bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2024–03–10
forty-two papers selected by
Christian Frezza, Universität zu Köln
  1. Inhibition of mitochondrial folate metabolism drives differentiation through mTORC1 mediated purine sensing.
  2. The metabolic domestication syndrome of budding yeast.
  3. Regulation of urea cycle by reversible high-stoichiometry lysine succinylation.
  4. Carnosine facilitates lysosomal release of inhibitors of T cell surveillance.
  5. Lipid droplets and cellular lipid flux.
  6. The metabolism of melanin synthesis-From melanocytes to melanoma.
  7. NDUFS4 regulates cristae remodeling in diabetic kidney disease.
  8. Immunometabolic Maladaptations to the Tumor Microenvironment.
  9. Integrated stress response signaling acts as a metabolic sensor in fat tissues to regulate oocyte maturation and ovulation.
  10. Metabolic collaboration between cells in the tumor microenvironment has a negligible effect on tumor growth.
  11. Growth Signaling Networks Orchestrate Cancer Metabolic Networks.
  12. LPD-3 as a megaprotein brake for aging and insulin-mTOR signaling in C. elegans.
  13. Metabolic remodeling in cancer and senescence and its therapeutic implications.
  14. ISGylation of DRP1 closely balances other post-translational modifications to mediate mitochondrial fission.
  15. A mitochondrial NADPH-cholesterol axis regulates extracellular vesicle biogenesis to support hematopoietic stem cell fate.
  16. Dissection of a CTCF topological boundary uncovers principles of enhancer-oncogene regulation.
  17. Fatty acid oxidation fuels natural killer cell responses against infection and cancer.
  18. Mitochondrial DNA marks multiple sclerosis.
  19. Heme metabolism in non-erythroid cells.
  20. Hepatic malonyl-CoA synthesis restrains gluconeogenesis by suppressing fat oxidation, pyruvate carboxylation, and amino acid availability.
  21. Supercharging cancer-fighting T cells with lithium carbonate.
  22. Severely polarized extracellular acidity around tumour cells.
  23. Lactate dehydrogenase A regulates tumor-macrophage symbiosis to promote glioblastoma progression.
  24. Itaconate boosts malaria via induction of PD-L1.
  25. Psat1-generated α-ketoglutarate and glutamine promote muscle stem cell activation and regeneration.
  26. Glycerophosphodiesters inhibit lysosomal phospholipid catabolism in Batten disease.
  27. Futile lipid cycling: from biochemistry to physiology.
  28. Loss of WIPI4 in neurodegeneration causes autophagy-independent ferroptosis.
  29. RTF2 controls replication repriming and ribonucleotide excision at the replisome.
  30. The PP2A-like phosphatase Ppg1 mediates assembly of the Far complex to balance gluconeogenic outputs and enables adaptation to glucose depletion.
  31. Metabolic regulation of mRNA splicing.
  32. Vitamin A resolves lineage plasticity to orchestrate stem cell lineage choices.
  33. Mitochondrial ATP generation is more proteome efficient than glycolysis.
  34. Aerobic glycolysis comes with an enzyme cost but robustness gain.
  35. Aging-induced tRNAGlu-derived fragment impairs glutamate biosynthesis by targeting mitochondrial translation-dependent cristae organization.
  36. International consensus guidelines for the definition, detection, and interpretation of autophagy-dependent ferroptosis.
  37. Decoding chromatin states by proteomic profiling of nucleosome readers.
  38. How mitochondrial cristae illuminate the important role of oxygen during eukaryogenesis.
  39. ARID1A orchestrates SWI/SNF-mediated sequential binding of transcription factors with ARID1A loss driving pre-memory B cell fate and lymphomagenesis.
  40. Two ancient membrane pores mediate mitochondrial-nucleus membrane contact sites.
  41. Age-related ciliopathy: Obesogenic shortening of melanocortin-4 receptor-bearing neuronal primary cilia.
  42. A comprehensive model for the biochemistry of ageing, senescence and longevity.
  1. Nat Commun. 2024 Mar 02. 15(1): 1931
    Inhibition of mitochondrial folate metabolism drives differentiation through mTORC1 mediated purine sensing.
    Martha M Zarou, Kevin M Rattigan, Daniele Sarnello, Engy Shokry, Amy Dawson, Angela Ianniciello, Karen Dunn, Mhairi Copland, David Sumpton, Alexei Vazquez, G Vignir Helgason.
      Supporting cell proliferation through nucleotide biosynthesis is an essential requirement for cancer cells. Hence, inhibition of folate-mediated one carbon (1C) metabolism, which is required for nucleotide synthesis, has been successfully exploited in anti-cancer therapy. Here, we reveal that mitochondrial folate metabolism is upregulated in patient-derived leukaemic stem cells (LSCs). We demonstrate that inhibition of mitochondrial 1C metabolism through impairment of de novo purine synthesis has a cytostatic effect on chronic myeloid leukaemia (CML) cells. Consequently, changes in purine nucleotide levels lead to activation of AMPK signalling and suppression of mTORC1 activity. Notably, suppression of mitochondrial 1C metabolism increases expression of erythroid differentiation markers. Moreover, we find that increased differentiation occurs independently of AMPK signalling and can be reversed through reconstitution of purine levels and reactivation of mTORC1. Of clinical relevance, we identify that combination of 1C metabolism inhibition with imatinib, a frontline treatment for CML patients, decreases the number of therapy-resistant CML LSCs in a patient-derived xenograft model. Our results highlight a role for folate metabolism and purine sensing in stem cell fate decisions and leukaemogenesis.
    DOI:  https://doi.org/10.1038/s41467-024-46114-0
  2. Proc Natl Acad Sci U S A. 2024 Mar 12. 121(11): e2313354121
    The metabolic domestication syndrome of budding yeast.
    Roland Tengölics, Balázs Szappanos, Michael Mülleder, Dorottya Kalapis, Gábor Grézal, Csilla Sajben, Federica Agostini, João Benhur Mokochinski, Balázs Bálint, László G Nagy, Markus Ralser, Balázs Papp.
      Cellular metabolism evolves through changes in the structure and quantitative states of metabolic networks. Here, we explore the evolutionary dynamics of metabolic states by focusing on the collection of metabolite levels, the metabolome, which captures key aspects of cellular physiology. Using a phylogenetic framework, we profiled metabolites in 27 populations of nine budding yeast species, providing a graduated view of metabolic variation across multiple evolutionary time scales. Metabolite levels evolve more rapidly and independently of changes in the metabolic network's structure, providing complementary information to enzyme repertoire. Although metabolome variation accumulates mainly gradually over time, it is profoundly affected by domestication. We found pervasive signatures of convergent evolution in the metabolomes of independently domesticated clades of Saccharomyces cerevisiae. Such recurring metabolite differences between wild and domesticated populations affect a substantial part of the metabolome, including rewiring of the TCA cycle and several amino acids that influence aroma production, likely reflecting adaptation to human niches. Overall, our work reveals previously unrecognized diversity in central metabolism and the pervasive influence of human-driven selection on metabolite levels in yeasts.
    Keywords:  Saccharomyces cerevisiae; convergent evolution; domestication; metabolomics; phylogenetic comparative methods
    DOI:  https://doi.org/10.1073/pnas.2313354121
  3. Nat Metab. 2024 Mar 06.
    Regulation of urea cycle by reversible high-stoichiometry lysine succinylation.
    Ran Zhang, Jingqi Fang, Xueshu Xie, Chris Carrico, Jesse G Meyer, Lei Wei, Joanna Bons, Jacob Rose, Rebeccah Riley, Ryan Kwok, Prasanna Vadhana Ashok Kumaar, Yini Zhang, Wenjuan He, Yuya Nishida, Xiaojing Liu, Jason W Locasale, Birgit Schilling, Eric Verdin.
