bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2024–12–01
sixty-two papers selected by
Christian Frezza, Universität zu Köln
  1. ACSS1-dependent acetate utilization rewires mitochondrial metabolism to support AML and melanoma tumor growth and metastasis.
  2. Tissue-specific adaptations to cytochrome c oxidase deficiency shape physiological outcomes.
  3. Glucose limitation protects cancer cells from apoptosis induced by pyrimidine restriction and replication inhibition.
  4. Cancer Therapies Targeting Cellular Metabolism.
  5. The nutrient-sensing Rag-GTPase complex in B cells controls humoral immunity via TFEB/TFE3-dependent mitochondrial fitness.
  6. Mitochondrial calcium uptake declines during aging and is directly activated by oleuropein to boost energy metabolism and skeletal muscle performance.
  7. PGC-1α drives small cell neuroendocrine cancer progression toward an ASCL1-expressing subtype with increased mitochondrial capacity.
  8. Inhibition of lung tumorigenesis by transient reprogramming in cancer cells.
  9. ER-tethered stress sensor CREBH regulates mitochondrial unfolded protein response to maintain energy homeostasis.
  10. Design principles of regulatory networks underlying epithelial mesenchymal plasticity in cancer cells.
  11. UGT8 mediated sulfatide synthesis modulates BAX localization and dictates apoptosis sensitivity of colorectal cancer.
  12. Cancer cells impair monocyte-mediated T cell stimulation to evade immunity.
  13. High-density sampling reveals volume growth in human tumours.
  14. Dietary Restriction Enhances CD8⁺ T Cell Ketolysis to Limit Exhaustion and Boost Anti-Tumor Immunity.
  15. MAT2a and AHCY inhibition disrupts antioxidant metabolism and reduces glioblastoma cell survival.
  16. Characterizing the evolutionary dynamics of cancer proliferation in single-cell clones with SPRINTER.
  17. Parameter Estimation and Identifiability in Kinetic Flux Profiling Models of Metabolism.
  18. Q&A with Ilaria Elia.
  19. IFN-γ-dependent regulation of intestinal epithelial homeostasis by NKT cells.
  20. Mechano-dependent sorbitol accumulation supports biomolecular condensate.
  21. Constitutive HIF-1α expression in the epidermis fuels proliferation and is essential for effective barrier formation.
  22. Cold-inducible GOT1 activates the malate-aspartate shuttle in brown adipose tissue to support fuel preference for fatty acids.
  23. Consensus on the key characteristics of metabolism disruptors.
  24. Developmental hematopoietic stem cell variation explains clonal hematopoiesis later in life.
  25. Identification of VISTA regulators in macrophages mediating cancer cell survival.
  26. Cholesterol metabolism and intrabacterial potassium homeostasis are intrinsically related in Mycobacterium tuberculosis.
  27. Fungal symbiont transmitted by free-living mice promotes type 2 immunity.
  28. Late-life protein or isoleucine restriction impacts physiological and molecular signatures of aging.
  29. Can bacteria think?
  30. Nucleo-cytosolic acetyl-CoA drives tumor immune evasion by regulating PD-L1 in melanoma.
  31. Language model-guided anticipation and discovery of unknown metabolites.
  32. Metabolomics and 13C labelled glucose tracing to identify carbon incorporation into aberrant cell membrane glycans in cancer.
  33. Human glyoxylate metabolism revisited: New insights pointing to multi-organ involvement with implications for siRNA-based therapies in primary hyperoxaluria.
  34. Metabolism and mRNA translation: a nexus of cancer plasticity.
  35. Q&A with Ping Gao.
  36. Serine metabolism in aging and age-related diseases.
  37. 13C Stable Isotope Tracing Reveals Distinct Fatty Acid Oxidation Pathways in Proliferative vs. Oxidative Cells.
  38. The cyanobacterial circadian clock couples to pulsatile processes using pulse amplitude modulation.
  39. Circadian immunometabolism: A future insight for targeted therapy in cancer.
  40. C/EBPβ-dependent autophagy inhibition hinders NK cell function in cancer.
  41. Human mitochondrial peroxiredoxin Prdx3 is dually localized in the intermembrane space and matrix subcompartments.
  42. The Mitochondrial Integrated Stress Response: A novel approach to anti-aging and pro-longevity.
  43. The Pivotal Role of One-Carbon Metabolism in Neoplastic Progression During the Aging Process.
  44. Branched-chain amino acid catabolism promotes M2 macrophage polarization.
  45. How proteins sense their cellular environment.
  46. Rotenone adaptation promotes migration and invasion of p53-wild-type colon cancer through lipid metabolism.
  47. Recurrent hyper-motif circuits in developmental programs.
  48. Introduction: The Influences of Religion and Spirituality on Human Biology.
  49. Racing the clock.
  50. Cancers adapt to their mutational load by buffering protein misfolding stress.
  51. How nature ties peptide knots.
  52. The contribution of mitochondria-associated ER membranes to cholesterol homeostasis.
  53. Mitochondria as sensors of intracellular pathogens.
  54. Reconstructing the last common ancestor of all eukaryotes.
  55. The redox sensor KEAP1 facilitates adaptation of T cells to chronic antigen stimulation by preventing hyperactivation.
  56. Understanding cancer from a biophysical, developmental and systems biology perspective using the landscapes-attractor model.
  57. Structural basis for growth factor and nutrient signal integration on the lysosomal membrane by mTORC1.
  58. New-to-nature CO2-dependent acetyl-CoA assimilation enabled by an engineered B12-dependent acyl-CoA mutase.
  59. Unveiling the power of mitochondrial transfer in cancer progression: a perspective in ovarian cancer.
  60. Chemotherapeutic agents and leucine deprivation induce codon-biased aberrant protein production in cancer.
  61. Selective metabolic regulations by p53 mutant variants in pancreatic cancer.
  62. My path to citrin deficiency.
  1. Cell Rep. 2024 Nov 21. pii: S2211-1247(24)01339-1. [Epub ahead of print]43(12): 114988
    ACSS1-dependent acetate utilization rewires mitochondrial metabolism to support AML and melanoma tumor growth and metastasis.
    Sabina I Hlavaty, Kelsey N Salcido, Katherine A Pniewski, Dzmitry Mukha, Weili Ma, Toshitha Kannan, Joel Cassel, Yellamelli V V Srikanth, Qin Liu, Andrew Kossenkov, Joseph M Salvino, Qing Chen, Zachary T Schug.
      Cancer cells often use alternative nutrient sources to support their metabolism and proliferation. One important alternative nutrient source for many cancers is acetate. Acetate is metabolized into acetyl-coenzyme A (CoA) by acetyl-CoA synthetases 1 and 2 (ACSS1 and ACSS2), which are found in the mitochondria and cytosol, respectively. We show that ACSS1 and ACSS2 are differentially expressed in cancer. Melanoma, breast cancer, and acute myeloid leukemia cells expressing ACSS1 readily use acetate for acetyl-CoA biosynthesis and to fuel mitochondrial metabolism. ACSS1-dependent acetate metabolism decreases the relative contributions of glucose and glutamine to the tricarboxylic acid (TCA) cycle and alters the pentose phosphate pathway and redox state of cancer cells. ACSS1 knockdown decreases acute myeloid leukemia burden in vivo and inhibits melanoma tumor and metastatic growth. Our study highlights a key role for ACSS1-dependent acetate metabolism for cancer growth, raising the potential for ACSS1-targeting therapies in cancer.
    Keywords:  ACSS1; ACSS2; ACSS2 inhibitor; AML; CP: Cancer; CP: Metabolism; acetate; cancer; melanoma; metabolism; metastasis
    DOI:  https://doi.org/10.1016/j.celrep.2024.114988
  2. Biochim Biophys Acta Mol Basis Dis. 2024 Nov 27. pii: S0925-4439(24)00561-1. [Epub ahead of print] 167567
    Tissue-specific adaptations to cytochrome c oxidase deficiency shape physiological outcomes.
    Milica Popovic, Lea Isermann, Simon Geißen, Katharina Senft, Theodoros Georgomanolis, Stephan Baldus, Christian Frezza, Aleksandra Trifunovic.
      It becomes increasingly clear that the tissue specificity of mitochondrial diseases might in part rely on their ability to compensate for mitochondrial defects, contributing to the heterogeneous nature of mitochondrial diseases. Here, we investigated tissue-specific responses to cytochrome c oxidase (CIV or COX) deficiency using a mouse model with heart and skeletal muscle-specific depletion of the COX assembly factor COX10. At three weeks of age, both tissues exhibit pronounced CIV depletion but respond differently to oxidative phosphorylation (OXPHOS) impairment. Heart-specific COX10 depletion caused severe dilated cardiomyopathy, while skeletal muscle experiences less damage. Cardiac CIV deficiency triggered extensive metabolic remodelling and stress response activation, potentially worsening cardiomyopathy, whereas skeletal muscle showed no stress response or significant metabolic changes. Our findings highlight distinct tissue capacities for managing CIV deficiency, explaining how identical primary defects can lead to different phenotypic outcomes and contribute to the heterogeneous progression of mitochondrial diseases.
    DOI:  https://doi.org/10.1016/j.bbadis.2024.167567
  3. Nat Metab. 2024 Nov 26.
    Glucose limitation protects cancer cells from apoptosis induced by pyrimidine restriction and replication inhibition.
    Minwoo Nam, Wenxin Xia, Abdul Hannan Mir, Alexandra Jerrett, Jessica B Spinelli, Tony T Huang, Richard Possemato.
      Cancer cells often experience nutrient-limiting conditions because of their robust proliferation and inadequate tumour vasculature, which results in metabolic adaptation to sustain proliferation. Most cancer cells rapidly consume glucose, which is severely reduced in the nutrient-scarce tumour microenvironment. In CRISPR-based genetic screens to identify metabolic pathways influenced by glucose restriction, we find that tumour-relevant glucose concentrations (low glucose) protect cancer cells from inhibition of de novo pyrimidine biosynthesis, a pathway that is frequently targeted by chemotherapy. We identify two mechanisms to explain this result, which is observed broadly across cancer types. First, low glucose limits uridine-5-diphosphate-glucose synthesis, preserving pyrimidine nucleotide availability and thereby prolonging the time to replication fork stalling. Second, low glucose directly modulates apoptosis downstream of replication fork stalling by suppressing BAK activation and subsequent cytochrome c release, key events that activate caspase-9-dependent mitochondrial apoptosis. These results indicate that the low glucose levels frequently observed in tumours may limit the efficacy of specific chemotherapeutic agents, highlighting the importance of considering the effects of the tumour nutrient environment on cancer therapy.
    DOI:  https://doi.org/10.1038/s42255-024-01166-w
  4. Cold Spring Harb Perspect Med. 2024 Nov 25. pii: a041657. [Epub ahead of print]
    Cancer Therapies Targeting Cellular Metabolism.
    Benjamin Morris, Alejandro Gutierrez.
      Cancer is caused by mutations that drive aberrant growth, proliferation, and invasion, thus overriding regulatory mechanisms that normally link these processes to organismal needs and cellular physiology. This imposes demands for the production of energy and biomass and for survival in microenvironments that are often nonphysiologic and nutrient-poor, which are met by rewiring of cellular metabolism. The resultant dependence of tumor cells on altered metabolism can induce sensitivity to specific metabolic perturbations that can be exploited for cancer therapy. Some cancers are caused by mutations that impart a novel function to metabolic enzymes, leading to the production of a tumor-promoting metabolite that is dispensable in normal cells, representing an ideal therapeutic target. Tumors can also exploit metabolic regulation of cellular immunity to evade antitumor immune responses, and deciphering this biology has revealed potential targets for therapeutic intervention. Here, we discuss a number of illustrative examples highlighting the therapeutic potential and the challenges of targeting metabolism for cancer therapy.
    DOI:  https://doi.org/10.1101/cshperspect.a041657
  5. Nat Commun. 2024 Nov 23. 15(1): 10163
    The nutrient-sensing Rag-GTPase complex in B cells controls humoral immunity via TFEB/TFE3-dependent mitochondrial fitness.
    Xingxing Zhu, Yue Wu, Yanfeng Li, Xian Zhou, Jens O Watzlawik, Yin Maggie Chen, Ariel L Raybuck, Daniel D Billadeau, Virginia Smith Shapiro, Wolfdieter Springer, Jie Sun, Mark R Boothby, Hu Zeng.
