bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2024‒08‒18
39 papers selected by
Christian Frezza, Universität zu Köln
  1. Defective mitochondrial COX1 translation due to loss of COX14 function triggers ROS-induced inflammation in mouse liver.
  2. ACLY and ACSS2 link nutrient-dependent chromatin accessibility to CD8 T cell effector responses.
  3. OPA1 promotes ferroptosis by augmenting mitochondrial ROS and suppressing an integrated stress response.
  4. Mitochondrial-derived compartments remove surplus proteins from the outer mitochondrial membrane.
  5. TFE3 fusions direct an oncogenic transcriptional program that drives OXPHOS and unveils vulnerabilities in translocation renal cell carcinoma.
  6. SLC17A1/3 transporters mediate renal excretion of Lac-Phe in mice and humans.
  7. Mitochondrial complex I promotes kidney cancer metastasis.
  8. Cysteine depletion triggers adipose tissue thermogenesis and weight-loss.
  9. GLUD1 determines murine muscle stem cell fate by controlling mitochondrial glutamate levels.
  10. Hypoxia-induced downregulation of PGK1 crotonylation promotes tumorigenesis by coordinating glycolysis and the TCA cycle.
  11. A spatial atlas of mitochondrial gene expression reveals dynamic translation hubs and remodeling in stress.
  12. An Immunometabolic Route for Activating cGAS/STING to Drive Anticancer Immunity.
  13. Manipulating mannose metabolism as a potential anticancer strategy.
  14. Type I interferon governs immunometabolic checkpoints that coordinate inflammation during Staphylococcal infection.
  15. Functional overlap of inborn errors of immunity and metabolism genes defines T cell metabolic vulnerabilities.
  16. Appendage regeneration requires IMPDH2 and creates a sensitized environment for enzyme filament formation.
  17. Adapt and shape: metabolic features within the metastatic niche.
  18. HMGA1 orchestrates chromatin compartmentalization and sequesters genes into 3D networks coordinating senescence heterogeneity.
  19. Differential utilization of vitamin B12-dependent and independent pathways for propionate metabolism across human cells.
  20. A fatty acid switch drives ferroptosis in EMT.
  21. Mitochondrial Probe for Glutathione Depletion Reveals NME3 Essentiality for Mitochondrial Redox Response.
  22. Mitochondrial-derived compartments are multilamellar domains that encase membrane cargo and cytosol.
  23. Macrophage-mediated myelin recycling fuels brain cancer malignancy.
  24. Dynamic interaction of REEP5-MFN1/2 enables mitochondrial hitchhiking on tubular ER.
  25. Unraveling cysteine deficiency-associated rapid weight loss.
  26. mTORC1 phosphorylates and stabilizes LST2 to negatively regulate EGFR.
  27. Ketogenic diet reshapes cancer metabolism through lysine β-hydroxybutyrylation.
  28. Broad-spectrum antibiotics disrupt homeostatic efferocytosis.
  29. S-acylation of ATGL is required for lipid droplet homoeostasis in hepatocytes.
  30. Circadian period is compensated for repressor protein turnover rates in single cells.
  31. Suprachiasmatic nucleus VIPergic fibers show a circadian rhythm of expansion and retraction.
  32. Remodelling of the translatome controls diet and its impact on tumorigenesis.
  33. Deregulation of mitochondrial gene expression in cancer: mechanisms and therapeutic opportunities.
  34. The influence of metabolic disorders on adaptive immunity.
  35. Molecular impact of mutations in RNA splicing factors in cancer.
  36. MDH2 regulates the sensitivity of clear cell renal cell carcinoma to ferroptosis through its interaction with FSP1.
  37. MAVS Cys508 palmitoylation promotes its aggregation on the mitochondrial outer membrane and antiviral innate immunity.
  38. Mitoclone2: an R package for elucidating clonal structure in single-cell RNA-sequencing data using mitochondrial variants.
  39. Single-nucleus chromatin accessibility and transcriptomic map of breast tissues of women of diverse genetic ancestry.
  1. Nat Commun. 2024 Aug 12. 15(1): 6914
    Defective mitochondrial COX1 translation due to loss of COX14 function triggers ROS-induced inflammation in mouse liver.
    Abhishek Aich, Angela Boshnakovska, Steffen Witte, Tanja Gall, Kerstin Unthan-Fechner, Roya Yousefi, Arpita Chowdhury, Drishan Dahal, Aditi Methi, Svenja Kaufmann, Ivan Silbern, Jan Prochazka, Zuzana Nichtova, Marcela Palkova, Miles Raishbrook, Gizela Koubkova, Radislav Sedlacek, Simon E Tröder, Branko Zevnik, Dietmar Riedel, Susann Michanski, Wiebke Möbius, Philipp Ströbel, Christian Lüchtenborg, Patrick Giavalisco, Henning Urlaub, Andre Fischer, Britta Brügger, Stefan Jakobs, Peter Rehling.
      Mitochondrial oxidative phosphorylation (OXPHOS) fuels cellular ATP demands. OXPHOS defects lead to severe human disorders with unexplained tissue specific pathologies. Mitochondrial gene expression is essential for OXPHOS biogenesis since core subunits of the complexes are mitochondrial-encoded. COX14 is required for translation of COX1, the central mitochondrial-encoded subunit of complex IV. Here we describe a COX14 mutant mouse corresponding to a patient with complex IV deficiency. COX14M19I mice display broad tissue-specific pathologies. A hallmark phenotype is severe liver inflammation linked to release of mitochondrial RNA into the cytosol sensed by RIG-1 pathway. We find that mitochondrial RNA release is triggered by increased reactive oxygen species production in the deficiency of complex IV. Additionally, we describe a COA3Y72C mouse, affected in an assembly factor that cooperates with COX14 in early COX1 biogenesis, which displays a similar yet milder inflammatory phenotype. Our study provides insight into a link between defective mitochondrial gene expression and tissue-specific inflammation.
    DOI:  https://doi.org/10.1038/s41467-024-51109-y
  2. J Exp Med. 2024 Sep 02. pii: e20231820. [Epub ahead of print]221(9):
    ACLY and ACSS2 link nutrient-dependent chromatin accessibility to CD8 T cell effector responses.
    Irem Kaymak, McLane J Watson, Brandon M Oswald, Shixin Ma, Benjamin K Johnson, Lisa M DeCamp, Batsirai M Mabvakure, Katarzyna M Luda, Eric H Ma, Kin Lau, Zhen Fu, Brejnev Muhire, Susan M Kitchen-Goosen, Alexandra Vander Ark, Michael S Dahabieh, Bozena Samborska, Matthew Vos, Hui Shen, Zi Peng Fan, Thomas P Roddy, Gillian A Kingsbury, Cristovão M Sousa, Connie M Krawczyk, Kelsey S Williams, Ryan D Sheldon, Susan M Kaech, Dominic G Roy, Russell G Jones.
      Coordination of cellular metabolism is essential for optimal T cell responses. Here, we identify cytosolic acetyl-CoA production as an essential metabolic node for CD8 T cell function in vivo. We show that CD8 T cell responses to infection depend on acetyl-CoA derived from citrate via the enzyme ATP citrate lyase (ACLY). However, ablation of ACLY triggers an alternative, acetate-dependent pathway for acetyl-CoA production mediated by acyl-CoA synthetase short-chain family member 2 (ACSS2). Mechanistically, acetate fuels both the TCA cycle and cytosolic acetyl-CoA production, impacting T cell effector responses, acetate-dependent histone acetylation, and chromatin accessibility at effector gene loci. When ACLY is functional, ACSS2 is not required, suggesting acetate is not an obligate metabolic substrate for CD8 T cell function. However, loss of ACLY renders CD8 T cells dependent on acetate (via ACSS2) to maintain acetyl-CoA production and effector function. Together, ACLY and ACSS2 coordinate cytosolic acetyl-CoA production in CD8 T cells to maintain chromatin accessibility and T cell effector function.
    DOI:  https://doi.org/10.1084/jem.20231820
  3. Mol Cell. 2024 Aug 09. pii: S1097-2765(24)00618-X. [Epub ahead of print]
    OPA1 promotes ferroptosis by augmenting mitochondrial ROS and suppressing an integrated stress response.
    Felix G Liang, Fereshteh Zandkarimi, Jaehoon Lee, Joshua L Axelrod, Ryan Pekson, Yisang Yoon, Brent R Stockwell, Richard N Kitsis.