      The post-translational modification lysine succinylation is implicated in the regulation of various metabolic pathways. However, its biological relevance remains uncertain due to methodological difficulties in determining high-impact succinylation sites. Here, using stable isotope labelling and data-independent acquisition mass spectrometry, we quantified lysine succinylation stoichiometries in mouse livers. Despite the low overall stoichiometry of lysine succinylation, several high-stoichiometry sites were identified, especially upon deletion of the desuccinylase SIRT5. In particular, multiple high-stoichiometry lysine sites identified in argininosuccinate synthase (ASS1), a key enzyme in the urea cycle, are regulated by SIRT5. Mutation of the high-stoichiometry lysine in ASS1 to succinyl-mimetic glutamic acid significantly decreased its enzymatic activity. Metabolomics profiling confirms that SIRT5 deficiency decreases urea cycle activity in liver. Importantly, SIRT5 deficiency compromises ammonia tolerance, which can be reversed by the overexpression of wild-type, but not succinyl-mimetic, ASS1. Therefore, lysine succinylation is functionally important in ammonia metabolism.
    DOI:  https://doi.org/10.1038/s42255-024-01005-y
  4. Cell Metab. 2024 Mar 05. pii: S1550-4131(24)00049-4. [Epub ahead of print]36(3): 461-462
    Carnosine facilitates lysosomal release of inhibitors of T cell surveillance.
    Pawel Swietach, Marja Jäättelä, Shari Pillon-Thomas, Ebbe Boedtkjer.
      Cancer metabolism produces large fluxes of lactate and H+, which are extruded by membrane transporters. However, H+ production and extrusion must be coupled by diffusion, facilitated by mobile buffers. Yan et al. propose that carnosine, generated by CARNS2, provides this mobile buffering and enables lysosomal functions that block T cell surveillance.
    DOI:  https://doi.org/10.1016/j.cmet.2024.02.003
  5. Nat Cell Biol. 2024 Mar 07.
    Lipid droplets and cellular lipid flux.
    Alyssa J Mathiowetz, James A Olzmann.
      Lipid droplets are dynamic organelles that store neutral lipids, serve the metabolic needs of cells, and sequester lipids to prevent lipotoxicity and membrane damage. Here we review the current understanding of the mechanisms of lipid droplet biogenesis and turnover, the transfer of lipids and metabolites at membrane contact sites, and the role of lipid droplets in regulating fatty acid flux in lipotoxicity and cell death.
    DOI:  https://doi.org/10.1038/s41556-024-01364-4
  6. Pigment Cell Melanoma Res. 2024 Mar 06.
    The metabolism of melanin synthesis-From melanocytes to melanoma.
    Marelize Snyman, Rachel Elizabeth Walsdorf, Sophia Nicole Wix, Jennifer Gibson Gill.
      Melanin synthesis involves the successful coordination of metabolic pathways across multiple intracellular compartments including the melanosome, mitochondria, ER/Golgi, and cytoplasm. While pigment production offers a communal protection from UV damage, the process also requires anabolic and redox demands that must be carefully managed by melanocytes. In this report we provide an updated review on melanin metabolism, including recent data leveraging new techniques, and technologies in the field of metabolism. We also discuss the many aspects of melanin synthesis that intersect with metabolic pathways known to impact melanoma phenotypes and behavior. By reviewing the metabolism of melanin synthesis, we hope to highlight outstanding questions and opportunities for future research that could improve patient outcomes in pigmentary and oncologic disease settings.
    Keywords:  cancer metabolism; melanin; melanogenesis; melanoma; metabolism; pigment; reactive oxygen species; tyrosine
    DOI:  https://doi.org/10.1111/pcmr.13165
  7. Nat Commun. 2024 Mar 04. 15(1): 1965
    NDUFS4 regulates cristae remodeling in diabetic kidney disease.
    Koki Mise, Jianyin Long, Daniel L Galvan, Zengchun Ye, Guizhen Fan, Rajesh Sharma, Irina I Serysheva, Travis I Moore, Collene R Jeter, M Anna Zal, Motoo Araki, Jun Wada, Paul T Schumacker, Benny H Chang, Farhad R Danesh.
      The mitochondrial electron transport chain (ETC) is a highly adaptive process to meet metabolic demands of the cell, and its dysregulation has been associated with diverse clinical pathologies. However, the role and nature of impaired ETC in kidney diseases remains poorly understood. Here, we generate diabetic mice with podocyte-specific overexpression of Ndufs4, an accessory subunit of mitochondrial complex I, as a model investigate the role of ETC integrity in diabetic kidney disease (DKD). We find that conditional male mice with genetic overexpression of Ndufs4 exhibit significant improvements in cristae morphology, mitochondrial dynamics, and albuminuria. By coupling proximity labeling with super-resolution imaging, we also identify the role of cristae shaping protein STOML2 in linking NDUFS4 with improved cristae morphology. Together, we provide the evidence on the central role of NDUFS4 as a regulator of cristae remodeling and mitochondrial function in kidney podocytes. We propose that targeting NDUFS4 represents a promising approach to slow the progression of DKD.
    DOI:  https://doi.org/10.1038/s41467-024-46366-w
  8. Cold Spring Harb Perspect Med. 2024 Mar 04. pii: a041547. [Epub ahead of print]
    Immunometabolic Maladaptations to the Tumor Microenvironment.
    Emma S Hathaway, Erin Q Jennings, Jeffrey C Rathmell.
      Tumors consist of cancer cells and a wide range of tissue resident and infiltrating cell types. Tumor metabolism, however, has largely been studied on whole tumors or cancer cells and the metabolism of infiltrating immune cells remains poorly understood. It is now clear from a range of analyses and metabolite rescue studies that metabolic adaptations to the tumor microenvironment (TME) directly impede T-cell and macrophage effector functions. The drivers of metabolic adaptation to the TME and metabolic immune suppression include depletion of essential nutrients, accumulation of waste products or immune suppression metabolites, and metabolic signaling through altered posttranslational modifications. Each infiltrating immune cell subset differs, however, with specific metabolic requirements and adaptations that can be maladaptive for antitumor immunity. Here, we review T-cell and macrophage adaptation and metabolic immune suppression in solid tumors. Ultimately, understanding and addressing these challenges will improve cancer immunotherapy and adoptive chimeric antigen receptor T-cell therapies.
    DOI:  https://doi.org/10.1101/cshperspect.a041547
  9. Cell Rep. 2024 Mar 06. pii: S2211-1247(24)00191-8. [Epub ahead of print]43(3): 113863
    Integrated stress response signaling acts as a metabolic sensor in fat tissues to regulate oocyte maturation and ovulation.
    Lydia Grmai, Manuel Michaca, Emily Lackner, Narayanan Nampoothiri V P, Deepika Vasudevan.
      Reproduction is an energy-intensive process requiring systemic coordination. However, the inter-organ signaling mechanisms that relay nutrient status to modulate reproductive output are poorly understood. Here, we use Drosophila melanogaster as a model to establish the integrated stress response (ISR) transcription factor, Atf4, as a fat tissue metabolic sensor that instructs oogenesis. We demonstrate that Atf4 regulates lipase activity to mediate yolk lipoprotein synthesis in the fat body. Depletion of Atf4 in the fat body also blunts oogenesis recovery after amino acid deprivation and re-feeding, suggestive of a nutrient-sensing role for Atf4. We also discovered that Atf4 promotes secretion of a fat-body-derived neuropeptide, CNMamide, which modulates neural circuits that promote egg-laying behavior (ovulation). Thus, we posit that ISR signaling in fat tissue acts as a "metabolic sensor" that instructs female reproduction-directly by impacting yolk lipoprotein production and follicle maturation and systemically by regulating ovulation.
    Keywords:  Atf4; CNMa; CP: Cell biology; CP: Developmental biology; adipocyte; bmm; egg retention; integrated stress response; oogenesis; ovulation; yolk protein
    DOI:  https://doi.org/10.1016/j.celrep.2024.113863
  10. Innovation (Camb). 2024 Mar 04. 5(2): 100583
    Metabolic collaboration between cells in the tumor microenvironment has a negligible effect on tumor growth.
    Johan Gustafsson, Fariba Roshanzamir, Anders Hagnestål, Sagar M Patel, Oseeyi I Daudu, Donald F Becker, Jonathan L Robinson, Jens Nielsen.