      Germinal center (GC) formation, which is an integrant part of humoral immunity, involves energy-consuming metabolic reprogramming. Rag-GTPases are known to signal amino acid availability to cellular pathways that regulate nutrient distribution such as the mechanistic target of rapamycin complex 1 (mTORC1) pathway and the transcription factors TFEB and TFE3. However, the contribution of these factors to humoral immunity remains undefined. Here, we show that B cell-intrinsic Rag-GTPases are critical for the development and activation of B cells. RagA/RagB deficient B cells fail to form GCs, produce antibodies, and to generate plasmablasts during both T-dependent (TD) and T-independent (TI) humoral immune responses. Deletion of RagA/RagB in GC B cells leads to abnormal dark zone (DZ) to light zone (LZ) ratio and reduced affinity maturation. Mechanistically, the Rag-GTPase complex constrains TFEB/TFE3 activity to prevent mitophagy dysregulation and maintain mitochondrial fitness in B cells, which are independent of canonical mTORC1 activation. TFEB/TFE3 deletion restores B cell development, GC formation in Peyer's patches and TI humoral immunity, but not TD humoral immunity in the absence of Rag-GTPases. Collectively, our data establish the Rag GTPase-TFEB/TFE3 pathway as a likely mTORC1 independent mechanism to coordinating nutrient sensing and mitochondrial metabolism in B cells.
    DOI:  https://doi.org/10.1038/s41467-024-54344-5
  6. Cell Metab. 2024 Nov 23. pii: S1550-4131(24)00417-0. [Epub ahead of print]
    Mitochondrial calcium uptake declines during aging and is directly activated by oleuropein to boost energy metabolism and skeletal muscle performance.
    Gaia Gherardi, Anna Weiser, Flavien Bermont, Eugenia Migliavacca, Benjamin Brinon, Guillaume E Jacot, Aurélie Hermant, Mattia Sturlese, Leonardo Nogara, Filippo Vascon, Agnese De Mario, Andrea Mattarei, Emma Garratt, Mark Burton, Karen Lillycrop, Keith M Godfrey, Laura Cendron, Denis Barron, Stefano Moro, Bert Blaauw, Rosario Rizzuto, Jerome N Feige, Cristina Mammucari, Umberto De Marchi.
      Mitochondrial calcium (mtCa2+) uptake via the mitochondrial calcium uniporter (MCU) couples calcium homeostasis and energy metabolism. mtCa2+ uptake via MCU is rate-limiting for mitochondrial activation during muscle contraction, but its pathophysiological role and therapeutic application remain largely uncharacterized. By profiling human muscle biopsies, patient-derived myotubes, and preclinical models, we discovered a conserved downregulation of mitochondrial calcium uniporter regulator 1 (MCUR1) during skeletal muscle aging that associates with human sarcopenia and impairs mtCa2+ uptake and mitochondrial respiration. Through a screen of 5,000 bioactive molecules, we identify the natural polyphenol oleuropein as a specific MCU activator that stimulates mitochondrial respiration via mitochondrial calcium uptake 1 (MICU1) binding. Oleuropein activates mtCa2+ uptake and energy metabolism to enhance endurance and reduce fatigue in young and aged mice but not in muscle-specific MCU knockout (KO) mice. Our work demonstrates that impaired mtCa2+ uptake contributes to mitochondrial dysfunction during aging and establishes oleuropein as a novel food-derived molecule that specifically targets MCU to stimulate mitochondrial bioenergetics and muscle performance.
    Keywords:  MCU; MCUR1; aging; calcium signaling; endurance; energy; fatigue; mitochondria; polyphenols; sarcopenia; skeletal muscle
    DOI:  https://doi.org/10.1016/j.cmet.2024.10.021
  7. Proc Natl Acad Sci U S A. 2024 Dec 03. 121(49): e2416882121
    PGC-1α drives small cell neuroendocrine cancer progression toward an ASCL1-expressing subtype with increased mitochondrial capacity.
    Grigor Varuzhanyan, Chia-Chun Chen, Jack Freeland, Tian He, Wendy Tran, Kai Song, Liang Wang, Donghui Cheng, Shili Xu, Gabriella A Dibernardo, Favour N Esedebe, Vipul Bhatia, Mingqi Han, Evan R Abt, Jung Wook Park, Sanaz Memarzadeh, David B Shackelford, John K Lee, Thomas G Graeber, Orian S Shirihai, Owen N Witte.
      Adenocarcinomas from multiple tissues can converge to treatment-resistant small cell neuroendocrine (SCN) cancers composed of ASCL1, POU2F3, NEUROD1, and YAP1 subtypes. We investigated how mitochondrial metabolism influences SCN cancer (SCNC) progression. Extensive bioinformatics analyses encompassing thousands of patient tumors and human cancer cell lines uncovered enhanced expression of proliferator-activatedreceptor gamma coactivator 1-alpha (PGC-1α), a potent regulator of mitochondrial oxidative phosphorylation (OXPHOS), across several SCNCs. PGC-1α correlated tightly with increased expression of the lineage marker Achaete-scute homolog 1, (ASCL1) through a positive feedback mechanism. Analyses using a human prostate tissue-based SCN transformation system showed that the ASCL1 subtype has heightened PGC-1α expression and OXPHOS activity. PGC-1α inhibition diminished OXPHOS, reduced SCNC cell proliferation, and blocked SCN prostate tumor formation. Conversely, PGC-1α overexpression enhanced OXPHOS, validated by small-animal Positron Emission Tomography mitochondrial imaging, tripled the SCN prostate tumor formation rate, and promoted commitment to the ASCL1 lineage. These results establish PGC-1α as a driver of SCNC progression and subtype determination, highlighting metabolic vulnerabilities in SCNCs across different tissues.
    Keywords:  ASCL1; PGC-1a; lung cancer; oxidative phosphorylation; prostate cancer
    DOI:  https://doi.org/10.1073/pnas.2416882121
  8. Cell Death Dis. 2024 Nov 25. 15(11): 857
    Inhibition of lung tumorigenesis by transient reprogramming in cancer cells.
    Pablo Pedrosa, Zhenguang Zhang, Victor Nuñez-Quintela, David Macias, Jianfeng Ge, Mary Denholm, Anna Dyas, Valentin Estevez-Souto, Patricia Lado-Fernandez, Patricia Gonzalez, Maria Gomez, Jose Ezequiel Martin, Sabela Da Silva-Alvarez, Manuel Collado, Daniel Muñoz-Espín.
      Oncogenic transformation and Oct4, Sox2, Klf4 and c-Myc (OSKM)-mediated induction of pluripotency are two independent and incompatible cellular fates. While continuous expression of OSKM can convert normal somatic cells into teratogenic pluripotent cells, it remains speculative what is the impact of transient OSKM expression in cancer cells. Here, we find that OSKM expression limits the growth of transformed lung cells by inducing apoptosis and senescence. We identify Oct4 and Klf4 as the main individual reprogramming factors responsible for this effect. Mechanistically, the induction of cell cycle inhibitor p21 downstream of the reprogramming factors acts as mediator of cell death and senescence. Using a variety of in vivo systems, including allografts, orthotopic transplantation and KRAS-driven lung cancer mouse models, we demonstrate that transient reprogramming by OSKM expression in cancer cells impairs tumor growth and reduces tumor burden. Altogether, our results show that the induction of transient reprogramming in cancer cells is antitumorigenic opening novel potential therapeutic avenues in oncology.
    DOI:  https://doi.org/10.1038/s41419-024-07207-2
  9. Proc Natl Acad Sci U S A. 2024 Dec 03. 121(49): e2410486121
    ER-tethered stress sensor CREBH regulates mitochondrial unfolded protein response to maintain energy homeostasis.
    Hyunbae Kim, Qi Chen, Donghong Ju, Neeraja Purandare, Xuequn Chen, Lobelia Samavati, Li Li, Ren Zhang, Lawrence I Grossman, Kezhong Zhang.
      The Mitochondrial Unfolded Protein Response (UPRmt), a mitochondria-originated stress response to altered mitochondrial proteostasis, plays important roles in various pathophysiological processes. In this study, we revealed that the endoplasmic reticulum (ER)-tethered stress sensor CREBH regulates UPRmt to maintain mitochondrial homeostasis and function in the liver. CREBH is enriched in and required for hepatic Mitochondria-Associated Membrane (MAM) expansion induced by energy demands. Under a fasting challenge or during the circadian cycle, CREBH is activated to promote expression of the genes encoding the key enzymes, chaperones, and regulators of UPRmt in the liver. Activated CREBH, cooperating with peroxisome proliferator-activated receptor α (PPARα), activates expression of Activating Transcription Factor (ATF) 5 and ATF4, two major UPRmt transcriptional regulators, independent of the ER-originated UPR (UPRER) pathways. Hepatic CREBH deficiency leads to accumulation of mitochondrial unfolded proteins, decreased mitochondrial membrane potential, and elevated cellular redox state. Dysregulation of mitochondrial function caused by CREBH deficiency coincides with increased hepatic mitochondrial oxidative phosphorylation (OXPHOS) but decreased glycolysis. CREBH knockout mice display defects in fatty acid oxidation and increased reliance on carbohydrate oxidation for energy production. In summary, our studies uncover that hepatic UPRmt is activated through CREBH under physiological challenges, highlighting a molecular link between ER and mitochondria in maintaining mitochondrial proteostasis and energy homeostasis under stress conditions.
    Keywords:  ER-mitochondria contact; cell metabolism; michondrial UPR; transcriptional regulation; unfolded protein response
    DOI:  https://doi.org/10.1073/pnas.2410486121
  10. Curr Opin Cell Biol. 2024 Nov 27. pii: S0955-0674(24)00124-8. [Epub ahead of print]92 102445
    Design principles of regulatory networks underlying epithelial mesenchymal plasticity in cancer cells.
    Sarthak Sahoo, Kishore Hari, Mohit Kumar Jolly.
      Phenotypic plasticity is a hallmark of cancer and drives metastatic disease and drug resistance. The dynamics of epithelial mesenchymal plasticity is driven by complex interactions involving multiple feedback loops in underlying networks operating at multiple regulatory levels such as transcriptional and epigenetic. The past decade has witnessed a surge in systems level analysis of structural and dynamical traits of these networks. Here, we highlight the key insights elucidated from such efforts-a) multistability in gene regulatory networks and the co-existence of many hybrid phenotypes, thus enabling a landscape with multiple 'attractors', b) mutually antagonistic 'teams' of genes in these networks, shaping the rates of cell state transition in this landscape, and c) chromatin level changes that can alter the landscape, thus controlling reversibility of cell state transitions, allowing cellular memory in the context of epithelial mesenchymal plasticity in cancer cells. Such approaches, in close integration with high-throughput longitudinal data, have improved our understanding of the dynamics of cell state transitions implicated in tumor cell plasticity.
    Keywords:  Attractor; Epigenetic memory; Epithelial-Mesenchymal Transition; Multistability; Phenotypic plasticity
    DOI:  https://doi.org/10.1016/j.ceb.2024.102445
  11. Cell Death Differ. 2024 Nov 23.
    UGT8 mediated sulfatide synthesis modulates BAX localization and dictates apoptosis sensitivity of colorectal cancer.
    Le Zhang, Prashanthi Ramesh, Lidia Atencia Taboada, Rebecca Roessler, Dick W Zijlmans, Michiel Vermeulen, Daisy I Picavet-Havik, Nicole N van der Wel, Frédéric M Vaz, Jan Paul Medema.
      Elevated de novo lipid synthesis is a remarkable adaptation of cancer cells that can be exploited for therapy. However, the role of altered lipid metabolism in the regulation of apoptosis is still poorly understood. Using thermal proteome profiling, we identified Manidipine-2HCl, targeting UGT8, a key enzyme in the synthesis of sulfatides. In agreement, lipidomic analysis indicated that sulfatides are strongly reduced in colorectal cancer cells upon treatment with Manidipine-2HCl. Intriguingly, this reduction led to severe mitochondrial swelling and a strong synergism with BH3 mimetics targeting BCL-XL, leading to the activation of mitochondria-dependent apoptosis. Mechanistically, Manidipine-2HCl enhanced mitochondrial BAX localization in a sulfatide-dependent fashion, facilitating its activation by BH3 mimetics. In conclusion, our data indicates that UGT8 mediated synthesis of sulfatides controls mitochondrial homeostasis and BAX localization, dictating apoptosis sensitivity of colorectal cancer cells.
    DOI:  https://doi.org/10.1038/s41418-024-01418-y
  12. Nature. 2024 Nov 27.
    Cancer cells impair monocyte-mediated T cell stimulation to evade immunity.
    Anais Elewaut, Guillem Estivill, Felix Bayerl, Leticia Castillon, Maria Novatchkova, Elisabeth Pottendorfer, Lisa Hoffmann-Haas, Martin Schönlein, Trung Viet Nguyen, Martin Lauss, Francesco Andreatta, Milica Vulin, Izabela Krecioch, Jonas Bayerl, Anna-Marie Pedde, Naomi Fabre, Felix Holstein, Shona M Cronin, Sarah Rieser, Denarda Dangaj Laniti, David Barras, George Coukos, Camelia Quek, Xinyu Bai, Miquel Muñoz I Ordoño, Thomas Wiesner, Johannes Zuber, Göran Jönsson, Jan P Böttcher, Sakari Vanharanta, Anna C Obenauf.
