bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2024‒08‒11
forty-two papers selected by
Christian Frezza, Universität zu Köln
  1. SLC25A48 controls mitochondrial choline import and metabolism.
  2. Glycosphingolipid synthesis mediates immune evasion in KRAS-driven cancer.
  3. Hierarchical tricarboxylic acid cycle regulation by hepatocyte arginase 2 links the urea cycle to oxidative metabolism.
  4. Host-microbe interactions rewire metabolism in a C. elegans model of leucine breakdown deficiency.
  5. Metabolic and transcriptomic reprogramming during contact inhibition-induced quiescence is mediated by YAP-dependent and YAP-independent mechanisms.
  6. PTER is a N-acetyltaurine hydrolase that regulates feeding and obesity.
  7. Hif1α-dependent mitochondrial acute O2 sensing and signaling to myocyte Ca2+ channels mediate arterial hypoxic vasodilation.
  8. Mitochondrial copper overload promotes renal fibrosis via inhibiting pyruvate dehydrogenase activity.
  9. Stanniocalcin 2 governs cancer cell adaptation to nutrient insufficiency through alleviation of oxidative stress.
  10. Lysosomal TBK1 responds to amino acid availability to relieve Rab7-dependent mTORC1 inhibition.
  11. Neuro-intestinal acetylcholine signalling regulates the mitochondrial stress response in Caenorhabditis elegans.
  12. Quantitative principles of microbial metabolism shared across scales.
  13. Regulation of cancer cell lipid metabolism and oxidative phosphorylation by microenvironmental acidosis.
  14. Itaconate uptake via SLC13A3 improves hepatic antibacterial innate immunity.
  15. The polyunsaturated fatty acid docosahexaenoic affects mitochondrial function in prostate cancer cells.
  16. Purinosomes spatially co-localize with mitochondrial transporters.
  17. Age-associated clonal B cells drive B cell lymphoma in mice.
  18. Titration of RAS alters senescent state and influences tumour initiation.
  19. Tumour-intrinsic endomembrane trafficking by ARF6 shapes an immunosuppressive microenvironment that drives melanomagenesis and response to checkpoint blockade therapy.
  20. Stress pathway outputs are encoded by pH-dependent clustering of kinase components.
  21. Real-time assessment of mitochondrial DNA heteroplasmy dynamics at the single-cell level.
  22. An artificial metabzyme for tumour-cell-specific metabolic therapy.
  23. Integrated single-cell RNA-seq analysis reveals mitochondrial calcium signaling as a modulator of endothelial-to-mesenchymal transition.
  24. Hepatic BMAL1 and HIF1α regulate a time-dependent hypoxic response and prevent hepatopulmonary-like syndrome.
  25. Epigenetic repression of de novo cysteine synthetases induces intra-cellular accumulation of cysteine in hepatocarcinoma by up-regulating the cystine uptake transporter xCT.
  26. Intermittent clearance of p21-highly-expressing cells extends lifespan and confers sustained benefits to health and physical function.
  27. PERK-ATAD3A interaction provides a subcellular safe haven for protein synthesis during ER stress.
  28. Hif-2α programmes oxygen chemosensitivity in chromaffin cells.
  29. Redox heterogeneity in mouse embryonic stem cells individualizes cell fate decisions.
  30. The origin of novel traits in cancer.
  31. Epigenetic reprogramming driving successful and failed repair in acute kidney injury.
  32. Engineering new-to-nature biochemical conversions by combining fermentative metabolism with respiratory modules.
  33. Histone-methyltransferase KMT2D deficiency impairs the Fanconi anemia/BRCA pathway upon glycolytic inhibition in squamous cell carcinoma.
  34. Exploring the unmapped cysteine redox proteoform landscape.
  35. The genomic landscape of 2,023 colorectal cancers.
  36. Single-cell sensor analyses reveal signaling programs enabling Ras-G12C drug resistance.
  37. GCN2 is a determinant of the response to WEE1 kinase inhibition in small-cell lung cancer.
  38. Targeting fatty acid oxidation enhances response to HER2-targeted therapy.
  39. p16-dependent increase of PD-L1 stability regulates immunosurveillance of senescent cells.
  40. Zinc transporter 1 functions in copper uptake and cuproptosis.
  41. eIF4E-independent translation is largely eIF3d-dependent.
  42. A molecular pathway for cancer cachexia-induced muscle atrophy revealed at single-nucleus resolution.
  1. Cell Metab. 2024 Aug 01. pii: S1550-4131(24)00281-X. [Epub ahead of print]
    SLC25A48 controls mitochondrial choline import and metabolism.
    Anthony R P Verkerke, Xu Shi, Mark Li, Yusuke Higuchi, Tadashi Yamamuro, Daisuke Katoh, Hiroshi Nishida, Christopher Auger, Ichitaro Abe, Robert E Gerszten, Shingo Kajimura.
      Choline is an essential nutrient for the biosynthesis of phospholipids, neurotransmitters, and one-carbon metabolism with a critical step being its import into mitochondria. However, the underlying mechanisms and biological significance remain poorly understood. Here, we report that SLC25A48, a previously uncharacterized mitochondrial inner-membrane carrier protein, controls mitochondrial choline transport and the synthesis of choline-derived methyl donors. We found that SLC25A48 was required for brown fat thermogenesis, mitochondrial respiration, and mitochondrial membrane integrity. Choline uptake into the mitochondrial matrix via SLC25A48 facilitated the synthesis of betaine and purine nucleotides, whereas loss of SLC25A48 resulted in increased production of mitochondrial reactive oxygen species and imbalanced mitochondrial lipids. Notably, human cells carrying a single nucleotide polymorphism on the SLC25A48 gene and cancer cells lacking SLC25A48 exhibited decreased mitochondrial choline import, increased oxidative stress, and impaired cell proliferation. Together, this study demonstrates that SLC25A48 regulates mitochondrial choline catabolism, bioenergetics, and cell survival.
    Keywords:  bioenergetics; brown adipose tissue; cancer metabolism; choline; mitochondria; purine nucleotides
    DOI:  https://doi.org/10.1016/j.cmet.2024.07.010
  2. Nature. 2024 Aug 07.
    Glycosphingolipid synthesis mediates immune evasion in KRAS-driven cancer.
    Mariluz Soula, Gokhan Unlu, Rachel Welch, Aleksey Chudnovskiy, Beste Uygur, Vyom Shah, Hanan Alwaseem, Paul Bunk, Vishvak Subramanyam, Hsi-Wen Yeh, Artem Khan, Søren Heissel, Hani Goodarzi, Gabriel D Victora, Semir Beyaz, Kıvanç Birsoy.
      Cancer cells frequently alter their lipids to grow and adapt to their environment1-3. Despite the critical functions of lipid metabolism in membrane physiology, signalling and energy production, how specific lipids contribute to tumorigenesis remains incompletely understood. Here, using functional genomics and lipidomic approaches, we identified de novo sphingolipid synthesis as an essential pathway for cancer immune evasion. Synthesis of sphingolipids is surprisingly dispensable for cancer cell proliferation in culture or in immunodeficient mice but required for tumour growth in multiple syngeneic models. Blocking sphingolipid production in cancer cells enhances the anti-proliferative effects of natural killer and CD8+ T cells partly via interferon-γ (IFNγ) signalling. Mechanistically, depletion of glycosphingolipids increases surface levels of IFNγ receptor subunit 1 (IFNGR1), which mediates IFNγ-induced growth arrest and pro-inflammatory signalling. Finally, pharmacological inhibition of glycosphingolipid synthesis synergizes with checkpoint blockade therapy to enhance anti-tumour immune response. Altogether, our work identifies glycosphingolipids as necessary and limiting metabolites for cancer immune evasion.
    DOI:  https://doi.org/10.1038/s41586-024-07787-1
  3. Cell Metab. 2024 Aug 01. pii: S1550-4131(24)00278-X. [Epub ahead of print]
    Hierarchical tricarboxylic acid cycle regulation by hepatocyte arginase 2 links the urea cycle to oxidative metabolism.
    Yiming Zhang, Cassandra B Higgins, Stefani Tica, Joshua A Adams, Jiameng Sun, Shannon C Kelly, Xiaoyu Zong, Dennis J Dietzen, Terri Pietka, Samuel J Ballentine, Leah Shriver, Gary Patti, Yin Cao, Brian J DeBosch.
      Urea cycle impairment and its relationship to obesity and inflammation remained elusive, partly due to the dramatic clinical presentation of classical urea cycle defects. We generated mice with hepatocyte-specific arginase 2 deletion (Arg2LKO) and revealed a mild compensated urea cycle defect. Stable isotope tracing and respirometry revealed hepatocyte urea and TCA cycle flux defects, impaired mitochondrial oxidative metabolism, and glutamine anaplerosis despite normal energy and glucose homeostasis during early adulthood. Yet during middle adulthood, chow- and diet-induced obese Arg2LKO mice develop exaggerated glucose and lipid derangements, which are reversible by replacing the TCA cycle oxidative substrate nicotinamide adenine dinucleotide. Moreover, serum-based hallmarks of urea, TCA cycle, and mitochondrial derangements predict incident fibroinflammatory liver disease in 106,606 patients nearly a decade in advance. The data reveal hierarchical urea-TCA cycle control via ARG2 to drive oxidative metabolism. Moreover, perturbations in this circuit may causally link urea cycle compromise to fibroinflammatory liver disease.