      The tumor microenvironment is composed of a complex mixture of different cell types interacting under conditions of nutrient deprivation, but the metabolism therein is not fully understood due to difficulties in measuring metabolic fluxes and exchange of metabolites between different cell types in vivo. Genome-scale metabolic modeling enables estimation of such exchange fluxes as well as an opportunity to gain insight into the metabolic behavior of individual cell types. Here, we estimated the availability of nutrients and oxygen within the tumor microenvironment using concentration measurements from blood together with a metabolite diffusion model. In addition, we developed an approach to efficiently apply enzyme usage constraints in a comprehensive metabolic model of human cells. The combined modeling reproduced severe hypoxic conditions and the Warburg effect, and we found that limitations in enzymatic capacity contribute to cancer cells' preferential use of glutamine as a substrate to the citric acid cycle. Furthermore, we investigated the common hypothesis that some stromal cells are exploited by cancer cells to produce metabolites useful for the cancer cells. We identified over 200 potential metabolites that could support collaboration between cancer cells and cancer-associated fibroblasts, but when limiting to metabolites previously identified to participate in such collaboration, no growth advantage was observed. Our work highlights the importance of enzymatic capacity limitations for cell behaviors and exemplifies the utility of enzyme-constrained models for accurate prediction of metabolism in cells and tumor microenvironments.
    DOI:  https://doi.org/10.1016/j.xinn.2024.100583
  11. Cold Spring Harb Perspect Med. 2024 Mar 04. pii: a041543. [Epub ahead of print]
    Growth Signaling Networks Orchestrate Cancer Metabolic Networks.
    Brendan D Manning, Christian C Dibble.
      Normal cells grow and divide only when instructed to by signaling pathways stimulated by exogenous growth factors. A nearly ubiquitous feature of cancer cells is their capacity to grow independent of such signals, in an uncontrolled, cell-intrinsic manner. This property arises due to the frequent oncogenic activation of core growth factor signaling pathway components, including receptor tyrosine kinases, PI3K-AKT, RAS-RAF, mTORC1, and MYC, leading to the aberrant propagation of pro-growth signals independent of exogenous growth factors. The growth of both normal and cancer cells requires the acquisition of nutrients and their anabolic conversion to the primary macromolecules underlying biomass production (protein, nucleic acids, and lipids). The core growth factor signaling pathways exert tight regulation of these metabolic processes and the oncogenic activation of these pathways drive the key metabolic properties of cancer cells and tumors. Here, we review the molecular mechanisms through which these growth signaling pathways control and coordinate cancer metabolism.
    DOI:  https://doi.org/10.1101/cshperspect.a041543
  12. Cell Rep. 2024 Mar 05. pii: S2211-1247(24)00227-4. [Epub ahead of print]43(3): 113899
    LPD-3 as a megaprotein brake for aging and insulin-mTOR signaling in C. elegans.
    Taruna Pandey, Bingying Wang, Changnan Wang, Jenny Zu, Huichao Deng, Kang Shen, Goncalo Dias do Vale, Jeffrey G McDonald, Dengke K Ma.
      Insulin-mechanistic target of rapamycin (mTOR) signaling drives anabolic growth during organismal development; its late-life dysregulation contributes to aging and limits lifespans. Age-related regulatory mechanisms and functional consequences of insulin-mTOR remain incompletely understood. Here, we identify LPD-3 as a megaprotein that orchestrates the tempo of insulin-mTOR signaling during C. elegans aging. We find that an agonist insulin, INS-7, is drastically overproduced from early life and shortens lifespan in lpd-3 mutants. LPD-3 forms a bridge-like tunnel megaprotein to facilitate non-vesicular cellular lipid trafficking. Lipidomic profiling reveals increased hexaceramide species in lpd-3 mutants, accompanied by up-regulation of hexaceramide biosynthetic enzymes, including HYL-1. Reducing the abundance of HYL-1, insulin receptor/DAF-2 or mTOR/LET-363, normalizes INS-7 levels and rescues the lifespan of lpd-3 mutants. LPD-3 antagonizes SINH-1, a key mTORC2 component, and decreases expression with age. We propose that LPD-3 acts as a megaprotein brake for organismal aging and that its age-dependent decline restricts lifespan through the sphingolipid-hexaceramide and insulin-mTOR pathways.
    Keywords:  CP: Metabolism; CP: Molecular biology; Caenorhabditis elegans; IIS-mTOR; INS-7; LPD-3; aging; hexaceramide; hyperfunction; mitochondrial pathway; molecular damages; sphingolipid
    DOI:  https://doi.org/10.1016/j.celrep.2024.113899
  13. Trends Endocrinol Metab. 2024 Mar 06. pii: S1043-2760(24)00037-7. [Epub ahead of print]
    Metabolic remodeling in cancer and senescence and its therapeutic implications.
    Yeonju Kim, Yeji Jang, Mi-Sung Kim, Chanhee Kang.
      Cellular metabolism is a flexible and plastic network that often dictates physiological and pathological states of the cell, including differentiation, cancer, and aging. Recent advances in cancer metabolism represent a tremendous opportunity to treat cancer by targeting its altered metabolism. Interestingly, despite their stable growth arrest, senescent cells - a critical component of the aging process - undergo metabolic changes similar to cancer metabolism. A deeper understanding of the similarities and differences between these disparate pathological conditions will help identify which metabolic reprogramming is most relevant to the therapeutic liabilities of senescence. Here, we compare and contrast cancer and senescence metabolism and discuss how metabolic therapies can be established as a new modality of senotherapy for healthy aging.
    Keywords:  aging; cancer; metabolism; senescence; senotherapy
    DOI:  https://doi.org/10.1016/j.tem.2024.02.008
  14. Cell Death Dis. 2024 Mar 02. 15(3): 184
    ISGylation of DRP1 closely balances other post-translational modifications to mediate mitochondrial fission.
    Palamou Das, Oishee Chakrabarti.
      Dynamin related protein 1 (DRP1), a pivotal mitochondrial fission protein, is post-translationally modified by multiple mechanisms. Here we identify a new post-translational modification of DRP1 by the ubiquitin-like protein, interferon-stimulated gene 15 (ISG15). DRP1 ISGylation is mediated by ISG15 E3 ligase, HERC5; this promotes mitochondrial fission. DeISGylation of DRP1 however leads to hyperfusion. Heterologous expression of SARS-CoV2 PLpro, a deISGylating enzyme, results in similar mitochondrial filamentation, significant decrease in total DRP1 protein levels and efflux of mtDNA. We report that deISGylated DRP1 gets ubiquitylated and degraded by TRIM25, instead of PARKIN and MITOL. While the cytosolic pool of DRP1 is primarily ISGylated, both mitochondrial and cytosolic fractions may be ubiquitylated. It is known that phosphorylation of DRP1 at S616 residue regulates its mitochondrial localisation; we show that ISGylation of phospho-DRP1 (S616) renders fission competence at mitochondria. This is significant because DRP1 ISGylation affects its functionality and mitochondrial dynamics in Alzheimer's disease pathophysiology.
    DOI:  https://doi.org/10.1038/s41419-024-06543-7
  15. Cell Stem Cell. 2024 Mar 07. pii: S1934-5909(24)00047-X. [Epub ahead of print]31(3): 359-377.e10
    A mitochondrial NADPH-cholesterol axis regulates extracellular vesicle biogenesis to support hematopoietic stem cell fate.
    Massimo Bonora, Claudia Morganti, Nick van Gastel, Kyoko Ito, Enrica Calura, Ilaria Zanolla, Letizia Ferroni, Yang Zhang, Yookyung Jung, Gabriele Sales, Paolo Martini, Takahisa Nakamura, Francesco Massimo Lasorsa, Toren Finkel, Charles P Lin, Barbara Zavan, Paolo Pinton, Irene Georgakoudi, Chiara Romualdi, David T Scadden, Keisuke Ito.
