bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2024–12–15
forty papers selected by
Christian Frezza, Universität zu Köln
  1. Disagreement on foundational principles of biological aging.
  2. Reactive oxygen species control protein degradation at the mitochondrial import gate.
  3. Nutrient-driven histone code determines exhausted CD8+ T cell fates.
  4. MULTIPLE, REDUNDANT CARBOXYLIC ACID TRANSPORTERS SUPPORT MITOCHONDRIAL METABOLISM IN PLASMODIUM FALCIPARUM.
  5. An Ionic Sensor acts in Parallel to dSarm to Promote Neurodegeneration.
  6. Cu in cancer metabolism.
  7. Lactate dehydrogenase B noncanonically promotes ferroptosis defense in KRAS-driven lung cancer.
  8. Reciprocal links between methionine metabolism, DNA repair and therapy resistance in glioblastoma.
  9. TBK1 Reprograms Metabolism in Breast Cancer: An Integrated Omics Approach.
  10. Cell-specific oxidative metabolism of the renal cortex.
  11. Fasting can reduce weight - but also hair growth.
  12. Ferroptosis: when metabolism meets cell death.
  13. Classification and functional characterization of regulators of intracellular STING trafficking identified by genome-wide optical pooled screening.
  14. Metabolic reprogramming, sensing, and cancer therapy.
  15. A lipid made by tumour cells reprograms immune cells.
  16. Stressing the importance of circadian time in treatment responses.
  17. Carnitine palmitoyltransferase 1 facilitates fatty acid oxidation in a non-cell-autonomous manner.
  18. Cold-induced shivering for metabolic health.
  19. Asparagine availability controls germinal center B cell homeostasis.
  20. A little bird flies high thanks to mighty mitochondria.
  21. PRDX6 as an additional piece in the puzzle of selenoprotein synthesis.
  22. Isoleucine-to-valine substitutions support cellular physiology during isoleucine deprivation.
  23. Mannose metabolism reshapes T cell differentiation to enhance anti-tumor immunity.
  24. Tissue specific roles of fatty acid oxidation.
  25. Genetic synchronization of the brain and liver molecular clocks defend against chrono-metabolic disease.
  26. Emerging debates and resolutions in brown adipose tissue research.
  27. Metabolic regulation in adult and aging skeletal muscle stem cells.
  28. Nuclear GTPSCS functions as a lactyl-CoA synthetase to promote histone lactylation and gliomagenesis.
  29. The adenine nucleotide translocase family underlies cardiac ischemia-reperfusion injury through the mitochondrial permeability pore independently of cyclophilin D.
  30. Mitochondrial respiratory capacity in kidney podocytes is high, age-dependent, and sexually dimorphic.
  31. Human body's ageing 'clock' ticks faster after heat stress.
  32. Bad bar charts are pervasive across biology.
  33. Considerations for building and using integrated single-cell atlases.
  34. How to build the virtual cell with artificial intelligence: Priorities and opportunities.
  35. Cytokines in cancer.
  36. Daily glucocorticoids promote glioblastoma growth and circadian synchrony to the host.
  37. Biological agency: a concept without a research program.
  38. Hallmarks of female reproductive aging in physiologic aging mice.
  39. Lactylation as a post-translational regulator of cGAS and immunity.
  40. Deep Learning of Cellular Metabolic Flux Distributions Predicts Lifespan.
  1. PNAS Nexus. 2024 Dec;3(12): pgae499
    Disagreement on foundational principles of biological aging.
    Vadim N Gladyshev, Benjamin Anderson, Hanna Barlit, Benjamin Barré, Samuel Beck, Bahareh Behrouz, Daniel W Belsky, Amandine Chaix, Manish Chamoli, Brian H Chen, Kaiyang Cheng, Jane Chuprin, Gary A Churchill, Andrea Cipriano, Alex Colville, Joris Deelen, Yuri Deigin, KeHuan K Edmonds, Bradley W English, Ruogu Fang, Michael Florea, Iosif M Gershteyn, Diljeet Gill, Laura H Goetz, Vera Gorbunova, Patrick T Griffin, Steve Horvath, Martin Borch Jensen, Xin Jin, Sara Jovanovska, Kathrin M Kajderowicz, Tomoko Kasahara, Csaba Kerepesi, Subhash Kulkarni, Vyacheslav M Labunskyy, Morgan E Levine, Sergiy Libert, J Yuyang Lu, Yuancheng Ryan Lu, Riccardo E Marioni, Brianah M McCoy, Wayne Mitchell, Mahdi Moqri, Farzaneh Nasirian, Peter Niimi, Hamilton Se-Hwee Oh, Brian Okundaye, Andrey A Parkhitko, Leonid Peshkin, Mia Petljak, Jesse R Poganik, Glen Pridham, Daniel E L Promislow, Weronika Prusisz, Margaux Quiniou, Ken Raj, Daniel Richard, Jose Luis Ricon, Jarod Rutledge, Morten Scheibye-Knudsen, Nicholas J Schork, Andrei Seluanov, Michael Shadpour, Anastasia V Shindyapina, Steven R Shuken, Sruthi Sivakumar, Thomas Stoeger, Ayumu Sugiura, Nadia R Sutton, Alexander Suvorov, Andrei E Tarkhov, Emma C Teeling, Alexandre Trapp, Alexander Tyshkovskiy, Maximilian Unfried, Cavin K Ward-Caviness, Sun Hee Yim, Kejun Ying, Jeffrey Yunes, Bohan Zhang, Alex Zhavoronkov.
      To gain insight into how researchers of aging perceive the process they study, we conducted a survey among experts in the field. While highlighting some common features of aging, the survey exposed broad disagreement on the foundational issues. What is aging? What causes it? When does it begin? What constitutes rejuvenation? Not only was there no consensus on these and other core questions, but none of the questions received a majority opinion-even regarding the need for consensus itself. Despite many researchers believing they understand aging, their understanding diverges considerably. Importantly, as different processes are labeled as "aging" by researchers, different experimental approaches are prioritized. The survey shed light on the need to better define which aging processes this field should target and what its goals are. It also allowed us to categorize contemporary views on aging and rejuvenation, revealing critical, yet largely unanswered, questions that appear disconnected from the current research focus. Finally, we discuss ways to address the disagreement, which we hope will ultimately aid progress in the field.
    DOI:  https://doi.org/10.1093/pnasnexus/pgae499
  2. Mol Cell. 2024 Dec 05. pii: S1097-2765(24)00909-2. [Epub ahead of print]84(23): 4612-4628.e13
    Reactive oxygen species control protein degradation at the mitochondrial import gate.
    Rachael McMinimy, Andrew G Manford, Christine L Gee, Srividya Chandrasekhar, Gergey Alzaem Mousa, Joelle Chuang, Lilian Phu, Karen Y Shih, Christopher M Rose, John Kuriyan, Baris Bingol, Michael Rapé.
      While reactive oxygen species (ROS) have long been known to drive aging and neurodegeneration, their persistent depletion below basal levels also disrupts organismal function. Cells counteract loss of basal ROS via the reductive stress response, but the identity and biochemical activity of ROS sensed by this pathway remain unknown. Here, we show that the central enzyme of the reductive stress response, the E3 ligase Cullin 2-FEM1 homolog B (CUL2FEM1B), specifically acts at mitochondrial TOM complexes, where it senses ROS produced by complex III of the electron transport chain (ETC). ROS depletion during times of low ETC activity triggers the localized degradation of CUL2FEM1B substrates, which sustains mitochondrial import and ensures the biogenesis of the rate-limiting ETC complex IV. As complex III yields most ROS when the ETC outpaces metabolic demands or oxygen availability, basal ROS are sentinels of mitochondrial activity that help cells adjust their ETC to changing environments, as required for cell differentiation and survival.