      Ferroptosis, an iron-dependent form of nonapoptotic cell death mediated by lipid peroxidation, has been implicated in the pathogenesis of multiple diseases. Subcellular organelles play pivotal roles in the regulation of ferroptosis, but the mechanisms underlying the contributions of the mitochondria remain poorly defined. Optic atrophy 1 (OPA1) is a mitochondrial dynamin-like GTPase that controls mitochondrial morphogenesis, fusion, and energetics. Here, we report that human and mouse cells lacking OPA1 are markedly resistant to ferroptosis. Reconstitution with OPA1 mutants demonstrates that ferroptosis sensitization requires the GTPase activity but is independent of OPA1-mediated mitochondrial fusion. Mechanistically, OPA1 confers susceptibility to ferroptosis by maintaining mitochondrial homeostasis and function, which contributes both to the generation of mitochondrial lipid reactive oxygen species (ROS) and suppression of an ATF4-mediated integrated stress response. Together, these results identify an OPA1-controlled mitochondrial axis of ferroptosis regulation and provide mechanistic insights for therapeutically manipulating this form of cell death in diseases.
    Keywords:  ATF4; GPx4; OPA1; cell death; ferroptosis; integrated stress response; mitochondria; system X(c)(−); xCT
    DOI:  https://doi.org/10.1016/j.molcel.2024.07.020
  4. J Cell Biol. 2024 Nov 04. pii: e202307036. [Epub ahead of print]223(11):
    Mitochondrial-derived compartments remove surplus proteins from the outer mitochondrial membrane.
    Zachary N Wilson, Sai Sangeetha Balasubramaniam, Sara Wong, Max-Hinderk Schuler, Mitchell J Wopat, Adam L Hughes.
      The outer mitochondrial membrane (OMM) creates a boundary that imports most of the mitochondrial proteome while removing extraneous or damaged proteins. How the OMM senses aberrant proteins and remodels to maintain OMM integrity remains unresolved. Previously, we identified a mitochondrial remodeling mechanism called the mitochondrial-derived compartment (MDC) that removes a subset of the mitochondrial proteome. Here, we show that MDCs specifically sequester proteins localized only at the OMM, providing an explanation for how select mitochondrial proteins are incorporated into MDCs. Remarkably, selective sorting into MDCs also occurs within the OMM, as subunits of the translocase of the outer membrane (TOM) complex are excluded from MDCs unless assembly of the TOM complex is impaired. Considering that overloading the OMM with mitochondrial membrane proteins or mistargeted tail-anchored membrane proteins induces MDCs to form and sequester these proteins, we propose that one functional role of MDCs is to create an OMM-enriched trap that segregates and sequesters excess proteins from the mitochondrial surface.
    DOI:  https://doi.org/10.1083/jcb.202307036
  5. bioRxiv. 2024 Aug 10. pii: 2024.08.09.607311. [Epub ahead of print]
    TFE3 fusions direct an oncogenic transcriptional program that drives OXPHOS and unveils vulnerabilities in translocation renal cell carcinoma.
    Jiao Li, Kaimeng Huang, Fiona McBride, Ananthan Sadagopan, Daniel S Gallant, Meha Thakur, Prateek Khanna, Bingchen Li, Maolin Ge, Cary N Weiss, Mingkee Achom, Qingru Xu, Kun Huang, Birgitta A Ryback, Miao Gui, Liron Bar-Peled, Srinivas R Viswanathan.
      Translocation renal cell carcinoma (tRCC) is an aggressive subtype of kidney cancer driven by TFE3 gene fusions, which act via poorly characterized downstream mechanisms. Here we report that TFE3 fusions transcriptionally rewire tRCCs toward oxidative phosphorylation (OXPHOS), contrasting with the highly glycolytic metabolism of most other renal cancers. This TFE3 fusion-driven OXPHOS program, together with heightened glutathione levels found in renal cancers, renders tRCCs sensitive to reductive stress - a metabolic stress state induced by an imbalance of reducing equivalents. Genome-scale CRISPR screening identifies tRCC-selective vulnerabilities linked to this metabolic state, including EGLN1 , which hydroxylates HIF-1α and targets it for proteolysis. Inhibition of EGLN1 compromises tRCC cell growth by stabilizing HIF-1a and promoting metabolic reprogramming away from OXPHOS, thus representing a vulnerability to OXPHOS-dependent tRCC cells. Our study defines a distinctive tRCC-essential metabolic program driven by TFE3 fusions and nominates EGLN1 inhibition as a therapeutic strategy to counteract fusion-induced metabolic rewiring.
    DOI:  https://doi.org/10.1101/2024.08.09.607311
  6. Nat Commun. 2024 Aug 12. 15(1): 6895
    SLC17A1/3 transporters mediate renal excretion of Lac-Phe in mice and humans.
    Veronica L Li, Shuke Xiao, Pascal Schlosser, Nora Scherer, Amanda L Wiggenhorn, Jan Spaas, Alan Sheng-Hwa Tung, Edward D Karoly, Anna Köttgen, Jonathan Z Long.
      N-lactoyl-phenylalanine (Lac-Phe) is a lactate-derived metabolite that suppresses food intake and body weight. Little is known about the mechanisms that mediate Lac-Phe transport across cell membranes. Here we identify SLC17A1 and SLC17A3, two kidney-restricted plasma membrane-localized solute carriers, as physiologic urine Lac-Phe transporters. In cell culture, SLC17A1/3 exhibit high Lac-Phe efflux activity. In humans, levels of Lac-Phe in urine exhibit a strong genetic association with the SLC17A1-4 locus. Urine Lac-Phe levels are increased following a Wingate sprint test. In mice, genetic ablation of either SLC17A1 or SLC17A3 reduces urine Lac-Phe levels. Despite these differences, both knockout strains have normal blood Lac-Phe and body weights, demonstrating SLC17A1/3-dependent de-coupling of urine and plasma Lac-Phe pools. Together, these data establish SLC17A1/3 family members as the physiologic urine Lac-Phe transporters and uncover a biochemical pathway for the renal excretion of this signaling metabolite.
    DOI:  https://doi.org/10.1038/s41467-024-51174-3
  7. Nature. 2024 Aug 14.
    Mitochondrial complex I promotes kidney cancer metastasis.
    Divya Bezwada, Luigi Perelli, Nicholas P Lesner, Ling Cai, Bailey Brooks, Zheng Wu, Hieu S Vu, Varun Sondhi, Daniel L Cassidy, Stacy Kasitinon, Sherwin Kelekar, Feng Cai, Arin B Aurora, McKenzie Patrick, Ashley Leach, Rashed Ghandour, Yuanyuan Zhang, Duyen Do, Phyllis McDaniel, Jessica Sudderth, Dennis Dumesnil, Sara House, Tracy Rosales, Alan M Poole, Yair Lotan, Solomon Woldu, Aditya Bagrodia, Xiaosong Meng, Jeffrey A Cadeddu, Prashant Mishra, Javier Garcia-Bermudez, Ivan Pedrosa, Payal Kapur, Kevin D Courtney, Craig R Malloy, Giannicola Genovese, Vitaly Margulis, Ralph J DeBerardinis.
      Most kidney cancers are metabolically dysfunctional1-4, but how this dysfunction affects cancer progression in humans is unknown. We infused 13C-labelled nutrients in over 80 patients with kidney cancer during surgical tumour resection. Labelling from [U-13C]glucose varies across subtypes, indicating that the kidney environment alone cannot account for all tumour metabolic reprogramming. Compared with the adjacent kidney, clear cell renal cell carcinomas (ccRCCs) display suppressed labelling of tricarboxylic acid (TCA) cycle intermediates in vivo and in ex vivo organotypic cultures, indicating that suppressed labelling is tissue intrinsic. [1,2-13C]acetate and [U-13C]glutamine infusions in patients, coupled with measurements of respiration in isolated human kidney and tumour mitochondria, reveal lower electron transport chain activity in ccRCCs that contributes to decreased oxidative and enhanced reductive TCA cycle labelling. However, ccRCC metastases unexpectedly have enhanced TCA cycle labelling compared with that of primary ccRCCs, indicating a divergent metabolic program during metastasis in patients. In mice, stimulating respiration or NADH recycling in kidney cancer cells is sufficient to promote metastasis, whereas inhibiting electron transport chain complex I decreases metastasis. These findings in humans and mice indicate that metabolic properties and liabilities evolve during kidney cancer progression, and that mitochondrial function is limiting for metastasis but not growth at the original site.
    DOI:  https://doi.org/10.1038/s41586-024-07812-3
  8. bioRxiv. 2024 Aug 08. pii: 2024.08.06.606880. [Epub ahead of print]
    Cysteine depletion triggers adipose tissue thermogenesis and weight-loss.
    Aileen H Lee, Lucie Orliaguet, Yun-Hee Youm, Rae Maeda, Tamara Dlugos, Yuanjiu Lei, Daniel Coman, Irina Shchukina, Sairam Andhey, Steven R Smith, Eric Ravussin, Krisztian Stadler, Fahmeed Hyder, Maxim N Artyomov, Yuki Sugiura, Vishwa Deep Dixit.