      Mitochondrial fatty acid oxidation (FAO) is essential for hematopoietic stem cell (HSC) self-renewal; however, the mechanism by which mitochondrial metabolism controls HSC fate remains unknown. Here, we show that within the hematopoietic lineage, HSCs have the largest mitochondrial NADPH pools, which are required for proper HSC cell fate and homeostasis. Bioinformatic analysis of the HSC transcriptome, biochemical assays, and genetic inactivation of FAO all indicate that FAO-generated NADPH fuels cholesterol synthesis in HSCs. Interference with FAO disturbs the segregation of mitochondrial NADPH toward corresponding daughter cells upon single HSC division. Importantly, we have found that the FAO-NADPH-cholesterol axis drives extracellular vesicle (EV) biogenesis and release in HSCs, while inhibition of EV signaling impairs HSC self-renewal. These data reveal the existence of a mitochondrial NADPH-cholesterol axis for EV biogenesis that is required for hematopoietic homeostasis and highlight the non-stochastic nature of HSC fate determination.
    Keywords:  HSC self-renewal; NADPH; cholesterol; exosomes; extracellular vesicles; fate determination; fatty acid oxidation; hematopoietic stem cell; metabolism; mitochondria
    DOI:  https://doi.org/10.1016/j.stem.2024.02.004
  16. Mol Cell. 2024 Feb 28. pii: S1097-2765(24)00126-6. [Epub ahead of print]
    Dissection of a CTCF topological boundary uncovers principles of enhancer-oncogene regulation.
    Kyung Lock Kim, Gilbert J Rahme, Viraat Y Goel, Chadi A El Farran, Anders S Hansen, Bradley E Bernstein.
      Enhancer-gene communication is dependent on topologically associating domains (TADs) and boundaries enforced by the CCCTC-binding factor (CTCF) insulator, but the underlying structures and mechanisms remain controversial. Here, we investigate a boundary that typically insulates fibroblast growth factor (FGF) oncogenes but is disrupted by DNA hypermethylation in gastrointestinal stromal tumors (GISTs). The boundary contains an array of CTCF sites that enforce adjacent TADs, one containing FGF genes and the other containing ANO1 and its putative enhancers, which are specifically active in GIST and its likely cell of origin. We show that coordinate disruption of four CTCF motifs in the boundary fuses the adjacent TADs, allows the ANO1 enhancer to contact FGF3, and causes its robust induction. High-resolution micro-C maps reveal specific contact between transcription initiation sites in the ANO1 enhancer and FGF3 promoter that quantitatively scales with FGF3 induction such that modest changes in contact frequency result in strong changes in expression, consistent with a causal relationship.
    Keywords:  ANO1; CTCF insulator; DNA methylation; FGF3; FGF4; SDH deficiency; chromatin; enhancer regulation; gastrointestinal stromal tumor; genome topology
    DOI:  https://doi.org/10.1016/j.molcel.2024.02.007
  17. Proc Natl Acad Sci U S A. 2024 Mar 12. 121(11): e2319254121
    Fatty acid oxidation fuels natural killer cell responses against infection and cancer.
    Sam Sheppard, Katja Srpan, Wendy Lin, Mariah Lee, Rebecca B Delconte, Mark Owyong, Peter Carmeliet, Daniel M Davis, Joao B Xavier, Katharine C Hsu, Joseph C Sun.
      Natural killer (NK) cells are a vital part of the innate immune system capable of rapidly clearing mutated or infected cells from the body and promoting an immune response. Here, we find that NK cells activated by viral infection or tumor challenge increase uptake of fatty acids and their expression of carnitine palmitoyltransferase I (CPT1A), a critical enzyme for long-chain fatty acid oxidation. Using a mouse model with an NK cell-specific deletion of CPT1A, combined with stable 13C isotope tracing, we observe reduced mitochondrial function and fatty acid-derived aspartate production in CPT1A-deficient NK cells. Furthermore, CPT1A-deficient NK cells show reduced proliferation after viral infection and diminished protection against cancer due to impaired actin cytoskeleton rearrangement. Together, our findings highlight that fatty acid oxidation promotes NK cell metabolic resilience, processes that can be optimized in NK cell-based immunotherapies.
    Keywords:  NK cells; T cells; cancer; metabolism; virus infection
    DOI:  https://doi.org/10.1073/pnas.2319254121
  18. Nat Rev Neurol. 2024 Mar 05.
    Mitochondrial DNA marks multiple sclerosis.
    Ian Fyfe.
      
    DOI:  https://doi.org/10.1038/s41582-024-00948-w
  19. J Biol Chem. 2024 Mar 01. pii: S0021-9258(24)01627-2. [Epub ahead of print] 107132
    Heme metabolism in non-erythroid cells.
    Luke S Dunaway, Skylar A Loeb, Sara Petrillo, Emanuela Tolosano, Brant E Isakson.
      Heme is an iron-containing prosthetic group necessary for the function of several proteins termed "hemoproteins". Erythrocytes contain most of the body's heme in the form of hemoglobin and contain high concentrations of free heme. In non-erythroid cells, where cytosolic heme concentrations are 2-3 orders of magnitude lower, heme plays an essential and often overlooked role in a variety of cellular processes. Indeed, hemoproteins are found in almost every subcellular compartment and are integral in cellular operations such as oxidative phosphorylation, amino acid metabolism, xenobiotic metabolism, and transcriptional regulation. Growing evidence reveals the participation of heme in dynamic processes such as circadian rhythms, NO signaling, and the modulation of enzyme activity. This dynamic view of heme biology uncovers exciting possibilities as to how hemoproteins may participate in a range of physiologic systems. Here we discuss how heme is regulated at the level of its synthesis, availability, redox state, transport, and degradation and highlight the implications for cellular function and whole organism physiology.
    Keywords:  Heme; Heme oxygenase; Iron; Metalloprotein; Oxidation-reduction (redox)
    DOI:  https://doi.org/10.1016/j.jbc.2024.107132
  20. Cell Metab. 2024 Mar 01. pii: S1550-4131(24)00050-0. [Epub ahead of print]
    Hepatic malonyl-CoA synthesis restrains gluconeogenesis by suppressing fat oxidation, pyruvate carboxylation, and amino acid availability.
    Stanislaw Deja, Justin A Fletcher, Chai-Wan Kim, Blanka Kucejova, Xiaorong Fu, Monika Mizerska, Morgan Villegas, Natalia Pudelko-Malik, Nicholas Browder, Melissa Inigo-Vollmer, Cameron J Menezes, Prashant Mishra, Eric D Berglund, Jeffrey D Browning, John P Thyfault, Jamey D Young, Jay D Horton, Shawn C Burgess.
      Acetyl-CoA carboxylase (ACC) promotes prandial liver metabolism by producing malonyl-CoA, a substrate for de novo lipogenesis and an inhibitor of CPT-1-mediated fat oxidation. We report that inhibition of ACC also produces unexpected secondary effects on metabolism. Liver-specific double ACC1/2 knockout (LDKO) or pharmacologic inhibition of ACC increased anaplerosis, tricarboxylic acid (TCA) cycle intermediates, and gluconeogenesis by activating hepatic CPT-1 and pyruvate carboxylase flux in the fed state. Fasting should have marginalized the role of ACC, but LDKO mice maintained elevated TCA cycle intermediates and preserved glycemia during fasting. These effects were accompanied by a compensatory induction of proteolysis and increased amino acid supply for gluconeogenesis, which was offset by increased protein synthesis during feeding. Such adaptations may be related to Nrf2 activity, which was induced by ACC inhibition and correlated with fasting amino acids. The findings reveal unexpected roles for malonyl-CoA synthesis in liver and provide insight into the broader effects of pharmacologic ACC inhibition.
    Keywords:  Nrf2; TCA cycle; acetyl-CoA carboxylase; anaplerosis; autophagy; gluconeogenesis; lipogenesis; malonyl-CoA; protein synthesis; proteolysis
    DOI:  https://doi.org/10.1016/j.cmet.2024.02.004
  21. Cell Metab. 2024 Mar 05. pii: S1550-4131(24)00052-4. [Epub ahead of print]36(3): 463-465
    Supercharging cancer-fighting T cells with lithium carbonate.
    Yue Xu, Kaili Ma, Lianjun Zhang, Guideng Li.