      The tumour microenvironment is programmed by cancer cells and substantially influences anti-tumour immune responses1,2. Within the tumour microenvironment, CD8+ T cells undergo full effector differentiation and acquire cytotoxic anti-tumour functions in specialized niches3-7. Although interactions with type 1 conventional dendritic cells have been implicated in this process3-5,8-10, the underlying cellular players and molecular mechanisms remain incompletely understood. Here we show that inflammatory monocytes can adopt a pivotal role in intratumoral T cell stimulation. These cells express Cxcl9, Cxcl10 and Il15, but in contrast to type 1 conventional dendritic cells, which cross-present antigens, inflammatory monocytes obtain and present peptide-major histocompatibility complex class I complexes from tumour cells through 'cross-dressing'. Hyperactivation of MAPK signalling in cancer cells hampers this process by coordinately blunting the production of type I interferon (IFN-I) cytokines and inducing the secretion of prostaglandin E2 (PGE2), which impairs the inflammatory monocyte state and intratumoral T cell stimulation. Enhancing IFN-I cytokine production and blocking PGE2 secretion restores this process and re-sensitizes tumours to T cell-mediated immunity. Together, our work uncovers a central role of inflammatory monocytes in intratumoral T cell stimulation, elucidates how oncogenic signalling disrupts T cell responses through counter-regulation of PGE2 and IFN-I, and proposes rational combination therapies to enhance immunotherapies.
    DOI:  https://doi.org/10.1038/s41586-024-08257-4
  13. Elife. 2024 Nov 26. pii: RP95338. [Epub ahead of print]13
    High-density sampling reveals volume growth in human tumours.
    Arman Angaji, Michel Owusu, Christoph Velling, Nicola Dick, Donate Weghorn, Johannes Berg.
      In growing cell populations such as tumours, mutations can serve as markers that allow tracking the past evolution from current samples. The genomic analyses of bulk samples and samples from multiple regions have shed light on the evolutionary forces acting on tumours. However, little is known empirically on the spatio-temporal dynamics of tumour evolution. Here, we leverage published data from resected hepatocellular carcinomas, each with several hundred samples taken in two and three dimensions. Using spatial metrics of evolution, we find that tumour cells grow predominantly uniformly within the tumour volume instead of at the surface. We determine how mutations and cells are dispersed throughout the tumour and how cell death contributes to the overall tumour growth. Our methods shed light on the early evolution of tumours in vivo and can be applied to high-resolution data in the emerging field of spatial biology.
    Keywords:  cancer biology; evolutionary biology; human; multi-region tumour samples; spatial genomics; tumour samples
    DOI:  https://doi.org/10.7554/eLife.95338
  14. bioRxiv. 2024 Nov 15. pii: 2024.11.14.621733. [Epub ahead of print]
    Dietary Restriction Enhances CD8⁺ T Cell Ketolysis to Limit Exhaustion and Boost Anti-Tumor Immunity.
    Brandon M Oswald, Lisa M DeCamp, Joseph Longo, Michael S Dahabieh, Nicholas Bunda, Shixin Ma, McLane J Watson, Ryan D Sheldon, Michael P Vincent, Benjamin K Johnson, Abigail E Ellis, Molly T Soper-Hopper, Christine N Isaguirre, Hui Shen, Kelsey S Williams, Peter A Crawford, Susan Kaech, H Josh Jang, Connie M Krawczyk, Russell G Jones.
      Reducing calorie intake without malnutrition limits tumor progression but the underlying mechanisms are poorly understood. Here we show that dietary restriction (DR) suppresses tumor growth by enhancing CD8 + T cell-mediated anti-tumor immunity. DR reshapes CD8 + T cell differentiation within the tumor microenvironment (TME), promoting the development of effector T cell subsets while limiting the accumulation of exhausted T (Tex) cells, and synergizes with anti-PD1 immunotherapy to restrict tumor growth. Mechanistically, DR enhances CD8 + T cell metabolic fitness through increased ketone body oxidation (ketolysis), which boosts mitochondrial membrane potential and fuels tricarboxylic acid (TCA) cycle-dependent pathways essential for T cell function. T cells deficient for ketolysis exhibit reduced mitochondrial function, increased exhaustion, and fail to control tumor growth under DR conditions. Our findings reveal a critical role for the immune system in mediating the anti-tumor effects of DR, highlighting nutritional modulation of CD8 + T cell fate in the TME as a critical determinant of anti-tumor immunity.
    DOI:  https://doi.org/10.1101/2024.11.14.621733
  15. bioRxiv. 2024 Nov 24. pii: 2024.11.23.624981. [Epub ahead of print]
    MAT2a and AHCY inhibition disrupts antioxidant metabolism and reduces glioblastoma cell survival.
    Emma C Rowland, Matthew D'Antuono, Anna Jermakowicz, Nagi G Ayad.
      Glioblastoma (GBM) is a highly aggressive primary malignant adult brain tumor that inevitably recurs with a fatal prognosis. This is due in part to metabolic reprogramming that allows tumors to evade treatment. We therefore must uncover the pathways mediating these adaptations to develop novel and effective treatments. We searched for genes that are essential in GBM cells as measured by a whole-genome pan-cancer CRISPR screen available from DepMap and identified the methionine metabolism genes MAT2A and AHCY . We conducted genetic knockdown, evaluated mitochondrial respiration, and performed targeted metabolomics to study the function of these genes in GBM. We demonstrate that MAT2A or AHCY knockdown induces oxidative stress, hinders cellular respiration, and reduces the survival of GBM cells. Furthermore, selective MAT2a or AHCY inhibition reduces GBM cell viability, impairs oxidative metabolism, and changes the metabolic profile of these cells towards oxidative stress and cell death. Mechanistically, MAT2a or AHCY regulates spare respiratory capacity, the redox buffer cystathionine, lipid and amino acid metabolism, and prevents DNA damage in GBM cells. Our results point to the methionine metabolic pathway as a novel vulnerability point in GBM.
    Significance: We demonstrated that methionine metabolism maintains antioxidant production to facilitate pro-tumorigenic ROS signaling and GBM tumor cell survival. Importantly, targeting this pathway in GBM can potentially reduce tumor growth and improve survival in patients.
    DOI:  https://doi.org/10.1101/2024.11.23.624981
  16. Nat Genet. 2024 Nov 29.
    Characterizing the evolutionary dynamics of cancer proliferation in single-cell clones with SPRINTER.
    TRACERx Consortium
      Proliferation is a key hallmark of cancer, but whether it differs between evolutionarily distinct clones co-existing within a tumor is unknown. We introduce the Single-cell Proliferation Rate Inference in Non-homogeneous Tumors through Evolutionary Routes (SPRINTER) algorithm that uses single-cell whole-genome DNA sequencing data to enable accurate identification and clone assignment of S- and G2-phase cells, as assessed by generating accurate ground truth data. Applied to a newly generated longitudinal, primary-metastasis-matched dataset of 14,994 non-small cell lung cancer cells, SPRINTER revealed widespread clone proliferation heterogeneity, orthogonally supported by Ki-67 staining, nuclei imaging and clinical imaging. We further demonstrated that high-proliferation clones have increased metastatic seeding potential, increased circulating tumor DNA shedding and clone-specific altered replication timing in proliferation- or metastasis-related genes associated with expression changes. Applied to previously generated datasets of 61,914 breast and ovarian cancer cells, SPRINTER revealed increased single-cell rates of different genomic variants and enrichment of proliferation-related gene amplifications in high-proliferation clones.
    DOI:  https://doi.org/10.1038/s41588-024-01989-z
  17. Bull Math Biol. 2024 Nov 27. 87(1): 7
    Parameter Estimation and Identifiability in Kinetic Flux Profiling Models of Metabolism.
    Breanna Guppy, Colleen Mitchell, Eric B Taylor.
      Metabolic fluxes are the rates of life-sustaining chemical reactions within a cell and metabolites are the components. Determining the changes in these fluxes is crucial to understanding diseases with metabolic causes and consequences. Kinetic flux profiling (KFP) is a method for estimating flux that utilizes data from isotope tracing experiments. In these experiments, the isotope-labeled nutrient is metabolized through a pathway and integrated into the downstream metabolite pools. Measurements of proportion labeled for each metabolite in the pathway are taken at multiple time points and used to fit an ordinary differential equations model with fluxes as parameters. We begin by generalizing the process of converting diagrams of metabolic pathways into mathematical models composed of differential equations and algebraic constraints. The scaled differential equations for proportions of unlabeled metabolite contain parameters related to the metabolic fluxes in the pathway. We investigate flux parameter identifiability given data collected only at the steady state of the differential equation. Next, we give criteria for valid parameter estimations in the case of a large separation of timescales with fast-slow analysis. Bayesian parameter estimation on simulated data from KFP experiments containing both irreversible and reversible reactions illustrates the accuracy and reliability of flux estimations. These analyses provide constraints that serve as guidelines for the design of KFP experiments to estimate metabolic fluxes.
    Keywords:  Bayesian parameter estimation; Kinetic flux profiling; Mathematical biology; Parameter identifiability
    DOI:  https://doi.org/10.1007/s11538-024-01386-x
  18. Cell Rep. 2024 Nov 26. pii: S2211-1247(24)01350-0. [Epub ahead of print]43(11): 114999
    Q&A with Ilaria Elia.
    Ilaria Elia.
      Ilaria Elia, guest editor of the cancer metabolism special issue, spoke with Cell Reports about her scientific interests and her lab's focus on investigating the metabolic interactions between cancer cells and immune cells within the tumor microenvironment. Ilaria also discussed recent developments and future directions in the field.
    Keywords:  CP: Cancer; CP: Metabolism
    DOI:  https://doi.org/10.1016/j.celrep.2024.114999
  19. Cell Rep. 2024 Nov 23. pii: S2211-1247(24)01299-3. [Epub ahead of print]43(12): 114948
    IFN-γ-dependent regulation of intestinal epithelial homeostasis by NKT cells.
    Marta Lebrusant-Fernandez, Tom Ap Rees, Rebeca Jimeno, Nikolaos Angelis, Joseph C Ng, Franca Fraternali, Vivian S W Li, Patricia Barral.
      Intestinal homeostasis is maintained through the combined functions of epithelial and immune cells that collaborate to preserve the integrity of the intestinal barrier. However, the mechanisms by which immune cell populations regulate intestinal epithelial cell (IEC) homeostasis remain unclear. Here, we use a multi-omics approach to study the immune-epithelial crosstalk and identify CD1d-restricted natural killer T (NKT) cells as key regulators of IEC biology. We find that NKT cells are abundant in the proximal small intestine and show hallmarks of activation at steady state. Subsequently, NKT cells regulate the survival and the transcriptional and cellular composition landscapes of IECs in intestinal organoids, through interferon-γ (IFN-γ) and interleukin-4 secretion. In vivo, lack of NKT cells results in an increase in IEC turnover, while NKT cell activation leads to IFN-γ-dependent epithelial apoptosis. Our findings propose NKT cells as potent producers of cytokines that contribute to the regulation of IEC homeostasis.
    Keywords:  CP: Immunology; IFN-γ; NKT cell; intestinal epithelial cell; intestinal organoids
    DOI:  https://doi.org/10.1016/j.celrep.2024.114948
  20. Cell. 2024 Nov 16. pii: S0092-8674(24)01271-6. [Epub ahead of print]
    Mechano-dependent sorbitol accumulation supports biomolecular condensate.
    Stephanie Torrino, William M Oldham, Andrés R Tejedor, Ignacio S Burgos, Lara Nasr, Nesrine Rachedi, Kéren Fraissard, Caroline Chauvet, Chaima Sbai, Brendan P O'Hara, Sophie Abélanet, Frederic Brau, Cyril Favard, Stephan Clavel, Rosana Collepardo-Guevara, Jorge R Espinosa, Issam Ben-Sahra, Thomas Bertero.
      Condensed droplets of protein regulate many cellular functions, yet the physiological conditions regulating their formation remain largely unexplored. Increasing our understanding of these mechanisms is paramount, as failure to control condensate formation and dynamics can lead to many diseases. Here, we provide evidence that matrix stiffening promotes biomolecular condensation in vivo. We demonstrate that the extracellular matrix links mechanical cues with the control of glucose metabolism to sorbitol. In turn, sorbitol acts as a natural crowding agent to promote biomolecular condensation. Using in silico simulations and in vitro assays, we establish that variations in the physiological range of sorbitol concentrations, but not glucose concentrations, are sufficient to regulate biomolecular condensates. Accordingly, pharmacological and genetic manipulation of intracellular sorbitol concentration modulates biomolecular condensates in breast cancer-a mechano-dependent disease. We propose that sorbitol is a mechanosensitive metabolite enabling protein condensation to control mechano-regulated cellular functions.