    Keywords:  arginase; diabetes; fasting; metabolic dysfunction-associated steatohepatitis; metabolic dysfunction-associated steatotic liver disease; nicotinamide adenine dinucleotide; nicotinamide riboside; obesity; tricarboxylic acid cycle; urea cycle
    DOI:  https://doi.org/10.1016/j.cmet.2024.07.007
  4. Nat Metab. 2024 Aug 08.
    Host-microbe interactions rewire metabolism in a C. elegans model of leucine breakdown deficiency.
    Yong-Uk Lee, Bennett W Fox, Rui Guo, Brian J Curtis, Jingfang Yu, Sookyung Kim, Shivani Nanda, Victor Baumann, L Safak Yilmaz, Cole M Haynes, Frank C Schroeder, Albertha J M Walhout.
      In humans, defects in leucine catabolism cause a variety of inborn errors in metabolism. Here, we use Caenorhabditis elegans to investigate the impact of mutations in mccc-1, an enzyme that functions in leucine breakdown. Through untargeted metabolomic and transcriptomic analyses we find extensive metabolic rewiring that helps to detoxify leucine breakdown intermediates via conversion into previously undescribed metabolites and to synthesize mevalonate, an essential metabolite. We also find that the leucine breakdown product 3,3-hydroxymethylbutyrate (HMB), commonly used as a human muscle-building supplement, is toxic to C. elegans and that bacteria modulate this toxicity. Unbiased genetic screens revealed interactions between the host and microbe, where components of bacterial pyrimidine biosynthesis mitigate HMB toxicity. Finally, upregulated ketone body metabolism genes in mccc-1 mutants provide an alternative route for biosynthesis of the mevalonate precursor 3-hydroxy-3-methylglutaryl-CoA. Our work demonstrates that a complex host-bacteria interplay rewires metabolism to allow host survival when leucine catabolism is perturbed.
    DOI:  https://doi.org/10.1038/s42255-024-01098-5
  5. Nat Commun. 2024 Aug 08. 15(1): 6777
    Metabolic and transcriptomic reprogramming during contact inhibition-induced quiescence is mediated by YAP-dependent and YAP-independent mechanisms.
    Soeun Kang, Maciek R Antoniewicz, Nissim Hay.
      Metabolic rewiring during the proliferation-to-quiescence transition is poorly understood. Here, using a model of contact inhibition-induced quiescence, we conducted 13C-metabolic flux analysis in proliferating (P) and quiescent (Q) mouse embryonic fibroblasts (MEFs) to investigate this process. Q cells exhibit reduced glycolysis but increased TCA cycle flux and mitochondrial respiration. Reduced glycolytic flux in Q cells correlates with reduced glycolytic enzyme expression mediated by yes-associated protein (YAP) inhibition. The increased TCA cycle activity and respiration in Q cells is mediated by induced mitochondrial pyruvate carrier (MPC) expression, rendering them vulnerable to MPC inhibition. The malate-to-pyruvate flux, which generates NADPH, is markedly reduced by modulating malic enzyme 1 (ME1) dimerization in Q cells. Conversely, the malate dehydrogenase 1 (MDH1)-mediated oxaloacetate-to-malate flux is reversed and elevated in Q cells, driven by high mitochondrial-derived malate levels, reduced cytosolic oxaloacetate, elevated MDH1 levels, and a high cytoplasmic NAD+/NADH ratio. Transcriptomic analysis revealed large number of genes are induced in Q cells, many of which are associated with the extracellular matrix (ECM), while YAP-dependent and cell cycle-related genes are repressed. The results suggest that high TCA cycle flux and respiration in Q cells are required to generate ATP and amino acids to maintain de-novo ECM protein synthesis and secretion.
    DOI:  https://doi.org/10.1038/s41467-024-51117-y
  6. Nature. 2024 Aug 07.
    PTER is a N-acetyltaurine hydrolase that regulates feeding and obesity.
    Wei Wei, Xuchao Lyu, Andrew L Markhard, Sipei Fu, Rachel E Mardjuki, Peter E Cavanagh, Xianfeng Zeng, Jakub Rajniak, Nannan Lu, Shuke Xiao, Meng Zhao, Maria Dolores Moya-Garzon, Steven D Truong, Jonathan Chiu-Chun Chou, Lianna W Wat, Saranya Chidambaranathan-Reghupaty, Laetitia Coassolo, Duo Xu, Fangfang Shen, Wentao Huang, Cuauhtemoc B Ramirez, Cholsoon Jang, Lingyin Li, Katrin J Svensson, Michael A Fischbach, Jonathan Z Long.
      Taurine is a conditionally essential micronutrient and one of the most abundant amino acids in humans1-3. In endogenous taurine metabolism, dedicated enzymes are involved in the biosynthesis of taurine from cysteine and in the downstream metabolism of secondary taurine metabolites4,5. One taurine metabolite is N-acetyltaurine6. Levels of N-acetyltaurine are dynamically regulated by stimuli that alter taurine or acetate flux, including endurance exercise7, dietary taurine supplementation8 and alcohol consumption6,9. So far, the identities of the enzymes involved in N-acetyltaurine metabolism, and the potential functions of N-acetyltaurine itself, have remained unknown. Here we show that the body mass index associated orphan enzyme phosphotriesterase-related (PTER)10 is a physiological N-acetyltaurine hydrolase. In vitro, PTER catalyses the hydrolysis of N-acetyltaurine to taurine and acetate. In mice, PTER is expressed in the kidney, liver and brainstem. Genetic ablation of Pter in mice results in complete loss of tissue N-acetyltaurine hydrolysis activity and a systemic increase in N-acetyltaurine levels. After stimuli that increase taurine levels, Pter knockout mice exhibit reduced food intake, resistance to diet-induced obesity and improved glucose homeostasis. Administration of N-acetyltaurine to obese wild-type mice also reduces food intake and body weight in a GFRAL-dependent manner. These data place PTER into a central enzymatic node of secondary taurine metabolism and uncover a role for PTER and N-acetyltaurine in body weight control and energy balance.
    DOI:  https://doi.org/10.1038/s41586-024-07801-6
  7. Nat Commun. 2024 Aug 05. 15(1): 6649
    Hif1α-dependent mitochondrial acute O2 sensing and signaling to myocyte Ca2+ channels mediate arterial hypoxic vasodilation.
    Alejandro Moreno-Domínguez, Olalla Colinas, Ignacio Arias-Mayenco, José M Cabeza, Juan L López-Ogayar, Navdeep S Chandel, Norbert Weissmann, Natascha Sommer, Alberto Pascual, José López-Barneo.
      Vasodilation in response to low oxygen (O2) tension (hypoxic vasodilation) is an essential homeostatic response of systemic arteries that facilitates O2 supply to tissues according to demand. However, how blood vessels react to O2 deficiency is not well understood. A common belief is that arterial myocytes are O2-sensitive. Supporting this concept, it has been shown that the activity of myocyte L-type Ca2+channels, the main ion channels responsible for vascular contractility, is reversibly inhibited by hypoxia, although the underlying molecular mechanisms have remained elusive. Here, we show that genetic or pharmacological disruption of mitochondrial electron transport selectively abolishes O2 modulation of Ca2+ channels and hypoxic vasodilation. Mitochondria function as O2 sensors and effectors that signal myocyte Ca2+ channels due to constitutive Hif1α-mediated expression of specific electron transport subunit isoforms. These findings reveal the acute O2-sensing mechanisms of vascular cells and may guide new developments in vascular pharmacology.
    DOI:  https://doi.org/10.1038/s41467-024-51023-3
  8. Cell Mol Life Sci. 2024 Aug 09. 81(1): 340
    Mitochondrial copper overload promotes renal fibrosis via inhibiting pyruvate dehydrogenase activity.
    Saiya Zhu, Yangyang Niu, Wenqian Zhou, Yuqing Liu, Jing Liu, Xi Liu, Limin Lu, Chen Yu.
      Copper is a trace element essential for numerous biological activities, whereas the mitochondria serve as both major sites of intracellular copper utilization and copper reservoir. Here, we investigated the impact of mitochondrial copper overload on the tricarboxylic acid cycle, renal senescence and fibrosis. We found that copper ion levels are significantly elevated in the mitochondria in fibrotic kidney tissues, which are accompanied by reduced pyruvate dehydrogenase (PDH) activity, mitochondrial dysfunction, cellular senescence and renal fibrosis. Conversely, lowering mitochondrial copper levels effectively restore PDH enzyme activity, improve mitochondrial function, mitigate cellular senescence and renal fibrosis. Mechanically, we found that mitochondrial copper could bind directly to lipoylated dihydrolipoamide acetyltransferase (DLAT), the E2 component of the PDH complex, thereby changing the interaction between the subunits of lipoylated DLAT, inducing lipoylated DLAT protein dimerization, and ultimately inhibiting PDH enzyme activity. Collectively, our study indicates that mitochondrial copper overload could inhibit PDH activity, subsequently leading to mitochondrial dysfunction, cellular senescence and renal fibrosis. Reducing mitochondrial copper overload might therefore serve as a strategy to rescue renal fibrosis.
    Keywords:  Copper; Mitochondria; Pyruvate dehydrogenase; Renal fibrosis; Tricarboxylic acid (TCA) cycle
    DOI:  https://doi.org/10.1007/s00018-024-05358-1
  9. Cell Death Dis. 2024 Aug 06. 15(8): 567
    Stanniocalcin 2 governs cancer cell adaptation to nutrient insufficiency through alleviation of oxidative stress.
    Shuo Qie, Haijuan Xiong, Yaqi Liu, Chenhui Yan, Yalei Wang, Lifeng Tian, Chenguang Wang, Nianli Sang.