      Lactate influences the behavior of various immune cell types. In a recent Nature Immunology study, Ma et al. revealed that lithium carbonate induces monocarboxylate transporter 1 translocation to mitochondria, enhancing cytoplasmic lactate transport into the mitochondria and increasing lactate mitochondrial metabolism, thereby promoting T cell effector function.
    DOI:  https://doi.org/10.1016/j.cmet.2024.02.006
  22. Nat Biomed Eng. 2024 Mar 04.
    Severely polarized extracellular acidity around tumour cells.
    Qiang Feng, Zachary Bennett, Anthony Grichuk, Raymundo Pantoja, Tongyi Huang, Brandon Faubert, Gang Huang, Mingyi Chen, Ralph J DeBerardinis, Baran D Sumer, Jinming Gao.
      Extracellular pH impacts many molecular, cellular and physiological processes, and hence is tightly regulated. Yet, in tumours, dysregulated cancer cell metabolism and poor vascular perfusion cause the tumour microenvironment to become acidic. Here by leveraging fluorescent pH nanoprobes with a transistor-like activation profile at a pH of 5.3, we show that, in cancer cells, hydronium ions are excreted into a small extracellular region. Such severely polarized acidity (pH <5.3) is primarily caused by the directional co-export of protons and lactate, as we show for a diverse panel of cancer cell types via the genetic knockout or inhibition of monocarboxylate transporters, and also via nanoprobe activation in multiple tumour models in mice. We also observed that such spot acidification in ex vivo stained snap-frozen human squamous cell carcinoma tissue correlated with the expression of monocarboxylate transporters and with the exclusion of cytotoxic T cells. Severely spatially polarized tumour acidity could be leveraged for cancer diagnosis and therapy.
    DOI:  https://doi.org/10.1038/s41551-024-01178-7
  23. Nat Commun. 2024 Mar 05. 15(1): 1987
    Lactate dehydrogenase A regulates tumor-macrophage symbiosis to promote glioblastoma progression.
    Fatima Khan, Yiyun Lin, Heba Ali, Lizhi Pang, Madeline Dunterman, Wen-Hao Hsu, Katie Frenis, R Grant Rowe, Derek A Wainwright, Kathleen McCortney, Leah K Billingham, Jason Miska, Craig Horbinski, Maciej S Lesniak, Peiwen Chen.
      Abundant macrophage infiltration and altered tumor metabolism are two key hallmarks of glioblastoma. By screening a cluster of metabolic small-molecule compounds, we show that inhibiting glioblastoma cell glycolysis impairs macrophage migration and lactate dehydrogenase inhibitor stiripentol emerges as the top hit. Combined profiling and functional studies demonstrate that lactate dehydrogenase A (LDHA)-directed extracellular signal-regulated kinase (ERK) pathway activates yes-associated protein 1 (YAP1)/ signal transducer and activator of transcription 3 (STAT3) transcriptional co-activators in glioblastoma cells to upregulate C-C motif chemokine ligand 2 (CCL2) and CCL7, which recruit macrophages into the tumor microenvironment. Reciprocally, infiltrating macrophages produce LDHA-containing extracellular vesicles to promote glioblastoma cell glycolysis, proliferation, and survival. Genetic and pharmacological inhibition of LDHA-mediated tumor-macrophage symbiosis markedly suppresses tumor progression and macrophage infiltration in glioblastoma mouse models. Analysis of tumor and plasma samples of glioblastoma patients confirms that LDHA and its downstream signals are potential biomarkers correlating positively with macrophage density. Thus, LDHA-mediated tumor-macrophage symbiosis provides therapeutic targets for glioblastoma.
    DOI:  https://doi.org/10.1038/s41467-024-46193-z
  24. Cell Metab. 2024 Mar 05. pii: S1550-4131(24)00051-2. [Epub ahead of print]36(3): 457-458
    Itaconate boosts malaria via induction of PD-L1.
    Yukun Min, Luke A J O'Neill.
      The Krebs-cycle-derived metabolite itaconate has been shown to be immunomodulatory, targeting multiple processes in macrophages. Ramalho et al. reveal an additional role for itaconate in malaria.1Plasmodium Chabaudi induces itaconate in dendritic cells (DCs), leading to programmed death-ligand 1 (PD-L1) induction. This suppresses CD8+ T cells, important for host defense against malaria, thereby promoting parasitemia.
    DOI:  https://doi.org/10.1016/j.cmet.2024.02.005
  25. Genes Dev. 2024 Mar 07.
    Psat1-generated α-ketoglutarate and glutamine promote muscle stem cell activation and regeneration.
    Veronica Ciuffoli, Xuesong Feng, Kan Jiang, Natalia Acevedo-Luna, Kyung Dae Ko, A Hong Jun Wang, Giulia Riparini, Mamduh Khateb, Brian Glancy, Stefania Dell'Orso, Vittorio Sartorelli.
      By satisfying bioenergetic demands, generating biomass, and providing metabolites serving as cofactors for chromatin modifiers, metabolism regulates adult stem cell biology. Here, we report that a branch of glycolysis, the serine biosynthesis pathway (SBP), is activated in regenerating muscle stem cells (MuSCs). Gene inactivation and metabolomics revealed that Psat1, one of the three SBP enzymes, controls MuSC activation and expansion of myogenic progenitors through production of the metabolite α-ketoglutarate (α-KG) and α-KG-generated glutamine. Psat1 ablation resulted in defective expansion of MuSCs and impaired regeneration. Psat1, α-KG, and glutamine were reduced in MuSCs of old mice. α-KG or glutamine re-established appropriate muscle regeneration of adult conditional Psat1 -/- mice and of old mice. These findings contribute insights into the metabolic role of Psat1 during muscle regeneration and suggest α-KG and glutamine as potential therapeutic interventions to ameliorate muscle regeneration during aging.
    Keywords:  aging; glutamine; ketoglutarate; muscle regeneration; muscle stem cells
    DOI:  https://doi.org/10.1101/gad.351428.123
  26. Mol Cell. 2024 Feb 28. pii: S1097-2765(24)00125-4. [Epub ahead of print]
    Glycerophosphodiesters inhibit lysosomal phospholipid catabolism in Batten disease.
    Kwamina Nyame, Andy Hims, Aya Aburous, Nouf N Laqtom, Wentao Dong, Uche N Medoh, Julia C Heiby, Jian Xiong, Alessandro Ori, Monther Abu-Remaileh.
      Batten disease, the most prevalent form of neurodegeneration in children, is caused by mutations in the CLN3 gene, which encodes a lysosomal transmembrane protein. CLN3 loss leads to significant accumulation of glycerophosphodiesters (GPDs), the end products of glycerophospholipid catabolism in the lysosome. Despite GPD storage being robustly observed upon CLN3 loss, the role of GPDs in neuropathology remains unclear. Here, we demonstrate that GPDs act as potent inhibitors of glycerophospholipid catabolism in the lysosome using human cell lines and mouse models. Mechanistically, GPDs bind and competitively inhibit the lysosomal phospholipases PLA2G15 and PLBD2, which we establish to possess phospholipase B activity. GPDs effectively inhibit the rate-limiting lysophospholipase activity of these phospholipases. Consistently, lysosomes of CLN3-deficient cells and tissues accumulate toxic lysophospholipids. Our work establishes that the storage material in Batten disease directly disrupts lysosomal lipid homeostasis, suggesting GPD clearance as a potential therapeutic approach to this fatal disease.
    Keywords:  Batten disease; CLN3; GPDs; PLA2G15; PLBD2; glycerophosphodiesters; lysosomal storage disease; lysosome; neurodegeneration; phospholipase; phospholipid metabolism
    DOI:  https://doi.org/10.1016/j.molcel.2024.02.006
  27. Nat Metab. 2024 Mar 08.
    Futile lipid cycling: from biochemistry to physiology.
    Anand Kumar Sharma, Radhika Khandelwal, Christian Wolfrum.