    Keywords:  LLPS; biomolecular condensate; breast cancer; cell metabolism; glucose metabolism; mechanobiology; phase transition; sorbitol
    DOI:  https://doi.org/10.1016/j.cell.2024.10.048
  21. J Invest Dermatol. 2024 Nov 21. pii: S0022-202X(24)02951-8. [Epub ahead of print]
    Constitutive HIF-1α expression in the epidermis fuels proliferation and is essential for effective barrier formation.
    Julia Boix, Jana Knuever, Nadine Niehoff, Ayesha Sen, David Pla-Martin, Olivier R Baris, Julia Etich, Bent Brachvogel, Harshita Kaul, Dirk Isbrandt, Ekaterina Soroka, Hisham Bazzi, Roland H Wenger, Patrick Giavalisco, Rudolf J Wiesner.
      Epidermis is one of the most rapidly proliferating tissues in the body with high demands for ATP and cellular building blocks. Here we show that, in order to meet these requirements, keratinocytes constitutively express hypoxia-inducible factor-1α (HIF-1α), even in the presence of oxygen levels sufficient for HIF-1α hydroxylation. We previously reported that mice with severe epidermal mitochondrial dysfunction actually showed a hyperproliferative epidermis, but rapidly died of systemic lactic acidosis and hypoglycemia, indicating excessive glycolysis. In the present work, we interrogated HIF-1α function in glycolysis by its epidermal ablation combined with mitochondrial dysfunction, which resulted in decreased proliferation but even earlier lethality due to a severe barrier defect. Our data demonstrate that HIF-1α is indispensable for maintaining a high aerobic glycolytic flux necessary for supplying energy, but also for synthetizing cellular building blocks like lipids, which are both essential for proliferation as well as barrier formation. HIF-1α is stabilized in keratinocytes in the presence of oxygen by high levels of HIF-1α transcripts, low levels of prolyl-4-hydroxylases (PHD2 and 3) and a low cellular α-ketoglutarate/lactate ratio, likely inhibiting PHD activity. Our data suggest a key role for constitutive HIF-1α expression allowing a Warburg-like metabolism in healthy, highly proliferative keratinocytes, similar to tumour cells.
    Keywords:  HIF-1α; epidermal barrier function; lipid synthesis; mitochondrial DNA; skin homeostasis
    DOI:  https://doi.org/10.1016/j.jid.2024.09.022
  22. bioRxiv. 2024 Nov 18. pii: 2024.11.18.623867. [Epub ahead of print]
    Cold-inducible GOT1 activates the malate-aspartate shuttle in brown adipose tissue to support fuel preference for fatty acids.
    Chul-Hong Park, Minsung Park, Miranda E Kelly, Helia Cheng, Sang Ryeul Lee, Cholsoon Jang, Ji Suk Chang.
      Brown adipose tissue (BAT) simultaneously metabolizes fatty acids (FA) and glucose under cold stress but favors FA as the primary fuel for heat production. It remains unclear how BAT steer fuel preference toward FA over glucose. Here we show that the malate-aspartate shuttle (MAS) is activated by cold in BAT and plays a crucial role in promoting mitochondrial FA utilization. Mechanistically, cold stress selectively induces glutamic-oxaloacetic transaminase (GOT1), a key MAS enzyme, via the β-adrenergic receptor-PKA-PGC-1α axis. The increase in GOT1 activates MAS, transferring reducing equivalents from the cytosol to mitochondria. This process enhances FA oxidation in mitochondria while limiting glucose oxidation. In contrast, loss of MAS activity by GOT1 deficiency reduces FA oxidation, leading to increased glucose oxidation. Together, our work uncovers a unique regulatory mechanism and role for MAS in mitochondrial fuel selection and advances our understanding of how BAT maintains fuel preference for FA under cold conditions.
    Highlights: Got1 is markedly induced by cold in BAT via a β-adrenergic receptor-PKA-PGC-1α axis The increase in cytosolic GOT1 activates the malate-aspartate shuttle (MAS)MAS activation promotes fatty acid oxidation while reducing glucose oxidation Loss of MAS activity in BAT by Got1 deletion shifts the fuel preference to glucose.
    DOI:  https://doi.org/10.1101/2024.11.18.623867
  23. Nat Rev Endocrinol. 2024 Nov 29.
    Consensus on the key characteristics of metabolism disruptors.
    Michele A La Merrill, Martyn T Smith, Cliona M McHale, Jerrold J Heindel, Ella Atlas, Matthew C Cave, David Collier, Kathryn Z Guyton, Suneil Koliwad, Angel Nadal, Christopher J Rhodes, Robert M Sargis, Lauren Zeise, Bruce Blumberg.
      Metabolism-disrupting agents (MDAs) are chemical, infectious or physical agents that increase the risk of metabolic disorders. Examples include pharmaceuticals, such as antidepressants, and environmental agents, such as bisphenol A. Various types of studies can provide evidence to identify MDAs, yet a systematic method is needed to integrate these data to help to identify such hazards. Inspired by work to improve hazard identification of carcinogens using key characteristics (KCs), we developed 12 KCs of MDAs based on our knowledge of processes underlying metabolic diseases and the effects of their causal agents: (1) alters function of the endocrine pancreas; (2) impairs function of adipose tissue; (3) alters nervous system control of metabolic function; (4) promotes insulin resistance; (5) disrupts metabolic signalling pathways; (6) alters development and fate of metabolic cell types; (7) alters energy homeostasis; (8) causes inappropriate nutrient handling and partitioning; (9) promotes chronic inflammation and immune dysregulation in metabolic tissues; (10) disrupts gastrointestinal tract function; (11) induces cellular stress pathways; and (12) disrupts circadian rhythms. In this Consensus Statement, we present the logic that revealed the KCs of MDAs and highlight evidence that supports the identification of KCs. We use chemical, infectious and physical agents as examples to illustrate how the KCs can be used to organize and use mechanistic data to help to identify MDAs.
    DOI:  https://doi.org/10.1038/s41574-024-01059-8
  24. Nat Commun. 2024 Nov 26. 15(1): 10268
    Developmental hematopoietic stem cell variation explains clonal hematopoiesis later in life.
    Jesse Kreger, Jazlyn A Mooney, Darryl Shibata, Adam L MacLean.
      Clonal hematopoiesis becomes increasingly common with age, but its cause is enigmatic because driver mutations are often absent. Serial observations infer weak selection indicating variants are acquired much earlier in life with unexplained initial growth spurts. Here we use fluctuating CpG methylation as a lineage marker to track stem cell clonal dynamics of hematopoiesis. We show, via the shared prenatal circulation of monozygotic twins, that weak selection conferred by stem cell variation created before birth can reliably yield clonal hematopoiesis later in life. Theory indicates weak selection will lead to dominance given enough time and large enough population sizes. Human hematopoiesis satisfies both these conditions. Stochastic loss of weakly selected variants is naturally prevented by the expansion of stem cell lineages during development. The dominance of stem cell clones created before birth is supported by blood fluctuating CpG methylation patterns that exhibit low correlation between unrelated individuals but are highly correlated between many elderly monozygotic twins. Therefore, clonal hematopoiesis driven by weak selection in later life appears to reflect variation created before birth.
    DOI:  https://doi.org/10.1038/s41467-024-54711-2
  25. Sci Adv. 2024 Nov 29. 10(48): eadq8122
    Identification of VISTA regulators in macrophages mediating cancer cell survival.
    Abdalla M Abdrabou, Sharif U Ahmed, Mengqi Jonathan Fan, Bill T V Duong, Kangfu Chen, Pei-Ying Lo, Julia M Mayes, Fatemeh Esmaeili, Amin GhavamiNejad, Hossein Zargartalebi, Randy Singh Atwal, Sichun Lin, Stephane Angers, Shana O Kelley.
      Numerous human cancers have exhibited the ability to elude immune checkpoint blockade (ICB) therapies. This type of resistance can be mediated by immune-suppressive macrophages that limit antitumor immunity in the tumor microenvironment (TME). Here, we elucidate a strategy to shift macrophages into a proinflammatory state that down-regulates V domain immunoglobulin suppressor of T cell activation (VISTA) via inhibiting AhR and IRAK1. We used a high-throughput microfluidic platform combined with a genome-wide CRISPR knockout screen to identify regulators of VISTA levels. Functional characterization showed that the knockdown of these hits diminished VISTA surface levels on macrophages and sustained an antitumor phenotype. Furthermore, targeting of both AhR and IRAK1 in mouse models overcame resistance to ICB treatment. Tumor immunophenotyping indicated that infiltration of cytotoxic CD8+ cells, natural killer cells, and antitumor macrophages was substantially increased in treated mice. Collectively, AhR and IRAK1 are implicated as regulators of VISTA that coordinate a multifaceted barrier to antitumor immune responses.
    DOI:  https://doi.org/10.1126/sciadv.adq8122
  26. bioRxiv. 2024 Nov 11. pii: 2024.11.10.622811. [Epub ahead of print]
    Cholesterol metabolism and intrabacterial potassium homeostasis are intrinsically related in Mycobacterium tuberculosis.
    Yue Chen, Berge Hagopian, Shumin Tan.
      Potassium (K + ) is the most abundant intracellular cation, but much remains unknown regarding how K + homeostasis is integrated with other key bacterial biology aspects. Here, we show that K + homeostasis disruption (CeoBC K + uptake system deletion) impedes Mycobacterium tuberculosis (Mtb) response to, and growth in, cholesterol, a critical carbon source during infection, with K + augmenting activity of the Mtb ATPase MceG that is vital for bacterial cholesterol import. Reciprocally, cholesterol directly binds to CeoB, modulating its function, with a residue critical for this interaction identified. Finally, cholesterol binding-deficient CeoB mutant Mtb are attenuated for growth in lipid-rich foamy macrophages and in vivo colonization. Our findings raise the concept of a role for cholesterol as a key co-factor, beyond its role as a carbon source, and illuminate how changes in bacterial intrabacterial K + levels can act as part of the metabolic adaptation critical for bacterial survival and growth in the host.
    DOI:  https://doi.org/10.1101/2024.11.10.622811
  27. Nature. 2024 Nov 27.
    Fungal symbiont transmitted by free-living mice promotes type 2 immunity.
    Yun Liao, Iris H Gao, Takato Kusakabe, Woan-Yu Lin, Alexander Grier, Xiangyu Pan, Olga Morzhanaeva, Terrance P Shea, Hiroshi Yano, Danielle Karo-Atar, Kaitlin A Olsen, Ji Hoon Oh, Kurt J Vandegrift, Irah L King, Christina A Cuomo, David Artis, Barbara Rehermann, Neil Lipman, Iliyan D Iliev.
      The gut mycobiota is crucial for intestinal homeostasis and immune function1. Yet its variability and inconsistent fungal colonization of laboratory mice hinders the study of the evolutionary and immune processes that underpin commensalism2,3. Here, we show that Kazachstania pintolopesii is a fungal commensal in wild urban and rural mice, with an exceptional ability to colonize the mouse gastrointestinal tract and dominate the gut mycobiome. Kazachstania pintolopesii colonization occurs in a bacteria-independent manner, results in enhanced colonization resistance to other fungi and is shielded from host immune surveillance, allowing commensal presence. Following changes in the mucosal environment, K. pintolopesii colonization triggers a type 2 immune response in mice and induces gastrointestinal eosinophilia. Mechanistically, we determined that K. pintolopesii activates type 2 immunity via the induction of epithelial IL-33 and downstream IL-33-ST2 signalling during mucus fluctuations. Kazachstania pintolopesii-induced type 2 immunity enhanced resistance to helminth infections or aggravated gastrointestinal allergy in a context-dependent manner. Our findings indicate that K. pintolopesii is a mouse commensal and serves as a valuable model organism for studying gut fungal commensalism and immunity in its native host. Its unnoticed presence in mouse facilities highlights the need to evaluate its influence on experimental outcomes and phenotypes.
    DOI:  https://doi.org/10.1038/s41586-024-08213-2
  28. Nat Aging. 2024 Nov 27.
    Late-life protein or isoleucine restriction impacts physiological and molecular signatures of aging.
    Chung-Yang Yeh, Lucas C S Chini, Jessica W Davidson, Gonzalo G Garcia, Meredith S Gallagher, Isaac T Freichels, Mariah F Calubag, Allison C Rodgers, Cara L Green, Reji Babygirija, Michelle M Sonsalla, Heidi H Pak, Michaela E Trautman, Timothy A Hacker, Richard A Miller, Judith A Simcox, Dudley W Lamming.