    Keywords:  FEM1B; TOM complex; electron transport chain; mitochondria; proteasome; reductive stress response; ubiquitin
    DOI:  https://doi.org/10.1016/j.molcel.2024.11.004
  3. Science. 2024 Dec 12. eadj3020
    Nutrient-driven histone code determines exhausted CD8+ T cell fates.
    Shixin Ma, Michael S Dahabieh, Thomas H Mann, Steven Zhao, Bryan McDonald, Won-Suk Song, H Kay Chung, Yagmur Farsakoglu, Lizmarie Garcia-Rivera, Filipe Araujo Hoffmann, Shihao Xu, Victor Y Du, Dan Chen, Jesse Furgiuele, Michael LaPorta, Emily Jacobs, Lisa M DeCamp, Brandon M Oswald, Ryan D Sheldon, Abigail E Ellis, Longwei Liu, Peixiang He, Yingxiao Wang, Cholsoon Jang, Russell G Jones, Susan M Kaech.
      Exhausted T cells (TEX) in cancer and chronic viral infections undergo metabolic and epigenetic remodeling, impairing their protective capabilities. However, the impact of nutrient metabolism on epigenetic modifications that control TEX differentiation remains unclear. We showed that TEX cells shifted from acetate to citrate metabolism by downregulating acetyl-CoA synthetase 2 (ACSS2) while maintaining ATP-citrate lyase (ACLY) activity. This metabolic switch increased citrate-dependent histone acetylation, mediated by histone acetyltransferase KAT2A-ACLY interactions, at TEX signature-genes while reducing acetate-dependent histone acetylation, dependent on p300-ACSS2 complexes, at effector and memory T cell genes. Nuclear ACSS2 overexpression or ACLY inhibition prevented TEX differentiation and enhanced tumor-specific T cell responses. These findings unveiled a nutrient-instructed histone code governing CD8+ T cell differentiation, with implications for metabolic- and epigenetic-based T cell therapies.
    DOI:  https://doi.org/10.1126/science.adj3020
  4. bioRxiv. 2024 Nov 27. pii: 2024.11.26.624872. [Epub ahead of print]
    MULTIPLE, REDUNDANT CARBOXYLIC ACID TRANSPORTERS SUPPORT MITOCHONDRIAL METABOLISM IN PLASMODIUM FALCIPARUM.
    Krithika Rajaram, Gabriel W Rangel, Justin T Munro, Sethu C Nair, Manuel Llinás, Sean T Prigge.
      The mitochondrion of the deadliest human malaria parasite, Plasmodium falciparum, is an essential source of cellular acetyl-CoA during the asexual blood-stage of the parasite life cycle. Blocking mitochondrial acetyl-CoA synthesis leads to a hypoacetylated proteome and parasite death. We previously determined that mitochondrial acetyl-CoA is primarily synthesized from glucose-derived pyruvate by α-ketoacid dehydrogenases. Here, we asked if inhibiting the import of glycolytic pyruvate across the mitochondrial inner membrane would affect acetyl-CoA production and, thus, could be a potential target for antimalarial drug development. We selected the two predicted mitochondrial pyruvate carrier proteins ( Pf MPC1 and Pf MPC2) for genetic knockout and isotopic metabolite tracing via HPLC-MS metabolomic analysis. Surprisingly, we observed that asexual blood-stage parasites could survive the loss of either or both Pf MPCs with only minor growth defects, despite a substantial reduction in the amount of glucose-derived isotopic labelling into acetyl-CoA. Furthermore, genetic deletion of two additional mitochondrial carboxylic acid transporters - DTC (di/tricarboxylic acid carrier) and YHM2 (a putative citrate/α-ketoglutarate carrier protein) - only mildly affected asexual blood-stage replication, even in the context of Pf MPC deficiency. Although we observed no added impact on the incorporation of glucose carbon into acetyl-CoA in these quadruple knockout mutants, we noted a large decrease in glutamine-derived label in tricarboxylic acid cycle metabolites, suggesting that DTC and YHM2 both import glutamine derivatives into the mitochondrion. Altogether, our results expose redundant routes used to fuel the blood-stage malaria parasite mitochondrion with imported carbon from two major sources - glucose and glutamine.
    SIGNIFICANCE: The mitochondrion of malaria parasites generates key molecules, such as acetyl-CoA, that are required for numerous cellular processes. To support mitochondrial biosynthetic pathways, the parasites must transport carbon sources into this organelle. By studying how the mitochondrion obtains pyruvate, a molecule derived from glucose, we have uncovered redundant carbon transport systems that ensure parasite survival in red blood cells. This metabolic redundancy poses a challenge for drug development, as it enables the parasite to adapt and survive by relying on alternative pathways when one is disrupted.
    DOI:  https://doi.org/10.1101/2024.11.26.624872
  5. bioRxiv. 2024 Nov 28. pii: 2024.10.29.620922. [Epub ahead of print]
    An Ionic Sensor acts in Parallel to dSarm to Promote Neurodegeneration.
    Adel Avetisyan, Romina Barria, Amy Sheehan, Marc R Freeman.
      How neurons to sense when they are terminally dysfunctional and activate neurodegeneration remains poorly defined. The pro-degenerative NAD + hydrolase dSarm/SARM1 can act as a metabolic sensor by detecting pathological changes in NAD + /NMN and subsequently induce catastrophic axon degeneration. Here we show Drosophila with-no-lysine kinase (dWnk), which can directly sense Cl - , K + and osmotic pressure, is required for neurodegeneration induced by depletion of the NAD + biosynthetic enzyme dNmnat. dWnk functions in parallel to dSarm and acts through the downstream kinase Frayed to promote axon degeneration and neuronal cell death. dWnk and dSarm ultimately converge on the BTB-Back domain molecule Axundead (Axed) to execute neurodegeneration. Our work argues that neurons use direct sensors of both metabolism (dSarm/SARM1) and ionic/osmotic status (dWnk) to evaluate cellular health and, when dysfunctional, promote neurodegeneration though a common axon death signaling molecule, Axundead.
    DOI:  https://doi.org/10.1101/2024.10.29.620922
  6. Nat Cell Biol. 2024 Dec;26(12): 2013
    Cu in cancer metabolism.
    Zhe Wang.
      
    DOI:  https://doi.org/10.1038/s41556-024-01578-6
  7. Cell Death Differ. 2024 Dec 07.
    Lactate dehydrogenase B noncanonically promotes ferroptosis defense in KRAS-driven lung cancer.
    Liang Zhao, Haibin Deng, Jingyi Zhang, Nicola Zamboni, Haitang Yang, Yanyun Gao, Zhang Yang, Duo Xu, Haiqing Zhong, Geert van Geest, Rémy Bruggmann, Qinghua Zhou, Ralph A Schmid, Thomas M Marti, Patrick Dorn, Ren-Wang Peng.