      Dietary interventions such as caloric restriction (CR) 1 and methionine restriction 2 that prolong lifespan induce the 'browning' of white adipose tissue (WAT), an adaptive metabolic response that increases heat production to maintain health 3,4 . However, how diet influences adipose browning and metabolic health is unclear. Here, we identified that weight-loss induced by CR in humans 5 reduces cysteine concentration in WAT suggesting depletion of this amino-acid may be involved in metabolic benefits of CR. To investigate the role of cysteine on organismal metabolism, we created a cysteine-deficiency mouse model in which dietary cysteine was eliminated and cystathionine γ-lyase (CTH) 6 , the enzyme that synthesizes cysteine was conditionally deleted. Using this animal model, we found that systemic cysteine-depletion causes drastic weight-loss with increased fat utilization and browning of adipose tissue. The restoration of dietary cysteine in cysteine-deficient mice rescued weight loss together with reversal of adipose browning and increased food-intake in an on-demand fashion. Mechanistically, cysteine deficiency induced browning and weight loss is dependent on sympathetic nervous system derived noradrenaline signaling via β3-adrenergic-receptors and does not require UCP1. Therapeutically, in high-fat diet fed obese mice, one week of cysteine-deficiency caused 30% weight-loss and reversed inflammation. These findings thus establish that cysteine is essential for organismal metabolism as removal of cysteine in the host triggers adipose browning and rapid weight loss.
    DOI:  https://doi.org/10.1101/2024.08.06.606880
  9. Dev Cell. 2024 Aug 02. pii: S1534-5807(24)00455-6. [Epub ahead of print]
    GLUD1 determines murine muscle stem cell fate by controlling mitochondrial glutamate levels.
    Inés Soro-Arnáiz, Gillian Fitzgerald, Sarah Cherkaoui, Jing Zhang, Paola Gilardoni, Adhideb Ghosh, Ori Bar-Nur, Evi Masschelein, Pierre Maechler, Nicola Zamboni, Martin Poms, Alessio Cremonesi, Juan Carlos Garcia-Cañaveras, Katrien De Bock, Raphael Johannes Morscher.
      Muscle stem cells (MuSCs) enable muscle growth and regeneration after exercise or injury, but how metabolism controls their regenerative potential is poorly understood. We describe that primary metabolic changes can determine murine MuSC fate decisions. We found that glutamine anaplerosis into the tricarboxylic acid (TCA) cycle decreases during MuSC differentiation and coincides with decreased expression of the mitochondrial glutamate deaminase GLUD1. Deletion of Glud1 in proliferating MuSCs resulted in precocious differentiation and fusion, combined with loss of self-renewal in vitro and in vivo. Mechanistically, deleting Glud1 caused mitochondrial glutamate accumulation and inhibited the malate-aspartate shuttle (MAS). The resulting defect in transporting NADH-reducing equivalents into the mitochondria induced compartment-specific NAD+/NADH ratio shifts. MAS activity restoration or directly altering NAD+/NADH ratios normalized myogenesis. In conclusion, GLUD1 prevents deleterious mitochondrial glutamate accumulation and inactivation of the MAS in proliferating MuSCs. It thereby acts as a compartment-specific metabolic brake on MuSC differentiation.
    Keywords:  GLUD1; glutamine metabolism; malate aspartate shuttle; metabolite compartmentalization; muscle stem cells; tricarboxylic acid cycle
    DOI:  https://doi.org/10.1016/j.devcel.2024.07.015
  10. Nat Commun. 2024 Aug 12. 15(1): 6915
    Hypoxia-induced downregulation of PGK1 crotonylation promotes tumorigenesis by coordinating glycolysis and the TCA cycle.
    Zihao Guo, Yang Zhang, Haoyue Wang, Liming Liao, Lingdi Ma, Yiliang Zhao, Ronghui Yang, Xuexue Li, Jing Niu, Qiaoyun Chu, Yanxia Fu, Binghui Li, Chuanzhen Yang.
      Protein post-translational modifications (PTMs) are crucial for cancer cells to adapt to hypoxia; however, the functional significance of lysine crotonylation (Kcr) in hypoxia remains unclear. Herein we report a quantitative proteomics analysis of global crotonylome under normoxia and hypoxia, and demonstrate 128 Kcr site alterations across 101 proteins in MDA-MB231 cells. Specifically, we observe a significant decrease in K131cr, K156cr and K220cr of phosphoglycerate kinase 1 (PGK1) upon hypoxia. Enoyl-CoA hydratase 1 (ECHS1) is upregulated and interacts with PGK1, leading to the downregulation of PGK1 Kcr under hypoxia. Abolishment of PGK1 Kcr promotes glycolysis and suppresses mitochondrial pyruvate metabolism by activating pyruvate dehydrogenase kinase 1 (PDHK1). A low PGK1 K131cr level is correlated with malignancy and poor prognosis of breast cancer. Our findings show that PGK1 Kcr is a signal in coordinating glycolysis and the tricarboxylic acid (TCA) cycle and may serve as a diagnostic indicator for breast cancer.
    DOI:  https://doi.org/10.1038/s41467-024-51232-w
  11. bioRxiv. 2024 Aug 06. pii: 2024.08.05.604215. [Epub ahead of print]
    A spatial atlas of mitochondrial gene expression reveals dynamic translation hubs and remodeling in stress.
    Adam Begeman, John A Smolka, Ahmad Shami, Tejashree Pradip Waingankar, Samantha C Lewis.
      Mitochondrial genome expression is important for cellular bioenergetics. How mitochondrial RNA processing and translation are spatially organized across dynamic mitochondrial networks is not well understood. Here, we report that processed mitochondrial RNAs are consolidated with mitoribosome components into translation hubs distal to either nucleoids or processing granules in human cells. During stress, these hubs are remodeled into translationally repressed mesoscale bodies containing messenger, ribosomal, and double-stranded RNA. We show that the highly conserved helicase SUV3 contributes to the distribution of processed RNA within mitochondrial networks, and that stress bodies form downstream of proteostatic stress in cells lacking SUV3 unwinding activity. We propose that the spatial organization of nascent chain synthesis into discrete domains serves to throttle the flow of genetic information in stress to ensure mitochondrial quality control.
    DOI:  https://doi.org/10.1101/2024.08.05.604215
  12. Cancer Res. 2024 Aug 15. 84(16): 2569-2571
    An Immunometabolic Route for Activating cGAS/STING to Drive Anticancer Immunity.
    Francisca Borges, Abhishek D Garg.
      The cGAS/STING pathway is a crucial immune activator in cancer biology, triggering innate immunosurveillance against tumors by sensing and reacting to endogenous mitochondrial DNA (mtDNA). In this issue of Cancer Research, research by Saha and colleagues highlights the significant impact of serine deprivation on this pathway, thereby unveiling its potential for anticancer therapy. Serine is essential for cellular metabolism and influences tumor growth and immune responses. Depriving cells of serine caused mitochondrial dysfunction and the release of mtDNA into the cytosol, activating the cGAS/STING pathway and inducing type I IFN responses. In mouse models, serine deprivation enhanced antitumor immunity, with increased tumoral immune infiltration, including CD4+/CD8+ T cells and type I IFN responses. Clinically, a genetic signature indicative of lower serine enrichment in colorectal cancer patients correlated with immune activation and improved survival. Furthermore, combining serine deprivation with PD1 blockade significantly reduced tumor volume and led to long-term immunity in mice, suggesting that serine depletion enhances the efficacy of immune checkpoint blockade. These findings propose serine deprivation as a promising strategy to boost antitumor immunity and improve cancer patient outcomes. See related article by Saha et al., p. 2645.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-1624
  13. FEBS J. 2024 Aug 11.
    Manipulating mannose metabolism as a potential anticancer strategy.
    Yoichiro Harada.
      Cancer cells acquire metabolic advantages over their normal counterparts regarding the use of nutrients for sustained cell proliferation and cell survival in the tumor microenvironment. Notable among the metabolic traits in cancer cells is the Warburg effect, which is a reprogrammed form of glycolysis that favors the rapid generation of ATP from glucose and the production of biological macromolecules by diverting glucose into various metabolic intermediates. Meanwhile, mannose, which is the C-2 epimer of glucose, has the ability to dampen the Warburg effect, resulting in slow-cycling cancer cells that are highly susceptible to chemotherapy. This anticancer effect of mannose appears when its catabolism is compromised in cancer cells. Moreover, de novo synthesis of mannose within cancer cells has also been identified as a potential target for enhancing chemosensitivity through targeting glycosylation pathways. The underlying mechanisms by which alterations in mannose metabolism induce cancer cell vulnerability are just beginning to emerge. This review summarizes the current state of our knowledge of mannose metabolism and provides insights into its manipulation as a potential anticancer strategy.