      Solid tumours often endure nutrient insufficiency during progression. How tumour cells adapt to temporal and spatial nutrient insufficiency remains unclear. We previously identified STC2 as one of the most upregulated genes in cells exposed to nutrient insufficiency by transcriptome screening, indicating the potential of STC2 in cellular adaptation to nutrient insufficiency. However, the molecular mechanisms underlying STC2 induction by nutrient insufficiency and subsequent adaptation remain elusive. Here, we report that STC2 protein is dramatically increased and secreted into the culture media by Gln-/Glc- deprivation. STC2 promoter contains cis-elements that are activated by ATF4 and p65/RelA, two transcription factors activated by a variety of cellular stress. Biologically, STC2 induction and secretion promote cell survival but attenuate cell proliferation during nutrient insufficiency, thus switching the priority of cancer cells from proliferation to survival. Loss of STC2 impairs tumour growth by inducing both apoptosis and necrosis in mouse xenografts. Mechanistically, under nutrient insufficient conditions, cells have increased levels of reactive oxygen species (ROS), and lack of STC2 further elevates ROS levels that lead to increased apoptosis. RNA-Seq analyses reveal STC2 induction suppresses the expression of monoamine oxidase B (MAOB), a mitochondrial membrane enzyme that produces ROS. Moreover, a negative correlation between STC2 and MAOB levels is also identified in human tumour samples. Importantly, the administration of recombinant STC2 to the culture media effectively suppresses MAOB expression as well as apoptosis, suggesting STC2 functions in an autocrine/paracrine manner. Taken together, our findings indicate that nutrient insufficiency induces STC2 expression, which in turn governs the adaptation of cancer cells to nutrient insufficiency through the maintenance of redox homoeostasis, highlighting the potential of STC2 as a therapeutic target for cancer treatment.
    DOI:  https://doi.org/10.1038/s41419-024-06961-7
  10. EMBO J. 2024 Aug 05.
    Lysosomal TBK1 responds to amino acid availability to relieve Rab7-dependent mTORC1 inhibition.
    Gabriel Talaia, Amanda Bentley-DeSousa, Shawn M Ferguson.
      Lysosomes play a pivotal role in coordinating macromolecule degradation and regulating cell growth and metabolism. Despite substantial progress in identifying lysosomal signaling proteins, understanding the pathways that synchronize lysosome functions with changing cellular demands remains incomplete. This study uncovers a role for TANK-binding kinase 1 (TBK1), well known for its role in innate immunity and organelle quality control, in modulating lysosomal responsiveness to nutrients. Specifically, we identify a pool of TBK1 that is recruited to lysosomes in response to elevated amino acid levels. This lysosomal TBK1 phosphorylates Rab7 on serine 72. This is critical for alleviating Rab7-mediated inhibition of amino acid-dependent mTORC1 activation. Furthermore, a TBK1 mutant (E696K) associated with amyotrophic lateral sclerosis and frontotemporal dementia constitutively accumulates at lysosomes, resulting in elevated Rab7 phosphorylation and increased mTORC1 activation. This data establishes the lysosome as a site of amino acid regulated TBK1 signaling that is crucial for efficient mTORC1 activation. This lysosomal pool of TBK1 has broader implications for lysosome homeostasis, and its dysregulation could contribute to the pathogenesis of ALS-FTD.
    Keywords:  ALS-FTD; Lysosome; Nutrient Sensing; TBK1; mTORC1
    DOI:  https://doi.org/10.1038/s44318-024-00180-8
  11. Nat Commun. 2024 Aug 03. 15(1): 6594
    Neuro-intestinal acetylcholine signalling regulates the mitochondrial stress response in Caenorhabditis elegans.
    Rebecca Cornell, Wei Cao, Bernie Harradine, Rasoul Godini, Ava Handley, Roger Pocock.
      Neurons coordinate inter-tissue protein homeostasis to systemically manage cytotoxic stress. In response to neuronal mitochondrial stress, specific neuronal signals coordinate the systemic mitochondrial unfolded protein response (UPRmt) to promote organismal survival. Yet, whether chemical neurotransmitters are sufficient to control the UPRmt in physiological conditions is not well understood. Here, we show that gamma-aminobutyric acid (GABA) inhibits, and acetylcholine (ACh) promotes the UPRmt in the Caenorhabditis elegans intestine. GABA controls the UPRmt by regulating extra-synaptic ACh release through metabotropic GABAB receptors GBB-1/2. We find that elevated ACh levels in animals that are GABA-deficient or lack ACh-degradative enzymes induce the UPRmt through ACR-11, an intestinal nicotinic α7 receptor. This neuro-intestinal circuit is critical for non-autonomously regulating organismal survival of oxidative stress. These findings establish chemical neurotransmission as a crucial regulatory layer for nervous system control of systemic protein homeostasis and stress responses.
    DOI:  https://doi.org/10.1038/s41467-024-50973-y
  12. Nat Microbiol. 2024 Aug;9(8): 1940-1953
    Quantitative principles of microbial metabolism shared across scales.
    Daniel Sher, Daniel Segrè, Michael J Follows.
      Metabolism is the complex network of chemical reactions occurring within every cell and organism, maintaining life, mediating ecosystem processes and affecting Earth's climate. Experiments and models of microbial metabolism often focus on one specific scale, overlooking the connectivity between molecules, cells and ecosystems. Here we highlight quantitative metabolic principles that exhibit commonalities across scales, which we argue could help to achieve an integrated perspective on microbial life. Mass, electron and energy balance provide quantitative constraints on their flow within metabolic networks, organisms and ecosystems, shaping how each responds to its environment. The mechanisms underlying these flows, such as enzyme-substrate interactions, often involve encounter and handling stages that are represented by equations similar to those for cells and resources, or predators and prey. We propose that these formal similarities reflect shared principles and discuss how their investigation through experiments and models may contribute to a common language for studying microbial metabolism across scales.
    DOI:  https://doi.org/10.1038/s41564-024-01764-0
  13. Am J Physiol Cell Physiol. 2024 Aug 05.
    Regulation of cancer cell lipid metabolism and oxidative phosphorylation by microenvironmental acidosis.
    Michala G Rolver, Marc Severin, Stine F Pedersen.
      The expansion of cancer cell mass in solid tumors generates a harsh environment characterized by dynamically varying levels of acidosis, hypoxia and nutrient deprivation. Because acidosis inhibits glycolytic metabolism and hypoxia inhibits oxidative phosphorylation, cancer cells that survive and grow in these environments must rewire their metabolism and develop a high degree of metabolic plasticity to meet their energetic and biosynthetic demands. Cancer cells frequently upregulate pathways enabling the uptake and utilization of lipids and other nutrients derived from dead or recruited stromal cells, and in particular lipid uptake is strongly enhanced in acidic microenvironments. The resulting lipid accumulation and increased reliance on β-oxidation and mitochondrial metabolism increases susceptibility to oxidative stress, lipotoxicity and ferroptosis, in turn driving changes that may mitigate such risks. The spatially and temporally heterogeneous tumor microenvironment thus selects for invasive, metabolically flexible, and resilient cancer cells capable of exploiting their local conditions as well as of seeking out more favorable surroundings. This phenotype relies on the interplay between metabolism, acidosis and oncogenic mutations, driving metabolic signaling pathways such as peroxisome proliferator-activated receptors (PPARs). Understanding the particular vulnerabilities of such cells may uncover novel therapeutic liabilities of the most aggressive cancer cells.
    Keywords:  ferroptosis; lipid metabolism; mitochondria; oxidative phosphorylation; peroxisomes
    DOI:  https://doi.org/10.1152/ajpcell.00429.2024
  14. Dev Cell. 2024 Aug 03. pii: S1534-5807(24)00448-9. [Epub ahead of print]
    Itaconate uptake via SLC13A3 improves hepatic antibacterial innate immunity.
    Chao Chen, Caiyun Liu, Pengkai Sun, Zhenxing Zhang, Zhimin Wang, Ping Liu, Xinjian Li.
      Itaconate is an immunoregulatory metabolite produced by the mitochondrial enzyme immune-responsive gene 1 (IRG1) in inflammatory macrophages. We recently identified an important mechanism by which itaconate is released from inflammatory macrophages. However, it remains unknown whether extracellular itaconate is taken up by non-myeloid cells to exert immunoregulatory functions. Here, we used a custom-designed CRISPR screen to identify the dicarboxylate transporter solute carrier family 13 member 3 (SLC13A3) as an itaconate importer and to characterize the role of SLC13A3 in itaconate-improved hepatic antibacterial innate immunity. Functionally, liver-specific deletion of Slc13a3 impairs hepatic antibacterial innate immunity in vivo and in vitro. Mechanistically, itaconate uptake via SLC13A3 induces transcription factor EB (TFEB)-dependent lysosomal biogenesis and subsequently improves antibacterial innate immunity in mouse hepatocytes. These findings identify SLC13A3 as a key itaconate importer in mouse hepatocytes and will aid in the development of potent itaconate-based antibacterial therapeutics.
    Keywords:  SLC13A3; TFEB; antibacterial innate immunity; importer; itaconate; lysosomal biogenesis
    DOI:  https://doi.org/10.1016/j.devcel.2024.07.011
  15. Cancer Metab. 2024 Aug 07. 12(1): 24
    The polyunsaturated fatty acid docosahexaenoic affects mitochondrial function in prostate cancer cells.