      Ferroptosis is an oxidative, non-apoptotic cell death frequently inactivated in cancer, but the underlying mechanisms in oncogene-specific tumors remain poorly understood. Here, we discover that lactate dehydrogenase (LDH) B, but not the closely related LDHA, subunits of active LDH with a known function in glycolysis, noncanonically promotes ferroptosis defense in KRAS-driven lung cancer. Using murine models and human-derived tumor cell lines, we show that LDHB silencing impairs glutathione (GSH) levels and sensitizes cancer cells to blockade of either GSH biosynthesis or utilization by unleashing KRAS-specific, ferroptosis-catalyzed metabolic synthetic lethality, culminating in increased glutamine metabolism, oxidative phosphorylation (OXPHOS) and mitochondrial reactive oxygen species (mitoROS). We further show that LDHB suppression upregulates STAT1, a negative regulator of SLC7A11, thereby reducing SLC7A11-dependent GSH metabolism. Our study uncovers a previously undefined mechanism of ferroptosis resistance involving LDH isoenzymes and provides a novel rationale for exploiting oncogene-specific ferroptosis susceptibility to treat KRAS-driven lung cancer.
    DOI:  https://doi.org/10.1038/s41418-024-01427-x
  8. bioRxiv. 2024 Nov 21. pii: 2024.11.20.624542. [Epub ahead of print]
    Reciprocal links between methionine metabolism, DNA repair and therapy resistance in glioblastoma.
    Navyateja Korimerla, Baharan Meghdadi, Isra Haq, Kari Wilder-Romans, Jie Xu, Nicole Becker, Ziqing Zhu, Peter Kalev, Nathan Qi, Charles Evans, Maureen Kachman, Zitong Zhao, Angelica Lin, Andrew J Scott, Alexandra O'Brien, Ayesha Kothari, Peter Sajjakulnukit, Li Zhang, Sravya Palavalasa, Erik R Peterson, Marc L Hyer, Katya Marjon, Taryn Sleger, Meredith A Morgan, Costas A Lyssiotis, Everett M Stone, Sean P Ferris, Theodore S Lawrence, Deepak Nagrath, Weihua Zhou, Daniel R Wahl.
      Glioblastoma (GBM) is uniformly lethal due to profound treatment resistance. Altered cellular metabolism is a key mediator of GBM treatment resistance. Uptake of the essential sulfur-containing amino acid methionine is drastically elevated in GBMs compared to normal cells, however, it is not known how this methionine is utilized or whether it relates to GBM treatment resistance. Here, we find that radiation acutely increases the levels of methionine-related metabolites in a variety of treatment-resistant GBM models. Stable isotope tracing studies further revealed that radiation acutely activates methionine to S-adenosyl methionine (SAM) conversion through an active signaling event mediated by the kinases of the DNA damage response. In vivo tumor SAM synthesis increases after radiation, while normal brain SAM production remains unchanged, indicating a tumor- specific metabolic alteration to radiation. Pharmacological and dietary strategies to block methionine to SAM conversion slowed DNA damage response and increased cell death following radiation in vitro. Mechanistically, these effects are due to depletion of DNA repair proteins and are reversed by SAM supplementation. These effects are selective to GBMs lacking the methionine salvage enzyme methylthioadenosine phosphorylase. Pharmacological inhibition of SAM synthesis hindered tumor growth in flank and orthotopic in vivo GBM models when combined with radiation. By contrast, methionine depletion does not reduce tumor SAM levels and fails to radiosensitize intracranial models, indicating depleting SAM, as opposed to simply lowering methionine, is critical for hindering tumor growth in intracranial models of GBM. These results highlight a new signaling link between DNA damage and SAM synthesis and define the metabolic fates of methionine in GBM in vivo . Inhibiting radiation-induced SAM synthesis slows DNA repair and augments radiation efficacy in GBM. Using MAT2A inhibitors to deplete SAM may selectively overcome treatment resistance in GBMs with defective methionine salvage while sparing normal brain.
    DOI:  https://doi.org/10.1101/2024.11.20.624542
  9. J Proteome Res. 2024 Dec 13.
    TBK1 Reprograms Metabolism in Breast Cancer: An Integrated Omics Approach.
    Meenu Maan, Neha Jaiswal, Min Liu, Harold I Saavedra, Srikumar P Chellappan, Mainak Dutta.
      Metabolic rewiring is required for cancer cells to survive in harsh microenvironments and is considered to be a hallmark of cancer. Specific metabolic adaptations are required for a tumor to become invasive and metastatic. Cell division and metabolism are inherently interconnected, and several cell cycle modulators directly regulate metabolism. Here, we report that TBK1, which is a noncanonical IKK kinase with known roles in cell cycle regulation and TLR signaling, affects cellular metabolism in cancer cells. While TBK1 is reported to be overexpressed in several cancers and its enhanced protein level correlates with poor prognosis, the underlying molecular mechanism involved in the tumor-promoting role of TBK1 is not fully understood. In this study, we show a novel role of TBK1 in regulating cancer cell metabolism using combined metabolomics, transcriptomics, and pharmacological approaches. We find that TBK1 mediates the regulation of nucleotide and energy metabolism through aldo-keto reductase B10 (AKRB10) and thymidine phosphorylase (TYMP) genes, suggesting that this TBK1-mediated metabolic rewiring contributes to its oncogenic function. In addition, we find that TBK1 inhibitors can act synergistically with AKRB10 and TYMP inhibitors to reduce cell viability. These findings raise the possibility that combining these inhibitors might be beneficial in combating cancers that show elevated levels of TBK1.
    Keywords:  AKR1B10; TBK1; TYMP; cancer metabolism; drug synergy; metabolomics; omics
    DOI:  https://doi.org/10.1021/acs.jproteome.4c00530
  10. bioRxiv. 2024 Nov 25. pii: 2024.11.24.622516. [Epub ahead of print]
    Cell-specific oxidative metabolism of the renal cortex.
    Kyle Feola, Andrea H Venable, Tatyana Broomfield, Claire B Llamas, Prashant Mishra, Sarah C Huen.
      The metabolic health of the kidney is a primary determinant of the risk of progressive kidney disease. Our understanding of the metabolic processes that fuel kidney functions is limited by the kidney's structural and functional heterogeneity. As the kidney contains many different cell types, we hypothesize that intra-renal mitochondrial heterogeneity contributes to cell-specific metabolism. To interrogate this, we utilized a recently developed mitochondrial tagging technique to isolate kidney cell-type specific mitochondria. Here, we investigate mitochondrial functional capacities and the metabolomes of the early and late proximal tubule (PT) and the distal convoluted tubule (DCT). The conditional MITO-Tag allele was combined with Slc34a1-CreERT2 , Ggt1-Cre , or Pvalb-Cre alleles to generate mouse models capable of cell-specific isolation of hemagglutinin (HA)-tagged mitochondria from the early PT, late PT, or the DCT, respectively. Functional assays measuring mitochondrial respiratory and fatty acid oxidation (FAO) capacities and metabolomics were performed on anti-HA immunoprecipitated mitochondria from kidneys of ad libitum fed and 24-hour fasted male mice. The renal MITO-Tag models targeting the early PT, late PT, and DCT revealed differential mitochondrial respiratory and FAO capacities which dynamically changed during fasting conditions. Changes with mitochondrial metabolomes induced by fasting suggest that the late PT significantly increases FAO during fasting. The renal MITO-Tag model captured differential mitochondrial metabolism and functional capacities across the early PT, late PT, and DCT at baseline and in response to fasting.
