops (TTFLs) that form the basis of circadian rhythm generation. The design principles of network switches and circadian clocks are illustrated by representative mathematical models that include bistable systems and negative feedback loops combined with Hill functions. This work underscores the importance of negative feedback loops and network switches as essential design principles for biological oscillations, emphasizing how an understanding of theoretical concepts can provide insights into the mechanism generating biological rhythms.
    Keywords:  bistability; circadian clock; feedback loops; mathematical models; network switches; ultrasensitivity
    DOI:  https://doi.org/10.1016/j.jbc.2024.107220
  42. Camb Prism Precis Med. 2023 ;1 e6
    Precision mitochondrial medicine.
    Patrick F Chinnery.
      Mitochondria play a key role in cell homeostasis as a major source of intracellular energy (adenosine triphosphate), and as metabolic hubs regulating many canonical cell processes. Mitochondrial dysfunction has been widely documented in many common diseases, and genetic studies point towards a causal role in the pathogenesis of specific late-onset disorder. Together this makes targeting mitochondrial genes an attractive strategy for precision medicine. However, the genetics of mitochondrial biogenesis is complex, with over 1,100 candidate genes found in two different genomes: the nuclear DNA and mitochondrial DNA (mtDNA). Here, we review the current evidence associating mitochondrial genetic variants with distinct clinical phenotypes, with some having clear therapeutic implications. The strongest evidence has emerged through the investigation of rare inherited mitochondrial disorders, but genome-wide association studies also implicate mtDNA variants in the risk of developing common diseases, opening to door for the incorporation of mitochondrial genetic variant analysis in population disease risk stratification.
    Keywords:  genetic polymorphism; genetic risk score; genetics; genomics; metabolic diseases
    DOI:  https://doi.org/10.1017/pcm.2022.8
  43. Nat Cancer. 2024 Mar 22.
    Trans-Atlantic twists and turns.
    Johanna A Joyce.
      
    DOI:  https://doi.org/10.1038/s43018-024-00747-8
  44. Biochim Biophys Acta Gen Subj. 2024 Mar 21. pii: S0304-4165(24)00046-1. [Epub ahead of print]1868(6): 130603
    Systemic and strict regulation of the glutathione redox state in mitochondria and cytosol is needed for zebrafish ontogeny.
    Kristin Hamre, Wuxiao Zhang, Maren Hoff Austgulen, Eva Mykkeltvedt, Peng Yin, Marc Berntssen, Marit Espe, Carsten Berndt.
       BACKGROUND: Redox control seems to be indispensable for proper embryonic development. The ratio between glutathione (GSH) and its oxidized disulfide (GSSG) is the most abundant cellular redox circuit.
    METHODS: We used zebrafish harboring the glutaredoxin 1-redox sensitive green fluorescent protein (Grx1-roGFP) probe either in mitochondria or cytosol to test the hypothesis that the GSH:GSSG ratio is strictly regulated through zebrafish embryogenesis to sustain the different developmental processes of the embryo.
    RESULTS: Following the GSSG:GSH ratio as a proxy for the GSH-dependent reduction potential (EhGSH) revealed increasing mitochondrial and cytosolic EhGSH during cleavage and gastrulation. During organogenesis, cytosolic EhGSH decreased, while that of mitochondria remained high. The similarity between EhGSH in brain and muscle suggests a central regulation. Modulation of GSH metabolism had only modest effects on the GSSG:GSH ratios of newly hatched larvae. However, inhibition of GSH reductase directly after fertilization led to dead embryos already 10 h later. Exposure to the emerging environmental pollutant Perfluorooctane Sulfonate (PFOS) disturbed the apparent regulated EhGSH as well.
    CONCLUSIONS: Mitochondrial and cytosolic GSSG:GSH ratios are almost identical in different organs during zebrafish development indicating that the EhGSH might follow H2O2 levels and rather indirectly affect specific enzymatic activities needed for proper embryogenesis.
    GENERAL SIGNIFICANCE: Our data confirm that vertebrate embryogenesis depends on strictly regulated redox homeostasis. Disturbance of the GSSG:GSH circuit, e.g. induced by environmental pollution, leads to malformation and death.
