bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2024–08–25
fifty-nine papers selected by
Christian Frezza, Universität zu Köln
  1. Rag-Ragulator is the central organizer of the physical architecture of the mTORC1 nutrient-sensing pathway.
  2. Lysosomes drive the piecemeal removal of mitochondrial inner membrane.
  3. Malic enzyme 2 maintains metabolic state and anti-tumor immunity of CD8+ T cells.
  4. Cancer tissue of origin constrains the growth and metabolism of metastases.
  5. Inner membrane turns inside out to exit mitochondrial organelles.
  6. The surprising cause of fasting's regenerative powers.
  7. Nutrient Sensing of mTORC1 signaling in cancer and aging.
  8. MICU1 and MICU2 control mitochondrial calcium signaling in the mammalian heart.
  9. Regulated insulin secretion from human and mouse islets exclusively composed of β-cells.
  10. Organismal metabolism regulates the expansion of oncogenic PIK3CA mutant clones in normal esophagus.
  11. A safety guide for transgenic Cre drivers in metabolism.
  12. FDX2, an iron-sulfur cluster assembly factor, is essential to prevent cellular senescence, apoptosis or ferroptosis of ovarian cancer cells.
  13. Alveolar epithelial cells mitigate neutrophilic inflammation in lung injury through regulating mitochondrial fatty acid oxidation.
  14. Misregulation of mitochondrial 6mA promotes the propagation of mutant mtDNA and causes aging in C. elegans.
  15. FAM210A: An emerging regulator of mitochondrial homeostasis.
  16. CRISPR screening identifies PRMT1 as a key pro-ferroptotic gene via a two-layer regulatory mechanism.
  17. How tumors hijack macrophages for immune evasion.
  18. Cytosolic calcium regulates hepatic mitochondrial oxidation, intrahepatic lipolysis, and gluconeogenesis via CAMKII activation.
  19. RIOK2 transcriptionally regulates TRiC and dyskerin complexes to prevent telomere shortening.
  20. RNA sequestration in P-bodies sustains myeloid leukaemia.
  21. Succinate dehydrogenase-complex II regulates skeletal muscle cellular respiration and contractility but not muscle mass in genetically induced pulmonary emphysema.
  22. Niacin supplementation in a child with novel MTTN variant m.5670A>G causing early onset mitochondrial myopathy and NAD+ deficiency.
  23. Non-canonical metabolic and molecular effects of calorie restriction are revealed by varying temporal conditions.
  24. Stem cells tightly regulate dead cell clearance to maintain tissue fitness.
  25. Metabolic specialization drives reduced pathogenicity in Pseudomonas aeruginosa isolates from cystic fibrosis patients.
  26. Somatic nuclear mitochondrial DNA insertions are prevalent in the human brain and accumulate over time in fibroblasts.
  27. PPARβ/δ-orchestrated metabolic reprogramming supports the formation and maintenance of memory CD8+ T cells.
  28. A class I PI3K signalling network regulates primary cilia disassembly in normal physiology and disease.
  29. Can ageing be stopped? A biologist explains.
  30. The effects of ENDOG on lipid metabolism may be tissue-dependent and may not require its translocation from mitochondria.
  31. Short-term post-fast refeeding enhances intestinal stemness via polyamines.
  32. Coordinated metabolic adaptation of Arabidopsis thaliana to high light.
  33. The Rubicon-WIPI axis regulates exosome biogenesis during ageing.
  34. Transcriptional Isoforms of NAD+ kinase regulate oxidative stress resistance and melanoma metastasis.
  35. Aerobic glycolysis but not GLS1-dependent glutamine metabolism is critical for anti-tumor immunity and response to checkpoint inhibition.
  36. A CLIC1 network coordinates matrix stiffness and the Warburg effect to promote tumor growth in pancreatic cancer.
  37. Phosphoglycerate kinase is a central leverage point in Parkinson's disease-driven neuronal metabolic deficits.
  38. Mdm2 requires Sprouty4 to regulate focal adhesion formation and metastasis independent of p53.
  39. Cell fate simulation reveals cancer cell features in the tumor microenvironment.
  40. SLC30A9: an evolutionarily conserved mitochondrial zinc transporter essential for mammalian early embryonic development.
  41. The periosteum provides a stromal defence against cancer invasion into the bone.
  42. Enhanced cellular longevity arising from environmental fluctuations.
  43. Circadian and environmental signal integration in a natural population of Arabidopsis.
  44. Of criminals and cancer: The importance of social bonds and innate morality on cellular societies.
  45. Jumonji histone demethylases are therapeutic targets in small cell lung cancer.
  46. Spatial diversity of in vivo tissue immunity.
  47. Exosome regulation by Rubicon in ageing.
  48. Multimodal analysis unveils tumor microenvironment heterogeneity linked to immune activity and evasion.
  49. A genetic basis for sex differences in Xp11 translocation renal cell carcinoma.
  50. Metabolic cycles: A unifying concept for energy transfer in the heart.
  51. Mouse models to investigate in situ cell fate decisions induced by p53.
  52. Negative feedback control of hypothalamic feeding circuits by the taste of food.
  53. A circadian clock output functions independently of phyB to sustain daytime PIF3 degradation.
  54. Acetate enables metabolic fitness and cognitive performance during sleep disruption.
  55. Enhanced metabolic entanglement emerges during the evolution of an interkingdom microbial community.
  56. Cells poised to divide can delay their commitment to proliferate.
  57. A somatic view of the genomic impact of mitochondrial endosymbiosis.
  58. Forever young: what science can and can't tell us about cheating ageing.
  59. Oxidative Phosphorylation Does Not Violate the Second Law of Thermodynamics.
  1. Proc Natl Acad Sci U S A. 2024 Aug 27. 121(35): e2322755121
    Rag-Ragulator is the central organizer of the physical architecture of the mTORC1 nutrient-sensing pathway.