      In the healthy state, the fat stored in our body isn't just inert. Rather, it is dynamically mobilized to maintain an adequate concentration of fatty acids (FAs) in our bloodstream. Our body tends to produce excess FAs to ensure that the FA availability is not limiting. The surplus FAs are actively re-esterified into glycerides, initiating a cycle of breakdown and resynthesis of glycerides. This cycle consumes energy without generating a new product and is commonly referred to as the 'futile lipid cycle' or the glyceride/FA cycle. Contrary to the notion that it's a wasteful process, it turns out this cycle is crucial for systemic metabolic homeostasis. It acts as a control point in intra-adipocyte and inter-organ cross-talk, a metabolic rheostat, an energy sensor and a lipid diversifying mechanism. In this Review, we discuss the metabolic regulation and physiological implications of the glyceride/FA cycle and its mechanistic underpinnings.
    DOI:  https://doi.org/10.1038/s42255-024-01003-0
  28. Nat Cell Biol. 2024 Mar 07.
    Loss of WIPI4 in neurodegeneration causes autophagy-independent ferroptosis.
    Ye Zhu, Motoki Fujimaki, Louisa Snape, Ana Lopez, Angeleen Fleming, David C Rubinsztein.
      β-Propeller protein-associated neurodegeneration (BPAN) is a rare X-linked dominant disease, one of several conditions that manifest with neurodegeneration and brain iron accumulation. Mutations in the WD repeat domain 45 (WDR45) gene encoding WIPI4 lead to loss of function in BPAN but the cellular mechanisms of how these trigger pathology are unclear. The prevailing view in the literature is that BPAN is simply the consequence of autophagy deficiency given that WIPI4 functions in this degradation pathway. However, our data indicate that WIPI4 depletion causes ferroptosis-a type of cell death induced by lipid peroxidation-via an autophagy-independent mechanism, as demonstrated both in cell culture and in zebrafish. WIPI4 depletion increases ATG2A localization at endoplasmic reticulum-mitochondrial contact sites, which enhances phosphatidylserine import into mitochondria. This results in increased mitochondrial synthesis of phosphatidylethanolamine, a major lipid prone to peroxidation, thus enabling ferroptosis. This mechanism has minimal overlap with classical ferroptosis stimuli but provides insights into the causes of neurodegeneration in BPAN and may provide clues for therapeutic strategies.
    DOI:  https://doi.org/10.1038/s41556-024-01373-3
  29. Nat Commun. 2024 Mar 02. 15(1): 1943
    RTF2 controls replication repriming and ribonucleotide excision at the replisome.
    Brooke A Conti, Penelope D Ruiz, Cayla Broton, Nicolas J Blobel, Molly C Kottemann, Sunandini Sridhar, Francis P Lach, Tom F Wiley, Nanda K Sasi, Thomas Carroll, Agata Smogorzewska.
      DNA replication through a challenging genomic landscape is coordinated by the replisome, which must adjust to local conditions to provide appropriate replication speed and respond to lesions that hinder its progression. We have previously shown that proteasome shuttle proteins, DNA Damage Inducible 1 and 2 (DDI1/2), regulate Replication Termination Factor 2 (RTF2) levels at stalled replisomes, allowing fork stabilization and restart. Here, we show that during unperturbed replication, RTF2 regulates replisome localization of RNase H2, a heterotrimeric enzyme that removes RNA from RNA-DNA heteroduplexes. RTF2, like RNase H2, is essential for mammalian development and maintains normal replication speed. However, persistent RTF2 and RNase H2 at stalled replication forks prevent efficient replication restart, which is dependent on PRIM1, the primase component of DNA polymerase α-primase. Our data show a fundamental need for RTF2-dependent regulation of replication-coupled ribonucleotide removal and reveal the existence of PRIM1-mediated direct replication restart in mammalian cells.
    DOI:  https://doi.org/10.1038/s41467-024-45947-z
  30. PLoS Genet. 2024 Mar 07. 20(3): e1011202
    The PP2A-like phosphatase Ppg1 mediates assembly of the Far complex to balance gluconeogenic outputs and enables adaptation to glucose depletion.
    Shreyas Niphadkar, Lavanya Karinje, Sunil Laxman.
      To sustain growth in changing nutrient conditions, cells reorganize outputs of metabolic networks and appropriately reallocate resources. Signaling by reversible protein phosphorylation can control such metabolic adaptations. In contrast to kinases, the functions of phosphatases that enable metabolic adaptation as glucose depletes are poorly studied. Using a Saccharomyces cerevisiae deletion screen, we identified the PP2A-like phosphatase Ppg1 as required for appropriate carbon allocations towards gluconeogenic outputs-trehalose, glycogen, UDP-glucose, UDP-GlcNAc-after glucose depletion. This Ppg1 function is mediated via regulation of the assembly of the Far complex-a multi-subunit complex that tethers to the ER and mitochondrial outer membranes forming localized signaling hubs. The Far complex assembly is Ppg1 catalytic activity-dependent. Ppg1 regulates the phosphorylation status of multiple ser/thr residues on Far11 to enable the proper assembly of the Far complex. The assembled Far complex is required to maintain gluconeogenic outputs after glucose depletion. Glucose in turn regulates Far complex amounts. This Ppg1-mediated Far complex assembly, and Ppg1-Far complex dependent control of gluconeogenic outputs enables adaptive growth under glucose depletion. Our study illustrates how protein dephosphorylation is required for the assembly of a multi-protein scaffold present in localized cytosolic pools, to thereby alter gluconeogenic flux and enable cells to metabolically adapt to nutrient fluctuations.
    DOI:  https://doi.org/10.1371/journal.pgen.1011202
  31. Trends Cell Biol. 2024 Mar 01. pii: S0962-8924(24)00025-4. [Epub ahead of print]
    Metabolic regulation of mRNA splicing.
    Haissi Cui, Qingyu Shi, Colette Maya Macarios, Paul Schimmel.
      Alternative mRNA splicing enables the diversification of the proteome from a static genome and confers plasticity and adaptiveness on cells. Although this is often explored in development, where hard-wired programs drive the differentiation and specialization, alternative mRNA splicing also offers a way for cells to react to sudden changes in outside stimuli such as small-molecule metabolites. Fluctuations in metabolite levels and availability in particular convey crucial information to which cells react and adapt. We summarize and highlight findings surrounding the metabolic regulation of mRNA splicing. We discuss the principles underlying the biochemistry and biophysical properties of mRNA splicing, and propose how these could intersect with metabolite levels. Further, we present examples in which metabolites directly influence RNA-binding proteins and splicing factors. We also discuss the interplay between alternative mRNA splicing and metabolite-responsive signaling pathways. We hope to inspire future research to obtain a holistic picture of alternative mRNA splicing in response to metabolic cues.
    Keywords:  RNA; amino acid; glucose; mRNA splicing; metabolite
    DOI:  https://doi.org/10.1016/j.tcb.2024.02.002
  32. Science. 2024 Mar 08. 383(6687): eadi7342
    Vitamin A resolves lineage plasticity to orchestrate stem cell lineage choices.
    Matthew T Tierney, Lisa Polak, Yihao Yang, Merve Deniz Abdusselamoglu, Inwha Baek, Katherine S Stewart, Elaine Fuchs.
      Lineage plasticity-a state of dual fate expression-is required to release stem cells from their niche constraints and redirect them to tissue compartments where they are most needed. In this work, we found that without resolving lineage plasticity, skin stem cells cannot effectively generate each lineage in vitro nor regrow hair and repair wounded epidermis in vivo. A small-molecule screen unearthed retinoic acid as a critical regulator. Combining high-throughput approaches, cell culture, and in vivo mouse genetics, we dissected its roles in tissue regeneration. We found that retinoic acid is made locally in hair follicle stem cell niches, where its levels determine identity and usage. Our findings have therapeutic implications for hair growth as well as chronic wounds and cancers, where lineage plasticity is unresolved.
    DOI:  https://doi.org/10.1126/science.adi7342
  33. Nat Chem Biol. 2024 Mar 06.
    Mitochondrial ATP generation is more proteome efficient than glycolysis.