      Restricting the intake of protein or the branched-chain amino acid isoleucine promotes healthspan and extends lifespan in young or adult mice. However, their effects when initiated in aged animals are unknown. Here we investigate the consequences of consuming a diet with 67% reduction of all amino acids (low AA) or of isoleucine alone (low Ile), in male and female C57BL/6J.Nia mice starting at 20 months of age. Both dietary regimens effectively promote overall metabolic health without reducing calorie intake. Both low AA and low Ile diets improve aspects of frailty and slow multiple molecular indicators of aging rate; however, the low Ile diet reduces grip strength in both sexes and has mixed, sexually dimorphic effects on the heart. These results demonstrate that low AA and low Ile diets can promote aspects of healthy aging in aged mice and suggest that similar interventions might promote healthy aging in older adults.
    DOI:  https://doi.org/10.1038/s43587-024-00744-7
  29. EMBO Rep. 2024 Nov 25.
    Can bacteria think?
    Howy Jacobs.
      
    DOI:  https://doi.org/10.1038/s44319-024-00334-z
  30. Cell Rep. 2024 Nov 26. pii: S2211-1247(24)01366-4. [Epub ahead of print]43(12): 115015
    Nucleo-cytosolic acetyl-CoA drives tumor immune evasion by regulating PD-L1 in melanoma.
    Huina Wang, Xiuli Yi, Xiangxu Wang, Yuqi Yang, Hengxiang Zhang, Hao Wang, Jianru Chen, Baolu Zhang, Sen Guo, Lili Wu, Juan Du, Yuhan Chen, Ningyue Sun, Tianwen Gao, Rui Zhang, Huijie Bian, Lintao Jia, Chunying Li, Weinan Guo.
      Acetyl coenzyme A (acetyl-CoA), a versatile central metabolite, plays a critical role in various metabolic processes and protein acetylation. While its impact on tumor cell properties is well established, the connection between acetyl-CoA metabolism and immune evasion in tumors remains unclear. Here, we uncover a mechanism by which nucleo-cytosolic acetyl-CoA contributes to immune evasion through regulation of programmed death ligand 1 (PD-L1). Specifically, bioinformatics analysis reveals a negative correlation between acetyl-CoA metabolism and anti-tumor immunity across multiple cancers. Inhibition of the acetyl-CoA-producing enzyme ATP-citrate lyase (ACLY) leads to a re-invigoration of cytotoxic T cells and enhances the efficacy of immunotherapy. Mechanistically, nucleo-cytosolic acetyl-CoA promotes PD-L1 transcription via P300-dependent histone H3K27 acetylation at the promoter region of CD274. The ACLY-H3K27ac-PD-L1 axis is verified in clinical specimens and predicts poor immunotherapy response. Our findings suggest that targeting acetyl-CoA metabolism may act as a promising strategy to overcome immune evasion and improve the outcomes of cancer immunotherapy.
    Keywords:  ACLY; Acetyl-CoA; CP: Cancer; PD-L1; histone acetylation; immune evasion; melanoma; metabolism
    DOI:  https://doi.org/10.1016/j.celrep.2024.115015
  31. bioRxiv. 2024 Nov 15. pii: 2024.11.13.623458. [Epub ahead of print]
    Language model-guided anticipation and discovery of unknown metabolites.
    Hantao Qiang, Fei Wang, Wenyun Lu, Xi Xing, Hahn Kim, Sandrine A M Merette, Lucas B Ayres, Eponine Oler, Jenna E AbuSalim, Asael Roichman, Michael Neinast, Ricardo A Cordova, Won Dong Lee, Ehud Herbst, Vishu Gupta, Samuel Neff, Mickel Hiebert-Giesbrecht, Adamo Young, Vasuk Gautam, Siyang Tian, Bo Wang, Hannes Röst, Russell Greiner, Li Chen, Chad W Johnston, Leonard J Foster, Aaron M Shapiro, David S Wishart, Joshua D Rabinowitz, Michael A Skinnider.
      Despite decades of study, large parts of the mammalian metabolome remain unexplored. Mass spectrometry-based metabolomics routinely detects thousands of small molecule-associated peaks within human tissues and biofluids, but typically only a small fraction of these can be identified, and structure elucidation of novel metabolites remains a low-throughput endeavor. Biochemical large language models have transformed the interpretation of DNA, RNA, and protein sequences, but have not yet had a comparable impact on understanding small molecule metabolism. Here, we present an approach that leverages chemical language models to discover previously uncharacterized metabolites. We introduce DeepMet, a chemical language model that learns the latent biosynthetic logic embedded within the structures of known metabolites and exploits this understanding to anticipate the existence of as-of-yet undiscovered metabolites. Prospective chemical synthesis of metabolites predicted to exist by DeepMet directs their targeted discovery. Integrating DeepMet with tandem mass spectrometry (MS/MS) data enables automated metabolite discovery within complex tissues. We harness DeepMet to discover several dozen structurally diverse mammalian metabolites. Our work demonstrates the potential for language models to accelerate the mapping of the metabolome.
    DOI:  https://doi.org/10.1101/2024.11.13.623458
  32. Commun Biol. 2024 Nov 26. 7(1): 1576
    Metabolomics and 13C labelled glucose tracing to identify carbon incorporation into aberrant cell membrane glycans in cancer.
    Alfredo Reyes-Oliveras, Abigail E Ellis, Ryan D Sheldon, Brian Haab.
      Cell membrane glycans contribute to immune recognition, signaling, and cellular adhesion and migration, and altered membrane glycosylation is a feature of cancer cells that contributes to cancer progression. The uptake and metabolism of glucose and other nutrients essential for glycan synthesis could underlie altered membrane glycosylation, but the relationship between shifts in nutrient metabolism and the effects on glycans have not been directly examined. We developed a method that combines stable isotope tracing with metabolomics to enable direct observations of glucose allocation to nucleotide sugars and cell-membrane glycans. We compared the glucose allocation to membrane glycans of two pancreatic cancer cell lines that are genetically identical but have differing energy requirements. The 8988-S cells had higher glucose allocation to membrane glycans and intracellular pathways relating to glycan synthesis, but the 8988-T cells had higher glucose uptake and commitment of glucose to non-glycosylation pathways. The cell lines differed in the requirements of glucose for energy production, resulting in differences in glucose bioavailability for glycan synthesis. The workflow demonstrated here enables studies on the effects of metabolic shifts on the commitment of nutrients to cell-membrane glycans. The results suggest that cell-membrane glycans are remodeled through shifts in glucose commitment to non-glycosylation pathways.
    DOI:  https://doi.org/10.1038/s42003-024-07277-0
  33. J Inherit Metab Dis. 2024 Nov 24.
    Human glyoxylate metabolism revisited: New insights pointing to multi-organ involvement with implications for siRNA-based therapies in primary hyperoxaluria.
    Ronald J A Wanders, Jaap W Groothoff, Lisa J Deesker, Eduardo Salido, Sander F Garrelfs.
      Glyoxylate is a toxic metabolite because of its rapid conversion into oxalate, as catalyzed by the ubiquitous enzyme lactate dehydrogenase. This requires the presence of efficient glyoxylate detoxification systems in multiple subcellular compartments, as glyoxylate is produced in peroxisomes, mitochondria, and the cytosol. Alanine glyoxylate aminotransferase (AGT) and glyoxylate reductase/hydroxypyruvate reductase (GRHPR) are the key enzymes involved in glyoxylate detoxification. Bi-allelic mutations in the genes coding for these enzymes cause primary hyperoxaluria type 1 (PH1) and 2 (PH2), respectively. Glyoxylate is derived from various sources, including 4-hydroxyproline, which is degraded in mitochondria, generating pyruvate and glyoxylate, as catalyzed by the mitochondrial enzyme 4-hydroxy-2-oxoglutarate aldolase (HOGA); however, counterintuitively, a defect in HOGA1 is the molecular basis of primary hyperoxaluria type 3 (PH3). Irrespective of its underlying cause, hyperoxaluria in humans leads to nephrocalcinosis, recurrent urolithiasis, and kidney damage, which may culminate in kidney failure requiring combined liver-kidney transplantation in severely affected patients. In the past few years, therapeutic options, especially for primary hyperoxaluria type 1 (PH1), have greatly been improved thanks to the introduction of two RNAi-based therapies that inhibit either the production of glycolate oxidase (lumasiran) or lactate dehydrogenase (nedosiran). While lumasiran only targets PH1 patients, nedosiran was specifically developed to target all three subtypes of PH. Inspired by the findings reported in the literature that nedosiran effectively reduced urinary oxalate excretion in PH1 patients but not in PH2 or PH3 patients, we have now revisited glyoxylate metabolism in humans and performed a thorough literature study which revealed that glyoxylate/oxalate metabolism is not confined to the liver but instead involves multiple different organs. This new view on glyoxylate/oxalate metabolism in humans may well explain the disappointing results of nedosiran in PH2 and PH3, and provides new clues for the future generation of new therapeutic strategies for PH2 and PH3.
    Keywords:  genetic diseases; glyoxylate‐oxalate; hyperoxaluria; mitochondria; peroxisomes
    DOI:  https://doi.org/10.1002/jimd.12817
  34. Trends Cell Biol. 2024 Nov 27. pii: S0962-8924(24)00225-3. [Epub ahead of print]
    Metabolism and mRNA translation: a nexus of cancer plasticity.
    Xinpu Tang, Kaixiu Li, Yuqing Wang, Stéphane Rocchi, Shensi Shen, Michael Cerezo.
      Tumors often face energy deprivation due to mutations, hypoxia, and nutritional deficiencies within the harsh tumor microenvironment (TME), and as an effect of anticancer treatments. This metabolic stress triggers adaptive reprogramming of mRNA translation, which in turn adjusts metabolic plasticity and associated signaling pathways to ensure tumor cell survival. Emerging evidence is beginning to reveal the complex interplay between metabolism and mRNA translation, shedding light on the mechanisms that synchronize ribosome assembly and reconfigure translation programs under metabolic stress. This review explores recent advances in our understanding of the coordination between metabolism and mRNA translation, offering insights that could inform therapeutic strategies targeting both cancer metabolism and translation, with the aim of disrupting cancer cell plasticity and survival.
    Keywords:  cancer cell plasticity; mRNA translation; tumor metabolism
    DOI:  https://doi.org/10.1016/j.tcb.2024.10.009
  35. Cell Rep. 2024 Nov 26. pii: S2211-1247(24)01351-2. [Epub ahead of print]43(11): 115000
    Q&A with Ping Gao.
    Ping Gao.
      Ping Gao, guest editor of the cancer metabolism special issue, spoke with Cell Reports about his scientific interests and his lab's focus on investigating the metabolic reprogramming in cancer cells and immune cells in the tumor microenvironment. Ping also discussed recent developments and future directions in the field.
    Keywords:  CP: Cancer; CP: Metabolism
    DOI:  https://doi.org/10.1016/j.celrep.2024.115000
  36. Geroscience. 2024 Nov 25.
    Serine metabolism in aging and age-related diseases.
    Shengshuai Shan, Jessica M Hoffman.
      Non-essential amino acids are often overlooked in biomedical research; however, they are crucial components of organismal metabolism. One such metabolite that is integral to physiological function is serine. Serine acts as a pivotal link connecting glycolysis with one-carbon and lipid metabolism, as well as with pyruvate and glutathione syntheses. Interestingly, increasing evidence suggests that serine metabolism may impact the aging process, and supplementation with serine may confer benefits in safeguarding against aging and age-related disorders. This review synthesizes recent insights into the regulation of serine metabolism during aging and its potential to promote healthy lifespan and mitigate a spectrum of age-related diseases.
    Keywords:  Age-related diseases; Aging; Longevity; Metabolism; Oxidative stress; Serine
    DOI:  https://doi.org/10.1007/s11357-024-01444-1
  37. Am J Physiol Cell Physiol. 2024 Nov 29.
    13C Stable Isotope Tracing Reveals Distinct Fatty Acid Oxidation Pathways in Proliferative vs. Oxidative Cells.
    Julia Ritterhoff, Timothy McMillen, Hanna Foundas, Roland Palkovacs, Gernot Poschet, Arianne Caudal, Yaxin Liu, Patrick Most, Matthew Walker, Rong Tian.
      The TCA cycle serves as a central hub to balance catabolic and anabolic needs of the cell, where carbon moieties can either contribute to oxidative metabolism or support biosynthetic reactions. This differential TCA cycle engagement for glucose-derived carbon has been extensively studied in cultured cells, but the fate of fatty acid (FA)-derived carbons is poorly understood. To fill the knowledge gap, we have developed a strategy to culture cells with long-chain FAs without altering cell viability. By tracing 13C-FA we show that FA oxidation (FAO) is robust in both proliferating and oxidative cells while the metabolic pathway after citrate formation is distinct. In proliferating cells, a significant portion of carbon derived from FAO exits canonical TCA cycle as citrate and converts to unlabeled malate in cytosol. Increasing FA supply or b-oxidation does not change the partition of FA-derived carbon between cytosol and mitochondria. Oxidation of glucose competes with FA derived carbon for the canonical TCA pathway thus promoting FA carbon flowing into the alternative TCA pathway. Moreover, the coupling between FAO and the canonical TCA pathway changes with the state of oxidative energy metabolism.