    Max L Valenstein, Pranav V Lalgudi, Xin Gu, Jibril F Kedir, Martin S Taylor, Raghu R Chivukula, David M Sabatini.
      The mechanistic target of rapamycin complex 1 (mTORC1) pathway regulates cell growth and metabolism in response to many environmental cues, including nutrients. Amino acids signal to mTORC1 by modulating the guanine nucleotide loading states of the heterodimeric Rag GTPases, which bind and recruit mTORC1 to the lysosomal surface, its site of activation. The Rag GTPases are tethered to the lysosome by the Ragulator complex and regulated by the GATOR1, GATOR2, and KICSTOR multiprotein complexes that localize to the lysosomal surface through an unknown mechanism(s). Here, we show that mTORC1 is completely insensitive to amino acids in cells lacking the Rag GTPases or the Ragulator component p18. Moreover, not only are the Rag GTPases and Ragulator required for amino acids to regulate mTORC1, they are also essential for the lysosomal recruitment of the GATOR1, GATOR2, and KICSTOR complexes, which stably associate and traffic to the lysosome as the "GATOR" supercomplex. The nucleotide state of RagA/B controls the lysosomal association of GATOR, in a fashion competitively antagonized by the N terminus of the amino acid transporter SLC38A9. Targeting of Ragulator to the surface of mitochondria is sufficient to relocalize the Rags and GATOR to this organelle, but not to enable the nutrient-regulated recruitment of mTORC1 to mitochondria. Thus, our results reveal that the Rag-Ragulator complex is the central organizer of the physical architecture of the mTORC1 nutrient-sensing pathway and underscore that mTORC1 activation requires signal transduction on the lysosomal surface.
    Keywords:  biochemistry; mTOR signaling; nutrient sensing
    DOI:  https://doi.org/10.1073/pnas.2322755121
  2. Nature. 2024 Aug 21.
    Lysosomes drive the piecemeal removal of mitochondrial inner membrane.
    Akriti Prashar, Claudio Bussi, Antony Fearns, Mariana I Capurro, Xiaodong Gao, Hiromi Sesaki, Maximiliano G Gutierrez, Nicola L Jones.
      Mitochondrial membranes define distinct structural and functional compartments. Cristae of the inner mitochondrial membrane (IMM) function as independent bioenergetic units that undergo rapid and transient remodelling, but the significance of this compartmentalized organization is unknown1. Using super-resolution microscopy, here we show that cytosolic IMM vesicles, devoid of outer mitochondrial membrane or mitochondrial matrix, are formed during resting state. These vesicles derived from the IMM (VDIMs) are formed by IMM herniation through pores formed by voltage-dependent anion channel 1 in the outer mitochondrial membrane. Live-cell imaging showed that lysosomes in proximity to mitochondria engulfed the herniating IMM and, aided by the endosomal sorting complex required for transport machinery, led to the formation of VDIMs in a microautophagy-like process, sparing the remainder of the organelle. VDIM formation was enhanced in mitochondria undergoing oxidative stress, suggesting their potential role in maintenance of mitochondrial function. Furthermore, the formation of VDIMs required calcium release by the reactive oxygen species-activated, lysosomal calcium channel, transient receptor potential mucolipin 1, showing an interorganelle communication pathway for maintenance of mitochondrial homeostasis. Thus, IMM compartmentalization could allow for the selective removal of damaged IMM sections via VDIMs, which should protect mitochondria from localized injury. Our findings show a new pathway of intramitochondrial quality control.
    DOI:  https://doi.org/10.1038/s41586-024-07835-w
  3. Mol Cell. 2024 Aug 06. pii: S1097-2765(24)00619-1. [Epub ahead of print]
    Malic enzyme 2 maintains metabolic state and anti-tumor immunity of CD8+ T cells.
    Zhenxi Zhang, Yanting Yang, Yang Chen, Jingyu Su, Wenjing Du.
      The functional integrity of CD8+ T cells is closely linked to metabolic reprogramming; therefore, understanding the metabolic basis of CD8+ T cell activation and antitumor immunity could provide insights into tumor immunotherapy. Here, we report that ME2 is critical for mouse CD8+ T cell activation and immune response against malignancy. ME2 deficiency suppresses CD8+ T cell activation and anti-tumor immune response in vitro and in vivo. Mechanistically, ME2 depletion blocks the TCA cycle flux, leading to the accumulation of fumarate. Fumarate directly binds to DAPK1 and inhibits its activity by competing with ATP for binding. Notably, pharmacological inhibition of DAPK1 abolishes the anti-tumor function conferred by ME2 to CD8+ T cells. Collectively, these findings demonstrate a role for ME2 in the regulation of CD8+ T cell metabolism and effector functions as well as an unexpected function for fumarate as a metabolic signal in the inhibition of DAPK1.