    Keywords:  Warburg effect; cancer; chemotherapy; glucose; glycolysis; glycosylation; mannose; metabolism; tumor
    DOI:  https://doi.org/10.1111/febs.17230
  14. Cell Rep. 2024 Aug 09. pii: S2211-1247(24)00957-4. [Epub ahead of print]43(8): 114607
    Type I interferon governs immunometabolic checkpoints that coordinate inflammation during Staphylococcal infection.
    Mack B Reynolds, Benjamin Klein, Michael J McFadden, Norah K Judge, Hannah E Navarrete, Britton C Michmerhuizen, Dominik Awad, Tracey L Schultz, Paul W Harms, Li Zhang, Teresa R O'Meara, Jonathan Z Sexton, Costas A Lyssiotis, J Michelle Kahlenberg, Mary X O'Riordan.
      Macrophage metabolic plasticity is central to inflammatory programming, yet mechanisms of coordinating metabolic and inflammatory programs during infection are poorly defined. Here, we show that type I interferon (IFN) temporally guides metabolic control of inflammation during methicillin-resistant Staphylococcus aureus (MRSA) infection. We find that staggered Toll-like receptor and type I IFN signaling in macrophages permit a transient energetic state of combined oxidative phosphorylation (OXPHOS) and aerobic glycolysis followed by inducible nitric oxide synthase (iNOS)-mediated OXPHOS disruption. This disruption promotes type I IFN, suppressing other pro-inflammatory cytokines, notably interleukin-1β. Upon infection, iNOS expression peaks at 24 h, followed by lactate-driven Nos2 repression via histone lactylation. Type I IFN pre-conditioning prolongs infection-induced iNOS expression, amplifying type I IFN. Cutaneous MRSA infection in mice constitutively expressing epidermal type I IFN results in elevated iNOS levels, impaired wound healing, vasculopathy, and lung infection. Thus, kinetically regulated type I IFN signaling coordinates immunometabolic checkpoints that control infection-induced inflammation.
    Keywords:  CP: Immunology; CP: Metabolism; Staphylococcus aureus; epigenetics; immunometabolism; inflammation; innate immunity; interferon; lactate; macrophage; nitric oxide; respiratory complex
    DOI:  https://doi.org/10.1016/j.celrep.2024.114607
  15. Sci Immunol. 2024 Aug 16. 9(98): eadh0368
    Functional overlap of inborn errors of immunity and metabolism genes defines T cell metabolic vulnerabilities.
    Andrew R Patterson, Gabriel A Needle, Ayaka Sugiura, Erin Q Jennings, Channing Chi, KayLee K Steiner, Emilie L Fisher, Gabriella L Robertson, Caroline Bodnya, Janet G Markle, Ryan D Sheldon, Russell G Jones, Vivian Gama, Jeffrey C Rathmell.
      Inborn errors of metabolism (IEMs) and immunity (IEIs) are Mendelian diseases in which complex phenotypes and patient rarity have limited clinical understanding. Whereas few genes have been annotated as contributing to both IEMs and IEIs, immunometabolic demands suggested greater functional overlap. Here, CRISPR screens tested IEM genes for immunologic roles and IEI genes for metabolic effects and found considerable previously unappreciated crossover. Analysis of IEMs showed that N-linked glycosylation and the hexosamine pathway enzyme Gfpt1 are critical for T cell expansion and function. Further, T helper (TH1) cells synthesized uridine diphosphate N-acetylglucosamine more rapidly and were more impaired by Gfpt1 deficiency than TH17 cells. Screening IEI genes found that Bcl11b promotes the CD4 T cell mitochondrial activity and Mcl1 expression necessary to prevent metabolic stress. Thus, a high degree of functional overlap exists between IEM and IEI genes, and immunometabolic mechanisms may underlie a previously underappreciated intersection of these disorders.
    DOI:  https://doi.org/10.1126/sciimmunol.adh0368
  16. bioRxiv. 2024 Jul 30. pii: 2024.07.29.605679. [Epub ahead of print]
    Appendage regeneration requires IMPDH2 and creates a sensitized environment for enzyme filament formation.
    Morgan E McCartney, Gavin M Wheeler, Audrey G O'Neill, Jeet H Patel, Zoey R Litt, S John Calise, Justin M Kollman, Andrea E Wills.
      The regeneration of lost tissue requires biosynthesis of metabolites needed for cell proliferation and growth. Among these are the purine nucleotides ATP and GTP, which are required for diverse cellular processes including DNA synthesis, cytoskeletal assembly, and energy production. The abundance and balance of these purines is regulated by inosine monophosphate dehydrogenase 2 (IMPDH2), which catalyzes the committing step of GTP synthesis. IMPDH2 is typically expressed at high levels in proliferating cells and assembles into filaments that resist allosteric inhibition under conditions of high GTP demand. Here we asked whether IMPDH2 is required in the highly proliferative context of regeneration, and whether its assembly into filaments takes place in regenerating tissue. We find that inhibition of IMPDH2 leads to impaired tail regeneration and reduced cell proliferation in the tadpole Xenopus tropicalis. Upon treatment with IMPDH inhibitors, we find that both endogenous and fluorescent fusions of IMPDH2 robustly assemble into filaments throughout the tadpole tail, and that the regenerating tail creates a sensitized condition for filament formation. These findings clarify the role of purine biosynthesis in regeneration and reveal that IMPDH2 enzyme filament formation is a biologically relevant mechanism of regulation in vertebrate regeneration.
    Keywords:  IMPDH2; Xenopus; enzyme filament; nucleotide metabolism; purine; regeneration
    DOI:  https://doi.org/10.1101/2024.07.29.605679
  17. Trends Endocrinol Metab. 2024 Aug 08. pii: S1043-2760(24)00197-8. [Epub ahead of print]
    Adapt and shape: metabolic features within the metastatic niche.
    Erica Pranzini, Luigi Ippolito, Elisa Pardella, Elisa Giannoni, Paola Chiarugi.
      The success of disseminating cancer cells (DTCs) at specific metastatic sites is influenced by several metabolic factors. Even before DTCs arrival, metabolic conditioning from the primary tumor participates in creating a favorable premetastatic niche at distant organs. In addition, DTCs adjust their metabolism to better survive along the metastatic journey and successfully colonize their ultimate destination. However, the idea that the environment of the target organs may metabolically impact the metastatic fate is often underestimated. Here, we review the coexistence of two distinct strategies by which cancer cells shape and/or adapt to the metabolic profile of colonized tissues, ultimately creating a proper soil for their seeding and proliferation.
    Keywords:  metabolic adaptation; metastatic niche; nutrient availability; organotropism; tissue metabolism
    DOI:  https://doi.org/10.1016/j.tem.2024.07.016
  18. Nat Commun. 2024 Aug 12. 15(1): 6891
    HMGA1 orchestrates chromatin compartmentalization and sequesters genes into 3D networks coordinating senescence heterogeneity.
    Ioana Olan, Masami Ando-Kuri, Aled J Parry, Tetsuya Handa, Stefan Schoenfelder, Peter Fraser, Yasuyuki Ohkawa, Hiroshi Kimura, Masako Narita, Masashi Narita.
      HMGA1 is an abundant non-histone chromatin protein that has been implicated in embryonic development, cancer, and cellular senescence, but its specific role remains elusive. Here, we combine functional genomics approaches with graph theory to investigate how HMGA1 genomic deposition controls high-order chromatin networks in an oncogene-induced senescence model. While the direct role of HMGA1 in gene activation has been described previously, we find little evidence to support this. Instead, we show that the heterogeneous linear distribution of HMGA1 drives a specific 3D chromatin organization. HMGA1-dense loci form highly interactive networks, similar to, but independent of, constitutive heterochromatic loci. This, coupled with the exclusion of HMGA1-poor chromatin regions, leads to coordinated gene regulation through the repositioning of genes. In the absence of HMGA1, the whole process is largely reversed, but many regulatory interactions also emerge, amplifying the inflammatory senescence-associated secretory phenotype. Such HMGA1-mediated fine-tuning of gene expression contributes to the heterogeneous nature of senescence at the single-cell level. A similar 'buffer' effect of HMGA1 on inflammatory signalling is also detected in lung cancer cells. Our study reveals a mechanism through which HMGA1 modulates chromatin compartmentalization and gene regulation in senescence and beyond.