    Yihui Shen, Hoang V Dinh, Edward R Cruz, Zihong Chen, Caroline R Bartman, Tianxia Xiao, Catherine M Call, Rolf-Peter Ryseck, Jimmy Pratas, Daniel Weilandt, Heide Baron, Arjuna Subramanian, Zia Fatma, Zong-Yen Wu, Sudharsan Dwaraknath, John I Hendry, Vinh G Tran, Lifeng Yang, Yasuo Yoshikuni, Huimin Zhao, Costas D Maranas, Martin Wühr, Joshua D Rabinowitz.
      Metabolic efficiency profoundly influences organismal fitness. Nonphotosynthetic organisms, from yeast to mammals, derive usable energy primarily through glycolysis and respiration. Although respiration is more energy efficient, some cells favor glycolysis even when oxygen is available (aerobic glycolysis, Warburg effect). A leading explanation is that glycolysis is more efficient in terms of ATP production per unit mass of protein (that is, faster). Through quantitative flux analysis and proteomics, we find, however, that mitochondrial respiration is actually more proteome efficient than aerobic glycolysis. This is shown across yeast strains, T cells, cancer cells, and tissues and tumors in vivo. Instead of aerobic glycolysis being valuable for fast ATP production, it correlates with high glycolytic protein expression, which promotes hypoxic growth. Aerobic glycolytic yeasts do not excel at aerobic growth but outgrow respiratory cells during oxygen limitation. We accordingly propose that aerobic glycolysis emerges from cells maintaining a proteome conducive to both aerobic and hypoxic growth.
    DOI:  https://doi.org/10.1038/s41589-024-01571-y
  34. Nat Chem Biol. 2024 Mar 08.
    Aerobic glycolysis comes with an enzyme cost but robustness gain.
      
    DOI:  https://doi.org/10.1038/s41589-024-01581-w
  35. Cell Metab. 2024 Mar 01. pii: S1550-4131(24)00057-3. [Epub ahead of print]
    Aging-induced tRNAGlu-derived fragment impairs glutamate biosynthesis by targeting mitochondrial translation-dependent cristae organization.
    Dingfeng Li, Xinyi Gao, Xiaolin Ma, Ming Wang, Chuandong Cheng, Tian Xue, Feng Gao, Yong Shen, Juan Zhang, Qiang Liu.
      Mitochondrial cristae, infoldings of the mitochondrial inner membrane, undergo aberrant changes in their architecture with age. However, the underlying molecular mechanisms and their contribution to brain aging are largely elusive. Here, we observe an age-dependent accumulation of Glu-5'tsRNA-CTC, a transfer-RNA-derived small RNA (tsRNA), derived from nuclear-encoded tRNAGlu in the mitochondria of glutaminergic neurons. Mitochondrial Glu-5'tsRNA-CTC disrupts the binding of mt-tRNALeu and leucyl-tRNA synthetase2 (LaRs2), impairing mt-tRNALeu aminoacylation and mitochondria-encoded protein translation. Mitochondrial translation defects disrupt cristae organization, leading to damaged glutaminase (GLS)-dependent glutamate formation and reduced synaptosomal glutamate levels. Moreover, reduction of Glu-5'tsRNA-CTC protects aged brains from age-related defects in mitochondrial cristae organization, glutamate metabolism, synaptic structures, and memory. Thus, beyond illustrating a physiological role for normal mitochondrial cristae ultrastructure in maintaining glutamate levels, our study defines a pathological role for tsRNAs in brain aging and age-related memory decline.
    Keywords:  angiogenin; brain aging; cristae organization; glutamate metabolism; memory decline; mitochondria; mitochondrial translation; tRNA-derived small RNAs
    DOI:  https://doi.org/10.1016/j.cmet.2024.02.011
  36. Autophagy. 2024 Mar 05.
    International consensus guidelines for the definition, detection, and interpretation of autophagy-dependent ferroptosis.
    Xin Chen, Andrey S Tsvetkov, Han-Ming Shen, Ciro Isidoro, Nicholas T Ktistakis, Andreas Linkermann, Werner J H Koopman, Hans-Uwe Simon, Lorenzo Galluzzi, Shouqing Luo, Daqian Xu, Wei Gu, Olivier Peulen, Qian Cai, David C Rubinsztein, Jen-Tsan Chi, Donna D Zhang, Changfeng Li, Shinya Toyokuni, Jinbao Liu, Jong-Lyel Roh, Enyong Dai, Gabor Juhasz, Wei Liu, Jianhua Zhang, Minghua Yang, Jiao Liu, Ling-Qiang Zhu, Weiping Zou, Mauro Piacentini, Wen-Xing Ding, Zhenyu Yue, Yangchun Xie, Morten Petersen, David A Gewirtz, Michael A Mandell, Charleen T Chu, Debasish Sinha, Eftekhar Eftekharpour, Boris Zhivotovsky, Sébastien Besteiro, Dmitry I Gabrilovich, Do-Hyung Kim, Valerian E Kagan, Hülya Bayir, Guang-Chao Chen, Scott Ayton, Jan D Lünemann, Masaaki Komatsu, Stefan Krautwald, Ben Loos, Eric H Baehrecke, Jiayi Wang, Jon D Lane, Junichi Sadoshima, Wan Seok Yang, Minghui Gao, Christian Münz, Michael Thumm, Martin Kampmann, Di Yu, Marta M Lipinski, Jace W Jones, Xuejun Jiang, Herbert J Zeh, Rui Kang, Daniel J Klionsky, Guido Kroemer, Daolin Tang.
      Macroautophagy/autophagy is a complex degradation process with a dual role in cell death that is influenced by the cell types that are involved and the stressors they are exposed to. Ferroptosis is an iron-dependent oxidative form of cell death characterized by unrestricted lipid peroxidation in the context of heterogeneous and plastic mechanisms. Recent studies have shed light on the involvement of specific types of autophagy (e.g. ferritinophagy, lipophagy, and clockophagy) in initiating or executing ferroptotic cell death through the selective degradation of anti-injury proteins or organelles. Conversely, other forms of selective autophagy (e.g. reticulophagy and lysophagy) enhance the cellular defense against ferroptotic damage. Dysregulated autophagy-dependent ferroptosis has implications for a diverse range of pathological conditions. This review aims to present an updated definition of autophagy-dependent ferroptosis, discuss influential substrates and receptors, outline experimental methods, and propose guidelines for interpreting the results.
    Keywords:  Cell death; ferritinophagy; iron; lipid peroxidation; lipophagy; lysosome
    DOI:  https://doi.org/10.1080/15548627.2024.2319901
  37. Nature. 2024 Mar 06.
    Decoding chromatin states by proteomic profiling of nucleosome readers.
    Saulius Lukauskas, Andrey Tvardovskiy, Nhuong V Nguyen, Mara Stadler, Peter Faull, Tina Ravnsborg, Bihter Özdemir Aygenli, Scarlett Dornauer, Helen Flynn, Rik G H Lindeboom, Teresa K Barth, Kevin Brockers, Stefanie M Hauck, Michiel Vermeulen, Ambrosius P Snijders, Christian L Müller, Peter A DiMaggio, Ole N Jensen, Robert Schneider, Till Bartke.
      DNA and histone modifications combine into characteristic patterns that demarcate functional regions of the genome1,2. While many 'readers' of individual modifications have been described3-5, how chromatin states comprising composite modification signatures, histone variants and internucleosomal linker DNA are interpreted is a major open question. Here we use a multidimensional proteomics strategy to systematically examine the interaction of around 2,000 nuclear proteins with over 80 modified dinucleosomes representing promoter, enhancer and heterochromatin states. By deconvoluting complex nucleosome-binding profiles into networks of co-regulated proteins and distinct nucleosomal features driving protein recruitment or exclusion, we show comprehensively how chromatin states are decoded by chromatin readers. We find highly distinctive binding responses to different features, many factors that recognize multiple features, and that nucleosomal modifications and linker DNA operate largely independently in regulating protein binding to chromatin. Our online resource, the Modification Atlas of Regulation by Chromatin States (MARCS), provides in-depth analysis tools to engage with our results and advance the discovery of fundamental principles of genome regulation by chromatin states.