    Keywords:  CD8(+) T cell; DAPK1; antitumor immunity; fumarate; malic enzyme 2; metabolite sensing
    DOI:  https://doi.org/10.1016/j.molcel.2024.07.021
  4. Nat Metab. 2024 Aug 19.
    Cancer tissue of origin constrains the growth and metabolism of metastases.
    Sharanya Sivanand, Yetis Gultekin, Peter S Winter, Sidney Y Vermeulen, Konstantine M Tchourine, Keene L Abbott, Laura V Danai, Florian Gourgue, Brian T Do, Kayla Crowder, Tenzin Kunchok, Allison N Lau, Alicia M Darnell, Alexandria Jefferson, Satoru Morita, Dan G Duda, Andrew J Aguirre, Brian M Wolpin, Nicole Henning, Virginia Spanoudaki, Laura Maiorino, Darrell J Irvine, Omer H Yilmaz, Caroline A Lewis, Dennis Vitkup, Alex K Shalek, Matthew G Vander Heiden.
      Metastases arise from subsets of cancer cells that disseminate from the primary tumour1,2. The ability of cancer cells to thrive in a new tissue site is influenced by genetic and epigenetic changes that are important for disease initiation and progression, but these factors alone do not predict if and where cancers metastasize3,4. Specific cancer types metastasize to consistent subsets of tissues, suggesting that primary tumour-associated factors influence where cancers can grow. We find primary and metastatic pancreatic tumours have metabolic similarities and that the tumour-initiating capacity and proliferation of both primary-derived and metastasis-derived cells is favoured in the primary site relative to the metastatic site. Moreover, propagating cells as tumours in the lung or the liver does not enhance their relative ability to form large tumours in those sites, change their preference to grow in the primary site, nor stably alter aspects of their metabolism relative to primary tumours. Primary liver and lung cancer cells also exhibit a preference to grow in their primary site relative to metastatic sites. These data suggest cancer tissue of origin influences both primary and metastatic tumour metabolism and may impact where cancer cells can metastasize.
    DOI:  https://doi.org/10.1038/s42255-024-01105-9
  5. Nature. 2024 Aug;632(8027): 987-988
    Inner membrane turns inside out to exit mitochondrial organelles.
    David Pla-Martín, Andreas S Reichert.
      
    Keywords:  Biochemistry; Cell biology
    DOI:  https://doi.org/10.1038/d41586-024-02528-w
  6. Nature. 2024 Aug 21.
    The surprising cause of fasting's regenerative powers.
    Max Kozlov.
      
    Keywords:  Ageing; Cancer; Metabolism
    DOI:  https://doi.org/10.1038/d41586-024-02700-2
  7. Semin Cancer Biol. 2024 Aug 14. pii: S1044-579X(24)00059-2. [Epub ahead of print]
    Nutrient Sensing of mTORC1 signaling in cancer and aging.
    Cong Jiang, Xiao Tan, Ning Liu, Peiqiang Yan, Tao Hou, Wenyi Wei.
      The mechanistic target of rapamycin complex 1 (mTORC1) is indispensable for preserving cellular and organismal homeostasis by balancing the anabolic and catabolic processes in response to various environmental cues, such as nutrients, growth factors, energy status, oxygen levels, and stress. Dysregulation of mTORC1 signaling is associated with the progression of many types of human disorders including cancer, age-related diseases, neurodegenerative disorders, and metabolic diseases. The way mTORC1 senses various upstream signals and converts them into specific downstream responses remains a crucial question with significant impacts for our perception of the related physiological and pathological process. In this review, we discuss the recent molecular and functional insights into the nutrient sensing of the mTORC1 signaling pathway, along with the emerging role of deregulating nutrient-mTORC1 signaling in cancer and age-related disorders.
    Keywords:  amino acid; kinase; mTOR; mTORC1; mTORC2; nutrient sensing; phosphorylation; tumorigenesis
    DOI:  https://doi.org/10.1016/j.semcancer.2024.08.001
  8. Proc Natl Acad Sci U S A. 2024 Aug 27. 121(35): e2402491121
    MICU1 and MICU2 control mitochondrial calcium signaling in the mammalian heart.
    Prottoy Hasan, Elena Berezhnaya, Macarena Rodríguez-Prados, David Weaver, Carmen Bekeova, Benjamin Cartes-Saavedra, Erin Birch, Andreas M Beyer, Janine H Santos, Erin L Seifert, John W Elrod, György Hajnóczky.