    DOI:  https://doi.org/10.1038/s41467-024-51153-8
  19. J Biol Chem. 2024 Aug 09. pii: S0021-9258(24)02163-X. [Epub ahead of print] 107662
    Differential utilization of vitamin B12-dependent and independent pathways for propionate metabolism across human cells.
    Harsha Gouda, Yuanyuan Ji, Sneha Rath, David Watkins, David Rosenblatt, Vamsi Mootha, Jace W Jones, Ruma Banerjee.
      Propionic acid links the oxidation of branched-chain amino acids and odd-chain fatty acids to the TCA cycle. Gut microbes ferment complex fiber remnants, generating high concentrations of short chain fatty acids, acetate, propionate and butyrate, which are shared with the host as fuel sources. Analysis of vitamin B12-dependent propionate utilization in skin biopsy samples has been used to characterize and diagnose underlying inborn errors of cobalamin (or B12) metabolism. In these cells, the B12-dependent enzyme, methylmalonyl-CoA mutase (MMUT), plays a central role in funneling propionate to the TCA cycle intermediate, succinate. Our understanding of the fate of propionate in other cell types, specifically, the involvement of the β-oxidation-like and methylcitrate pathways, is limited. In this study, we have used [14C]-propionate tracing in combination with genetic ablation or inhibition of MMUT, to reveal the differential utilization of the B12-dependent and independent pathways for propionate metabolism in fibroblast versus colon cell lines. We demonstrate that itaconate can be used as a tool to investigate MMUT-dependent propionate metabolism in cultured cell lines. While MMUT gates the entry of propionate carbons into the TCA cycle in fibroblasts, colon-derived cell lines exhibit a quantitatively significant or exclusive reliance on the β-oxidation-like pathway. Lipidomics and metabolomics analyses reveal that propionate elicits pleiotropic changes, including an increase in odd-chain glycerophospholipids, and perturbations in the purine nucleotide cycle and arginine/nitric oxide metabolism. The metabolic rationale and the regulatory mechanisms underlying the differential reliance on propionate utilization pathways at a cellular, and possibly tissue level, warrant further elucidation.
    DOI:  https://doi.org/10.1016/j.jbc.2024.107662
  20. Nat Cell Biol. 2024 Aug 13.
    A fatty acid switch drives ferroptosis in EMT.
    Alina M Winkelkotte, Almut Schulze.
      
    DOI:  https://doi.org/10.1038/s41556-024-01483-y
  21. ACS Chem Biol. 2024 Aug 12.
    Mitochondrial Probe for Glutathione Depletion Reveals NME3 Essentiality for Mitochondrial Redox Response.
    Piriththiv Dhavarasa, Tanja Sack, Carmine P Cerrato, Ashley P Cheng, Yi Y Zhang, Kangfu Chen, Shana O Kelley.
      Maintenance of the mitochondrial thiol redox state is essential for cell survival. However, we lack a comprehensive understanding of the redox response to mitochondrial glutathione depletion. We developed a mitochondria-penetrating peptide, mtCDNB, to specifically deplete mitochondrial glutathione. A genome-wide CRISPR/Cas9 screen in tandem with mtCDNB treatment was employed to uncover regulators of the redox response to mitochondrial glutathione depletion. We identified nucleoside diphosphate kinase 3 (NME3) as a regulator of mitochondrial dynamics. We show that NME3 is recruited to the mitochondrial outer membrane when under redox stress. In the absence of NME3, there is impaired mitophagy, which leads to the accumulation of dysfunctional mitochondria. NME3 knockouts depleted of mitochondrial glutathione have increased mitochondrial ROS production, accumulate mtDNA lesions, and present a senescence-associated secretory phenotype. Our findings suggest a novel role for NME3 in selecting mitochondria for degradation through mitophagy under conditions of mitochondrial redox stress.
    DOI:  https://doi.org/10.1021/acschembio.4c00287
  22. J Cell Biol. 2024 Nov 04. pii: e202307035. [Epub ahead of print]223(11):
    Mitochondrial-derived compartments are multilamellar domains that encase membrane cargo and cytosol.
    Zachary N Wilson, Matt West, Alyssa M English, Greg Odorizzi, Adam L Hughes.
      Preserving the health of the mitochondrial network is critical to cell viability and longevity. To do so, mitochondria employ several membrane remodeling mechanisms, including the formation of mitochondrial-derived vesicles (MDVs) and compartments (MDCs) to selectively remove portions of the organelle. In contrast to well-characterized MDVs, the distinguishing features of MDC formation and composition remain unclear. Here, we used electron tomography to observe that MDCs form as large, multilamellar domains that generate concentric spherical compartments emerging from mitochondrial tubules at ER-mitochondria contact sites. Time-lapse fluorescence microscopy of MDC biogenesis revealed that mitochondrial membrane extensions repeatedly elongate, coalesce, and invaginate to form these compartments that encase multiple layers of membrane. As such, MDCs strongly sequester portions of the outer mitochondrial membrane, securing membrane cargo into a protected domain, while also enclosing cytosolic material within the MDC lumen. Collectively, our results provide a model for MDC formation and describe key features that distinguish MDCs from other previously identified mitochondrial structures and cargo-sorting domains.
    DOI:  https://doi.org/10.1083/jcb.202307035
  23. Cell. 2024 Aug 07. pii: S0092-8674(24)00824-9. [Epub ahead of print]
    Macrophage-mediated myelin recycling fuels brain cancer malignancy.
    Daan J Kloosterman, Johanna Erbani, Menno Boon, Martina Farber, Shanna M Handgraaf, Masami Ando-Kuri, Elena Sánchez-López, Bauke Fontein, Marjolijn Mertz, Marja Nieuwland, Ning Qing Liu, Gabriel Forn-Cuni, Nicole N van der Wel, Anita E Grootemaat, Luuk Reinalda, Sander I van Kasteren, Elzo de Wit, Brian Ruffell, Ewa Snaar-Jagalska, Kevin Petrecca, Dieta Brandsma, Alexander Kros, Martin Giera, Leila Akkari.
      Tumors growing in metabolically challenged environments, such as glioblastoma in the brain, are particularly reliant on crosstalk with their tumor microenvironment (TME) to satisfy their high energetic needs. To study the intricacies of this metabolic interplay, we interrogated the heterogeneity of the glioblastoma TME using single-cell and multi-omics analyses and identified metabolically rewired tumor-associated macrophage (TAM) subpopulations with pro-tumorigenic properties. These TAM subsets, termed lipid-laden macrophages (LLMs) to reflect their cholesterol accumulation, are epigenetically rewired, display immunosuppressive features, and are enriched in the aggressive mesenchymal glioblastoma subtype. Engulfment of cholesterol-rich myelin debris endows subsets of TAMs to acquire an LLM phenotype. Subsequently, LLMs directly transfer myelin-derived lipids to cancer cells in an LXR/Abca1-dependent manner, thereby fueling the heightened metabolic demands of mesenchymal glioblastoma. Our work provides an in-depth understanding of the immune-metabolic interplay during glioblastoma progression, thereby laying a framework to unveil targetable metabolic vulnerabilities in glioblastoma.
    Keywords:  cancer immunity; cholesterol; glioblastoma; lipid metabolism; macrophages; myelin recycling; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.cell.2024.07.030
  24. J Cell Biol. 2024 Oct 07. pii: e202304031. [Epub ahead of print]223(10):
    Dynamic interaction of REEP5-MFN1/2 enables mitochondrial hitchhiking on tubular ER.
    Shue Chen, Yang Sun, Yuling Qin, Lan Yang, Zhenhua Hao, Zhihao Xu, Mikael Björklund, Wei Liu, Zhi Hong.
      Mitochondrial functions can be regulated by membrane contact sites with the endoplasmic reticulum (ER). These mitochondria-ER contact sites (MERCs) are functionally heterogeneous and maintained by various tethers. Here, we found that REEP5, an ER tubule-shaping protein, interacts with Mitofusins 1/2 to mediate mitochondrial distribution throughout the cytosol by a new transport mechanism, mitochondrial "hitchhiking" with tubular ER on microtubules. REEP5 depletion led to reduced tethering and increased perinuclear localization of mitochondria. Conversely, increasing REEP5 expression facilitated mitochondrial distribution throughout the cytoplasm. Rapamycin-induced irreversible REEP5-MFN1/2 interaction led to mitochondrial hyperfusion, implying that the dynamic release of mitochondria from tethering is necessary for normal mitochondrial distribution and dynamics. Functionally, disruption of MFN2-REEP5 interaction dynamics by forced dimerization or silencing REEP5 modulated the production of mitochondrial reactive oxygen species (ROS). Overall, our results indicate that dynamic REEP5-MFN1/2 interaction mediates cytosolic distribution and connectivity of the mitochondrial network by "hitchhiking" and this process regulates mitochondrial ROS, which is vital for multiple physiological functions.