    Translational Statement: While the renal cortex is often considered a single metabolic compartment, we discovered significant diversity of mitochondrial metabolomes and functional capacities across the proximal tubule and the distal convoluted tubule. As mitochondrial dysfunction is a major biochemical pathway related to kidney disease progression, understanding the differences in mitochondrial metabolism across distinct kidney cell populations is thus critical in the development of effective and targeted therapeutic therapies for acute and chronic kidney disease.
    DOI:  https://doi.org/10.1101/2024.11.24.622516
  11. Nature. 2024 Dec 13.
    Fasting can reduce weight - but also hair growth.
    Max Kozlov.
      
    Keywords:  Cell biology; Metabolism; Regeneration; Stem cells
    DOI:  https://doi.org/10.1038/d41586-024-04084-9
  12. Physiol Rev. 2024 Dec 11.
    Ferroptosis: when metabolism meets cell death.
    Jiashuo Zheng 郑嘉烁, Marcus Conrad.
      We present here a comprehensive update on recent advancements in the field of ferroptosis, with a particular emphasis on its metabolic underpinnings and physiological impacts. After briefly introducing landmark studies that have helped to shape the concept of ferroptosis as a distinct form of cell death, we critically evaluate the key metabolic determinants involved in its regulation. These include the metabolism of essential trace elements such as selenium and iron; amino acids such as cyst(e)ine, methionine, glutamine/glutamate and tryptophan; and carbohydrates, covering glycolysis, the citric acid cycle, the electron transport chain and the pentose phosphate pathway. We also delve into the mevalonate pathway and subsequent cholesterol biosynthesis, including intermediate metabolites like dimethylallyl pyrophosphate, squalene, coenzyme Q (CoQ), vitamin K and 7-dehydrocholesterol, as well as fatty acid and phospholipid metabolism, including the biosynthesis and remodeling of ester and ether phospholipids and lipid peroxidation. Next, we highlight major ferroptosis surveillance systems, specifically the cyst(e)ine/glutathione/glutathione peroxidase 4 axis, the NAD(P)H/ferroptosis suppressor protein 1/CoQ/vitamin K system and the guanosine triphosphate cyclohydrolase 1/tetrahydrobiopterin/dihydrofolate reductase axis. We also discuss other potential anti- and pro-ferroptotic systems, including glutathione S-transferase P1, peroxiredoxin 6, dihydroorotate dehydrogenase, glycerol-3-phosphate dehydrogenase 2, vitamin K epoxide reductase complex subunit 1 like 1, nitric oxide and acyl-CoA synthetase long-chain family member 4. Finally, we explore ferroptosis's physiological roles in aging, tumor suppression and infection control, its pathological implications in tissue ischemia-reperfusion injury and neurodegeneration, and its potential therapeutic applications in cancer treatment. Existing drugs and compounds that may regulate ferroptosis in vivo are enumerated.
    Keywords:  cancer therapy; cell metabolism; ferroptosis; pathology; physiology
    DOI:  https://doi.org/10.1152/physrev.00031.2024
  13. Cell Syst. 2024 Dec 05. pii: S2405-4712(24)00337-5. [Epub ahead of print]
    Classification and functional characterization of regulators of intracellular STING trafficking identified by genome-wide optical pooled screening.
    Matteo Gentili, Rebecca J Carlson, Bingxu Liu, Quentin Hellier, Jocelyn Andrews, Yue Qin, Paul C Blainey, Nir Hacohen.
      Stimulator of interferon genes (STING) traffics across intracellular compartments to trigger innate responses. Mutations in factors regulating this process lead to inflammatory disorders. To systematically identify factors involved in STING trafficking, we performed a genome-wide optical pooled screen (OPS). Based on the subcellular localization of STING in 45 million cells, we defined 464 clusters of gene perturbations based on their cellular phenotypes. A secondary, higher-dimensional OPS identified 73 finer clusters. We show that the loss of the gene of unknown function C19orf25, which clustered with USE1, a protein involved in Golgi-to-endoplasmic reticulum (ER) transport, enhances STING signaling. Additionally, HOPS deficiency delayed STING degradation and consequently increased signaling. Similarly, GARP/RIC1-RGP1 loss increased STING signaling by delaying STING Golgi exit. Our findings demonstrate that genome-wide genotype-phenotype maps based on high-content cell imaging outperform other screening approaches and provide a community resource for mining factors that impact STING trafficking and other cellular processes.
    Keywords:  DNA sensing; STING; STING trafficking; functional genomics; genome-wide CRISPR screen; innate immunity; optical pooled screen
    DOI:  https://doi.org/10.1016/j.cels.2024.11.004
  14. Cell Rep. 2024 Dec 12. pii: S2211-1247(24)01415-3. [Epub ahead of print]43(12): 115064
    Metabolic reprogramming, sensing, and cancer therapy.
    Youxiang Mao, Ziyan Xia, Wenjun Xia, Peng Jiang.
      The metabolic reprogramming of tumor cells is a crucial strategy for their survival and proliferation, involving tissue- and condition-dependent remodeling of certain metabolic pathways. While it has become increasingly clear that tumor cells integrate extracellular and intracellular signals to adapt and proliferate, nutrient and metabolite sensing also exert direct or indirect influences, although the underlying mechanisms remain incompletely understood. Furthermore, metabolic changes not only support the rapid growth and dissemination of tumor cells but also promote immune evasion by metabolically "educating" immune cells in the tumor microenvironment (TME). Recent studies have highlighted the profound impact of metabolic reprogramming on the TME and the potential of targeting metabolic pathways as a therapeutic strategy, with several enzyme inhibitors showing promising results in clinical trials. Thus, understanding how tumor cells alter their metabolic pathways and metabolically remodel the TME to support their survival and proliferation may offer new strategies for metabolic therapy and immunotherapy.
    Keywords:  CP: Metabolism; immunometabolism; metabolic reprogramming; metabolite sensing; tumor metabolism; tumor therapy
    DOI:  https://doi.org/10.1016/j.celrep.2024.115064
  15. Nature. 2024 Dec 11.
    A lipid made by tumour cells reprograms immune cells.
    Anthony C Buzzai, Thomas Tüting.
      
    Keywords:  Cancer; Immunology; Medical research
    DOI:  https://doi.org/10.1038/d41586-024-03855-8
  16. Cancer Cell. 2024 Nov 26. pii: S1535-6108(24)00439-2. [Epub ahead of print]
    Stressing the importance of circadian time in treatment responses.
    Katja A Lamia.
      Circadian disruption increases cancer risk, but connections between circadian clocks and cancer biology are diverse and depend on tumor type. In this issue of Cancer Cell, Gonzalez-Aponte et al. demonstrate that circadian timing of glucocorticoid exposure affects glioblastoma growth. These findings underscore the importance of timing in designing therapeutic interventions.
    DOI:  https://doi.org/10.1016/j.ccell.2024.11.004
  17. Cell Rep. 2024 Dec 12. pii: S2211-1247(24)01357-3. [Epub ahead of print]43(12): 115006
    Carnitine palmitoyltransferase 1 facilitates fatty acid oxidation in a non-cell-autonomous manner.
    Joseph Choi, Danielle M Smith, Susanna Scafidi, Ryan C Riddle, Michael J Wolfgang.