    Guilherme Henrique Tamarindo, Caroline Fidalgo Ribeiro, Alana Della Torre Silva, Alex Castro, Ícaro Putinhon Caruso, Fátima Pereira Souza, Sebastião Roberto Taboga, Massimo Loda, Rejane Maira Góes.
      BACKGROUND: Prostate cancer (PCa) shows a rewired metabolism featuring increased fatty acid uptake and synthesis via de novo lipogenesis, both sharply related to mitochondrial physiology. The docosahexaenoic acid (DHA) is an omega-3 polyunsaturated fatty acid (PUFA) that exerts its antitumoral properties via different mechanisms, but its specific action on mitochondria in PCa is not clear. Therefore, we investigated whether the DHA modulates mitochondrial function in PCa cell lines.METHODS: Here, we evaluated mitochondrial function of non-malignant PNT1A and the castration-resistant (CRPC) prostate 22Rv1 and PC3 cell lines in response to DHA incubation. For this purpose, we used Seahorse extracellular flux assay to assess mitochondria function, [14C]-glucose to evaluate its oxidation as well as its contribution to fatty acid synthesis, 1H-NMR for metabolite profile determination, MitoSOX for superoxide anion production, JC-1 for mitochondrial membrane polarization, mass spectrometry for determination of phosphatidylglycerol levels and composition, staining with MitoTracker dye to assess mitochondrial morphology under super-resolution in addition to Transmission Electron Microscopy, In-Cell ELISA for COX-I and SDH-A protein expression and flow cytometry (Annexin V and 7-AAD) for cell death estimation.
    RESULTS: In all cell lines DHA decreased basal respiratory activity, ATP production, and the spare capacity in mitochondria. Also, the omega-3 induced mitochondrial hyperpolarization, ROS overproduction and changes in membrane phosphatidylglycerol composition. In PNT1A, DHA led to mitochondrial fragmentation and it increased glycolysis while in cancer cells it stimulated glucose oxidation, but decreased de novo lipogenesis specifically in 22Rv1, indicating a metabolic shift. In all cell lines, DHA modulated several metabolites related to energy metabolism and it was incorporated in phosphatidylglycerol, a precursor of cardiolipin, increasing the unsaturation index in the mitochondrial membrane. Accordingly, DHA triggered cell death mainly in PNT1A and 22Rv1.
    CONCLUSION: In conclusion, mitochondrial metabolism is significantly affected by the PUFA supplementation to the point that cells are not able to proliferate or survive under DHA-enriched condition. Moreover, combination of DHA supplementation with inhibition of metabolism-related pathways, such as de novo lipogenesis, may be synergistic in castration-resistant prostate cancer.
    Keywords:  Docosahexaenoic acid; Lipid metabolism; Mitochondria; Omega-3 polyunsaturated fatty acids; Prostate cancer cells
    DOI:  https://doi.org/10.1186/s40170-024-00348-0
  16. J Biol Chem. 2024 Aug 02. pii: S0021-9258(24)02121-5. [Epub ahead of print] 107620
    Purinosomes spatially co-localize with mitochondrial transporters.
    Zhou Sha, Stephen J Benkovic.
      In this study, we advance our understanding of the spatial relationship between the purinosome, a liquid condensate consisting of six enzymes involved in de novo purine biosynthesis, and mitochondria. Previous research has shown that purinosomes move along tubulin toward mitochondria, suggesting a direct uptake of glycine from mitochondria. Here, we propose that the purinosome is located proximally to the mitochondrial transporters SLC25A13 and SLC25A38, facilitating the uptake of glycine, aspartate, and glutamate, essential factors for purine synthesis. We utilized the proximity ligation assay (PLA) and APEX proximity labeling to investigate the association between purinosome proteins and mitochondrial transporters. Our results indicate that purinosome assembly occurs close to the mitochondrial membrane under purine-deficient conditions, with the transporters migrating to be adjacent to the purinosome. Furthermore, both targeted and non-targeted analyses suggest that the SLC25A13-APEX2-V5 probe accurately reflects endogenous cellular status. These findings provide insights into the spatial organization of purine biosynthesis and lay the groundwork for further investigations into additional proteins involved in this pathway.
    Keywords:  APEX; Purinosomes; de novo purine biosynthesis; mitochondrial transporter; proximity ligation assay (PLA)
    DOI:  https://doi.org/10.1016/j.jbc.2024.107620
  17. Nat Aging. 2024 Aug 08.
    Age-associated clonal B cells drive B cell lymphoma in mice.
    José P Castro, Anastasia V Shindyapina, Alessandro Barbieri, Kejun Ying, Olga S Strelkova, João A Paulo, Alexander Tyshkovskiy, Rico Meinl, Csaba Kerepesi, Anna P Petrashen, Marco Mariotti, Margarita V Meer, Yan Hu, Alexander Karamyshev, Grigoriy Losyev, Mafalda Galhardo, Elsa Logarinho, Artur A Indzhykulian, Steven P Gygi, John M Sedivy, John P Manis, Vadim N Gladyshev.
      Although cancer is an age-related disease, how the processes of aging contribute to cancer progression is not well understood. In this study, we uncovered how mouse B cell lymphoma develops as a consequence of a naturally aged system. We show here that this malignancy is associated with an age-associated clonal B cell (ACBC) population that likely originates from age-associated B cells. Driven by c-Myc activation, promoter hypermethylation and somatic mutations, IgM+ ACBCs clonally expand independently of germinal centers and show increased biological age. ACBCs become self-sufficient and support malignancy when transferred into young recipients. Inhibition of mTOR or c-Myc in old mice attenuates pre-malignant changes in B cells during aging. Although the etiology of mouse and human B cell lymphomas is considered distinct, epigenetic changes in transformed mouse B cells are enriched for changes observed in human B cell lymphomas. Together, our findings characterize the spontaneous progression of cancer during aging through both cell-intrinsic and microenvironmental changes and suggest interventions for its prevention.
    DOI:  https://doi.org/10.1038/s43587-024-00671-7
  18. Nature. 2024 Aug 07.
    Titration of RAS alters senescent state and influences tumour initiation.
    Adelyne S L Chan, Haoran Zhu, Masako Narita, Liam D Cassidy, Andrew R J Young, Camino Bermejo-Rodriguez, Aleksandra T Janowska, Hung-Chang Chen, Sarah Gough, Naoki Oshimori, Lars Zender, Sarah J Aitken, Matthew Hoare, Masashi Narita.
      Oncogenic RAS-induced senescence (OIS) is an autonomous tumour suppressor mechanism associated with premalignancy1,2. Achieving this phenotype typically requires a high level of oncogenic stress, yet the phenotype provoked by lower oncogenic dosage remains unclear. Here we develop oncogenic RAS dose-escalation models in vitro and in vivo, revealing a RAS dose-driven non-linear continuum of downstream phenotypes. In a hepatocyte OIS model in vivo, ectopic expression of NRAS(G12V) does not induce tumours, in part owing to OIS-driven immune clearance3. Single-cell RNA sequencing analyses reveal distinct hepatocyte clusters with typical OIS or progenitor-like features, corresponding to high and intermediate levels of NRAS(G12V), respectively. When titred down, NRAS(G12V)-expressing hepatocytes become immune resistant and develop tumours. Time-series monitoring at single-cell resolution identifies two distinct tumour types: early-onset aggressive undifferentiated and late-onset differentiated hepatocellular carcinoma. The molecular signature of each mouse tumour type is associated with different progenitor features and enriched in distinct human hepatocellular carcinoma subclasses. Our results define the oncogenic dosage-driven OIS spectrum, reconciling the senescence and tumour initiation phenotypes in early tumorigenesis.
    DOI:  https://doi.org/10.1038/s41586-024-07797-z
  19. Nat Commun. 2024 Aug 04. 15(1): 6613
    Tumour-intrinsic endomembrane trafficking by ARF6 shapes an immunosuppressive microenvironment that drives melanomagenesis and response to checkpoint blockade therapy.
    Yinshen Wee, Junhua Wang, Emily C Wilson, Coulson P Rich, Aaron Rogers, Zongzhong Tong, Evelyn DeGroot, Y N Vashisht Gopal, Michael A Davies, H Atakan Ekiz, Joshua K H Tay, Chris Stubben, Kenneth M Boucher, Juan M Oviedo, Keke C Fairfax, Matthew A Williams, Sheri L Holmen, Roger K Wolff, Allie H Grossmann.
      Tumour-host immune interactions lead to complex changes in the tumour microenvironment (TME), impacting progression, metastasis and response to therapy. While it is clear that cancer cells can have the capacity to alter immune landscapes, our understanding of this process is incomplete. Herein we show that endocytic trafficking at the plasma membrane, mediated by the small GTPase ARF6, enables melanoma cells to impose an immunosuppressive TME that accelerates tumour development. This ARF6-dependent TME is vulnerable to immune checkpoint blockade therapy (ICB) but in murine melanoma, loss of Arf6 causes resistance to ICB. Likewise, downregulation of ARF6 in patient tumours correlates with inferior overall survival after ICB. Mechanistically, these phenotypes are at least partially explained by ARF6-dependent recycling, which controls plasma membrane density of the interferon-gamma receptor. Collectively, our findings reveal the importance of endomembrane trafficking in outfitting tumour cells with the ability to shape their immune microenvironment and respond to immunotherapy.
    DOI:  https://doi.org/10.1038/s41467-024-50881-1
  20. Nat Commun. 2024 Aug 05. 15(1): 6614
    Stress pathway outputs are encoded by pH-dependent clustering of kinase components.