    DOI:  https://doi.org/10.1083/jcb.202304031
  25. bioRxiv. 2024 Jul 31. pii: 2024.07.30.605703. [Epub ahead of print]
    Unraveling cysteine deficiency-associated rapid weight loss.
    Alan Varghese, Ivan Gusarov, Begoña Gamallo-Lana, Daria Dolgonos, Yatin Mankan, Ilya Shamovsky, Mydia Phan, Rebecca Jones, Maria Gomez-Jenkins, Eileen White, Rui Wang, Drew Jones, Thales Papagiannakopoulos, Michael E Pacold, Adam C Mar, Dan R Littman, Evgeny Nudler.
      Forty percent of the US population and 1 in 6 individuals worldwide are obese, and the incidence of this disease is surging globally1,2. Various dietary interventions, including carbohydrate and fat restriction, and more recently amino acid restriction, have been explored to combat this epidemic3-6. We sought to investigate the impact of removing individual amino acids on the weight profiles of mice. Compared to essential amino acid restriction, induction of conditional cysteine restriction resulted in the most dramatic weight loss, amounting to 20% within 3 days and 30% within one week, which was readily reversed. This weight loss occurred despite the presence of substantial cysteine reserves stored in glutathione (GSH) across various tissues7. Further analysis demonstrated that the weight reduction primarily stemmed from an increase in the utilization of fat mass, while locomotion, circadian rhythm and histological appearance of multiple other tissues remained largely unaffected. Cysteine deficiency activated the integrated stress response (ISR) and NRF2-mediated oxidative stress response (OSR), which amplify each other, leading to the induction of GDF15 and FGF21, hormones associated with increased lipolysis, energy homeostasis and food aversion8-10. We additionally observed rapid tissue coenzyme A (CoA) depletion, resulting in energetically inefficient anaerobic glycolysis and TCA cycle, with sustained urinary excretion of pyruvate, orotate, citrate, α-ketoglutarate, nitrogen rich compounds and amino acids. In summary, our investigation highlights that cysteine restriction, by depleting GSH and CoA, exerts a maximal impact on weight loss, metabolism, and stress signaling compared to other amino acid restrictions. These findings may pave the way for innovative strategies for addressing a range of metabolic diseases and the growing obesity crisis.
    DOI:  https://doi.org/10.1101/2024.07.30.605703
  26. Proc Natl Acad Sci U S A. 2024 Aug 20. 121(34): e2405959121
    mTORC1 phosphorylates and stabilizes LST2 to negatively regulate EGFR.
    Stefania Battaglioni, Louise-Marie Craigie, Sofia Filippini, Timm Maier, Michael N Hall.
      TORC1 (target of rapamycin complex 1) is a highly conserved protein kinase that plays a central role in regulating cell growth. Given the role of mammalian TORC1 (mTORC1) in metabolism and disease, understanding mTORC1 downstream signaling and feedback loops is important. mTORC1 recognizes some of its substrates via a five amino acid binding sequence called the TOR signaling (TOS) motif. mTORC1 binding to a TOS motif facilitates phosphorylation of a distinct, distal site. Here, we show that LST2, also known as ZFYVE28, contains a TOS motif (amino acids 401 to 405) and is directly phosphorylated by mTORC1 at serine 670 (S670). mTORC1-mediated S670 phosphorylation promotes LST2 monoubiquitination on lysine 87 (K87). Monoubiquitinated LST2 is stable and displays a broad reticular distribution. When mTORC1 is inactive, unphosphorylated LST2 is degraded by the proteasome. The absence of LST2 enhances EGFR (epidermal growth factor receptor) signaling. We propose that mTORC1 negatively feeds back on its upstream receptor EGFR via LST2.
    Keywords:  LST2; TOS motif; mTOR signaling; negative feedback; phosphorylation substrate
    DOI:  https://doi.org/10.1073/pnas.2405959121
  27. Nat Metab. 2024 Aug 12.
    Ketogenic diet reshapes cancer metabolism through lysine β-hydroxybutyrylation.
    Junhong Qin, Xinhe Huang, Shengsong Gou, Sitao Zhang, Yujie Gou, Qian Zhang, Hongyu Chen, Lin Sun, Miaomiao Chen, Dan Liu, Cheng Han, Min Tang, Zihao Feng, Shenghui Niu, Lin Zhao, Yingfeng Tu, Zexian Liu, Weimin Xuan, Lunzhi Dai, Da Jia, Yu Xue.
      Lysine β-hydroxybutyrylation (Kbhb) is a post-translational modification induced by the ketogenic diet (KD), a diet showing therapeutic effects on multiple human diseases. Little is known how cellular processes are regulated by Kbhb. Here we show that protein Kbhb is strongly affected by the KD through a multi-omics analysis of mouse livers. Using a small training dataset with known functions, we developed a bioinformatics method for the prediction of functionally important lysine modification sites (pFunK), which revealed functionally relevant Kbhb sites on various proteins, including aldolase B (ALDOB) Lys108. KD consumption or β-hydroxybutyrate supplementation in hepatocellular carcinoma cells increases ALDOB Lys108bhb and inhibits the enzymatic activity of ALDOB. A Kbhb-mimicking mutation (p.Lys108Gln) attenuates ALDOB activity and its binding to substrate fructose-1,6-bisphosphate, inhibits mammalian target of rapamycin signalling and glycolysis, and markedly suppresses cancer cell proliferation. Our study reveals a critical role of Kbhb in regulating cancer cell metabolism and provides a generally applicable algorithm for predicting functionally important lysine modification sites.
    DOI:  https://doi.org/10.1038/s42255-024-01093-w
  28. Nat Metab. 2024 Aug 09.
    Broad-spectrum antibiotics disrupt homeostatic efferocytosis.
    Pedro H V Saavedra, Alissa J Trzeciak, Allie Lipshutz, Andrew W Daman, Anya J O'Neal, Zong-Lin Liu, Zhaoquan Wang, Jesús E Romero-Pichardo, Waleska Saitz Rojas, Giulia Zago, Marcel R M van den Brink, Steven Z Josefowicz, Christopher D Lucas, Christopher J Anderson, Alexander Y Rudensky, Justin S A Perry.
      The clearance of apoptotic cells, termed efferocytosis, is essential for tissue homeostasis and prevention of autoimmunity1. Although past studies have elucidated local molecular signals that regulate homeostatic efferocytosis in a tissue2,3, whether signals arising distally also regulate homeostatic efferocytosis remains elusive. Here, we show that large peritoneal macrophage (LPM) display impairs efferocytosis in broad-spectrum antibiotics (ABX)-treated, vancomycin-treated and germ-free mice in vivo, all of which have a depleted gut microbiota. Mechanistically, the microbiota-derived short-chain fatty acid butyrate directly boosts efferocytosis efficiency and capacity in mouse and human macrophages, and rescues ABX-induced LPM efferocytosis defects in vivo. Bulk messenger RNA sequencing of butyrate-treated macrophages in vitro and single-cell messenger RNA sequencing of LPMs isolated from ABX-treated and butyrate-rescued mice reveals regulation of efferocytosis-supportive transcriptional programmes. Specifically, we find that the efferocytosis receptor T cell immunoglobulin and mucin domain containing 4 (TIM-4, Timd4) is downregulated in LPMs of ABX-treated mice but rescued by oral butyrate. We show that TIM-4 is required for the butyrate-induced enhancement of LPM efferocytosis capacity and that LPM efferocytosis is impaired beyond withdrawal of ABX. ABX-treated mice exhibit significantly worse disease in a mouse model of lupus. Our results demonstrate that homeostatic efferocytosis relies on distal metabolic signals and suggest that defective homeostatic efferocytosis may explain the link between ABX use and inflammatory disease4-7.
    DOI:  https://doi.org/10.1038/s42255-024-01107-7
  29. Nat Metab. 2024 Aug 14.
    S-acylation of ATGL is required for lipid droplet homoeostasis in hepatocytes.
    Yuping Zheng, Jishun Chen, Vinitha Macwan, Charneal L Dixon, Xinran Li, Shengjie Liu, Yuyun Yu, Pinglong Xu, Qiming Sun, Qi Hu, Wei Liu, Brian Raught, Gregory D Fairn, Dante Neculai.