    Keywords:  13C stable isotope tracing; FAO; TCA cycle; oxygen consumption rate
    DOI:  https://doi.org/10.1152/ajpcell.00611.2023
  38. Curr Biol. 2024 Nov 20. pii: S0960-9822(24)01442-8. [Epub ahead of print]
    The cyanobacterial circadian clock couples to pulsatile processes using pulse amplitude modulation.
    Chao Ye, Chris N Micklem, Teresa Saez, Arijit K Das, Bruno M C Martins, James C W Locke.
      Cellular processes are dynamic and often oscillatory, requiring precise coordination for optimal cell function.1,2,3,4,5,6,7 How distinct oscillatory processes can couple within a single cell remains an open question. Here, we use the cyanobacterial circadian clock8,9 as a model system to explore the coupling of oscillatory and pulsatile gene circuits. The cyanobacterial circadian clock generates 24-h oscillations in downstream targets10,11,12,13,14,15 to time processes across the day/night cycle.9,16,17,18,19,20,21,22 This timing is partly mediated by the clock's modulation of the activity of alternative sigma factors,14,23,24,25 which direct RNA polymerase to specific promoters.26 Using single-cell time-lapse microscopy and modeling, we find that the clock modulates the amplitude of expression pulses of the alternative sigma factor RpoD4, which occurs only at cell division. This pulse amplitude modulation (PAM), analogous to AM regulation in radio transmission,27 allows the clock to robustly generate a 24-h rhythm in rpoD4 expression despite rpoD4's pulsing frequency being non-circadian. By modulating cell division rates, we find that, as predicted by our model, PAM regulation generates the same 24-h period in rpoD4 pulse amplitude over a range of rpoD4 pulse frequencies. Furthermore, we identify a functional significance of rpoD4 expression levels: deletion of rpoD4 results in smaller cell sizes, whereas an increase in rpoD4 expression leads to larger cell sizes in a dose-dependent manner. Thus, our work reveals a link between the cell cycle, clock, and RpoD4 in cyanobacteria and suggests that PAM regulation can be a general mechanism for biological clocks to robustly modulate pulsatile downstream processes.
    Keywords:  Synechococcus elongatus PCC 7942; cell division; cell size; circadian clock; cyanobacteria; gene expression pulsing; pulse amplitude modulation; sigma factors; single-cell live imaging; systems biology
    DOI:  https://doi.org/10.1016/j.cub.2024.10.047
  39. Sleep Med Rev. 2024 Nov 19. pii: S1087-0792(24)00135-7. [Epub ahead of print]80 102031
    Circadian immunometabolism: A future insight for targeted therapy in cancer.
    Manendra Singh Tomar, Mohit, Ashok Kumar, Ashutosh Shrivastava.
      Circadian rhythms send messages to regulate the sleep-wake cycle in living beings, which, regulate various biological activities. It is well known that altered sleep-wake cycles affect host metabolism and significantly deregulate the host immunity. The dysregulation of circadian-related genes is critical for various malignancies. One of the hallmarks of cancer is altered metabolism, the effects of which spill into surrounding microenvironments. Here, we review the emerging literature linking the circadian immunometabolic axis to cancer. Small metabolites are the products of various metabolic pathways, that are usually perturbed in cancer. Genes that regulate circadian rhythms also regulate host metabolism and control metabolite content in the tumor microenvironment. Immune cell infiltration into the tumor site is critical to perform anticancer functions, and altered metabolite content affects their trafficking to the tumor site. A compromised immune response in the tumor microenvironment aids cancer cell proliferation and immune evasion, resulting in metastases. The role of circadian rhythms in these processes is largely overlooked and demands renewed attention in the search for targets against cancer growth and spread. The precision medicine approach requires targeting the circadian immune metabolism in cancer.
    Keywords:  Cancer; Circadian rhythms; Clock genes; Immune cells; Immunometabolism; Metabolism
    DOI:  https://doi.org/10.1016/j.smrv.2024.102031
  40. Nat Commun. 2024 Nov 28. 15(1): 10343
    C/EBPβ-dependent autophagy inhibition hinders NK cell function in cancer.
    Federica Portale, Roberta Carriero, Marta Iovino, Paolo Kunderfranco, Marta Pandini, Giulia Marelli, Nicolò Morina, Massimo Lazzeri, Paolo Casale, Piergiuseppe Colombo, Gabriele De Simone, Chiara Camisaschi, Enrico Lugli, Gianluca Basso, Javier Cibella, Sergio Marchini, Matteo Bordi, Greta Meregalli, Anna Garbin, Monica Dambra, Elena Magrini, Wiebke Rackwitz, Francesco Cecconi, Alessandro Corbelli, Fabio Fiordaliso, Jiri Eitler, Torsten Tonn, Diletta Di Mitri.
      NK cells are endowed with tumor killing ability, nevertheless most cancers impair NK cell functionality, and cell-based therapies have limited efficacy in solid tumors. How cancers render NK cell dysfunctional is unclear, and overcoming resistance is an important immune-therapeutic aim. Here, we identify autophagy as a central regulator of NK cell anti-tumor function. Analysis of differentially expressed genes in tumor-infiltrating versus non-tumor NK cells from our previously published scRNA-seq data of advanced human prostate cancer shows deregulation of the autophagic pathway in tumor-infiltrating NK cells. We confirm this by flow cytometry in patients and in diverse cancer models in mice. We further demonstrate that exposure of NK cells to cancer deregulates the autophagic process, decreases mitochondrial polarization and impairs effector functions. Mechanistically, CCAAT enhancer binding protein beta (C/EBPβ), downstream of CXCL12-CXCR4 interaction, acts as regulator of NK cell metabolism. Accordingly, inhibition of CXCR4 and C/EBPβ restores NK cell fitness. Finally, genetic and pharmacological activation of autophagy improves NK cell effector and cytotoxic functions, which enables tumour control by NK and CAR-NK cells. In conclusion, our study identifies autophagy as an intracellular checkpoint in NK cells and introduces autophagy regulation as an approach to strengthen NK-cell-based immunotherapies.
    DOI:  https://doi.org/10.1038/s41467-024-54355-2
  41. Redox Biol. 2024 Nov 21. pii: S2213-2317(24)00414-2. [Epub ahead of print]78 103436
    Human mitochondrial peroxiredoxin Prdx3 is dually localized in the intermembrane space and matrix subcompartments.
    Fernando Gomes, Helena Turano, Luciana A Haddad, Luis E S Netto.
      Peroxiredoxin 3 (Prdx3) is the major sink for H2O2 and other hydroperoxides within mitochondria, yet the mechanisms guiding the import of its cytosolic precursor into mitochondrial sub-compartments remain elusive. Prdx3 is synthesized in the cytosol as a precursor with an N-terminal cleavable presequence, which is frequently proposed to target the protein exclusively to the mitochondrial matrix. Here, we present a comprehensive analysis of the human Prdx3 biogenesis, using highly purified mitochondria from HEK293T cells. Subfractionation and probing for specific mitochondrial markers confirmed Prdx3 localization in the matrix, while unexpectedly revealed its presence in the mitochondrial intermembrane space (IMS). Both matrix and IMS isoforms were found to be soluble proteins, as demonstrated by alkaline carbonate extraction. By combining in silico analysis, in organello import assays and heterologous expression in yeast, we found that Prdx3 undergoes sequential proteolytic processing steps by mitochondrial processing peptidase (MPP) and mitochondrial intermediate peptidase (MIP) during its import into the matrix. Additionally, heterologous expression of Prdx3 in yeast revealed that its sorting to the IMS is dependent on the inner membrane peptidase (IMP) complex. Collectively, these findings uncover a complex submitochondrial distribution of Prdx3, supporting its multifaceted role in mitochondrial H2O2 metabolism.
    Keywords:  Intermembrane space (IMS); Matrix; Mitochondria; Peroxiredoxin; Prdx3
    DOI:  https://doi.org/10.1016/j.redox.2024.103436
  42. Ageing Res Rev. 2024 Nov 26. pii: S1568-1637(24)00421-5. [Epub ahead of print] 102603
    The Mitochondrial Integrated Stress Response: A novel approach to anti-aging and pro-longevity.
    Xiaoding Wang, Guangyu Zhang.
      The ISR is a cellular signaling pathway that responds to various physiological changes and types of stimulation. The mitochondrial integrated stress response (ISRmt) is a stress response specific to mitochondria which is initiated by eIF2α phosphorylation and is responsive to mitochondrial stressors. The ISRmt triggers diverse metabolic responses reliant on activating transcription factor 4 (ATF4). The preliminary phases of ISRmt can provoke an adaptive stress response that antagonizes age-related diseases and promotes longevity. In this review, we provide an overview of the molecular mechanisms of the ISRmt, with a particular focus on its potential as a therapeutic target for age-related disease and the promotion of longevity.
    Keywords:  FGF21; Mitochondrial integrated stress response; aging; longevity
    DOI:  https://doi.org/10.1016/j.arr.2024.102603
  43. Biomolecules. 2024 Oct 31. pii: 1387. [Epub ahead of print]14(11):
    The Pivotal Role of One-Carbon Metabolism in Neoplastic Progression During the Aging Process.
    Avisek Majumder, Shabana Bano, Kasturi Bala Nayak.
      One-carbon (1C) metabolism is a complex network of metabolic reactions closely related to producing 1C units (as methyl groups) and utilizing them for different anabolic processes, including nucleotide synthesis, methylation, protein synthesis, and reductive metabolism. These pathways support the high proliferative rate of cancer cells. While drugs that target 1C metabolism (like methotrexate) have been used for cancer treatment, they often have significant side effects. Therefore, developing new drugs with minimal side effects is necessary for effective cancer treatment. Methionine, glycine, and serine are the main three precursors of 1C metabolism. One-carbon metabolism is vital not only for proliferative cells but also for non-proliferative cells in regulating energy homeostasis and the aging process. Understanding the potential role of 1C metabolism in aging is crucial for advancing our knowledge of neoplastic progression. This review provides a comprehensive understanding of the molecular complexities of 1C metabolism in the context of cancer and aging, paving the way for researchers to explore new avenues for developing advanced therapeutic interventions for cancer.
    Keywords:  Warburg effect; anti-cancer therapeutics; antioxidants; antiproliferative response; cancer prevention; cancer therapy; chemotherapeutic agents; diet; epigenetics; folate; glutathione; glycine biosynthesis; homocysteine; hydrogen sulfide (H2S); hyperhomocysteinemia; inflammation; lifestyle; methionine addition; oxidative stress; redox statuses; senescence; serine biosynthesis
    DOI:  https://doi.org/10.3390/biom14111387
  44. Front Immunol. 2024 ;15 1469163
    Branched-chain amino acid catabolism promotes M2 macrophage polarization.
    Manxi Lu, Da Luo, Zixuan Zhang, Feng Ouyang, Yihong Shi, Changyong Hu, Hang Su, Yining Li, Jiayi Zhang, Qian Gui, Tian-Shu Yang.
       Introduction: During an immune response, macrophages undergo systematic metabolic rewiring tailored to support their functions. Branched-chain amino acid (BCAA) metabolism has been reported to modulate macrophage function; however, its role in macrophage alternative activation remain unclear. We aimed to investigate the role of BCAA metabolism in macrophage alternative activation.
    Method: The metabolomics of BMDM-derived M0 and M2 macrophages were analyzed using LC-MS. BCAAs were supplemented and genes involved in BCAA catabolism were inhibited during M2 macrophage polarization. The expression of M2 marker genes was assessed through RT-qPCR, immunofluorescence, and flow cytometry.
    Results and discussion: Metabolomic analysis identified increased BCAA metabolism as one of the most significantly rewired pathways upon alternative activation. M2 macrophages had significantly lower BCAA levels compared to controls. BCAA supplementation promoted M2 macrophage polarization both in vitro and in vivo and increased oxidative phosphorylation in M2 macrophages. Blocking BCAA entry into mitochondria by knockdown of SLC25A44 inhibited M2 macrophage polarization. Furthermore, M2 macrophages polarization was suppressed by knockdown of Branched-chain amino-acid transaminase 2 (BCAT2) and branched chain keto acid dehydrogenase E1 subunit alpha (BCKDHA), both of which are key enzymes involved in BCAA oxidation. Overall, our findings suggest that BCAA catabolism plays an important role in polarization toward M2 macrophages.