    Yuliia Didan, Milad Ghomlaghi, Lan K Nguyen, Dominic C H Ng.
      Signal processing by intracellular kinases controls near all biological processes but how signal pathway functions evolve with changed cellular context is poorly understood. Functional specificity of c-Jun N-terminal Kinases (JNK) are partly encoded by signal strength. Here we reveal that intracellular pH (pHi) is a significant component of the JNK network and defines signal response to specific stimuli. We show pHi regulates JNK activity in response to cell stress, with the relationship between pHi and JNK activity dependent on specific stimuli and upstream kinases activated. Using the optogenetic clustering tag CRY2, we show that an increase in pHi promotes the light-induced phase transition of ASK1 to augment JNK activation. While increased pHi similarly promoted CRY2-tagged JNK2 to form light-induced condensates, this attenuated JNK activity. Mathematical modelling of feedback signalling incorporating pHi and differential contributions by ASK1 and JNK2 condensates was sufficient to delineate signal responses to specific stimuli. Taking pHi and ASK1/JNK2 signal contributions into consideration may delineate oncogenic versus tumour suppressive JNK functions and cancer cell drug responses.
    DOI:  https://doi.org/10.1038/s41467-024-50638-w
  21. EMBO J. 2024 Aug 05.
    Real-time assessment of mitochondrial DNA heteroplasmy dynamics at the single-cell level.
    Rodaria Roussou, Dirk Metzler, Francesco Padovani, Felix Thoma, Rebecca Schwarz, Boris Shraiman, Kurt M Schmoller, Christof Osman.
      Mitochondrial DNA (mtDNA) is present in multiple copies within cells and is required for mitochondrial ATP generation. Even within individual cells, mtDNA copies can differ in their sequence, a state known as heteroplasmy. The principles underlying dynamic changes in the degree of heteroplasmy remain incompletely understood, due to the inability to monitor this phenomenon in real time. Here, we employ mtDNA-based fluorescent markers, microfluidics, and automated cell tracking, to follow mtDNA variants in live heteroplasmic yeast populations at the single-cell level. This approach, in combination with direct mtDNA tracking and data-driven mathematical modeling reveals asymmetric partitioning of mtDNA copies during cell division, as well as limited mitochondrial fusion and fission frequencies, as critical driving forces for mtDNA variant segregation. Given that our approach also facilitates assessment of segregation between intact and mutant mtDNA, we anticipate that it will be instrumental in elucidating the mechanisms underlying the purifying selection of mtDNA.
    Keywords:  Heteroplasmy; Mathematical Modeling; Mitochondria; Mitochondrial Fission; mtDNA
    DOI:  https://doi.org/10.1038/s44318-024-00183-5
  22. Nat Nanotechnol. 2024 Aug 05.
    An artificial metabzyme for tumour-cell-specific metabolic therapy.
    Xi Hu, Bo Zhang, Miao Zhang, Wenshi Liang, Bangzhen Hong, Zhiyuan Ma, Jianpeng Sheng, Tianqi Liu, Shengfei Yang, Zeyu Liang, Jichao Zhang, Chunhai Fan, Fangyuan Li, Daishun Ling.
      Metabolic dysregulation constitutes a pivotal feature of cancer progression. Enzymes with multiple metal active sites play a major role in this process. Here we report the first metabolic-enzyme-like FeMoO4 nanocatalyst, dubbed 'artificial metabzyme'. It showcases dual active centres, namely, Fe2+ and tetrahedral Mo4+, that mirror the characteristic architecture of the archetypal metabolic enzyme xanthine oxidoreductase. Employing spatially dynamic metabolomics in conjunction with the assessments of tumour-associated metabolites, we demonstrate that FeMoO4 metabzyme catalyses the metabolic conversion of tumour-abundant xanthine into uric acid. Subsequent metabolic adjustments orchestrate crosstalk with immune cells, suggesting a potential therapeutic pathway for cancer. Our study introduces an innovative paradigm in cancer therapy, where tumour cells are metabolically reprogrammed to autonomously modulate and directly interface with immune cells through the intervention of an artificial metabzyme, for tumour-cell-specific metabolic therapy.
    DOI:  https://doi.org/10.1038/s41565-024-01733-y
  23. Sci Adv. 2024 Aug 09. 10(32): eadp6182
    Integrated single-cell RNA-seq analysis reveals mitochondrial calcium signaling as a modulator of endothelial-to-mesenchymal transition.
    Mathilde Lebas, Giorgia Chinigò, Evan Courmont, Louay Bettaieb, Amani Machmouchi, Jermaine Goveia, Aleksandar Beatovic, Job Van Kerckhove, Cyril Robil, Fabiola Silva Angulo, Mauro Vedelago, Alina Errerd, Lucas Treps, Vance Gao, Hilda C Delgado De la Herrán, Alicia Mayeuf-Louchart, Laurent L'homme, Mohamed Chamlali, Camille Dejos, Valérie Gouyer, Venkata Naga Srikanth Garikipati, Dhanendra Tomar, Hao Yin, Hajime Fukui, Stefan Vinckier, Anneke Stolte, Lena-Christin Conradi, Fabrice Infanti, Loic Lemonnier, Elisabeth Zeisberg, Yonglun Luo, Lin Lin, Jean-Luc Desseyn, J Pickering, Raj Kishore, Muniswamy Madesh, David Dombrowicz, Fabiana Perocchi, Bart Staels, Alessandra Fiorio Pla, Dimitra Gkika, Anna Rita Cantelmo.
      Endothelial cells (ECs) are highly plastic, capable of differentiating into various cell types. Endothelial-to-mesenchymal transition (EndMT) is crucial during embryonic development and contributes substantially to vascular dysfunction in many cardiovascular diseases (CVDs). While targeting EndMT holds therapeutic promise, understanding its mechanisms and modulating its pathways remain challenging. Using single-cell RNA sequencing on three in vitro EndMT models, we identified conserved gene signatures. We validated original regulators in vitro and in vivo during embryonic heart development and peripheral artery disease. EndMT induction led to global expression changes in all EC subtypes rather than in mesenchymal clusters. We identified mitochondrial calcium uptake as a key driver of EndMT; inhibiting mitochondrial calcium uniporter (MCU) prevented EndMT in vitro, and conditional Mcu deletion in ECs blocked mesenchymal activation in a hind limb ischemia model. Tissues from patients with critical limb ischemia with EndMT features exhibited significantly elevated endothelial MCU. These findings highlight MCU as a regulator of EndMT and a potential therapeutic target.
    DOI:  https://doi.org/10.1126/sciadv.adp6182
  24. Cell Metab. 2024 Jul 30. pii: S1550-4131(24)00274-2. [Epub ahead of print]
    Hepatic BMAL1 and HIF1α regulate a time-dependent hypoxic response and prevent hepatopulmonary-like syndrome.
    Vaishnavi Dandavate, Nityanand Bolshette, Rachel Van Drunen, Gal Manella, Hanna Bueno-Levy, Mirie Zerbib, Ippei Kawano, Marina Golik, Yaarit Adamovich, Gad Asher.
      The transcriptional response to hypoxia is temporally regulated, yet the molecular underpinnings and physiological implications are unknown. We examined the roles of hepatic Bmal1 and Hif1α in the circadian response to hypoxia in mice. We found that the majority of the transcriptional response to hypoxia is dependent on either Bmal1 or Hif1α, through shared and distinct roles that are daytime determined. We further show that hypoxia-inducible factor (HIF)1α accumulation upon hypoxia is temporally regulated and Bmal1 dependent. Unexpectedly, mice lacking both hepatic Bmal1 and Hif1α are hypoxemic and exhibit increased mortality upon hypoxic exposure in a daytime-dependent manner. These mice display mild liver dysfunction with pulmonary vasodilation likely due to extracellular signaling regulated kinase (ERK) activation, endothelial nitric oxide synthase, and nitric oxide accumulation in lungs, suggestive of hepatopulmonary syndrome. Our findings indicate that hepatic BMAL1 and HIF1α are key time-dependent regulators of the hypoxic response and can provide molecular insights into the pathophysiology of hepatopulmonary syndrome.
    Keywords:  BMAL1; HIF1α; circadian clocks; contrast echocardiography; hepatopulmonary syndrome; hypoxia; lung single-cell RNA-seq; nitric oxide; pulmonary vasodilation
    DOI:  https://doi.org/10.1016/j.cmet.2024.07.003
  25. Cancer Metab. 2024 Aug 07. 12(1): 23
    Epigenetic repression of de novo cysteine synthetases induces intra-cellular accumulation of cysteine in hepatocarcinoma by up-regulating the cystine uptake transporter xCT.
    Tomoaki Yamauchi, Yumi Okano, Daishu Terada, Sai Yasukochi, Akito Tsuruta, Yuya Tsurudome, Kentaro Ushijima, Naoya Matsunaga, Satoru Koyanagi, Shigehiro Ohdo.
      BACKGROUND: The metabolic reprogramming of amino acids is critical for cancer cell growth and survival. Notably, intracellular accumulation of cysteine is often observed in various cancers, suggesting its potential role in alleviating the oxidative stress associated with rapid proliferation. The liver is the primary organ for cysteine biosynthesis, but much remains unknown about the metabolic alterations of cysteine and their mechanisms in hepatocellular carcinoma cells.METHODS: RNA-seq data from patients with hepatocarcinoma were analyzed using the TNMplot database. The underlying mechanism of the oncogenic alteration of cysteine metabolism was studied in mice implanted with BNL 1ME A.7 R.1 hepatocarcinoma.