      Activating Ca2+-sensitive enzymes of oxidative metabolism while preventing calcium overload that leads to mitochondrial and cellular injury requires dynamic control of mitochondrial Ca2+ uptake. This is ensured by the mitochondrial calcium uptake (MICU)1/2 proteins that gate the pore of the mitochondrial calcium uniporter (mtCU). MICU1 is relatively sparse in the heart, and recent studies claimed the mammalian heart lacks MICU1 gating of mtCU. However, genetic models have not been tested. We find that MICU1 is present in a complex with MCU in nonfailing human hearts. Furthermore, using murine genetic models and pharmacology, we show that MICU1 and MICU2 control cardiac mitochondrial Ca2+ influx, and that MICU1 deletion alters cardiomyocyte mitochondrial calcium signaling and energy metabolism. MICU1 loss causes substantial compensatory changes in the mtCU composition and abundance, increased turnover of essential MCU regulator (EMRE) early on and, later, of MCU, that limit mitochondrial Ca2+ uptake and allow cell survival. Thus, both the primary consequences of MICU1 loss and the ensuing robust compensation highlight MICU1's relevance in the beating heart.
    Keywords:  MICU1; MICU2; calcium; cardiomyocyte; mitochondrial calcium uniporter gating
    DOI:  https://doi.org/10.1073/pnas.2402491121
  9. Nat Metab. 2024 Aug 21.
    Regulated insulin secretion from human and mouse islets exclusively composed of β-cells.
      
    DOI:  https://doi.org/10.1038/s42255-024-01117-5
  10. Nat Genet. 2024 Aug 21.
    Organismal metabolism regulates the expansion of oncogenic PIK3CA mutant clones in normal esophagus.
    Albert Herms, Bartomeu Colom, Gabriel Piedrafita, Argyro Kalogeropoulou, Ujjwal Banerjee, Charlotte King, Emilie Abby, Kasumi Murai, Irene Caseda, David Fernandez-Antoran, Swee Hoe Ong, Michael W J Hall, Christopher Bryant, Roshan K Sood, Joanna C Fowler, Albert Pol, Christian Frezza, Bart Vanhaesebroeck, Philip H Jones.
      Oncogenic PIK3CA mutations generate large clones in aging human esophagus. Here we investigate the behavior of Pik3ca mutant clones in the normal esophageal epithelium of transgenic mice. Expression of a heterozygous Pik3caH1047R mutation drives clonal expansion by tilting cell fate toward proliferation. CRISPR screening and inhibitor treatment of primary esophageal keratinocytes confirmed the PI3K-mTOR pathway increased mutant cell competitive fitness. The antidiabetic drug metformin reduced mutant cell advantage in vivo and in vitro. Conversely, metabolic conditions such as type 1 diabetes or diet-induced obesity enhanced the competitive fitness of Pik3caH1047R cells. Consistently, we found a higher density of PIK3CA gain-of-function mutations in the esophagus of individuals with high body mass index compared with those with normal weight. We conclude that the metabolic environment selectively influences the evolution of the normal epithelial mutational landscape. Clinically feasible interventions to even out signaling imbalances between wild-type and mutant cells may limit the expansion of oncogenic mutants in normal tissues.
    DOI:  https://doi.org/10.1038/s41588-024-01891-8
  11. Nat Metab. 2024 Aug 19.
    A safety guide for transgenic Cre drivers in metabolism.
    Carla Horvath, Christian Wolfrum, Pawel Pelczar.
      
    DOI:  https://doi.org/10.1038/s42255-024-01087-8
  12. J Biol Chem. 2024 Aug 14. pii: S0021-9258(24)02179-3. [Epub ahead of print] 107678
    FDX2, an iron-sulfur cluster assembly factor, is essential to prevent cellular senescence, apoptosis or ferroptosis of ovarian cancer cells.
    Shuko Miyahara, Mai Ohuchi, Miyuki Nomura, Eifumi Hashimoto, Tomoyoshi Soga, Rintaro Saito, Kayoko Hayashi, Taku Sato, Masatoshi Saito, Yoji Yamashita, Muneaki Shimada, Nobuo Yaegashi, Hidekazu Yamada, Nobuhiro Tanuma.
      Recent studies reveal that biosynthesis of iron-sulfur clusters (Fe-Ss) is essential for cell proliferation, including that of cancer cells. Nonetheless, it remains unclear how Fe-S biosynthesis functions in cell proliferation/survival. Here, we report that proper Fe-S biosynthesis is essential to prevent cellular senescence, apoptosis or ferroptosis, depending on cell context. To assess these outcomes in cancer, we developed an ovarian cancer line with conditional KO of FDX2, a component of the core Fe-S assembly complex. FDX2 loss induced global down-regulation of Fe-S-containing proteins and Fe2+ overload, resulting in DNA damage and p53 pathway activation, and driving the senescence program. p53-deficiency augmented DNA damage responses upon FDX2 loss, resulting in apoptosis rather than senescence. FDX2 loss also sensitized cells to ferroptosis, as evidenced by compromised redox homeostasis of membrane phospholipids (PLs). Our results suggest that p53 status and PL homeostatic activity are critical determinants of diverse biological outcomes of Fe-S deficiency in cancer cells.
    Keywords:  DNA damage response; cancer biology; cell death; cellular senescence; gene knockout; iron metabolism; iron-sulfur protein; ovarian cancer; p53; reactive oxygen species (ROS); redox regulation; tumor metabolism
    DOI:  https://doi.org/10.1016/j.jbc.2024.107678
  13. Nat Commun. 2024 Aug 22. 15(1): 7241
    Alveolar epithelial cells mitigate neutrophilic inflammation in lung injury through regulating mitochondrial fatty acid oxidation.