    Keywords:  Embryonic development; Glutathione metabolism; PFOS; Zebrafish model; roGFP probe
    DOI:  https://doi.org/10.1016/j.bbagen.2024.130603
  45. Nat Genet. 2024 Mar 28.
    A single-cell atlas enables mapping of homeostatic cellular shifts in the adult human breast.
    Austin D Reed, Sara Pensa, Adi Steif, Jack Stenning, Daniel J Kunz, Linsey J Porter, Kui Hua, Peng He, Alecia-Jane Twigger, Abigail J Q Siu, Katarzyna Kania, Rachel Barrow-McGee, Iain Goulding, Jennifer J Gomm, Valerie Speirs, J Louise Jones, John C Marioni, Walid T Khaled.
      Here we use single-cell RNA sequencing to compile a human breast cell atlas assembled from 55 donors that had undergone reduction mammoplasties or risk reduction mastectomies. From more than 800,000 cells we identified 41 cell subclusters across the epithelial, immune and stromal compartments. The contribution of these different clusters varied according to the natural history of the tissue. Age, parity and germline mutations, known to modulate the risk of developing breast cancer, affected the homeostatic cellular state of the breast in different ways. We found that immune cells from BRCA1 or BRCA2 carriers had a distinct gene expression signature indicative of potential immune exhaustion, which was validated by immunohistochemistry. This suggests that immune-escape mechanisms could manifest in non-cancerous tissues very early during tumor initiation. This atlas is a rich resource that can be used to inform novel approaches for early detection and prevention of breast cancer.
    DOI:  https://doi.org/10.1038/s41588-024-01688-9
  46. Nature. 2024 Mar 22.
    Pregnancy advances your 'biological' age - but giving birth turns it back.
    Saima Sidik.
      
    Keywords:  Ageing; Epigenetics; Medical research
    DOI:  https://doi.org/10.1038/d41586-024-00843-w
  47. Cancer Discov. 2024 Mar 28.
    Spatially Segregated Macrophage Populations Predict Distinct Outcomes In Colon Cancer.
    Magdalena Matusiak, John W Hickey, David G P van IJzendoorn, Guolan Lu, Lukasz Kidzinski, Shirley Zhu, Deana R C Colburg, Bogdan Luca, Darci J Phillips, Sky W Brubaker, Gregory W Charville, Jeanne Shen, Kyle M Loh, Derick K Okwan-Duodu, Garry P Nolan, Aaron M Newman, Robert B West, Matt van de Rijn.
      Tumor-associated macrophages are transcriptionally heterogeneous, but the spatial distribution and cell interactions that shape macrophage tissue roles remain poorly characterized. Here, we spatially resolve five distinct human macrophage populations in normal and malignant human breast and colon tissue and reveal their cellular associations. This spatial map reveals that distinct macrophage populations reside in spatially segregated micro-environmental niches with conserved cellular compositions that are repeated across healthy and diseased tissue. We show that IL4I1+ macrophages phagocytose dying cells in areas with high cell turnover and predict good outcome in colon cancer. In contrast, SPP1+ macrophages are enriched in hypoxic and necrotic tumor regions and portend worse outcome in colon cancer. A subset of FOLR2+ macrophages is embedded in plasma cell niches. NLRP3+ macrophages co-localize with neutrophils and activate an inflammasome in tumors. Our findings indicate that a limited number of unique human macrophage niches function as fundamental building blocks in tissue.
    DOI:  https://doi.org/10.1158/2159-8290.CD-23-1300
  48. J Biol Chem. 2024 Mar 25. pii: S0021-9258(24)01729-0. [Epub ahead of print] 107232
    The constitutively active form of a key cholesterol synthesis enzyme is lipid droplet-localized and upregulated in endometrial cancer tissues.
    Hudson W Coates, Tina B Nguyen, Ximing Du, Ellen M Olzomer, Rhonda Farrell, Frances L Byrne, Hongyuan Yang, Andrew J Brown.