    RESULTS: Database analysis of patients with hepatocellular carcinoma revealed that the expression of enzymes involved in de novo cysteine synthesis was down-regulated accompanying with increased expression of the cystine uptake transporter xCT. Similar alterations in gene expression have also been observed in a syngeneic mouse model of hepatocarcinoma. The enhanced expression of DNA methyltransferase in murine hepatocarcinoma cells caused methylation of the upstream regions of cysteine synthesis genes, thereby repressing their expression. Conversely, suppression of de novo cysteine synthesis in healthy liver cells induced xCT expression by up-regulating the oxidative-stress response factor NRF2, indicating that reduced de novo cysteine synthesis repulsively increases cystine uptake via enhanced xCT expression, leading to intracellular cysteine accumulation. Furthermore, the pharmacological inhibition of xCT activity decreased intracellular cysteine levels and suppressed hepatocarcinoma tumor growth in mice.
    CONCLUSIONS: Our findings indicate an underlying mechanism of the oncogenic alteration of cysteine metabolism in hepatocarcinoma and highlight the efficacy of alteration of cysteine metabolism as a viable therapeutic target in cancer.
    Keywords:  Cysteine metabolism; DNA methylation; Erastin; Hepatocarcinoma; NRF2; de novo cysteine synthesis; xCT
    DOI:  https://doi.org/10.1186/s40170-024-00352-4
  26. Cell Metab. 2024 Aug 06. pii: S1550-4131(24)00277-8. [Epub ahead of print]36(8): 1795-1805.e6
    Intermittent clearance of p21-highly-expressing cells extends lifespan and confers sustained benefits to health and physical function.
    Binsheng Wang, Lichao Wang, Nathan S Gasek, Chia-Ling Kuo, Jia Nie, Taewan Kim, Pengyi Yan, Junyu Zhu, Blake L Torrance, Yueying Zhou, Lisa C Flores, Colton Allen, Allison M Andrade, Chun Guo, Rachel L Cohn, Evan R Jellison, Jenna M Bartley, George A Kuchel, Sheng Li, Tamar Pirtskhalava, Tamar Tchkonia, Sumit Yadav, Laura Haynes, James L Kirkland, Yuji Ikeno, Ming Xu.
      A key challenge in aging research is extending lifespan in tandem with slowing down functional decline so that life with good health (healthspan) can be extended. Here, we show that monthly clearance, starting from 20 months, of a small number of cells that highly express p21Cip1 (p21high) improves cardiac and metabolic function and extends both median and maximum lifespans in mice. Importantly, by assessing the health and physical function of these mice monthly until death, we show that clearance of p21high cells improves physical function at all remaining stages of life, suggesting healthspan extension. Mechanistically, p21high cells encompass several cell types with a relatively conserved proinflammatory signature. Clearance of p21high cells reduces inflammation and alleviates age-related transcriptomic signatures of various tissues. These findings demonstrate the feasibility of healthspan extension in mice and indicate p21high cells as a therapeutic target for healthy aging.
    Keywords:  aging; cellular senescence; frailty; inflammation; morbidity compression
    DOI:  https://doi.org/10.1016/j.cmet.2024.07.006
  27. Science. 2024 Aug 08. eadp7114
    PERK-ATAD3A interaction provides a subcellular safe haven for protein synthesis during ER stress.
    Karinder K Brar, Daniel T Hughes, Jordan L Morris, Kelly Subramanian, Shivaani Krishna, Fei Gao, Lara-Sophie Rieder, Sebastian Uhrig, Joshua Freeman, Heather L Smith, Rebekkah Jukes-Jones, Edward Avezov, Jodi Nunnari, Julien Prudent, Adrian J Butcher, Giovanna R Mallucci.
      Endoplasmic Reticulum (ER) stress induces repression of protein synthesis throughout the cell. Attempts to understand how localized stress leads to widespread repression have been limited by difficulties in resolving translation rates at the subcellular level. Here, using live-cell imaging of reporter mRNA translation, we unexpectedly found that during ER stress active translation at mitochondria was significantly protected. The mitochondrial protein, ATAD3A, interacted with PERK and mediated this effect on localized translation by competing for binding with PERK's target, eIF2. PERK-ATAD3A interactions increased during ER stress, forming mitochondria-ER contact sites. Furthermore, ATAD3A binding attenuated local PERK signaling and rescued the expression of some mitochondrial proteins. Thus, PERK-ATAD3A interactions can control translational repression at a subcellular level, mitigating the impact of ER stress on the cell.
    DOI:  https://doi.org/10.1126/science.adp7114
  28. J Clin Invest. 2024 Aug 06. pii: e174661. [Epub ahead of print]
    Hif-2α programmes oxygen chemosensitivity in chromaffin cells.
    Maria Prange-Barczynska, Holly A Jones, Yoichiro Sugimoto, Xiaotong Cheng, Joanna Dcc Lima, Indrika Ratnayaka, Gillian Douglas, Keith J Buckler, Peter J Ratcliffe, Thomas P Keeley, Tammie Bishop.
      The study of transcription factors that determine specialised neuronal functions has provided invaluable insights into the physiology of the nervous system. Peripheral chemoreceptors are neurone-like electro-physiologically excitable cells that link the oxygen content of arterial blood to the neuronal control of breathing. In the adult, this oxygen chemosensitivity is exemplified by the Type I cells of the carotid body and recent work has revealed one isoform of the transcription factor HIF, HIF-2α, to have a non-redundant role in the development and function of that organ. Here we show that the activation of HIF-2α, including isolated overexpression alone, is sufficient to induce oxygen chemosensitivity in the otherwise unresponsive adult adrenal medulla. This phenotypic change in the adrenal medulla was associated with retention of extra-adrenal paraganglioma-like tissues that resemble the foetal organ of Zuckerkandl and also manifest oxygen chemosensitivity. Acquisition of chemosensitivity was associated with changes in the adrenal medullary expression of classes of genes that are ordinarily characteristic of the carotid body, including G-protein regulators and atypical subunits of mitochondrial cytochrome oxidase. Overall, the findings suggest that, at least in certain tissues, HIF-2α acts as a phenotypic driver for cells that display oxygen chemosensitivity, thus linking two major oxygen sensing systems.
    Keywords:  Development; Embryonic development; Hypoxia; Oncology
    DOI:  https://doi.org/10.1172/JCI174661
  29. Dev Cell. 2024 Jul 30. pii: S1534-5807(24)00445-3. [Epub ahead of print]
    Redox heterogeneity in mouse embryonic stem cells individualizes cell fate decisions.
    Agnes Ulfig, Ursula Jakob.
      Pluripotent embryonic stem cells (ESCs) can develop into any cell type in the body. Yet, the regulatory mechanisms that govern cell fate decisions during embryogenesis remain largely unknown. We now demonstrate that mouse ESCs (mESCs) display large natural variations in mitochondrial reactive oxygen species (mitoROS) levels that individualize their nuclear redox state, H3K4me3 landscape, and cell fate. While mESCs with high mitoROS levels (mitoROSHIGH) differentiate toward mesendoderm and form the primitive streak during gastrulation, mESCs, which generate less ROS, choose the alternative neuroectodermal fate. Temporal studies demonstrated that mesendodermal (ME) specification of mitoROSHIGH mESCs is mediated by a Nrf2-controlled switch in the nuclear redox state, triggered by the accumulation of redox-sensitive H3K4me3 marks, and executed by a hitherto unknown ROS-dependent activation process of the Wnt signaling pathway. In summary, our study explains how ESC heterogeneity is generated and used by individual cells to decide between distinct cellular fates.
    Keywords:  H3K4me3 epigenome; Nrf2 signaling; Wnt signaling pathway; cell fate decision; embryonic stem cells; mesendoderm; neuroectoderm; reactive oxygen species; redox; stem cell heterogeneity
    DOI:  https://doi.org/10.1016/j.devcel.2024.07.008
  30. Trends Cancer. 2024 Aug 06. pii: S2405-8033(24)00145-6. [Epub ahead of print]
    The origin of novel traits in cancer.
    Steven A Frank, Itai Yanai.
      The traditional view of cancer emphasizes a genes-first process. Novel cancer traits arise by genetic mutations that spread to drive phenotypic change. However, recent data support a phenotypes-first process in which nonheritable cellular variability creates novel traits that later become heritably stabilized by genetic and epigenetic changes. Single-cell measurements reinforce the idea that phenotypes lead genotypes, showing how cancer evolution follows normal developmental plasticity and creates novel traits by recombining parts of different cellular developmental programs. In parallel, studies in evolutionary biology also support a phenotypes-first process driven by developmental plasticity and developmental recombination. These advances in cancer research and evolutionary biology mutually reinforce a revolution in our understanding of how cells and organisms evolve novel traits in response to environmental challenges.
    Keywords:  cancer progression; cellular plasticity; drug resistance; evolution
    DOI:  https://doi.org/10.1016/j.trecan.2024.07.005
  31. Sci Adv. 2024 Aug 09. 10(32): eado2849
    Epigenetic reprogramming driving successful and failed repair in acute kidney injury.
    Yoshiharu Muto, Eryn E Dixon, Yasuhiro Yoshimura, Nicolas Ledru, Yuhei Kirita, Haojia Wu, Benjamin D Humphreys.