    Keywords:  BCAA; BCAT2; BCKDHA; M2 macrophages; SLC25A44
    DOI:  https://doi.org/10.3389/fimmu.2024.1469163
  45. Nat Rev Mol Cell Biol. 2024 Nov 28.
    How proteins sense their cellular environment.
    Monika Fuxreiter.
      
    DOI:  https://doi.org/10.1038/s41580-024-00812-1
  46. Clin Transl Oncol. 2024 Nov 29.
    Rotenone adaptation promotes migration and invasion of p53-wild-type colon cancer through lipid metabolism.
    Yingying Shi, Zhen Cao, Ling Ge, Lin Lei, Dan Tao, Juan Zhong, Dan Xu, Tao Geng, Xuetao Li, Ziwei Li, Shuaishuai Xing, Xinyu Wu, Zhongxu Wang, Linjun Li.
       BACKGROUND: The association between mitochondrial dysfunction and multiple metabolic adaptations is increasingly being proven. We previously elucidated that mitochondrial complex I deficiency can promote glycolysis in mut-p53 SW480 cells. However, studies have revealed a phenotype with attenuated glycolysis but enhanced fatty acid oxidation (FAO) in invasive tumors. The interplay between complex I and FAO in carcinogenesis remains obscure.
    METHODS: The p53 wild-type RKO cells were exposed to rotenone over at least 2 months to acquire rotenone adaptation cells. Then the transwell invasion assays and expression of metabolic enzymes were first detected in rotenone adaptation cells to illustrate whether rotenone adaptation is correlated with the invasion and FAO. The levels of epithelial-to-mesenchymal transition (EMT)-related proteins and acetyl-CoA in rotenone adaptation cells treated with etomoxir (ETO) and acetate were evaluated to verify the role of CPT1A in regulating invasion. Finally, the levels of reactive oxygen species (ROS) were detected. Meanwhile, the invasiveness and histone acetylation levels of rotenone adaptation cells were observed after adding an ROS inhibitor (N-acetyl-L-cysteine NAC) to demonstrate the molecular connection between FAO and invasion during rotenone adaptation.
    RESULTS: We found long-term exposure to rotenone (a mitochondrial complex I inhibitor) led to EMT and high CPT1A expression in wt-p53 colon cancer. The inhibition of CPT1A suppressed the invasion and reduced histone acetylation, which was rescued by supplementing with acetate. Mechanistically, ROS is crucial for lipid metabolism remodeling.
    CONCLUSION: Our study provides a novel understanding of the role of complex I in lipid reprogramming facilitating colon cancer invasion and metastasis.
    Keywords:  CPT1A; Histone acetylation; Migration and invasion; Mitochondrial complex I; Rotenone
    DOI:  https://doi.org/10.1007/s12094-024-03785-x
  47. bioRxiv. 2024 Nov 20. pii: 2024.11.20.624466. [Epub ahead of print]
    Recurrent hyper-motif circuits in developmental programs.
    Miri Adler, Ruslan Medzhitov.
      During embryogenesis, homogenous groups of cells self-organize into stereotypic spatial and temporal patterns that make up tissues and organs. These emergent patterns are controlled by transcription factors and secreted signals that regulate cellular fate and behaviors through intracellular regulatory circuits and cell-cell communication circuits. However, the principles of these circuits and how their properties are combined to provide the spatio-temporal properties of tissues remain unclear. Here we develop a framework to explore building-block circuits of developmental programs. We use single-cell gene expression data across developmental stages of the human intestine to infer the key intra- and inter-cellular circuits that control developmental programs. We study how these circuits are joined into higher-level hyper-motif circuits and explore their emergent dynamical properties. This framework uncovers design principles of developmental programs and reveals the rules that allow cells to develop robust and diverse patterns.
    DOI:  https://doi.org/10.1101/2024.11.20.624466
  48. Am J Hum Biol. 2024 Nov 28. e24195
    Introduction: The Influences of Religion and Spirituality on Human Biology.
    Christopher D Lynn.
      The objective of this special issue is to highlight the absence of religion and spirituality in the human biological enterprise. We have assembled a set of articles covering physiology, psychology, cognition, and neurophenomenology. The influences on human biology are diverse, yet many have been historically overlooked, which we hope this special issue takes a large step in remedying. Here, we outline how this issue came together and introduce readers to the articles to follow.
    Keywords:  human biology; human variation; religion; spirituality
    DOI:  https://doi.org/10.1002/ajhb.24195
  49. Science. 2024 Nov 29. 386(6725): 1062
    Racing the clock.
    Cecilia Padilla Iglesias, Erika C Freeman.
      
    DOI:  https://doi.org/10.1126/science.adu7742
  50. Elife. 2024 Nov 25. pii: RP87301. [Epub ahead of print]12
    Cancers adapt to their mutational load by buffering protein misfolding stress.
    Susanne Tilk, Judith Frydman, Christina Curtis, Dmitri A Petrov.
      In asexual populations that don't undergo recombination, such as cancer, deleterious mutations are expected to accrue readily due to genome-wide linkage between mutations. Despite this mutational load of often thousands of deleterious mutations, many tumors thrive. How tumors survive the damaging consequences of this mutational load is not well understood. Here, we investigate the functional consequences of mutational load in 10,295 human tumors by quantifying their phenotypic response through changes in gene expression. Using a generalized linear mixed model (GLMM), we find that high mutational load tumors up-regulate proteostasis machinery related to the mitigation and prevention of protein misfolding. We replicate these expression responses in cancer cell lines and show that the viability in high mutational load cancer cells is strongly dependent on complexes that degrade and refold proteins. This indicates that the upregulation of proteostasis machinery is causally important for high mutational burden tumors and uncovers new therapeutic vulnerabilities.
    Keywords:  cancer; cancer biology; evolutionary biology; human; mutational load; proteostasis; somatic evolution
    DOI:  https://doi.org/10.7554/eLife.87301
  51. Nat Chem Biol. 2024 Nov 26.
    How nature ties peptide knots.
    Andrew G Roberts, Jessica M J Swanson.
      
    DOI:  https://doi.org/10.1038/s41589-024-01775-2
  52. bioRxiv. 2024 Nov 11. pii: 2024.11.11.622945. [Epub ahead of print]
    The contribution of mitochondria-associated ER membranes to cholesterol homeostasis.
    J Montesinos, K Kabra, M Uceda, D Larrea, R R Agrawal, K A Tamucci, M Pera, A C Ferre, N Gomez-Lopez, T D Yun, K R Velasco, E A Schon, E Area-Gomez.
      Cellular demands for cholesterol are met by a balance between its biosynthesis in the endoplasmic reticulum (ER) and its uptake from lipoproteins. Cholesterol levels in intracellular membranes form a gradient maintained by a complex network of mechanisms including the control of the expression, compartmentalization and allosteric modulation of the enzymes that balance endogenous and exogenous sources of cholesterol. Low-density lipoproteins (LDLs) are internalized and delivered to lysosomal compartments to release their cholesterol content, which is then distributed within cellular membranes. High-density lipoproteins (HDLs), on the other hand, can transfer their cholesterol content directly into cellular membranes through the action of receptors such as the scavenger receptor B type 1 (SR-B1; gene SCARB1 ). We show here that SR-B1-mediated exogenous cholesterol internalization from HDL stimulates the formation of lipid-raft subdomains in the ER known as mitochondria-associated ER membranes (MAM), that, in turn, suppress de novo cholesterol biosynthesis machinery. We propose that MAM is a regulatory hub for cholesterol homeostasis that offers a novel dimension for understanding the intracellular regulation of this important lipid.
    DOI:  https://doi.org/10.1101/2024.11.11.622945
  53. Trends Endocrinol Metab. 2024 Nov 22. pii: S1043-2760(24)00291-1. [Epub ahead of print]
    Mitochondria as sensors of intracellular pathogens.
    Jose M Delgado, Lena Pernas.
      Mitochondria must sense their environment to enable cells and organisms to adapt to diverse environments and survive during stress. However, during microbial infection, an evolutionary pressure since the inception of the eukaryotic cell, these organelles are traditionally viewed as targets for microbes. In this opinion we consider the perspective that mitochondria are domesticated microbes that sense and guard their 'host' cell against pathogens. We explore potential mechanisms by which mitochondria detect intracellular pathogens and induce mitochondria-autonomous responses that activate cellular defenses.
    Keywords:  MAVS; PAMPs; domesticated microbes; import receptors; microbial sensors; mitochondria
    DOI:  https://doi.org/10.1016/j.tem.2024.10.009
  54. PLoS Biol. 2024 Nov 25. 22(11): e3002917
    Reconstructing the last common ancestor of all eukaryotes.
    Thomas A Richards, Laura Eme, John M Archibald, Guy Leonard, Susana M Coelho, Alex de Mendoza, Christophe Dessimoz, Pavel Dolezal, Lillian K Fritz-Laylin, Toni Gabaldón, Vladimír Hampl, Geert J P L Kops, Michelle M Leger, Purificacion Lopez-Garcia, James O McInerney, David Moreira, Sergio A Muñoz-Gómez, Daniel J Richter, Iñaki Ruiz-Trillo, Alyson E Santoro, Arnau Sebé-Pedrós, Berend Snel, Courtney W Stairs, Eelco C Tromer, Jolien J E van Hooff, Bill Wickstead, Tom A Williams, Andrew J Roger, Joel B Dacks, Jeremy G Wideman.
      Understanding the origin of eukaryotic cells is one of the most difficult problems in all of biology. A key challenge relevant to the question of eukaryogenesis is reconstructing the gene repertoire of the last eukaryotic common ancestor (LECA). As data sets grow, sketching an accurate genomics-informed picture of early eukaryotic cellular complexity requires provision of analytical resources and a commitment to data sharing. Here, we summarise progress towards understanding the biology of LECA and outline a community approach to inferring its wider gene repertoire. Once assembled, a robust LECA gene set will be a useful tool for evaluating alternative hypotheses about the origin of eukaryotes and understanding the evolution of traits in all descendant lineages, with relevance in diverse fields such as cell biology, microbial ecology, biotechnology, agriculture, and medicine. In this Consensus View, we put forth the status quo and an agreed path forward to reconstruct LECA's gene content.
    DOI:  https://doi.org/10.1371/journal.pbio.3002917
  55. Sci Immunol. 2024 Nov 29. 9(101): eadk2954
    The redox sensor KEAP1 facilitates adaptation of T cells to chronic antigen stimulation by preventing hyperactivation.
    Ziang Zhu, Ying Luo, Guohua Lou, Kiddist Yihunie, Safuwra Wizzard, Andrew W DeVilbiss, Sarah Muh, Chaoyu Ma, Sejal S Shinde, Jonathan Hoar, Taidou Hu, Nu Zhang, Shyam Biswal, Ralph J DeBerardinis, Tuoqi Wu, Chen Yao.
      During persistent antigen stimulation, exhausted CD8+ T cells are continuously replenished by self-renewing stem-like T cells. However, how CD8+ T cells adapt to chronic stimulation remains unclear. Here, we show that persistent antigen stimulation primes chromatin for regulation by the redox-sensing KEAP1-NRF2 pathway. Loss of KEAP1 in T cells impaired control of chronic viral infection. T cell-intrinsic KEAP1 suppressed NRF2 to promote expansion and persistence of virus-specific CD8+ T cells, drive a stem-like T cell response, down-regulate immune checkpoint molecules, and limit T cell receptor (TCR) hyperactivation and apoptosis. NRF2 epigenetically derepressed BACH2 targets and opposed a stem-like program driven by BACH2. In exhausted T cells induced by tonic GD2 chimeric antigen receptor (CAR) signaling, the effects of KEAP1 deficiency were rescued by inhibiting proximal TCR signaling. Enhancing mitochondrial oxidation improved the expansion and survival of KEAP1-deficient CD8+ GD2 CAR T cells and up-regulated markers associated with stem-like cells. Thus, the KEAP1-NRF2 axis regulates stem-like CD8+ T cells and long-term T cell immunity during chronic antigen exposure.
    DOI:  https://doi.org/10.1126/sciimmunol.adk2954
  56. Biosystems. 2024 Nov 22. pii: S0303-2647(24)00261-2. [Epub ahead of print]247 105376
    Understanding cancer from a biophysical, developmental and systems biology perspective using the landscapes-attractor model.
    Thomas W Grunt.