      Mitochondrial fatty acid oxidation is facilitated by the combined activities of carnitine palmitoyltransferase 1 (Cpt1) and Cpt2, which generate and utilize acylcarnitines, respectively. We compare the response of mice with liver-specific deficiencies in the liver-enriched Cpt1a or the ubiquitously expressed Cpt2 and discover that they display unique metabolic, physiological, and molecular phenotypes. The loss of Cpt1a or Cpt2 results in the induction of the muscle-enriched isoenzyme Cpt1b in hepatocytes in a Pparα-dependent manner. However, hepatic Cpt1b does not contribute substantively to hepatic fatty acid oxidation when Cpt1a is absent. Liver-specific double knockout of Cpt1a and Cpt1b or Cpt2 eliminates the mitochondrial oxidation of non-esterified fatty acids. However, Cpt1a/Cpt1b double knockout mice retain fatty acid oxidation by utilizing extracellular long-chain acylcarnitines that are dependent on Cpt2. These data demonstrate the non-cell-autonomous intercellular metabolism of fatty acids in hepatocytes.
    Keywords:  CP: Metabolism; Cpt1; Cpt2; acylcarnitine; biochemistry; fasting; liver; metabolism
    DOI:  https://doi.org/10.1016/j.celrep.2024.115006
  18. Nat Metab. 2024 Dec 06.
    Cold-induced shivering for metabolic health.
    Rodrigo Fernández-Verdejo, Jose E Galgani.
      
    DOI:  https://doi.org/10.1038/s42255-024-01147-z
  19. Sci Immunol. 2024 Dec 13. 9(102): eadl4613
    Asparagine availability controls germinal center B cell homeostasis.
    Yavuz F Yazicioglu, Eros Marin, Hana F Andrew, Karolina Bentkowska, Julia C Johnstone, Robert Mitchell, Zhi Yi Wong, Kristina Zec, Joannah Fergusson, Mariana Borsa, Iwan G A Raza, Moustafa Attar, Mohammad Ali, Barbara Kronsteiner, Izadora L Furlani, James I MacRae, Michael J Devine, Mark Coles, Christopher D Buckley, Susanna J Dunachie, Alexander J Clarke.
      The rapid proliferation of germinal center (GC) B cells requires metabolic reprogramming to meet energy demands, yet these metabolic processes are poorly understood. By integrating metabolomic and transcriptomic profiling of GC B cells, we identified that asparagine (Asn) metabolism was highly up-regulated and essential for B cell function. Asparagine synthetase (ASNS) was up-regulated after B cell activation through the integrated stress response sensor GCN2. Conditional deletion of Asns in B cells impaired survival and proliferation in low Asn conditions. Removal of environmental Asn by asparaginase or dietary restriction compromised the GC reaction, impairing affinity maturation and the humoral response to influenza infection. Furthermore, metabolic adaptation to the absence of Asn required ASNS, and oxidative phosphorylation, mitochondrial homeostasis, and synthesis of nucleotides were particularly sensitive to Asn deprivation. These findings demonstrate that Asn metabolism acts as a key regulator of B cell function and GC homeostasis.
    DOI:  https://doi.org/10.1126/sciimmunol.adl4613
  20. Nature. 2024 Dec 11.
    A little bird flies high thanks to mighty mitochondria.
      
    Keywords:  Physiology
    DOI:  https://doi.org/10.1038/d41586-024-04010-z
  21. Mol Cell. 2024 Dec 05. pii: S1097-2765(24)00915-8. [Epub ahead of print]84(23): 4475-4477
    PRDX6 as an additional piece in the puzzle of selenoprotein synthesis.
    Maria Schwarz, Anna Patricia Kipp.
      In this issue of Molecular Cell, Ito et al.1 and Chen et al.2 identify peroxiredoxin 6 (PRDX6) as member of the selenoprotein (re)synthesis machinery, thereby linking PRDX6 to ferroptosis susceptibility of cancer cells.
    DOI:  https://doi.org/10.1016/j.molcel.2024.11.010
  22. Nucleic Acids Res. 2024 Dec 09. pii: gkae1184. [Epub ahead of print]
    Isoleucine-to-valine substitutions support cellular physiology during isoleucine deprivation.
    Gautam Kok, Imre F Schene, Eveline F Ilcken, Paula Sobrevals Alcaraz, Marisa I Mendes, Desiree E C Smith, Gajja Salomons, Sawsan Shehata, Judith J M Jans, Reza Maroofian, Tim A Hoek, Robert M van Es, Holger Rehmann, Edward E S Nieuwenhuis, Harmjan R Vos, Sabine A Fuchs.
      Aminoacyl-tRNA synthetases (ARSs) couple tRNAs with their corresponding amino acids. While ARSs can bind structurally similar amino acids, extreme specificity is ensured by subsequent editing activity. Yet, we found that upon isoleucine (I) restriction, healthy fibroblasts consistently incorporated valine (V) into proteins at isoleucine codons, resulting from misacylation of tRNAIle with valine by wildtype IARS1. Using a dual-fluorescent reporter of translation, we found that valine supplementation could fully compensate for isoleucine depletion and restore translation to normal levels in healthy, but not IARS1 deficient cells. Similarly, the antiproliferative effects of isoleucine deprivation could be fully restored by valine supplementation in healthy, but not IARS1 deficient cells. This indicates I > V substitutions help prevent translational termination and maintain cellular function in human primary cells during isoleucine deprivation. We suggest that this is an example of a more general mechanism in mammalian cells to preserve translational speed at the cost of translational fidelity in response to (local) amino acid deficiencies.
    DOI:  https://doi.org/10.1093/nar/gkae1184
  23. Cancer Cell. 2024 Dec 03. pii: S1535-6108(24)00438-0. [Epub ahead of print]
    Mannose metabolism reshapes T cell differentiation to enhance anti-tumor immunity.
    Yajing Qiu, Yapeng Su, Ermei Xie, Hongcheng Cheng, Jing Du, Yue Xu, Xiaoli Pan, Zhe Wang, Daniel G Chen, Hong Zhu, Philip D Greenberg, Guideng Li.
      Cellular metabolic status profoundly influences T cell differentiation, persistence, and anti-tumor efficacy. Our single-cell metabolic analyses of T cells reveal that diminished mannose metabolism is a prominent feature of T cell dysfunction. Conversely, experimental augmentation/restoration of mannose metabolism in adoptively transferred T cells via D-mannose supplementation enhances anti-tumor activity and restricts exhaustion differentiation both in vitro and in vivo. Mechanistically, D-mannose treatment induces intracellular metabolic programming and increases the O-GlcNAc transferase (OGT)-mediated O-GlcNAcylation of β-catenin, which preserves Tcf7 expression and epigenetic stemness, thereby promoting stem-like programs in T cells. Furthermore, in vitro expansion with D-mannose supplementation yields T cell products for adoptive therapy with stemness characteristics, even after extensive long-term expansion, that exhibits enhanced anti-tumor efficacy. These findings reveal cell-intrinsic mannose metabolism as a physiological regulator of CD8+ T cell fate, decoupling proliferation/expansion from differentiation, and underscoring the therapeutic potential of mannose modulation in cancer immunotherapy.
    DOI:  https://doi.org/10.1016/j.ccell.2024.11.003
  24. Adv Biol Regul. 2024 Dec 05. pii: S2212-4926(24)00058-7. [Epub ahead of print] 101070
    Tissue specific roles of fatty acid oxidation.
    Danielle M Smith, Joseph Choi, Michael J Wolfgang.