      Acute kidney injury (AKI) causes epithelial damage followed by subsequent repair. While successful repair restores kidney function, this process is often incomplete and can lead to chronic kidney disease (CKD) in a process called failed repair. To better understand the epigenetic reprogramming driving this AKI-to-CKD transition, we generated a single-nucleus multiomic atlas for the full mouse AKI time course, consisting of ~280,000 single-nucleus transcriptomes and epigenomes. We reveal cell-specific dynamic alterations in gene regulatory landscapes reflecting, especially, activation of proinflammatory pathways. We further generated single-nucleus multiomic data from four human AKI samples including validation by genome-wide identification of nuclear factor κB binding sites. A regularized regression analysis identifies key regulators involved in both successful and failed repair cell fate, identifying the transcription factor CREB5 as a regulator of both successful and failed tubular repair that also drives proximal tubular cell proliferation after injury. Our interspecies multiomic approach provides a foundation to comprehensively understand cell states in AKI.
    DOI:  https://doi.org/10.1126/sciadv.ado2849
  32. Nat Commun. 2024 Aug 07. 15(1): 6725
    Engineering new-to-nature biochemical conversions by combining fermentative metabolism with respiratory modules.
    Helena Schulz-Mirbach, Jan Lukas Krüsemann, Theofania Andreadaki, Jana Natalie Nerlich, Eleni Mavrothalassiti, Simon Boecker, Philipp Schneider, Moritz Weresow, Omar Abdelwahab, Nicole Paczia, Beau Dronsella, Tobias J Erb, Arren Bar-Even, Steffen Klamt, Steffen N Lindner.
      Anaerobic microbial fermentations provide high product yields and are a cornerstone of industrial bio-based processes. However, the need for redox balancing limits the array of fermentable substrate-product combinations. To overcome this limitation, here we design an aerobic fermentative metabolism that allows the introduction of selected respiratory modules. These can use oxygen to re-balance otherwise unbalanced fermentations, hence achieving controlled respiro-fermentative growth. Following this design, we engineer and characterize an obligate fermentative Escherichia coli strain that aerobically ferments glucose to stoichiometric amounts of lactate. We then re-integrate the quinone-dependent glycerol 3-phosphate dehydrogenase and demonstrate glycerol fermentation to lactate while selectively transferring the surplus of electrons to the respiratory chain. To showcase the potential of this fermentation mode, we direct fermentative flux from glycerol towards isobutanol production. In summary, our design permits using oxygen to selectively re-balance fermentations. This concept is an advance freeing highly efficient microbial fermentation from the limitations imposed by traditional redox balancing.
    DOI:  https://doi.org/10.1038/s41467-024-51029-x
  33. Nat Commun. 2024 Aug 08. 15(1): 6755
    Histone-methyltransferase KMT2D deficiency impairs the Fanconi anemia/BRCA pathway upon glycolytic inhibition in squamous cell carcinoma.
    Wei Liu, Hongchao Cao, Jing Wang, Areeg Elmusrati, Bing Han, Wei Chen, Ping Zhou, Xiyao Li, Stephen Keysar, Antonio Jimeno, Cun-Yu Wang.
      Histone lysine methyltransferase 2D (KMT2D) is the most frequently mutated epigenetic modifier in head and neck squamous cell carcinoma (HNSCC). However, the role of KMT2D in HNSCC tumorigenesis and whether its mutations confer any therapeutic vulnerabilities remain unknown. Here we show that KMT2D deficiency promotes HNSCC growth through increasing glycolysis. Additionally, KMT2D loss decreases the expression of Fanconi Anemia (FA)/BRCA pathway genes under glycolytic inhibition. Mechanistically, glycolytic inhibition facilitates the occupancy of KMT2D to the promoter/enhancer regions of FA genes. KMT2D loss reprograms the epigenomic landscapes of FA genes by transiting their promoter/enhancer states from active to inactive under glycolytic inhibition. Therefore, combining the glycolysis inhibitor 2-DG with DNA crosslinking agents or poly (ADP-ribose) polymerase (PARP) inhibitors preferentially inhibits tumor growth of KMT2D-deficient mouse HNSCC and patient-derived xenografts (PDXs) harboring KMT2D-inactivating mutations. These findings provide an epigenomic basis for developing targeted therapies for HNSCC patients with KMT2D-inactivating mutations.
    DOI:  https://doi.org/10.1038/s41467-024-50861-5
  34. Am J Physiol Cell Physiol. 2024 Aug 05.
    Exploring the unmapped cysteine redox proteoform landscape.
    James N Cobley.
      Cysteine redox proteoforms define the diverse molecular states that proteins with cysteine residues can adopt. A protein with one cysteine residue must adopt one of two binary proteoforms: reduced or oxidised. Their numbers scale: A protein with ten cysteine residues must assume one of 1,024 proteoforms. Although they play pivotal biological roles, the vast cysteine redox proteoform landscape comprising vast numbers of theoretical proteoforms remains largely uncharted. Progress is hampered by a general underappreciation of cysteine redox proteoforms, their intricate complexity, and the formidable challenges that they pose to existing methods. The present review advances cysteine redox proteoform theory, scrutinises methodological barriers, and elaborates innovative technologies for detecting unique residue-defined cysteine redox proteoforms. For example, chemistry-enabled hybrid approaches combining the strengths of top-down and bottom-up mass spectrometry for systematically cataloguing cysteine redox proteoforms are delineated. These methods provide the technological means to map uncharted redox terrain. To unravel hidden redox regulatory mechanisms, discover new biomarkers, and pinpoint therapeutic targets by mining the theoretical cysteine redox proteoform space, a community-wide initiative termed the 'Human Cysteine Redox Proteoform Project' is proposed. Exploring the cysteine redox proteoform landscape could transform current understanding of redox biology.
    Keywords:  Cysteine; Proteoform; ROS; Redox regulation; Technology
    DOI:  https://doi.org/10.1152/ajpcell.00152.2024
  35. Nature. 2024 Aug 07.
    The genomic landscape of 2,023 colorectal cancers.
    Alex J Cornish, Andreas J Gruber, Ben Kinnersley, Daniel Chubb, Anna Frangou, Giulio Caravagna, Boris Noyvert, Eszter Lakatos, Henry M Wood, Steve Thorn, Richard Culliford, Claudia Arnedo-Pac, Jacob Househam, William Cross, Amit Sud, Philip Law, Maire Ni Leathlobhair, Aliah Hawari, Connor Woolley, Kitty Sherwood, Nathalie Feeley, Güler Gül, Juan Fernandez-Tajes, Luis Zapata, Ludmil B Alexandrov, Nirupa Murugaesu, Alona Sosinsky, Jonathan Mitchell, Nuria Lopez-Bigas, Philip Quirke, David N Church, Ian P M Tomlinson, Andrea Sottoriva, Trevor A Graham, David C Wedge, Richard S Houlston.
      Colorectal carcinoma (CRC) is a common cause of mortality1, but a comprehensive description of its genomic landscape is lacking2-9. Here we perform whole-genome sequencing of 2,023 CRC samples from participants in the UK 100,000 Genomes Project, thereby providing a highly detailed somatic mutational landscape of this cancer. Integrated analyses identify more than 250 putative CRC driver genes, many not previously implicated in CRC or other cancers, including several recurrent changes outside the coding genome. We extend the molecular pathways involved in CRC development, define four new common subgroups of microsatellite-stable CRC based on genomic features and show that these groups have independent prognostic associations. We also characterize several rare molecular CRC subgroups, some with potential clinical relevance, including cancers with both microsatellite and chromosomal instability. We demonstrate a spectrum of mutational profiles across the colorectum, which reflect aetiological differences. These include the role of Escherichia colipks+ colibactin in rectal cancers10 and the importance of the SBS93 signature11-13, which suggests that diet or smoking is a risk factor. Immune-escape driver mutations14 are near-ubiquitous in hypermutant tumours and occur in about half of microsatellite-stable CRCs, often in the form of HLA copy number changes. Many driver mutations are actionable, including those associated with rare subgroups (for example, BRCA1 and IDH1), highlighting the role of whole-genome sequencing in optimizing patient care.
    DOI:  https://doi.org/10.1038/s41586-024-07747-9
  36. Nat Chem Biol. 2024 Aug 05.
    Single-cell sensor analyses reveal signaling programs enabling Ras-G12C drug resistance.
    Jason Z Zhang, Shao-En Ong, David Baker, Dustin J Maly.
      Clinical resistance to rat sarcoma virus (Ras)-G12C inhibitors is a challenge. A subpopulation of cancer cells has been shown to undergo genomic and transcriptional alterations to facilitate drug resistance but the immediate adaptive effects on Ras signaling in response to these drugs at the single-cell level is not well understood. Here, we used Ras biosensors to profile the activity and signaling environment of endogenous Ras at the single-cell level. We found that a subpopulation of KRas-G12C cells treated with Ras-G12C-guanosine-diphosphate inhibitors underwent adaptive signaling and metabolic changes driven by wild-type Ras at the Golgi and mutant KRas at the mitochondria, respectively. Our Ras biosensors identified major vault protein as a mediator of Ras activation through its scaffolding of Ras signaling pathway components and metabolite channels. Overall, methods including ours that facilitate direct analysis on the single-cell level can report the adaptations that subpopulations of cells adopt in response to cancer therapies, thus providing insight into drug resistance.
    DOI:  https://doi.org/10.1038/s41589-024-01684-4
  37. Cell Rep. 2024 Aug 08. pii: S2211-1247(24)00956-2. [Epub ahead of print]43(8): 114606
    GCN2 is a determinant of the response to WEE1 kinase inhibition in small-cell lung cancer.