    Kuei-Pin Chung, Chih-Ning Cheng, Yi-Jung Chen, Chia-Lang Hsu, Yen-Lin Huang, Min-Shu Hsieh, Han-Chun Kuo, Ya-Ting Lin, Yi-Hsiu Juan, Kiichi Nakahira, Yen-Fu Chen, Wei-Lun Liu, Sheng-Yuan Ruan, Jung-Yien Chien, Maria Plataki, Suzanne M Cloonan, Peter Carmeliet, Augustine M K Choi, Ching-Hua Kuo, Chong-Jen Yu.
      Type 2 alveolar epithelial (AT2) cells of the lung are fundamental in regulating alveolar inflammation in response to injury. Impaired mitochondrial long-chain fatty acid β-oxidation (mtLCFAO) in AT2 cells is assumed to aggravate alveolar inflammation in acute lung injury (ALI), yet the importance of mtLCFAO to AT2 cell function needs to be defined. Here we show that expression of carnitine palmitoyltransferase 1a (CPT1a), a mtLCFAO rate limiting enzyme, in AT2 cells is significantly decreased in acute respiratory distress syndrome (ARDS). In mice, Cpt1a deletion in AT2 cells impairs mtLCFAO without reducing ATP production and alters surfactant phospholipid abundance in the alveoli. Impairing mtLCFAO in AT2 cells via deleting either Cpt1a or Acadl (acyl-CoA dehydrogenase long chain) restricts alveolar inflammation in ALI by hindering the production of the neutrophilic chemokine CXCL2 from AT2 cells. This study thus highlights mtLCFAO as immunometabolism to injury in AT2 cells and suggests impaired mtLCFAO in AT2 cells as an anti-inflammatory response in ARDS.
    DOI:  https://doi.org/10.1038/s41467-024-51683-1
  14. Cell Metab. 2024 Aug 16. pii: S1550-4131(24)00291-2. [Epub ahead of print]
    Misregulation of mitochondrial 6mA promotes the propagation of mutant mtDNA and causes aging in C. elegans.
    Anne Hahn, Grace Ching Ching Hung, Arnaud Ahier, Chuan-Yang Dai, Ina Kirmes, Brian M Forde, Daniel Campbell, Rachel Shin Yie Lee, Josiah Sucic, Tessa Onraet, Steven Zuryn.
      In virtually all eukaryotes, the mitochondrial DNA (mtDNA) encodes proteins necessary for oxidative phosphorylation (OXPHOS) and RNAs required for their synthesis. The mechanisms of regulation of mtDNA copy number and expression are not completely understood but crucially ensure the correct stoichiometric assembly of OXPHOS complexes from nuclear- and mtDNA-encoded subunits. Here, we detect adenosine N6-methylation (6mA) on the mtDNA of diverse animal and plant species. This modification is regulated in C. elegans by the DNA methyltransferase DAMT-1 and demethylase ALKB-1. Misregulation of mtDNA 6mA through targeted modulation of these activities inappropriately alters mtDNA copy number and transcript levels, impairing OXPHOS function, elevating oxidative stress, and shortening lifespan. Compounding these defects, mtDNA 6mA hypomethylation promotes the cross-generational propagation of a deleterious mtDNA. Together, these results reveal that mtDNA 6mA is highly conserved among eukaryotes and regulates lifespan by influencing mtDNA copy number, expression, and heritable mutation levels in vivo.
    Keywords:  6mA; ROS; aging; epigenetics; heteroplasmy; lifespan; mitochondria; mitochondrial genome; mtDNA; oxidative stress
    DOI:  https://doi.org/10.1016/j.cmet.2024.07.020
  15. Bioessays. 2024 Aug 19. e2400090
    FAM210A: An emerging regulator of mitochondrial homeostasis.
    Yubo Wang, Feng Yue.
      Mitochondrial homeostasis serves as a cornerstone of cellular function, orchestrating a delicate balance between energy production, redox status, and cellular signaling transduction. This equilibrium involves a myriad of interconnected processes, including mitochondrial dynamics, quality control mechanisms, and biogenesis and degradation. Perturbations in mitochondrial homeostasis have been implicated in a wide range of diseases, including neurodegenerative diseases, metabolic syndromes, and aging-related disorders. In the past decades, the discovery of numerous mitochondrial proteins and signaling has led to a more complete understanding of the intricate mechanisms underlying mitochondrial homeostasis. Recent studies have revealed that Family with sequence similarity 210 member A (FAM210A) is a novel nuclear-encoded mitochondrial protein involved in multiple aspects of mitochondrial homeostasis, including mitochondrial quality control, dynamics, cristae remodeling, metabolism, and proteostasis. Here, we review the function and physiological role of FAM210A in cellular and organismal health. This review discusses how FAM210A acts as a regulator on mitochondrial inner membrane to coordinate mitochondrial dynamics and metabolism.