      Lipid droplets (LDs) are organelles specialized in the storage of neutral lipids, cholesterol esters and triglycerides, thereby protecting cells from the toxicity of excess lipids while allowing for the mobilization of lipids in times of nutrient deprivation. Defects in LD function are associated with many diseases. S-acylation mediated by zDHHC acyltransferases modifies thousands of proteins, yet the physiological impact of this post-translational modification on individual proteins is poorly understood. Here, we show that zDHHC11 regulates LD catabolism by modifying adipose triacylglyceride lipase (ATGL), the rate-limiting enzyme of lipolysis, both in hepatocyte cultures and in mice. zDHHC11 S-acylates ATGL at cysteine 15. Preventing the S-acylation of ATGL renders it catalytically inactive despite proper localization. Overexpression of zDHHC11 reduces LD size, whereas its elimination enlarges LDs. Mutating ATGL cysteine 15 phenocopies zDHHC11 loss, causing LD accumulation, defective lipolysis and lipophagy. Our results reveal S-acylation as a mode of regulation of ATGL function and LD homoeostasis. Modulating this pathway may offer therapeutic potential for treating diseases linked to defective lipolysis, such as fatty liver disease.
    DOI:  https://doi.org/10.1038/s42255-024-01085-w
  30. Proc Natl Acad Sci U S A. 2024 Aug 20. 121(34): e2404738121
    Circadian period is compensated for repressor protein turnover rates in single cells.
    Christian H Gabriel, Marta Del Olmo, Arunya Rizki Widini, Rashin Roshanbin, Jonas Woyde, Ebrahim Hamza, Nica-Nicoleta Gutu, Amin Zehtabian, Helge Ewers, Adrian Granada, Hanspeter Herzel, Achim Kramer.
      Most mammalian cells have molecular circadian clocks that generate widespread rhythms in transcript and protein abundance. While circadian clocks are robust to fluctuations in the cellular environment, little is known about the mechanisms by which the circadian period compensates for fluctuating metabolic states. Here, we exploit the heterogeneity of single cells both in circadian period and a metabolic parameter-protein stability-to study their interdependence without the need for genetic manipulation. We generated cells expressing key circadian proteins (CRYPTOCHROME1/2 (CRY1/2) and PERIOD1/2 (PER1/2)) as endogenous fusions with fluorescent proteins and simultaneously monitored circadian rhythms and degradation in thousands of single cells. We found that the circadian period compensates for fluctuations in the turnover rates of circadian repressor proteins and uncovered possible mechanisms using a mathematical model. In addition, the stabilities of the repressor proteins are circadian phase dependent and correlate with the circadian period in a phase-dependent manner, in contrast to the prevailing model.
    Keywords:  circadian rhythms; fluorescence microscopy; metabolic compensation; protein degradation; single-cell imaging
    DOI:  https://doi.org/10.1073/pnas.2404738121
  31. Curr Biol. 2024 Aug 05. pii: S0960-9822(24)00954-0. [Epub ahead of print]
    Suprachiasmatic nucleus VIPergic fibers show a circadian rhythm of expansion and retraction.
    Alexandra F Neitz, Bryn M Carter, M Fernanda Ceriani, Mark H Ellisman, Horacio O de la Iglesia.
      In animals, overt circadian rhythms of physiology and behavior are centrally regulated by a circadian clock located in specific brain regions. In the fruit fly Drosophila and in mammals, these clocks rely on single-cell oscillators, but critical for their function as central circadian pacemakers are network properties that change dynamically throughout the circadian cycle as well as in response to environmental stimuli.1,2,3 In the fly, this plasticity involves circadian rhythms of expansion and retraction of clock neuron fibers.4,5,6,7,8,9,10,11,12,13,14 Whether these drastic structural changes are a universal property of central neuronal pacemakers is unknown. To address this question, we studied neurons of the mouse suprachiasmatic nucleus (SCN) that express vasoactive intestinal polypeptide (VIP), which are critical for the SCN to function as a central circadian pacemaker. By targeting the expression of the fluorescent protein tdTomato to these neurons and using tissue clearing techniques to visualize all SCN VIPergic neurons and their fibers, we show that, similar to clock neurons in the fly, VIPergic fibers undergo a daily rhythm of expansion and retraction, with maximal branching during the day. This rhythm is circadian, as it persists under constant environmental conditions and is present in both males and females. We propose that circadian structural remodeling of clock neurons represents a key feature of central circadian pacemakers that is likely critical to regulate network properties, the response to environmental stimuli, and the regulation of circadian outputs.
    Keywords:  circadian plasticity; circadian remodeling; neuronal plasticity; neuronal structural plasticity
    DOI:  https://doi.org/10.1016/j.cub.2024.07.051
  32. Nature. 2024 Aug 14.
    Remodelling of the translatome controls diet and its impact on tumorigenesis.
    Haojun Yang, Vincenzo Andrea Zingaro, James Lincoff, Harrison Tom, Satoshi Oikawa, Juan A Oses-Prieto, Quinn Edmondson, Ian Seiple, Hardik Shah, Shingo Kajimura, Alma L Burlingame, Michael Grabe, Davide Ruggero.
      Fasting is associated with a range of health benefits1-6. How fasting signals elicit changes in the proteome to establish metabolic programmes remains poorly understood. Here we show that hepatocytes selectively remodel the translatome while global translation is paradoxically downregulated during fasting7,8. We discover that phosphorylation of eukaryotic translation initiation factor 4E (P-eIF4E) is induced during fasting. We show that P-eIF4E is responsible for controlling the translation of genes involved in lipid catabolism and the production of ketone bodies. Inhibiting P-eIF4E impairs ketogenesis in response to fasting and a ketogenic diet. P-eIF4E regulates those messenger RNAs through a specific translation regulatory element within their 5' untranslated regions (5' UTRs). Our findings reveal a new signalling property of fatty acids, which are elevated during fasting. We found that fatty acids bind and induce AMP-activated protein kinase (AMPK) kinase activity that in turn enhances the phosphorylation of MAP kinase-interacting protein kinase (MNK), the kinase that phosphorylates eIF4E. The AMPK-MNK-eIF4E axis controls ketogenesis, revealing a new lipid-mediated kinase signalling pathway that links ketogenesis to translation control. Certain types of cancer use ketone bodies as an energy source9,10 that may rely on P-eIF4E. Our findings reveal that on a ketogenic diet, treatment with eFT508 (also known as tomivosertib; a P-eIF4E inhibitor) restrains pancreatic tumour growth. Thus, our findings unveil a new fatty acid-induced signalling pathway that activates selective translation, which underlies ketogenesis and provides a tailored diet intervention therapy for cancer.
    DOI:  https://doi.org/10.1038/s41586-024-07781-7
  33. Br J Cancer. 2024 Aug 14.
    Deregulation of mitochondrial gene expression in cancer: mechanisms and therapeutic opportunities.
    Mariah J Berner, Steven W Wall, Gloria V Echeverria.
      "Reprogramming of energy metabolism" was first considered an emerging hallmark of cancer in 2011 by Hanahan & Weinberg and is now considered a core hallmark of cancer. Mitochondria are the hubs of metabolism, crucial for energetic functions and cellular homeostasis. The mitochondrion's bacterial origin and preservation of their own genome, which encodes proteins and RNAs essential to their function, make them unique organelles. Successful generation of mitochondrial gene products requires coordinated functioning of the mitochondrial 'central dogma,' encompassing all steps necessary for mtDNA to yield mitochondrial proteins. Each of these processes has several levels of regulation, including mtDNA accessibility and protection through mtDNA packaging and epigenetic modifications, mtDNA copy number through mitochondrial replication, mitochondrial transcription through mitochondrial transcription factors, and mitochondrial translation through mitoribosome formation. Deregulation of these mitochondrial processes in the context of cancers has only recently been appreciated, with most studies being correlative in nature. Nonetheless, numerous significant associations of the mitochondrial central dogma with pro-tumor phenotypes have been documented. Several studies have even provided mechanistic insights and further demonstrated successful pharmacologic targeting strategies. Based on the emergent importance of mitochondria for cancer biology and therapeutics, it is becoming increasingly important that we gain an understanding of the underpinning mechanisms so they can be successfully therapeutically targeted. It is expected that this mechanistic understanding will result in mitochondria-targeting approaches that balance anticancer potency with normal cell toxicity. This review will focus on current evidence for the dysregulation of mitochondrial gene expression in cancers, as well as therapeutic opportunities on the horizon.
    DOI:  https://doi.org/10.1038/s41416-024-02817-1
  34. Cell Mol Immunol. 2024 Aug 12.
    The influence of metabolic disorders on adaptive immunity.
    Thomas J C Collins, Pooranee K Morgan, Kevin Man, Graeme I Lancaster, Andrew J Murphy.