      Biophysical, developmental and systems-biology considerations enable deeper understanding why cancer is life threatening despite intensive research. Here we use two metaphors. Both conceive the cell genome and the encoded molecular system as an interacting gene regulatory network (GRN). According to Waddington's epigenetic (quasi-potential)-landscape, an instrumental tool in ontogenetics, individual interaction patterns ( = expression profiles) within this GRN represent possible cell states with different stabilities. Network interactions with low stability are represented on peaks. Unstable interactions strive towards regions with higher stability located at lower altitude in valleys termed attractors that correspond to stable cell phenotypes. Cancer cells are seen as GRNs adopting aberrant semi-stable attractor states (cancer attractor). In the second metaphor, Wright's phylogenetic fitness (adaptive) landscape, each genome ( = GRN) is assigned a specific position in the landscape according to its structure and reproductive fitness in the specific environment. High elevation signifies high fitness and low altitude low fitness. Selection ensures that mutant GRNs evolve and move from valleys to peaks. The genetic flexibility is highlighted in the fitness landscape, while non-genetic flexibility is captured in the quasi-potential landscape. These models resolve several inconsistencies that have puzzled cancer researchers, such as the fact that phenotypes generated by non-genetic mechanisms coexist in a single tumor with phenotypes caused by mutations and they mitigate conflicts between cancer theories that claim cancer is caused by mutation (somatic mutation theory) or by disruption of tissue architecture (tissue organization field theory). Nevertheless, spontaneous mutations play key roles in cancer. Remarkable, fundamental natural laws such as the second law of thermodynamics and quantum mechanics state that mutations are inevitable events. The good side of this is that without mutational variability in DNA, evolutionary development would not have occurred, but its bad side is that the occurrence of cancer is essentially inevitable. In summary, both landscapes together fully describe the behavior of cancer under normal and stressful conditions such as chemotherapy. Thus, the landscapes-attractor model fully describes cancer cell behavior and offers new perspectives for future treatment.
    Keywords:  Cancer attractor; Entropy; Epigenetic landscape; Fitness landscape; Mutation; Quantum biology
    DOI:  https://doi.org/10.1016/j.biosystems.2024.105376
  57. bioRxiv. 2024 Nov 15. pii: 2024.11.15.623810. [Epub ahead of print]
    Structural basis for growth factor and nutrient signal integration on the lysosomal membrane by mTORC1.
    Zhicheng Cui, Alessandra Esposito, Gennaro Napolitano, Andrea Ballabio, James H Hurley.
      Mechanistic target of rapamycin complex 1 (mTORC1), which consists of mTOR, Raptor, and mLST8, receives signaling inputs from growth factor signals and nutrients. These signals are mediated by the Rheb and Rag small GTPases, respectively, which activate mTORC1 on the cytosolic face of the lysosome membrane. We biochemically reconstituted the activation of mTORC1 on membranes by physiological submicromolar concentrations of Rheb, Rags, and Ragulator. We determined the cryo-EM structure and found that Raptor and mTOR directly interact with the membrane at anchor points separated by up to 230 Å across the membrane surface. Full engagement of the membrane anchors is required for maximal activation, which is brought about by alignment of the catalytic residues in the mTOR kinase active site. The observations show at the molecular and atomic scale how converging signals from growth factors and nutrients drive mTORC1 recruitment to and activation on the lysosomal membrane in a three-step process, consisting of (1) Rag-Ragulator-driven recruitment to within ∼100 Å of the lysosomal membrane, (2) Rheb-driven recruitment to within ∼40 Å, and finally (3) direct engagement of mTOR and Raptor with the membrane. The combination of Rheb and membrane engagement leads to full catalytic activation, providing a structural explanation for growth factor and nutrient signal integration at the lysosome.
    DOI:  https://doi.org/10.1101/2024.11.15.623810
  58. Nat Commun. 2024 Nov 26. 15(1): 10235
    New-to-nature CO2-dependent acetyl-CoA assimilation enabled by an engineered B12-dependent acyl-CoA mutase.
    Helena Schulz-Mirbach, Philipp Wichmann, Ari Satanowski, Helen Meusel, Tong Wu, Maren Nattermann, Simon Burgener, Nicole Paczia, Arren Bar-Even, Tobias J Erb.
      Acetyl-CoA is a key metabolic intermediate and the product of various natural and synthetic one-carbon (C1) assimilation pathways. While an efficient conversion of acetyl-CoA into other central metabolites, such as pyruvate, is imperative for high biomass yields, available aerobic pathways typically release previously fixed carbon in the form of CO2. To overcome this loss of carbon, we develop a new-to-nature pathway, the Lcm module, in this study. The Lcm module provides a direct link between acetyl-CoA and pyruvate, is shorter than any other oxygen-tolerant route and notably fixes CO2, instead of releasing it. The Lcm module relies on the new-to-nature activity of a coenzyme B12-dependent mutase for the conversion of 3-hydroxypropionyl-CoA into lactyl-CoA. We demonstrate Lcm activity of the scaffold enzyme 2-hydroxyisobutyryl-CoA mutase from Bacillus massiliosenegalensis, and further improve catalytic efficiency 10-fold by combining in vivo targeted hypermutation and adaptive evolution in an engineered Escherichia coli selection strain. Finally, in a proof-of-principle, we demonstrate the complete Lcm module in vitro. Overall, our work demonstrates a synthetic CO2-incorporating acetyl-CoA assimilation route that expands the metabolic solution space of central carbon metabolism, providing options for synthetic biology and metabolic engineering.
    DOI:  https://doi.org/10.1038/s41467-024-53762-9
  59. J Ovarian Res. 2024 Nov 23. 17(1): 233
    Unveiling the power of mitochondrial transfer in cancer progression: a perspective in ovarian cancer.
    Caixia Wang, Chuan Xie.
      Mitochondria are dynamic organelles integral to metabolic processes, coordination of essential biological pathways, and oncogenesis and tumor progression. Recent studies have revealed that mitochondria can be transferred between cells via multiple mechanisms, implicating their involvement in the pathogenesis and progression of ovarian cancer. This review provides a comprehensive analysis of intercellular mitochondrial transfer within the context of ovarian cancer and its tumor microenvironment. We also propose targeted pathways and therapeutic strategies that could be utilized to modulate diseases associated with mitochondrial transfer therapy. Finally, we examine recent advancements in this field and identify several unresolved questions.
    Keywords:  Mitochondrial transfer; Ovarian Cancer; Targeted therapy; Tumor Microenvironment
    DOI:  https://doi.org/10.1186/s13048-024-01560-8
  60. Nucleic Acids Res. 2024 Nov 26. pii: gkae1110. [Epub ahead of print]
    Chemotherapeutic agents and leucine deprivation induce codon-biased aberrant protein production in cancer.
    Adva Kochavi, Remco Nagel, Pierre-Rene Körner, Onno B Bleijerveld, Chun-Pu Lin, Zowi Huinen, Yuval Malka, Natalie Proost, Marieke van de Ven, Xiaodong Feng, Jasmine Montenegro Navarro, Abhijeet Pataskar, Daniel S Peeper, Julien Champagne, Reuven Agami.
      Messenger RNA (mRNA) translation is a tightly controlled process frequently deregulated in cancer. Key to this deregulation are transfer RNAs (tRNAs), whose expression, processing and post-transcriptional modifications are often altered in cancer to support cellular transformation. In conditions of limiting levels of amino acids, this deregulated control of protein synthesis leads to aberrant protein production in the form of ribosomal frameshifting or misincorporation of non-cognate amino acids. Here, we studied leucine, an essential amino acid coded by six different codons. Surprisingly, we found that leucine deprivation leads to ribosomal stalling and aberrant protein production in various cancer cell types, predominantly at one codon, UUA. Similar effects were observed after treatment with chemotherapeutic agents, implying a shared mechanism controlling the downstream effects on mRNA translation. In both conditions, a limitation in the availability of tRNALeu(UAA) for protein production was shown to be the cause for this dominant effect on UUA codons. The induced aberrant proteins can be processed and immune-presented as neoepitopes and can direct T-cell killing. Altogether, we uncovered a novel mode of interplay between DNA damage, regulation of tRNA availability for mRNA translation and aberrant protein production in cancer that could be exploited for anti-cancer therapy.
    DOI:  https://doi.org/10.1093/nar/gkae1110
  61. J Exp Clin Cancer Res. 2024 Nov 26. 43(1): 310
    Selective metabolic regulations by p53 mutant variants in pancreatic cancer.
    Sabrina Caporali, Alessio Butera, Alessia Ruzza, Carlotta Zampieri, Marina Bantula', Sandra Scharsich, Anna-Katerina Ückert, Ivana Celardo, Ian U Kouzel, Luigi Leanza, Andreas Gruber, Joan Montero, Angelo D'Alessandro, Thomas Brunner, Marcel Leist, Ivano Amelio.
       BACKGROUND: Approximately half of all human cancers harbour mutations in the p53 gene, leading to the generation of neomorphic p53 mutant proteins. These mutants can exert gain-of-function (GOF) effects, potentially promoting tumour progression. However, the clinical significance of p53 GOF mutations, as well as the selectivity of individual variants, remains controversial and unclear.
    METHODS: To elucidate the metabolic regulations and molecular underpinnings associated with the specific p53R270H and p53R172H mutant variants (the mouse equivalents of human p53R273H and p53R175H, respectively), we employed a comprehensive approach. This included integrating global metabolomic analysis with epigenomic and transcriptomic profiling in mouse pancreatic cancer cells. Additionally, we assessed metabolic parameters such as oxygen consumption rate and conducted analyses of proliferation and cell-cell competition to validate the biological impact of metabolic changes on pancreatic ductal adenocarcinoma (PDAC) phenotype. Our findings were further corroborated through analysis of clinical datasets from human cancer cohorts.
    RESULTS: Our investigation revealed that the p53R270H variant, but not p53R172H, sustains mitochondrial function and energy production while also influencing cellular antioxidant capacity. Conversely, p53R172H, while not affecting mitochondrial metabolism, attenuates the activation of pro-tumorigenic metabolic pathways such as the urea cycle. Thus, the two variants selectively control different metabolic pathways in pancreatic cancer cells. Mechanistically, p53R270H induces alterations in the expression of genes associated with oxidative stress and reduction in mitochondrial respiration. In contrast, p53R172H specifically impacts the expression levels of enzymes involved in the urea metabolism. However, our analysis of cell proliferation and cell competition suggested that the expression of either p53R270H or p53R172H does not influence confer any selective advantage to this cellular model in vitro. Furthermore, assessment of mitochondrial priming indicated that the p53R270H-driven mitochondrial effect does not alter cytochrome c release or the apoptotic propensity of pancreatic cancer cells.
    CONCLUSIONS: Our study elucidates the mutant-specific impact of p53R270H and p53R172H on metabolism of PDAC cancer cells, highlighting the need to shift from viewing p53 mutant variants as a homogeneous group of entities to a systematic assessment of each specific p53 mutant protein. Moreover, our finding underscores the importance of further exploring the significance of p53 mutant proteins using models that more accurately reflect tumor ecology.
    Keywords:  Anti-oxidant capacity; Cancer Metabolism; Gain-of-function; Tumour suppressor
    DOI:  https://doi.org/10.1186/s13046-024-03232-3
  62. J Inherit Metab Dis. 2024 Nov 24.
    My path to citrin deficiency.
    John E Walker.
      Citrin belongs to the SLC25 transport protein family found mostly in inner mitochondrial membranes. The family prototype, the ADP-ATP carrier, delivers ATP made inside mitochondria to the cellular cytoplasm and returns ADP to the mitochondrion for resynthesis of ATP. In pre-genomic 1981, I noticed that the protein sequence of the bovine ADP-ATP carrier consists of three related sequences, each containing two transmembrane α-helices traveling in opposite senses. Colleagues and I demonstrated that two other mitochondrial carriers had similar features. From emergent genomic sequences, it became apparent that they represented a large family of transport proteins with the same characteristic threefold repeats. The human genome encodes 53 members, but the functions of many were unknown. So, colleagues and I determined how to make these proteins in Escherichia coli and introduce them into liposomes to allow exploration of their transport functions. The 27 human family members to have been thus identified include citrin and the closely related protein aralar. Both exchange aspartate from the mitochondrial matrix for cytosolic glutamate plus a proton. Citrin is expressed predominantly in liver and non-excitable tissues, whereas aralar is the dominant form in the brain. Each has a membrane extrinsic N-terminal Ca2+-binding domain, a transport domain, and a C-terminal amphipathic α-helix. Human mutations in citrin impair the urea cycle, malate-aspartate shuttle, gluconeogenesis, amino acid breakdown, and energy metabolism leading to citrin deficiency. Currently, the complex etiology of this condition is poorly understood and new knowledge would help to improve diagnosis, therapies, and finding a cure. My aims are to seek a basic understanding of the etiology of citrin deficiency and to use that knowledge in improving diagnostic procedures and in developing new treatments and a cure.
    Keywords:  citrin deficiency; cure; diagnosis; mitochondria; treatment; urea cycle
    DOI:  https://doi.org/10.1002/jimd.12818
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