    Keywords:  FAM210A; cristae remodeling; energy metabolism; mitochondrial dynamics; proteostasis; quality control
    DOI:  https://doi.org/10.1002/bies.202400090
  16. Cell Rep. 2024 Aug 22. pii: S2211-1247(24)01013-1. [Epub ahead of print]43(9): 114662
    CRISPR screening identifies PRMT1 as a key pro-ferroptotic gene via a two-layer regulatory mechanism.
    Xin Zhang, Yajun Duan, Su Li, Zhenyuan Zhang, Linyuan Peng, Xiaoyu Ma, Tianzhi Wang, Siliang Xiang, Guo Chen, Danyang Zhou, Desheng Lu, Minxian Qian, Zhongyuan Wang.
      Ferroptosis is a form of nonapoptotic cell death characterized by iron-dependent peroxidation of polyunsaturated phospholipids. However, much remains unknown about the regulators of ferroptosis. Here, using CRISPR-Cas9-mediated genetic screening, we identify protein arginine methyltransferase 1 (PRMT1) as a crucial promoter of ferroptosis. We find that PRMT1 decreases the expression of solute carrier family 7 member 11 (SLC7A11) to limit the abundance of intracellular glutathione (GSH). Moreover, we show that PRMT1 interacts with ferroptosis suppressor protein 1 (FSP1), a GSH-independent ferroptosis suppressor, to inhibit the membrane localization and enzymatic activity of FSP1 through arginine dimethylation at R316, thus reducing CoQ10H2 content and inducing ferroptosis sensitivity. Importantly, genetic depletion or pharmacological inhibition of PRMT1 in mice prevents ferroptotic events in the liver and improves the overall survival under concanavalin A (ConA) exposure. Hence, our findings suggest that PRMT1 is a key regulator of ferroptosis and a potential target for antiferroptosis therapeutics.
    Keywords:  ADMA; CP: Immunology; CP: Metabolism; FSP1; PRMT1; SLC7A11; acute liver injury; ferroptosis
    DOI:  https://doi.org/10.1016/j.celrep.2024.114662
  17. Nat Cancer. 2024 Aug 16.
    How tumors hijack macrophages for immune evasion.
    Anders Hofer.
      
    DOI:  https://doi.org/10.1038/s43018-024-00808-y
  18. Cell Metab. 2024 Aug 13. pii: S1550-4131(24)00287-0. [Epub ahead of print]
    Cytosolic calcium regulates hepatic mitochondrial oxidation, intrahepatic lipolysis, and gluconeogenesis via CAMKII activation.
    Traci E LaMoia, Brandon T Hubbard, Mateus T Guerra, Ali Nasiri, Ikki Sakuma, Mario Kahn, Dongyan Zhang, Russell P Goodman, Michael H Nathanson, Yasemin Sancak, Mark Perelis, Vamsi K Mootha, Gerald I Shulman.
      To examine the roles of mitochondrial calcium Ca2+ ([Ca2+]mt) and cytosolic Ca2+ ([Ca2+]cyt) in the regulation of hepatic mitochondrial fat oxidation, we studied a liver-specific mitochondrial calcium uniporter knockout (MCU KO) mouse model with reduced [Ca2+]mt and increased [Ca2+]cyt content. Despite decreased [Ca2+]mt, deletion of hepatic MCU increased rates of isocitrate dehydrogenase flux, α-ketoglutarate dehydrogenase flux, and succinate dehydrogenase flux in vivo. Rates of [14C16]palmitate oxidation and intrahepatic lipolysis were increased in MCU KO liver slices, which led to decreased hepatic triacylglycerol content. These effects were recapitulated with activation of CAMKII and abrogated with CAMKII knockdown, demonstrating that [Ca2+]cyt activation of CAMKII may be the primary mechanism by which MCU deletion promotes increased hepatic mitochondrial oxidation. Together, these data demonstrate that hepatic mitochondrial oxidation can be dissociated from [Ca2+]mt and reveal a key role for [Ca2+]cyt in the regulation of hepatic fat mitochondrial oxidation, intrahepatic lipolysis, gluconeogenesis, and lipid accumulation.
    Keywords:  CAMKII; Q-Flux; calcium; fat oxidation; glucose oxidation; isocitrate dehydrogenase flux; metabolic dysfunction-associated steatotic liver disease; mitochondria; mitochondrial calcium uniporter; succinate dehydrogenase flux; tricarboxylic acid cycle; type 2 diabetes; α-ketoglutarate dehydrogenase flux
    DOI:  https://doi.org/10.1016/j.cmet.2024.07.016
  19. Nat Commun. 2024 Aug 20. 15(1): 7138
    RIOK2 transcriptionally regulates TRiC and dyskerin complexes to prevent telomere shortening.
    Shrestha Ghosh, Mileena T Nguyen, Ha Eun Choi, Maximilian Stahl, Annemarie Luise Kühn, Sandra Van der Auwera, Hans J Grabe, Henry Völzke, Georg Homuth, Samuel A Myers, Cory M Hogaboam, Imre Noth, Fernando J Martinez, Gregory A Petsko, Laurie H Glimcher.