      Mitochondrial long chain fatty acid β-oxidation is a critical central carbon catabolic process. The importance of fatty acid oxidation is made evident by the life-threatening disease associated with diverse inborn errors in the pathway. While inborn errors show multisystemic requirements for fatty acid oxidation, it is not clear from the clinical presentation of these enzyme deficiencies what the tissue specific roles of the pathway are compared to secondary systemic effects. To understand the cell or tissue specific contributions of fatty acid oxidation to systemic physiology, conditional knockouts in mice have been employed to determine the requirements of fatty acid oxidation in disparate cell types. This has produced a host of surprising results that sometimes run counter to the canonical view of this metabolic pathway. The rigor of conditional knockouts has also provided clarity over previous research utilizing cell lines in vitro or small molecule inhibitors with dubious specificity. Here we will summarize current research using mouse models of Carnitine Palmitoyltransferases to determine the tissue specific roles and requirements of long chain mitochondrial fatty acid β-oxidation.
    DOI:  https://doi.org/10.1016/j.jbior.2024.101070
  25. Proc Natl Acad Sci U S A. 2024 Dec 17. 121(51): e2417678121
    Genetic synchronization of the brain and liver molecular clocks defend against chrono-metabolic disease.
    Lauren N Woodie, Ahren J Alberto, Brianna M Krusen, Lily C Melink, Mitchell A Lazar.
      Nearly every cell of the body contains a circadian clock mechanism that is synchronized with the light-entrained clock in the suprachiasmatic nucleus (SCN). Desynchrony between the SCN and the external environment leads to metabolic dysfunction in shift workers. Similarly, mice with markedly shortened endogenous period due to the deletion of circadian REV-ERBα/β nuclear receptors in the SCN (SCN DKO) exhibit increased sensitivity to diet-induced obesity (DIO) on a 24 h light:dark cycle while mice with REV-ERBs deleted in hepatocytes (HepDKO) display exacerbated hepatosteatosis in response to a high-fat diet. Here, we show that inducing deletion of hepatocyte REV-ERBs in SCN DKO mice (Hep-SCN DDKO) rescued the exacerbated DIO and hepatic triglyceride accumulation, without affecting the shortened behavioral period. These findings suggest that metabolic disturbances due to environmental desynchrony with the central clock are due to effects on peripheral clocks which can be mitigated by matching peripheral and central clock periods even in a desynchronous environment. Thus, maintaining synchrony within an organism, rather than between endogenous and exogenous clocks, may be a viable target for the treatment of metabolic disorders associated with circadian disruption.
    Keywords:  REV-ERB; circadian rhythms; metabolism; obesity; suprachiasmatic Nucleus
    DOI:  https://doi.org/10.1073/pnas.2417678121
  26. Cell Metab. 2024 Dec 04. pii: S1550-4131(24)00448-0. [Epub ahead of print]
    Emerging debates and resolutions in brown adipose tissue research.
    Aaron M Cypess, Barbara Cannon, Jan Nedergaard, Lawrence Kazak, Douglas C Chang, Jonathan Krakoff, Yu-Hua Tseng, Camilla Schéele, Jeremie Boucher, Natasa Petrovic, Denis P Blondin, André C Carpentier, Kirsi A Virtanen, Sander Kooijman, Patrick C N Rensen, Cheryl Cero, Shingo Kajimura.
      Until two decades ago, brown adipose tissue (BAT) was studied primarily as a thermogenic organ of small rodents in the context of cold adaptation. The discovery of functional human BAT has opened new opportunities to understand its physiological role in energy balance and therapeutic applications for metabolic disorders. Significantly, the role of BAT extends far beyond thermogenesis, including glucose and lipid homeostasis, by releasing mediators that communicate with other cells and organs. The field has made major advances by using new model systems, ranging from subcellular studies to clinical trials, which have also led to debates. In this perspective, we identify six fundamental issues that are currently controversial and comprise dichotomous models. Each side presents supporting evidence and, critically, the necessary methods and falsifiable experiments that would resolve the dispute. With this collaborative approach, the field will continue to productively advance the understanding of BAT physiology, appreciate the importance of thermogenic adipocytes as a central area of ongoing research, and realize the therapeutic potential.
    Keywords:  brown adipose tissue; clinical trials; metabolism; pharmacology; thermogenesis
    DOI:  https://doi.org/10.1016/j.cmet.2024.11.002
  27. Genes Dev. 2024 Dec 11.
    Metabolic regulation in adult and aging skeletal muscle stem cells.
    Vittorio Sartorelli, Veronica Ciuffoli.
      Adult stem cells maintain homeostasis and enable regeneration of most tissues. Quiescence, proliferation, and differentiation of stem cells and their progenitors are tightly regulated processes governed by dynamic transcriptional, epigenetic, and metabolic programs. Previously thought to merely reflect a cell's energy state, metabolism is now recognized for its critical regulatory functions, controlling not only energy and biomass production but also the cell's transcriptome and epigenome. In this review, we explore how metabolic pathways, metabolites, and transcriptional and epigenetic regulators are functionally interlinked in adult and aging skeletal muscle stem cells.
    Keywords:  adult stem cells; epigenetics; metabolism; muscle regeneration; muscle stem cells; transcription
    DOI:  https://doi.org/10.1101/gad.352277.124
  28. Cell Metab. 2024 Dec 04. pii: S1550-4131(24)00451-0. [Epub ahead of print]
    Nuclear GTPSCS functions as a lactyl-CoA synthetase to promote histone lactylation and gliomagenesis.
    Ruilong Liu, Xuelian Ren, Yae Eun Park, Huixu Feng, Xinlei Sheng, Xiaohan Song, Roya AminiTabrizi, Hardik Shah, Lingting Li, Yu Zhang, Kalil G Abdullah, Sarah Dubois-Coyne, Hening Lin, Philip A Cole, Ralph J DeBerardinis, Samuel K McBrayer, He Huang, Yingming Zhao.
      Histone lysine lactylation is a physiologically and pathologically relevant epigenetic pathway that can be stimulated by the Warburg effect-associated L-lactate. Nevertheless, the mechanism by which cells use L-lactate to generate lactyl-coenzyme A (CoA) and how this process is regulated remains unknown. Here, we report the identification of guanosine triphosphate (GTP)-specific SCS (GTPSCS) as a lactyl-CoA synthetase in the nucleus. The mechanism was elucidated through the crystallographic structure of GTPSCS in complex with L-lactate, followed by mutagenesis experiments. GTPSCS translocates into the nucleus and interacts with p300 to elevate histone lactylation but not succinylation. This process depends on a nuclear localization signal in the GTPSCS G1 subunit and acetylation at G2 subunit residue K73, which mediates the interaction with p300. GTPSCS/p300 collaboration synergistically regulates histone H3K18la and GDF15 expression, promoting glioma proliferation and radioresistance. GTPSCS represents the inaugural enzyme to catalyze lactyl-CoA synthesis for epigenetic histone lactylation and regulate oncogenic gene expression in glioma.
    Keywords:  GDF15; histone marks; hypoxia; lactyl-CoA; lactyl-CoA synthetase; lactylation; p300; succinyl-CoA synthetase; the Warburg effect; tumorigenesis
    DOI:  https://doi.org/10.1016/j.cmet.2024.11.005
  29. Sci Adv. 2024 Dec 13. 10(50): eadp7444
    The adenine nucleotide translocase family underlies cardiac ischemia-reperfusion injury through the mitochondrial permeability pore independently of cyclophilin D.
    Pooja Patel, Arielys Mendoza, Daniel Ramirez, Dexter Robichaux, Jeffery D Molkentin, Jason Karch.