    Alexandros P Drainas, Wen-Hao Hsu, Alec E Dallas, Carson D Poltorack, Jun W Kim, Andy He, Garry L Coles, Maya Baron, Michael C Bassik, Julien Sage.
      Patients with small-cell lung cancer (SCLC) are in dire need of more effective therapeutic options. Frequent disruption of the G1 checkpoint in SCLC cells creates a dependency on the G2/M checkpoint to maintain genomic integrity. Indeed, in pre-clinical models, inhibiting the G2/M checkpoint kinase WEE1 shows promise in inhibiting SCLC growth. However, toxicity and acquired resistance limit the clinical effectiveness of this strategy. Here, using CRISPR-Cas9 knockout screens in vitro and in vivo, we identified multiple factors influencing the response of SCLC cells to the WEE1 kinase inhibitor AZD1775, including the GCN2 kinase and other members of its signaling pathway. Rapid activation of GCN2 upon AZD1775 treatment triggers a stress response in SCLC cells. Pharmacological or genetic activation of the GCN2 pathway enhances cancer cell killing by AZD1775. Thus, activation of the GCN2 pathway represents a promising strategy to increase the efficacy of WEE1 inhibitors in SCLC.
    Keywords:  AZD1775; CP: Cancer; CRISPR-Cas9; GCN2; ISR; PP1; Raphin1; SCLC; WEE1; drug resistance
    DOI:  https://doi.org/10.1016/j.celrep.2024.114606
  38. Nat Commun. 2024 Aug 03. 15(1): 6587
    Targeting fatty acid oxidation enhances response to HER2-targeted therapy.
    Ipshita Nandi, Linjia Ji, Harvey W Smith, Daina Avizonis, Vasilios Papavasiliou, Cynthia Lavoie, Alain Pacis, Sherif Attalla, Virginie Sanguin-Gendreau, William J Muller.
      Metabolic reprogramming, a hallmark of tumorigenesis, involves alterations in glucose and fatty acid metabolism. Here, we investigate the role of Carnitine palmitoyl transferase 1a (Cpt1a), a key enzyme in long-chain fatty acid (LCFA) oxidation, in ErbB2-driven breast cancers. In ErbB2+ breast cancer models, ablation of Cpt1a delays tumor onset, growth, and metastasis. However, Cpt1a-deficient cells exhibit increased glucose dependency that enables survival and eventual tumor progression. Consequently, these cells exhibit heightened oxidative stress and upregulated nuclear factor erythroid 2-related factor 2 (Nrf2) activity. Inhibiting Nrf2 or silencing its expression reduces proliferation and glucose consumption in Cpt1a-deficient cells. Combining the ketogenic diet, composed of LCFAs, or an anti-ErbB2 monoclonal antibody (mAb) with Cpt1a deficiency significantly perturbs tumor growth, enhances apoptosis, and reduces lung metastasis. Using an immunocompetent model, we show that Cpt1a inhibition promotes an antitumor immune microenvironment, thereby enhancing the efficacy of anti-ErbB2 mAbs. Our findings underscore the importance of targeting fatty acid oxidation alongside HER2-targeted therapies to combat resistance in HER2+ breast cancer patients.
    DOI:  https://doi.org/10.1038/s41467-024-50998-3
  39. Nat Cell Biol. 2024 Aug 05.
    p16-dependent increase of PD-L1 stability regulates immunosurveillance of senescent cells.
    Julia Majewska, Amit Agrawal, Avi Mayo, Lior Roitman, Rishita Chatterjee, Jarmila Sekeresova Kralova, Tomer Landsberger, Yonatan Katzenelenbogen, Tomer Meir-Salame, Efrat Hagai, Ilanit Sopher, Juan-Felipe Perez-Correa, Wolfgang Wagner, Avi Maimon, Ido Amit, Uri Alon, Valery Krizhanovsky.
      The accumulation of senescent cells promotes ageing and age-related diseases, but molecular mechanisms that senescent cells use to evade immune clearance and accumulate in tissues remain to be elucidated. Here we report that p16-positive senescent cells upregulate the immune checkpoint protein programmed death-ligand 1 (PD-L1) to accumulate in ageing and chronic inflammation. We show that p16-mediated inhibition of cell cycle kinases CDK4/6 induces PD-L1 stability in senescent cells via downregulation of its ubiquitin-dependent degradation. p16-expressing senescent alveolar macrophages elevate PD-L1 to promote an immunosuppressive environment that can contribute to an increased burden of senescent cells. Treatment with activating anti-PD-L1 antibodies engaging Fcγ receptors on effector cells leads to the elimination of PD-L1 and p16-positive cells. Our study uncovers a molecular mechanism of p16-dependent regulation of PD-L1 protein stability in senescent cells and reveals the potential of targeting PD-L1 to improve immunosurveillance of senescent cells and ameliorate senescence-associated inflammation.
    DOI:  https://doi.org/10.1038/s41556-024-01465-0
  40. Cell Metab. 2024 Jul 31. pii: S1550-4131(24)00279-1. [Epub ahead of print]
    Zinc transporter 1 functions in copper uptake and cuproptosis.
    Yehua Li, Jiahao Ma, Rui Wang, Yuanhanyu Luo, Sanduo Zheng, Xiaodong Wang.
      Copper (Cu) is a co-factor for several essential metabolic enzymes. Disruption of Cu homeostasis results in genetic diseases such as Wilson's disease. Here, we show that the zinc transporter 1 (ZnT1), known to export zinc (Zn) out of the cell, also mediates Cu2+ entry into cells and is required for Cu2+-induced cell death, cuproptosis. Structural analysis and functional characterization indicate that Cu2+ and Zn2+ share the same primary binding site, allowing Zn2+ to compete for Cu2+ uptake. Among ZnT members, ZnT1 harbors a unique inter-subunit disulfide bond that stabilizes the outward-open conformations of both protomers to facilitate efficient Cu2+ transport. Specific knockout of the ZnT1 gene in the intestinal epithelium caused the loss of Lgr5+ stem cells due to Cu deficiency. ZnT1, therefore, functions as a dual Zn2+ and Cu2+ transporter and potentially serves as a target for using Zn2+ in the treatment of Wilson's disease caused by Cu overload.
    Keywords:  Cu transporter; Wilson's disease; ZnT1; cryo-EM; cuproptosis
    DOI:  https://doi.org/10.1016/j.cmet.2024.07.009
  41. Nat Commun. 2024 Aug 06. 15(1): 6692
    eIF4E-independent translation is largely eIF3d-dependent.
    Mykola Roiuk, Marilena Neff, Aurelio A Teleman.
      Translation initiation is a highly regulated step needed for protein synthesis. Most cell-based mechanistic work on translation initiation has been done using non-stressed cells growing in medium with sufficient nutrients and oxygen. This has yielded our current understanding of 'canonical' translation initiation, involving recognition of the mRNA cap by eIF4E1 followed by successive recruitment of initiation factors and the ribosome. Many cells, however, such as tumor cells, are exposed to stresses such as hypoxia, low nutrients or proteotoxic stress. This leads to inactivation of mTORC1 and thereby inactivation of eIF4E1. Hence the question arises how cells translate mRNAs under such stress conditions. We study here how mRNAs are translated in an eIF4E1-independent manner by blocking eIF4E1 using a constitutively active version of eIF4E-binding protein (4E-BP). Via ribosome profiling we identify a subset of mRNAs that are still efficiently translated when eIF4E1 is inactive. We find that these mRNAs preferentially release eIF4E1 when eIF4E1 is inactive and bind instead to eIF3d via its cap-binding pocket. eIF3d then enables these mRNAs to be efficiently translated due to its cap-binding activity. In sum, our work identifies eIF3d-dependent translation as a major mechanism enabling mRNA translation in an eIF4E-independent manner.
    DOI:  https://doi.org/10.1038/s41467-024-51027-z
  42. Cell Rep. 2024 Aug 07. pii: S2211-1247(24)00916-1. [Epub ahead of print]43(8): 114587
    A molecular pathway for cancer cachexia-induced muscle atrophy revealed at single-nucleus resolution.
    Yichi Zhang, Matthieu Dos Santos, Huocong Huang, Kenian Chen, Puneeth Iyengar, Rodney Infante, Patricio M Polanco, Rolf A Brekken, Chunyu Cai, Ambar Caijgas, Karla Cano Hernandez, Lin Xu, Rhonda Bassel-Duby, Ning Liu, Eric N Olson.
      Cancer cachexia is a prevalent and often fatal wasting condition that cannot be fully reversed with nutritional interventions. Muscle atrophy is a central component of the syndrome, but the mechanisms whereby cancer leads to skeletal muscle atrophy are not well understood. We performed single-nucleus multi-omics on skeletal muscles from a mouse model of cancer cachexia and profiled the molecular changes in cachexic muscle. Our results revealed the activation of a denervation-dependent gene program that upregulates the transcription factor myogenin. Further studies showed that a myogenin-myostatin pathway promotes muscle atrophy in response to cancer cachexia. Short hairpin RNA inhibition of myogenin or inhibition of myostatin through overexpression of its endogenous inhibitor follistatin prevented cancer cachexia-induced muscle atrophy in mice. Our findings uncover a molecular basis of muscle atrophy associated with cancer cachexia and highlight potential therapeutic targets for this disorder.
    Keywords:  AAV; CP: Cancer; CP: Metabolism; atrophy; cachexia; denervation; myogenin; myostatin; single nucleus ATAC-seq; single nucleus RNA-seq; single nucleus multiome
    DOI:  https://doi.org/10.1016/j.celrep.2024.114587
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