      Cholesterol is essential for both normal cell viability and cancer cell proliferation. Aberrant activity of squalene monooxygenase (SM, also known as squalene epoxidase or SQLE), the rate-limiting enzyme of the committed cholesterol synthesis pathway, is accordingly implicated in a growing list of cancers. We previously reported that hypoxia triggers the truncation of SM to a constitutively active form, thus preserving sterol synthesis during oxygen shortfalls. Here, we show SM truncation is upregulated and correlates with the magnitude of hypoxia in endometrial cancer tissues, supporting the in vivo relevance of our earlier work. To further investigate the pathophysiological consequences of SM truncation, we examine using complementary immunofluorescence and cell fractionation approaches its lipid droplet-localized pool and find that it exclusively comprises the truncated enzyme. This partitioning is facilitated by the loss of an endoplasmic reticulum-embedded region at the SM N-terminus, whereas the catalytic domain containing membrane-associated C-terminal helices is spared. Moreover, we determined multiple amphipathic helices contribute to the lipid droplet localization of trunSM. Taken together, our results expand on the striking differences between the two forms of SM and suggest upregulated truncation may contribute to SM-related oncogenesis.
    Keywords:  cancer; cholesterol; lipid droplets; protein degradation; squalene monooxygenase
    DOI:  https://doi.org/10.1016/j.jbc.2024.107232
  49. Commun Biol. 2024 Mar 28. 7(1): 377
    A semi-automatic method for extracting mitochondrial cristae characteristics from 3D focused ion beam scanning electron microscopy data.
    Chenhao Wang, Leif Østergaard, Stine Hasselholt, Jon Sporring.
      Mitochondria are the main suppliers of energy for cells and their bioenergetic function is regulated by mitochondrial dynamics: the constant changes in mitochondria size, shape, and cristae morphology to secure cell homeostasis. Although changes in mitochondrial function are implicated in a wide range of diseases, our understanding is challenged by a lack of reliable ways to extract spatial features from the cristae, the detailed visualization of which requires electron microscopy (EM). Here, we present a semi-automatic method for the segmentation, 3D reconstruction, and shape analysis of mitochondria, cristae, and intracristal spaces based on 2D EM images of the murine hippocampus. We show that our method provides a more accurate characterization of mitochondrial ultrastructure in 3D than common 2D approaches and propose an operational index of mitochondria's internal organization. With an improved consistency of 3D shape analysis and a decrease in the workload needed for large-scale analysis, we speculate that this tool will help increase our understanding of mitochondrial dynamics in health and disease.
    DOI:  https://doi.org/10.1038/s42003-024-06045-4
  50. Cancer Discov. 2024 Mar 28.
    BRCA1-mediated dual regulation of ferroptosis exposes a vulnerability to GPX4 and PARP co-inhibition in BRCA1-deficient cancers.
    Guang Lei, Chao Mao, Amber D Horbath, Yuelong Yan, Shirong Cai, Jun Yao, Yan Jiang, Mingchuang Sun, Xiaoguang Liu, Jun Cheng, Zhihao Xu, Hyemin Lee, Qidong Li, Zhengze Lu, Li Zhuang, Mei-Kuang Chen, Anagha Alapati, Timothy A Yap, Mien-Chie Hung, M James You, Helen Piwnica-Worms, Boyi Gan.
      Resistance to poly (ADP-ribose) polymerase inhibitors (PARPi) limits the therapeutic efficacy of PARP inhibition in treating breast cancer susceptibility gene 1 (BRCA1)-deficient cancers. Here we reveal that BRCA1 has a dual role in regulating ferroptosis. BRCA1 promotes the transcription of voltage-dependent anion channel 3 (VDAC3) and glutathione peroxidase 4 (GPX4); consequently, BRCA1 deficiency promotes cellular resistance to erastin-induced ferroptosis but sensitizes cancer cells to ferroptosis induced by GPX4 inhibitors (GPX4i). In addition, nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy and defective GPX4 induction unleash potent ferroptosis in BRCA1-deficient cancer cells upon PARPi and GPX4i co-treatment. Finally, we show that xenograft tumors derived from BRCA1-mutant breast cancer patients with PARPi resistance exhibit decreased GPX4 expression and high sensitivity to PARP and GPX4 co-inhibition. Our results show that BRCA1 deficiency induces a ferroptosis vulnerability to PARP and GPX4 co-inhibition and inform a therapeutic strategy for overcoming PARPi resistance in BRCA1-deficient cancers.
    DOI:  https://doi.org/10.1158/2159-8290.CD-23-1220
  51. J Cell Biol. 2024 May 06. pii: e202306051. [Epub ahead of print]223(5):
    OMA1 protease eliminates arrested protein import intermediates upon mitochondrial depolarization.