      Telomere shortening is a prominent hallmark of aging and is emerging as a characteristic feature of Myelodysplastic Syndromes (MDS) and Idiopathic Pulmonary Fibrosis (IPF). Optimal telomerase activity prevents progressive shortening of telomeres that triggers DNA damage responses. However, the upstream regulation of telomerase holoenzyme components remains poorly defined. Here, we identify RIOK2, a master regulator of human blood cell development, as a critical transcription factor for telomere maintenance. Mechanistically, loss of RIOK2 or its DNA-binding/transactivation properties downregulates mRNA expression of both TRiC and dyskerin complex subunits that impairs telomerase activity, thereby causing telomere shortening. We further show that RIOK2 expression is diminished in aged individuals and IPF patients, and it strongly correlates with shortened telomeres in MDS patient-derived bone marrow cells. Importantly, ectopic expression of RIOK2 alleviates telomere shortening in IPF patient-derived primary lung fibroblasts. Hence, increasing RIOK2 levels prevents telomere shortening, thus offering therapeutic strategies for telomere biology disorders.
    DOI:  https://doi.org/10.1038/s41467-024-51336-3
  20. Nat Cell Biol. 2024 Aug 21.
    RNA sequestration in P-bodies sustains myeloid leukaemia.
    Srikanth Kodali, Ludovica Proietti, Gemma Valcarcel, Anna V López-Rubio, Patrizia Pessina, Thomas Eder, Junchao Shi, Annie Jen, Núria Lupión-Garcia, Anne C Starner, Mason D Bartels, Yingzhi Cui, Caroline M Sands, Ainoa Planas-Riverola, Alba Martínez, Talia Velasco-Hernandez, Laureano Tomás-Daza, Bernhard Alber, Gabriele Manhart, Isabella Maria Mayer, Karoline Kollmann, Alessandro Fatica, Pablo Menendez, Evgenia Shishkova, Rachel E Rau, Biola M Javierre, Joshua Coon, Qi Chen, Eric L Van Nostrand, Jose L Sardina, Florian Grebien, Bruno Di Stefano.
      Post-transcriptional mechanisms are fundamental safeguards of progenitor cell identity and are often dysregulated in cancer. Here, we identified regulators of P-bodies as crucial vulnerabilities in acute myeloid leukaemia (AML) through genome-wide CRISPR screens in normal and malignant haematopoietic progenitors. We found that leukaemia cells harbour aberrantly elevated numbers of P-bodies and show that P-body assembly is crucial for initiation and maintenance of AML. Notably, P-body loss had little effect upon homoeostatic haematopoiesis but impacted regenerative haematopoiesis. Molecular characterization of P-bodies purified from human AML cells unveiled their critical role in sequestering messenger RNAs encoding potent tumour suppressors from the translational machinery. P-body dissolution promoted translation of these mRNAs, which in turn rewired gene expression and chromatin architecture in leukaemia cells. Collectively, our findings highlight the contrasting and unique roles of RNA sequestration in P-bodies during tissue homoeostasis and oncogenesis. These insights open potential avenues for understanding myeloid leukaemia and future therapeutic interventions.
    DOI:  https://doi.org/10.1038/s41556-024-01489-6
  21. Sci Adv. 2024 Aug 23. 10(34): eado8549
    Succinate dehydrogenase-complex II regulates skeletal muscle cellular respiration and contractility but not muscle mass in genetically induced pulmonary emphysema.
    Joseph Balnis, Ankita Tufts, Emily L Jackson, Lisa A Drake, Diane V Singer, David Lacomis, Chun Geun Lee, Jack A Elias, Jason D Doles, L James Maher, Annie Jen, Joshua J Coon, David Jourd'heuil, Harold A Singer, Catherine E Vincent, Ariel Jaitovich.
      Reduced skeletal muscle mass and oxidative capacity coexist in patients with pulmonary emphysema and are independently associated with higher mortality. If reduced cellular respiration contributes to muscle atrophy in that setting remains unknown. Using a mouse with genetically induced pulmonary emphysema that recapitulates muscle dysfunction, we found that reduced activity of succinate dehydrogenase (SDH) is a hallmark of its myopathic changes. We generated an inducible, muscle-specific SDH knockout mouse that demonstrates lower mitochondrial oxygen consumption, myofiber contractility, and exercise endurance. Respirometry analyses show that in vitro complex I respiration is unaffected by loss of SDH subunit C in muscle mitochondria, which is consistent with the pulmonary emphysema animal data. SDH knockout initially causes succinate accumulation associated with a down-regulated transcriptome but modest proteome effects. Muscle mass, myofiber type composition, and overall body mass constituents remain unaltered in the transgenic mice. Thus, while SDH regulates myofiber respiration in experimental pulmonary emphysema, it does not control muscle mass or other body constituents.
    DOI:  https://doi.org/10.1126/sciadv.ado8549
  22. Neuromuscul Disord. 2024 Aug 02. pii: S0960-8966(24)00146-9. [Epub ahead of print]43 14-19
    Niacin supplementation in a child with novel MTTN variant m.5670A>G causing early onset mitochondrial myopathy and NAD+ deficiency.