      The mitochondrial permeability transition pore (mPTP) is implicated in cardiac ischemia-reperfusion (I/R) injury. During I/R, elevated mitochondrial Ca2+ triggers mPTP opening, leading to necrotic cell death. Although nonessential regulators of this pore are characterized, the molecular identity of the pore-forming component remains elusive. Two of these genetically verified regulators are cyclophilin D (CypD) and the adenine nucleotide translocase (ANT) family. We investigated the ANT/CypD relationship in mPTP dynamics and I/R injury. Despite lacking all ANT isoforms, Ca2+-dependent mPTP opening persisted in cardiac mitochondria but was desensitized. This desensitization conferred resistance to I/R injury in ANT-deficient mice. CypD is hypothesized to trigger mPTP opening through isomerization of ANTs at proline-62. To test this, we generated mice that expressed a P62A mutated version of ANT1. These mice showed similar mPTP dynamics and I/R sensitivity as the wild type, indicating that P62 is dispensable for CypD regulation. Together, these data indicate that the ANT family contributes to mPTP opening independently of CypD.
    DOI:  https://doi.org/10.1126/sciadv.adp7444
  30. bioRxiv. 2024 Nov 26. pii: 2024.11.24.625104. [Epub ahead of print]
    Mitochondrial respiratory capacity in kidney podocytes is high, age-dependent, and sexually dimorphic.
    Matthew D Campbell, Monica Sanchez-Contreras, Britta D Sibley, Phoebe Keiser, Carla Ruiz Sanchez, Carolyn N Mann, David J Marcinek, Behzad Najafian, Mariya T Sweetwyne.
      Whether and how podocytes depend on mitochondria across their long post-mitotic lifespan is yet unclear. With limited cell numbers and broad kidney distribution, isolation of podocyte mitochondria typically requires first isolating podocytes themselves. Disassociation of podocytes from their basement membrane, however, recapitulates an injured state that may stress mitochondria. To address this, we crossed floxed hemagglutinin (HA) -mitochondria tagged (MITO-Tag) mice with those expressing Cre in either podocytes (NPHS2) or distal tubule and collecting duct (CDH16), thus allowing for rapid, kidney cell-specific, isolation of mitochondria via immunoprecipitation. Mitochondrial respiration in fresh isolates from young (4-7 mo) and aged (22-26 mo) mice of both sexes demonstrated several previously unreported significant differences between podocyte and tubule mitochondria. First, although podocytes contain fewer mitochondria than do tubule cells, mitochondria isolated from podocytes averaged twice the respiratory capacity of tubule mitochondria when normalized to mitochondrial content by citrate synthase (CS) levels. Second, age-related decline in respiration was detected only in podocyte mitochondria and only in aged male mice. Finally, disassociating podocytes for cell culture initiates functional decline in mitochondria as those from cultured primary podocytes have half the respiratory capacity, but twice the hydrogen peroxide production of podocyte mitochondria isolated directly from fresh kidneys. Thus, podocytes maintain sexually dimorphic mitochondria with greater oxidative phosphorylation capacity than mitochondria-dependent tubules per organelle. Previous studies may not have detected these differences due to reliance on podocyte cell culture conditions, which results in artifactual suppression of mitochondrial function.
    DOI:  https://doi.org/10.1101/2024.11.24.625104
  31. Nature. 2024 Dec 09.
    Human body's ageing 'clock' ticks faster after heat stress.
    Heidi Ledford.
      
    Keywords:  Ageing; Climate change; Epigenetics
    DOI:  https://doi.org/10.1038/d41586-024-04007-8
  32. Nature. 2024 Dec;636(8042): 512
    Bad bar charts are pervasive across biology.
    Amanda Heidt.
      
    Keywords:  Publishing; Research data; Technology
    DOI:  https://doi.org/10.1038/d41586-024-03996-w
  33. Nat Methods. 2024 Dec 13.
    Considerations for building and using integrated single-cell atlases.
    Karin Hrovatin, Lisa Sikkema, Vladimir A Shitov, Graham Heimberg, Maiia Shulman, Amanda J Oliver, Michaela F Mueller, Ignacio L Ibarra, Hanchen Wang, Ciro Ramírez-Suástegui, Peng He, Anna C Schaar, Sarah A Teichmann, Fabian J Theis, Malte D Luecken.
      The rapid adoption of single-cell technologies has created an opportunity to build single-cell 'atlases' integrating diverse datasets across many laboratories. Such atlases can serve as a reference for analyzing and interpreting current and future data. However, it has become apparent that atlasing approaches differ, and the impact of these differences are often unclear. Here we review the current atlasing literature and present considerations for building and using atlases. Importantly, we find that no one-size-fits-all protocol for atlas building exists, but rather we discuss context-specific considerations and workflows, including atlas conceptualization, data collection, curation and integration, atlas evaluation and atlas sharing. We further highlight the benefits of integrated atlases for analyses of new datasets and deriving biological insights beyond what is possible from individual datasets. Our overview of current practices and associated recommendations will improve the quality of atlases to come, facilitating the shift to a unified, reference-based understanding of single-cell biology.
    DOI:  https://doi.org/10.1038/s41592-024-02532-y
  34. Cell. 2024 Dec 12. pii: S0092-8674(24)01332-1. [Epub ahead of print]187(25): 7045-7063
    How to build the virtual cell with artificial intelligence: Priorities and opportunities.
    Charlotte Bunne, Yusuf Roohani, Yanay Rosen, Ankit Gupta, Xikun Zhang, Marcel Roed, Theo Alexandrov, Mohammed AlQuraishi, Patricia Brennan, Daniel B Burkhardt, Andrea Califano, Jonah Cool, Abby F Dernburg, Kirsty Ewing, Emily B Fox, Matthias Haury, Amy E Herr, Eric Horvitz, Patrick D Hsu, Viren Jain, Gregory R Johnson, Thomas Kalil, David R Kelley, Shana O Kelley, Anna Kreshuk, Tim Mitchison, Stephani Otte, Jay Shendure, Nicholas J Sofroniew, Fabian Theis, Christina V Theodoris, Srigokul Upadhyayula, Marc Valer, Bo Wang, Eric Xing, Serena Yeung-Levy, Marinka Zitnik, Theofanis Karaletsos, Aviv Regev, Emma Lundberg, Jure Leskovec, Stephen R Quake.
      Cells are essential to understanding health and disease, yet traditional models fall short of modeling and simulating their function and behavior. Advances in AI and omics offer groundbreaking opportunities to create an AI virtual cell (AIVC), a multi-scale, multi-modal large-neural-network-based model that can represent and simulate the behavior of molecules, cells, and tissues across diverse states. This Perspective provides a vision on their design and how collaborative efforts to build AIVCs will transform biological research by allowing high-fidelity simulations, accelerating discoveries, and guiding experimental studies, offering new opportunities for understanding cellular functions and fostering interdisciplinary collaborations in open science.
    Keywords:  AI; ML; cell biology; virtual cell
    DOI:  https://doi.org/10.1016/j.cell.2024.11.015
  35. Cancer Cell. 2024 Dec 07. pii: S1535-6108(24)00446-X. [Epub ahead of print]
    Cytokines in cancer.
    Courtney T Kureshi, Stephanie K Dougan.