    Magda Krakowczyk, Anna M Lenkiewicz, Tomasz Sitarz, Dominika Malinska, Mayra Borrero, Ben Hur Marins Mussulini, Vanessa Linke, Andrzej A Szczepankiewicz, Joanna M Biazik, Agata Wydrych, Hanna Nieznanska, Remigiusz A Serwa, Agnieszka Chacinska, Piotr Bragoszewski.
      Most mitochondrial proteins originate from the cytosol and require transport into the organelle. Such precursor proteins must be unfolded to pass through translocation channels in mitochondrial membranes. Misfolding of transported proteins can result in their arrest and translocation failure. Arrested proteins block further import, disturbing mitochondrial functions and cellular proteostasis. Cellular responses to translocation failure have been defined in yeast. We developed the cell line-based translocase clogging model to discover molecular mechanisms that resolve failed import events in humans. The mechanism we uncover differs significantly from these described in fungi, where ATPase-driven extraction of blocked protein is directly coupled with proteasomal processing. We found human cells to rely primarily on mitochondrial factors to clear translocation channel blockage. The mitochondrial membrane depolarization triggered proteolytic cleavage of the stalled protein, which involved mitochondrial protease OMA1. The cleavage allowed releasing the protein fragment that blocked the translocase. The released fragment was further cleared in the cytosol by VCP/p97 and the proteasome.
    DOI:  https://doi.org/10.1083/jcb.202306051
  52. Elife. 2024 Mar 26. pii: RP90390. [Epub ahead of print]12
    A novel machine learning algorithm selects proteome signature to specifically identify cancer exosomes.
    Bingrui Li, Fernanda G Kugeratski, Raghu Kalluri.
      Non-invasive early cancer diagnosis remains challenging due to the low sensitivity and specificity of current diagnostic approaches. Exosomes are membrane-bound nanovesicles secreted by all cells that contain DNA, RNA, and proteins that are representative of the parent cells. This property, along with the abundance of exosomes in biological fluids makes them compelling candidates as biomarkers. However, a rapid and flexible exosome-based diagnostic method to distinguish human cancers across cancer types in diverse biological fluids is yet to be defined. Here, we describe a novel machine learning-based computational method to distinguish cancers using a panel of proteins associated with exosomes. Employing datasets of exosome proteins from human cell lines, tissue, plasma, serum, and urine samples from a variety of cancers, we identify Clathrin Heavy Chain (CLTC), Ezrin, (EZR), Talin-1 (TLN1), Adenylyl cyclase-associated protein 1 (CAP1), and Moesin (MSN) as highly abundant universal biomarkers for exosomes and define three panels of pan-cancer exosome proteins that distinguish cancer exosomes from other exosomes and aid in classifying cancer subtypes employing random forest models. All the models using proteins from plasma, serum, or urine-derived exosomes yield AUROC scores higher than 0.91 and demonstrate superior performance compared to Support Vector Machine, K Nearest Neighbor Classifier and Gaussian Naive Bayes. This study provides a reliable protein biomarker signature associated with cancer exosomes with scalable machine learning capability for a sensitive and specific non-invasive method of cancer diagnosis.
    Keywords:  Cancer; Exosomes; Machine learning; cancer biology; computational biology; diagnosis; human; systems biology
    DOI:  https://doi.org/10.7554/eLife.90390
  53. Nat Chem Biol. 2024 Mar 27.
    Fructose-1,6-bisphosphatase 1 dephosphorylates and inhibits TERT for tumor suppression.
    Min Li, Zheng Wang, Jingjing Tao, Hongfei Jiang, Huang Yang, Dong Guo, Hong Zhao, Xuxiao He, Shudi Luo, Xiaoming Jiang, Li Yuan, Liwei Xiao, Haiyan He, Rilei Yu, Jing Fang, Tingbo Liang, Zhengwei Mao, Daqian Xu, Zhimin Lu.