    DOI:  https://doi.org/10.1038/s41586-024-07141-5
  38. Bioessays. 2024 Mar 06. e2300193
    How mitochondrial cristae illuminate the important role of oxygen during eukaryogenesis.
    Dave Speijer.
      Inner membranes of mitochondria are extensively folded, forming cristae. The observed overall correlation between efficient eukaryotic ATP generation and the area of internal mitochondrial inner membranes both in unicellular organisms and metazoan tissues seems to explain why they evolved. However, the crucial use of molecular oxygen (O2 ) as final acceptor of the electron transport chain is still not sufficiently appreciated. O2 was an essential prerequisite for cristae development during early eukaryogenesis and could be the factor allowing cristae retention upon loss of mitochondrial ATP generation. Here I analyze illuminating bacterial and unicellular eukaryotic examples. I also discuss formative influences of intracellular O2 consumption on the evolution of the last eukaryotic common ancestor (LECA). These considerations bring about an explanation for the many genes coming from other organisms than the archaeon and bacterium merging at the start of eukaryogenesis.
    Keywords:  ROS; cristae; eukaryogenesis; mitochondria; molecular oxygen; symbiogenesis
    DOI:  https://doi.org/10.1002/bies.202300193
  39. Cancer Cell. 2024 Mar 04. pii: S1535-6108(24)00054-0. [Epub ahead of print]
    ARID1A orchestrates SWI/SNF-mediated sequential binding of transcription factors with ARID1A loss driving pre-memory B cell fate and lymphomagenesis.
    Darko Barisic, Christopher R Chin, Cem Meydan, Matt Teater, Ioanna Tsialta, Coraline Mlynarczyk, Amy Chadburn, Xuehai Wang, Margot Sarkozy, Min Xia, Sandra E Carson, Santo Raggiri, Sonia Debek, Benedikt Pelzer, Ceyda Durmaz, Qing Deng, Priya Lakra, Martin Rivas, Christian Steidl, David W Scott, Andrew P Weng, Christopher E Mason, Michael R Green, Ari Melnick.
      ARID1A, a subunit of the canonical BAF nucleosome remodeling complex, is commonly mutated in lymphomas. We show that ARID1A orchestrates B cell fate during the germinal center (GC) response, facilitating cooperative and sequential binding of PU.1 and NF-kB at crucial genes for cytokine and CD40 signaling. The absence of ARID1A tilts GC cell fate toward immature IgM+CD80-PD-L2- memory B cells, known for their potential to re-enter new GCs. When combined with BCL2 oncogene, ARID1A haploinsufficiency hastens the progression of aggressive follicular lymphomas (FLs) in mice. Patients with FL with ARID1A-inactivating mutations preferentially display an immature memory B cell-like state with increased transformation risk to aggressive disease. These observations offer mechanistic understanding into the emergence of both indolent and aggressive ARID1A-mutant lymphomas through the formation of immature memory-like clonal precursors. Lastly, we demonstrate that ARID1A mutation induces synthetic lethality to SMARCA2/4 inhibition, paving the way for potential precision therapy for high-risk patients.
    Keywords:  BAF complex; chromatin; chromatin remodeling; clonal precursor cells; epigenetics; humoral immunity; lymphoma; pioneer transcription factors; plasticity; precision therapy
    DOI:  https://doi.org/10.1016/j.ccell.2024.02.010
  40. J Cell Biol. 2024 Apr 01. pii: e202304075. [Epub ahead of print]223(4):
    Two ancient membrane pores mediate mitochondrial-nucleus membrane contact sites.
    Jana Ovciarikova, Shikha Shikha, Alice Lacombe, Flavie Courjol, Rosalind McCrone, Wasim Hussain, Andrew Maclean, Leandro Lemgruber, Erica S Martins-Duarte, Mathieu Gissot, Lilach Sheiner.
      Coordination between nucleus and mitochondria is essential for cell survival, and thus numerous communication routes have been established between these two organelles over eukaryotic cell evolution. One route for organelle communication is via membrane contact sites, functional appositions formed by molecular tethers. We describe a novel nuclear-mitochondrial membrane contact site in the protozoan Toxoplasma gondii. We have identified specific contacts occurring at the nuclear pore and demonstrated an interaction between components of the nuclear pore and the mitochondrial protein translocon, highlighting them as molecular tethers. Genetic disruption of the nuclear pore or the TOM translocon components, TgNup503 or TgTom40, respectively, result in contact site reduction, supporting their potential involvement in this tether. TgNup503 depletion further leads to specific mitochondrial morphology and functional defects, supporting a role for nuclear-mitochondrial contacts in mediating their communication. The discovery of a contact formed through interaction between two ancient mitochondrial and nuclear complexes sets the ground for better understanding of mitochondrial-nuclear crosstalk in eukaryotes.
    DOI:  https://doi.org/10.1083/jcb.202304075
  41. Cell Metab. 2024 Feb 27. pii: S1550-4131(24)00056-1. [Epub ahead of print]
    Age-related ciliopathy: Obesogenic shortening of melanocortin-4 receptor-bearing neuronal primary cilia.
    Manami Oya, Yoshiki Miyasaka, Yoshiko Nakamura, Miyako Tanaka, Takayoshi Suganami, Tomoji Mashimo, Kazuhiro Nakamura.
      Obesity is often associated with aging. However, the mechanism of age-related obesity is unknown. The melanocortin-4 receptor (MC4R) mediates leptin-melanocortin anti-obesity signaling in the hypothalamus. Here, we discovered that MC4R-bearing primary cilia of hypothalamic neurons progressively shorten with age in rats, correlating with age-dependent metabolic decline and increased adiposity. This "age-related ciliopathy" is promoted by overnutrition-induced upregulation of leptin-melanocortin signaling and inhibited or reversed by dietary restriction or the knockdown of ciliogenesis-associated kinase 1 (CILK1). Forced shortening of MC4R-bearing cilia in hypothalamic neurons by genetic approaches impaired neuronal sensitivity to melanocortin and resulted in decreased brown fat thermogenesis and energy expenditure and increased appetite, finally developing obesity and leptin resistance. Therefore, despite its acute anti-obesity effect, chronic leptin-melanocortin signaling increases susceptibility to obesity by promoting the age-related shortening of MC4R-bearing cilia. This study provides a crucial mechanism for age-related obesity, which increases the risk of metabolic syndrome.
    Keywords:  aging; brown adipose tissue; cilia; dorsomedial hypothalamus; intraflagellar transport; leptin; melanocortin; obesity; paraventricular hypothalamic nucleus; thermoregulation
    DOI:  https://doi.org/10.1016/j.cmet.2024.02.010
  42. Biogerontology. 2024 Mar 05.
    A comprehensive model for the biochemistry of ageing, senescence and longevity.
    Hiskias Gerrit Keizer, R Brands, Ronald Sake Oosting, Willem Seinen.
      Various models for ageing, each focussing on different biochemical and/or cellular pathways have been proposed. This has resulted in a complex and non-coherent portrayal of ageing. Here, we describe a concise and comprehensive model for the biochemistry of ageing consisting of three interacting signalling hubs. These are the nuclear factor kappa B complex (NFκB), controlling the innate immune system, the mammalian target for rapamycin complex, controlling cell growth, and the integrated stress responses, controlling homeostasis. This model provides a framework for most other, more detailed, biochemical pathways involved in ageing, and explains why ageing involves chronic inflammation, cellular senescence, and vulnerability to environmental stress, while starting with the spontaneous formation of advanced glycation end products. The totality of data underlying this model suggest that the gradual inhibition of the AMPK-ISR probably determines the maximal lifespan. Based on this model, anti-ageing drugs in general, are expected to show hormetic dose response curves. This complicates the process of dose-optimization. Due to its specific mechanism of action, the anti-aging drug alkaline phosphatase is an exception to this rule, because it probably exhibits saturation kinetics.
    Keywords:  AMPK; ATF4; Advanced glycation end products; DAMPs; Hormesis; Integrated stress response; Longevity; NFκB; PAMPs; mTOR
    DOI:  https://doi.org/10.1007/s10522-024-10097-8
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