      Cytokines are proteins used by immune cells to communicate with each other and with cells in their environment. The pleiotropic effects of cytokine networks are determined by which cells express cytokines and which cells express cytokine receptors, with downstream outcomes that can differ based on cell type and environmental cues. Certain cytokines, such as interferon (IFN)-γ, have been clearly linked to anti-tumor immunity, while others, such as the innate inflammatory cytokines, promote oncogenesis. Here we provide an overview of the functional roles of cytokines in the tumor microenvironment. Although we have a sophisticated understanding of cytokine networks, therapeutically targeting cytokine pathways in cancer has been challenging. We discuss current progress in cytokine blockade, cytokine-based therapies, and engineered cytokine therapeutics as emerging cancer treatments of interest.
    Keywords:  IFN-α; IFN-γ; IL-2; JAK; TGF-β; TNF-α; chemokine; cytokine; interferon; interleukin
    DOI:  https://doi.org/10.1016/j.ccell.2024.11.011
  36. Cancer Cell. 2024 Dec 06. pii: S1535-6108(24)00447-1. [Epub ahead of print]
    Daily glucocorticoids promote glioblastoma growth and circadian synchrony to the host.
    Maria F Gonzalez-Aponte, Anna R Damato, Tatiana Simon, Nigina Aripova, Fabrizio Darby, Myung Sik Jeon, Jingqin Luo, Joshua B Rubin, Erik D Herzog.
      Glioblastoma (GBM) is the most common primary malignant brain tumor in adults with a poor prognosis despite aggressive therapy. Here, we hypothesized that daily host signaling regulates tumor growth and synchronizes circadian rhythms in GBM. We find daily glucocorticoids promote or suppress GBM growth through glucocorticoid receptor (GR) signaling depending on time of day and the clock genes, Bmal1 and Cry. Blocking circadian signals, like vasoactive intestinal peptide or glucocorticoids, dramatically slows GBM growth and disease progression. Analysis of human GBM samples from The Cancer Genome Atlas (TCGA) shows that high GR expression significantly increases hazard of mortality. Finally, mouse and human GBM models have intrinsic circadian rhythms in clock gene expression in vitro and in vivo that entrain to the host through glucocorticoid signaling, regardless of tumor type or host immune status. We conclude that GBM entrains to the circadian circuit of the brain, modulating its growth through clock-controlled cues, like glucocorticoids.
    Keywords:  Bmal1; TMZ; VIP; cancer neuroscience; circadian rhythms; clock genes; dexamethasone; glioblastoma; glucocorticoids; period gene; temozolomide; vasoactive intestinal peptide
    DOI:  https://doi.org/10.1016/j.ccell.2024.11.012
  37. J Evol Biol. 2024 Dec 10. pii: voae153. [Epub ahead of print]
    Biological agency: a concept without a research program.
    James DiFrisco, Richard Gawne.
      This paper evaluates recent work purporting to show that the "agency" of organisms is an important phenomenon for evolutionary biology to study. Biological agency is understood as the capacity for goal-directed, self-determining activity-a capacity that is present in all organisms irrespective of their complexity and whether or not they have a nervous system. Proponents of the "agency perspective" on biological systems have claimed that agency is not explainable by physiological or developmental mechanisms, or by adaptation via natural selection. We show that this idea is theoretically unsound and unsupported by current biology. There is no empirical evidence that the agency perspective has the potential to advance experimental research in the life sciences. Instead, the phenomena that the agency perspective purports to make sense of are better explained using the well-established idea that complex multiscale feedback mechanisms evolve through natural selection.
    Keywords:  adaptation; agency; goal-directedness; mechanism; natural selection; self-determination
    DOI:  https://doi.org/10.1093/jeb/voae153
  38. Nat Aging. 2024 Dec;4(12): 1711-1730
    Hallmarks of female reproductive aging in physiologic aging mice.
    Julia L Balough, Shweta S Dipali, Karen Velez, T Rajendra Kumar, Francesca E Duncan.
      The female reproductive axis is one of the first organ systems to age, which has consequences for fertility and overall health. Here, we provide a comprehensive overview of the biological process of female reproductive aging across reproductive organs, tissues and cells based on research with widely used physiologic aging mouse models, and describe the mechanisms that underpin these phenotypes. Overall, aging is associated with dysregulation of the hypothalamic-pituitary-ovarian axis, perturbations of the ovarian stroma, reduced egg quantity and quality, and altered uterine morphology and function that contributes to reduced capacity for fertilization and impaired embryo development. Ultimately, these age-related phenotypes contribute to altered pregnancy outcomes and adverse consequences in offspring. Conserved mechanisms of aging, as well as those unique to the reproductive system, underlie these phenotypes. The knowledge of such mechanisms will lead to development of therapeutics to extend female reproductive longevity and support endocrine function and overall health.
    DOI:  https://doi.org/10.1038/s43587-024-00769-y
  39. Mol Cell. 2024 Dec 05. pii: S1097-2765(24)00923-7. [Epub ahead of print]84(23): 4483-4485
    Lactylation as a post-translational regulator of cGAS and immunity.
    Haipeng Liu, Baoxue Ge.
      In a recent paper at Nature, Li et al.1 reported that alanine-tRNA synthetases AARS1 and AARS2 are lactate sensors and mediate lactylation of cGAS, leading to its inactivation.
    DOI:  https://doi.org/10.1016/j.molcel.2024.11.018
  40. bioRxiv. 2024 Nov 25. pii: 2024.11.22.623650. [Epub ahead of print]
    Deep Learning of Cellular Metabolic Flux Distributions Predicts Lifespan.
    Tyler A U Hilsabeck, Shane L Rea.
      It is a common observation that individuals within a species age at different rates. Variation in both genetics and environmental interaction are generally thought responsible. Surprisingly, even genetically identical organisms cultured under environmentally homogeneous conditions age at different rates, implying a more fundamental cause of aging. Here we have examined the basis for lifespan variance in haploid, single-celled yeast of Saccharomyces cerevisiae . The probabilistic nature of metabolism means metabolites often, but not always, follow the same route through the metabolic network. We speculate redundancy in metabolic pathway choice is sufficient to explain lifespan variance. To interrogate the reaction flux space of S. cerevisiae we used a model of its intermediary metabolism, comprising 1,150 genes, 4,058 reactions, and 2,742 metabolites (yeast GEM_v8.5.0). We restricted traffic through the metabolic network by knocking out each of the 1,150 genes, then generated a total of 406,500 flux distributions spanning the solution space of the resulting 812 viable mutants. We collected replicative life span (RLS) data for the 812 viable mutants, corresponding to 66,400 individual cells. Four approaches were then employed to test whether reaction flux configuration could be used to predict lifespan: Principal Component Analysis (PCA) in conjunction with non-linear modeling of RLS; deep learning of RLS using either a Regression Neural Network (RNN) or a Classification Neural Network (CfNN); and deep learning using a convolutional neural network (CNN) following conversion of flux distributions to pixelated images. The four approaches reveal a core network of highly correlated reactions controlling aging rate that is sufficient to explain all lifespan variance. It includes biosynthetic pathways encompassing ceramides, monolysocardiolipins, phosphoinositides, porphyrin and glycerolipids. Our data lead to two novel conclusions. First, variance in the replicative lifespan of S. cerevisiae is an emergent property of its metabolic network. Second, there is convergence among metabolic configurations toward three meta-stable flux states - one associated with extended life, another with shortened life, and a third with wild type life span.
    One Sentence Summary: Traffic routes and rates through the metabolic network of S. cerevisiae fully account for variance in replicative lifespan.
    DOI:  https://doi.org/10.1101/2024.11.22.623650
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