      Telomere dysfunction is intricately linked to the aging process and stands out as a prominent cancer hallmark. Here we demonstrate that telomerase activity is differentially regulated in cancer and normal cells depending on the expression status of fructose-1,6-bisphosphatase 1 (FBP1). In FBP1-expressing cells, FBP1 directly interacts with and dephosphorylates telomerase reverse transcriptase (TERT) at Ser227. Dephosphorylated TERT fails to translocate into the nucleus, leading to the inhibition of telomerase activity, reduction in telomere lengths, enhanced senescence and suppressed tumor cell proliferation and growth in mice. Lipid nanoparticle-mediated delivery of FBP1 mRNA inhibits liver tumor growth. Additionally, FBP1 expression levels inversely correlate with TERT pSer227 levels in renal and hepatocellular carcinoma specimens and with poor prognosis of the patients. These findings demonstrate that FBP1 governs cell immortality through its protein phosphatase activity and uncover a unique telomerase regulation in tumor cells attributed to the downregulation or deficiency of FBP1 expression.
    DOI:  https://doi.org/10.1038/s41589-024-01597-2
  54. Mol Cell. 2024 Mar 22. pii: S1097-2765(24)00184-9. [Epub ahead of print]
    Molecular determinants and signaling effects of PKA RIα phase separation.
    Julia C Hardy, Emily H Pool, Jessica G H Bruystens, Xin Zhou, Qingrong Li, Daojia R Zhou, Max Palay, Gerald Tan, Lisa Chen, Jaclyn L C Choi, Ha Neul Lee, Stefan Strack, Dong Wang, Susan S Taylor, Sohum Mehta, Jin Zhang.
      Spatiotemporal regulation of intracellular signaling molecules, such as the 3',5'-cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA), ensures proper cellular function. Liquid-liquid phase separation (LLPS) of the ubiquitous PKA regulatory subunit RIα promotes cAMP compartmentation and signaling specificity. However, the molecular determinants of RIα LLPS remain unclear. Here, we reveal that two separate dimerization interfaces, combined with the cAMP-induced unleashing of the PKA catalytic subunit (PKA-C) from the pseudosubstrate inhibitory sequence, drive RIα condensate formation in the cytosol of mammalian cells, which is antagonized by docking to A-kinase anchoring proteins. Strikingly, we find that the RIα pseudosubstrate region is critically involved in forming a non-canonical R:C complex, which recruits active PKA-C to RIα condensates to maintain low basal PKA activity in the cytosol. Our results suggest that RIα LLPS not only facilitates cAMP compartmentation but also spatially restrains active PKA-C, thus highlighting the functional versatility of biomolecular condensates in driving signaling specificity.
    Keywords:  biomolecular condensates; intrinsically disordered region; protein kinase; signaling compartmentation
    DOI:  https://doi.org/10.1016/j.molcel.2024.03.002
  55. Int J Mol Sci. 2024 Mar 20. pii: 3510. [Epub ahead of print]25(6):
    KEAP1-Mutant Lung Cancers Weaken Anti-Tumor Immunity and Promote an M2-like Macrophage Phenotype.
    Christopher J Occhiuto, Karen T Liby.
      Considerable advances have been made in lung cancer therapies, but there is still an unmet clinical need to improve survival for lung cancer patients. Immunotherapies have improved survival, although only 20-30% of patients respond to these treatments. Interestingly, cancers with mutations in Kelch-like ECH-associated protein 1 (KEAP1), the negative regulator of the nuclear factor erythroid 2-related factor 2 (NRF2) transcription factor, are resistant to immune checkpoint inhibition and correlate with decreased lymphoid cell infiltration. NRF2 is known for promoting an anti-inflammatory phenotype when activated in immune cells, but the study of NRF2 activation in cancer cells has not been adequately assessed. The objective of this study was to determine how lung cancer cells with constitutive NRF2 activity interact with the immune microenvironment to promote cancer progression. To assess, we generated CRISPR-edited mouse lung cancer cell lines by knocking out the KEAP1 or NFE2L2 genes and utilized a publicly available single-cell dataset through the Gene Expression Omnibus to investigate tumor/immune cell interactions. We show here that KEAP1-mutant cancers promote immunosuppression of the tumor microenvironment. Our data suggest KEAP1 deletion is sufficient to alter the secretion of cytokines, increase expression of immune checkpoint markers on cancer cells, and alter recruitment and differential polarization of immunosuppressive macrophages that ultimately lead to T-cell suppression.
    Keywords:  KEAP1; M2 polarization; NRF2 pathway; immunosuppression; lung cancer; macrophages
    DOI:  https://doi.org/10.3390/ijms25063510
  56. Cell Rep. 2024 Mar 23. pii: S2211-1247(24)00323-1. [Epub ahead of print]43(4): 113995
    ATF4-SLC7A11-GSH axis mediates the acquisition of immunosuppressive properties by activated CD4+ T cells in low arginine condition.