      The immune system plays a crucial role in protecting the body from invading pathogens and maintaining tissue homoeostasis. Maintaining homoeostatic lipid metabolism is an important aspect of efficient immune cell function and when disrupted immune cell function is impaired. There are numerous metabolic diseases whereby systemic lipid metabolism and cellular function is impaired. In the context of metabolic disorders, chronic inflammation is suggested to be a major contributor to disease progression. A major contributor to tissue dysfunction in metabolic disease is ectopic lipid deposition, which is generally caused by diet and genetic factors. Thus, we propose the idea, that similar to tissue and organ damage in metabolic disorders, excessive accumulation of lipid in immune cells promotes a dysfunctional immune system (beyond the classical foam cell) and contributes to disease pathology. Herein, we review the evidence that lipid accumulation through diet can modulate the production and function of immune cells by altering cellular lipid content. This can impact immune cell signalling, activation, migration, and death, ultimately affecting key aspects of the immune system such as neutralising pathogens, antigen presentation, effector cell activation and resolving inflammation.
    Keywords:  Cancer; Cell Metabolism; Immunity; Immunometabolism; Lipid Metabolism; Metabolic Disorders
    DOI:  https://doi.org/10.1038/s41423-024-01206-1
  35. Mol Cell. 2024 Aug 05. pii: S1097-2765(24)00617-8. [Epub ahead of print]
    Molecular impact of mutations in RNA splicing factors in cancer.
    Qian Zhang, Yuxi Ai, Omar Abdel-Wahab.
      Somatic mutations in genes encoding components of the RNA splicing machinery occur frequently in multiple forms of cancer. The most frequently mutated RNA splicing factors in cancer impact intronic branch site and 3' splice site recognition. These include mutations in the core RNA splicing factor SF3B1 as well as mutations in the U2AF1/2 heterodimeric complex, which recruits the SF3b complex to the 3' splice site. Additionally, mutations in splicing regulatory proteins SRSF2 and RBM10 are frequent in cancer, and there has been a recent suggestion that variant forms of small nuclear RNAs (snRNAs) may contribute to splicing dysregulation in cancer. Here, we describe molecular mechanisms by which mutations in these factors alter splice site recognition and how studies of this process have yielded new insights into cancer pathogenesis and the molecular regulation of splicing. We also discuss data linking mutant RNA splicing factors to RNA metabolism beyond splicing.
    Keywords:  RBM10; RNA; SF3B1; SRSF2; SUGP1; U2AF1; ZRSR2; introns; spliceosome; splicing
    DOI:  https://doi.org/10.1016/j.molcel.2024.07.019
  36. Cell Death Discov. 2024 Aug 13. 10(1): 363
    MDH2 regulates the sensitivity of clear cell renal cell carcinoma to ferroptosis through its interaction with FSP1.
    Baijie Feng, Wei Su, Xianzhi Guo, Tingting Ding, Yingchun Duan, Lina Hu, Minghua Yu.
      Malate dehydrogenase 2 is a pivotal enzyme in the tricarboxylic acid cycle. Recent studies have highlighted the significant involvement of MDH2 in the pathogenesis and progression of diverse types of tumors, yet its precise mechanistic underpinnings remain elusive. This study revealed a significant decrease in MDH2 expression in renal cancer tissues. And knocking out MDH2 was observed to hinder the proliferation of normal renal tubular epithelial cells but notably enhance the proliferation of ccRCC. Furthermore, mechanistically, we found that MDH2 inhibits the proliferation of ccRCC by promoting ferroptosis, while enhancing the sensitivity of ccRCC to ferroptosis inducers, promoting lipid peroxidation. We also demonstrated that MDH2 regulates the ubiquitination of FSP1 through protein-protein interactions, leading to a decrease in FSP1 protein levels and maintaining high sensitivity of ccRCC to ferroptosis. In conclusion, our study demonstrates that the reduced MDH2 expression in ccRCC results in increased expression of FSP1, thereby reducing its sensitivity to ferroptosis. It unveils a non-metabolic role for the downregulation of MDH2 in ccRCC progression.
    DOI:  https://doi.org/10.1038/s41420-024-02137-6
  37. Proc Natl Acad Sci U S A. 2024 Aug 20. 121(34): e2403392121
    MAVS Cys508 palmitoylation promotes its aggregation on the mitochondrial outer membrane and antiviral innate immunity.
    Yinong Liu, Dan Hou, Wenzhe Chen, Xuan Lu, Garrison P Komaniecki, Yilai Xu, Tao Yu, Sophia M Zhang, Maurine E Linder, Hening Lin.
      Cysteine palmitoylation or S-palmitoylation catalyzed by the ZDHHC family of acyltransferases regulates the biological function of numerous mammalian proteins as well as viral proteins. However, understanding of the role of S-palmitoylation in antiviral immunity against RNA viruses remains very limited. The adaptor protein MAVS forms functionally essential prion-like aggregates upon activation by viral RNA-sensing RIG-I-like receptors. Here, we identify that MAVS, a C-terminal tail-anchored mitochondrial outer membrane protein, is S-palmitoylated by ZDHHC7 at Cys508, a residue adjacent to the tail-anchor transmembrane helix. Using superresolution microscopy and other biochemical techniques, we found that the mitochondrial localization of MAVS at resting state mainly depends on its transmembrane tail-anchor, without regulation by Cys508 S-palmitoylation. However, upon viral infection, MAVS S-palmitoylation stabilizes its aggregation on the mitochondrial outer membrane and thus promotes subsequent propagation of antiviral signaling. We further show that inhibition of MAVS S-palmitoylation increases the host susceptibility to RNA virus infection, highlighting the importance of S-palmitoylation in the antiviral innate immunity. Also, our results indicate ZDHHC7 as a potential therapeutic target for MAVS-related autoimmune diseases.
    Keywords:  MAVS; ZDHHC7; antiviral innate immunity; palmitoylation; tail-anchored proteins
    DOI:  https://doi.org/10.1073/pnas.2403392121
  38. NAR Genom Bioinform. 2024 Sep;6(3): lqae095
    Mitoclone2: an R package for elucidating clonal structure in single-cell RNA-sequencing data using mitochondrial variants.
    Benjamin Story, Lars Velten, Gregor Mönke, Ahrmad Annan, Lars Steinmetz.
      Clonal cell population dynamics play a critical role in both disease and development. Due to high mitochondrial mutation rates under both healthy and diseased conditions, mitochondrial genomic variability is a particularly useful resource in facilitating the identification of clonal population structure. Here we present mitoClone2, an all-inclusive R package allowing for the identification of clonal populations through integration of mitochondrial heteroplasmic variants discovered from single-cell sequencing experiments. Our package streamlines the investigation of this phenomenon by providing: built-in compatibility with commonly used tools for the delineation of clonal structure, the ability to directly use multiplexed BAM files as input, annotations for both human and mouse mitochondrial genomes, and helper functions for calling, filtering, clustering, and visualizing variants.
    DOI:  https://doi.org/10.1093/nargab/lqae095
  39. Nat Med. 2024 Aug 09.
    Single-nucleus chromatin accessibility and transcriptomic map of breast tissues of women of diverse genetic ancestry.
    Poornima Bhat-Nakshatri, Hongyu Gao, Aditi S Khatpe, Adedeji K Adebayo, Patrick C McGuire, Cihat Erdogan, Duojiao Chen, Guanglong Jiang, Felicia New, Rana German, Lydia Emmert, George Sandusky, Anna Maria Storniolo, Yunlong Liu, Harikrishna Nakshatri.
      Single-nucleus analysis allows robust cell-type classification and helps to establish relationships between chromatin accessibility and cell-type-specific gene expression. Here, using samples from 92 women of several genetic ancestries, we developed a comprehensive chromatin accessibility and gene expression atlas of the breast tissue. Integrated analysis revealed ten distinct cell types, including three major epithelial subtypes (luminal hormone sensing, luminal adaptive secretory precursor (LASP) and basal-myoepithelial), two endothelial and adipocyte subtypes, fibroblasts, T cells, and macrophages. In addition to the known cell identity genes FOXA1 (luminal hormone sensing), EHF and ELF5 (LASP), TP63 and KRT14 (basal-myoepithelial), epithelial subtypes displayed several uncharacterized markers and inferred gene regulatory networks. By integrating breast epithelial cell gene expression signatures with spatial transcriptomics, we identified gene expression and signaling differences between lobular and ductal epithelial cells and age-associated changes in signaling networks. LASP cells and fibroblasts showed genetic ancestry-dependent variability. An estrogen receptor-positive subpopulation of LASP cells with alveolar progenitor cell state was enriched in women of Indigenous American ancestry. Fibroblasts from breast tissues of women of African and European ancestry clustered differently, with accompanying gene expression differences. Collectively, these data provide a vital resource for further exploring genetic ancestry-dependent variability in healthy breast biology.
    DOI:  https://doi.org/10.1038/s41591-024-03011-9
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