    Ziqi Zou, Qian Cheng, Jiajie Zhou, Chenyao Guo, Andreas V Hadjinicolaou, Mariolina Salio, Xinghua Liang, Cuiyu Yang, Yue Du, Weiran Yao, Dongrui Wang, Vincenzo Cerundolo, Qingqing Wang, Meng Xia.
      The tumor microenvironment (TME) is restricted in metabolic nutrients including the semi-essential amino acid arginine. While complete arginine deprivation causes T cell dysfunction, it remains unclear how arginine levels fluctuate in the TME to shape T cell fates. Here, we find that the 20-μM low arginine condition, representing the levels found in the plasma of patients with cancers, confers Treg-like immunosuppressive capacities upon activated T cells. In vivo mouse tumor models and human single-cell RNA-sequencing datasets reveal positive correlations between low arginine condition and intratumoral Treg accumulation. Mechanistically, low arginine-activated T cells engage in metabolic and transcriptional reprogramming, using the ATF4-SLC7A11-GSH axis, to preserve their suppressive function. These findings improve our understanding of the role of arginine in human T cell biology with potential applications for immunotherapy strategies.
    Keywords:  CP: Immunology; SLC7A11; T cells; arginine; immunosuppression; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.celrep.2024.113995
  57. Trends Cancer. 2024 Mar 22. pii: S2405-8033(24)00050-5. [Epub ahead of print]
    Poised epigenetic states dictate metastatic fitness.
    Rebeka Tomasin, Cyrus M Ghajar.
      Seeking to define early events that regulate disseminated tumor cell (DTC) fate upon their arrival to the lung, Jakab et al. reach the surprising conclusion that dormancy is determined by a cell autonomous poised epigenetic state that renders DTCs responsive to angiocrine Wnt signaling.
    Keywords:  Wnt; dormancy; epigenetics; metastasis; niche; plasticity
    DOI:  https://doi.org/10.1016/j.trecan.2024.03.001
  58. Elife. 2024 Mar 27. pii: RP89938. [Epub ahead of print]12
    Membrane contact sites regulate vacuolar fission via sphingolipid metabolism.
    Kazuki Hanaoka, Kensuke Nishikawa, Atsuko Ikeda, Philipp Schlarmann, Saku Sasaki, Sotaro Fujii, Sayumi Yamashita, Aya Nakaji, Kouichi Funato.
      Membrane contact sites (MCSs) are junctures that perform important roles including coordinating lipid metabolism. Previous studies have indicated that vacuolar fission/fusion processes are coupled with modifications in the membrane lipid composition. However, it has been still unclear whether MCS-mediated lipid metabolism controls the vacuolar morphology. Here, we report that deletion of tricalbins (Tcb1, Tcb2, and Tcb3), tethering proteins at endoplasmic reticulum (ER)-plasma membrane (PM) and ER-Golgi contact sites, alters fusion/fission dynamics and causes vacuolar fragmentation in the yeast Saccharomyces cerevisiae. In addition, we show that the sphingolipid precursor phytosphingosine (PHS) accumulates in tricalbin-deleted cells, triggering the vacuolar division. Detachment of the nucleus-vacuole junction (NVJ), an important contact site between the vacuole and the perinuclear ER, restored vacuolar morphology in both cells subjected to high exogenous PHS and Tcb3-deleted cells, supporting that PHS transport across the NVJ induces vacuole division. Thus, our results suggest that vacuolar morphology is maintained by MCSs through the metabolism of sphingolipids.
    Keywords:  S. cerevisiae; cell biology; membrane contact sites; sphingolipid; tricalbin; vacuolar morphology
    DOI:  https://doi.org/10.7554/eLife.89938
  59. EMBO Rep. 2024 Mar 28.
    Cell consciousness: a dissenting opinion : The cellular basis of consciousness theory lacks empirical evidence for its claims that all cells have consciousness.
    David G Robinson, Jon Mallatt, Wendy Ann Peer, Victor Sourjik, Lincoln Taiz.
      
    DOI:  https://doi.org/10.1038/s44319-024-00127-4
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