    Juho Aaltio, Liliya Euro, Olli Tynninen, Hieu S Vu, Min Ni, Ralph J DeBerardinis, Anu Suomalainen, Pirjo Isohanni.
      Myopathy is a common manifestation in mitochondrial disorders, but the pathomechanisms are still insufficiently studied in children. Here, we report a severe, progressive mitochondrial myopathy in a four-year-old child, who died at eight years. He developed progressive loss of muscle strength with nocturnal hypoventilation and dilated cardiomyopathy. Skeletal muscle showed ragged red fibers and severe combined respiratory chain deficiency. Mitochondrial DNA sequencing revealed a novel m.5670A>G mutation in mitochondrial tRNAAsn (MTTN) with 88 % heteroplasmy in muscle. The proband also had systemic NAD+ deficiency but rescuing this with the NAD+ precursor niacin did not stop disease progression. Targeted metabolomics revealed an overall shift of metabolism towards controls after niacin supplementation, with normalized tryptophan metabolites and lipid-metabolic markers, but most amino acids did not respond to niacin therapy. To conclude, we report a new MTTN mutation, secondary NAD+ deficiency in childhood-onset mitochondrial myopathy with metabolic but meager clinical response to niacin supplementation.
    Keywords:  MTTN; Mitochondrial myopathy; NAD+ deficiency; Niacin; Niacin supplementation; tRNA-Asn
    DOI:  https://doi.org/10.1016/j.nmd.2024.07.005
  23. Cell Rep. 2024 Aug 20. pii: S2211-1247(24)01014-3. [Epub ahead of print]43(9): 114663
    Non-canonical metabolic and molecular effects of calorie restriction are revealed by varying temporal conditions.
    Heidi H Pak, Allison N Grossberg, Rachel R Sanderfoot, Reji Babygirija, Cara L Green, Mikaela Koller, Monika Dzieciatkowska, Daniel A Paredes, Dudley W Lamming.
      Calorie restriction (CR) extends lifespan and healthspan in diverse species. Comparing ad libitum- and CR-fed mice is challenging due to their significantly different feeding patterns, with CR-fed mice consuming their daily meal in 2 h and then subjecting themselves to a prolonged daily fast. Here, we examine how ad libitum- and CR-fed mice respond to tests performed at various times and fasting durations and find that the effects of CR-insulin sensitivity, circulating metabolite levels, and mechanistic target of rapamycin 1 (mTORC1) activity-result from the specific temporal conditions chosen, with CR-induced improvements in insulin sensitivity observed only after a prolonged fast, and the observed differences in mTORC1 activity between ad libitum- and CR-fed mice dependent upon both fasting duration and the specific tissue examined. Our results demonstrate that much of our understanding of the effects of CR are related to when, relative to feeding, we choose to examine the mice.
    Keywords:  CP: Metabolism; aging; calorie restriction; dietary restriction; fasting; lifespan; mTOR; time-restricted feeding
    DOI:  https://doi.org/10.1016/j.celrep.2024.114663
  24. Nature. 2024 Aug 21.
    Stem cells tightly regulate dead cell clearance to maintain tissue fitness.
    Katherine S Stewart, Merve Deniz Abdusselamoglu, Matthew T Tierney, Anita Gola, Yun Ha Hur, Kevin A U Gonzales, Shaopeng Yuan, Alain R Bonny, Yihao Yang, Nicole R Infarinato, Christopher J Cowley, John M Levorse, Hilda Amalia Pasolli, Sourav Ghosh, Carla V Rothlin, Elaine Fuchs.
      Billions of cells are eliminated daily from our bodies1-4. Although macrophages and dendritic cells are dedicated to migrating and engulfing dying cells and debris, many epithelial and mesenchymal tissue cells can digest nearby apoptotic corpses1-4. How these non-motile, non-professional phagocytes sense and eliminate dying cells while maintaining their normal tissue functions is unclear. Here we explore the mechanisms that underlie their multifunctionality by exploiting the cyclical bouts of tissue regeneration and degeneration during hair cycling. We show that hair follicle stem cells transiently unleash phagocytosis at the correct time and place through local molecular triggers that depend on both lipids released by neighbouring apoptotic corpses and retinoids released by healthy counterparts. We trace the heart of this dual ligand requirement to RARγ-RXRα, whose activation enables tight regulation of apoptotic cell clearance genes and provides an effective, tunable mechanism to offset phagocytic duties against the primary stem cell function of preserving tissue integrity during homeostasis. Finally, we provide functional evidence that hair follicle stem cell-mediated phagocytosis is not simply redundant with professional phagocytes but rather has clear benefits to tissue fitness. Our findings have broad implications for other non-motile tissue stem or progenitor cells that encounter cell death in an immune-privileged niche.
    DOI:  https://doi.org/10.1038/s41586-024-07855-6
  25. PLoS Biol. 2024 Aug 23. 22(8): e3002781
    Metabolic specialization drives reduced pathogenicity in Pseudomonas aeruginosa isolates from cystic fibrosis patients.
    Bjarke Haldrup Pedersen, Filipa Bica Simões, Ivan Pogrebnyakov, Martin Welch, Helle Krogh Johansen, Søren Molin, Ruggero La Rosa.
      Metabolism provides the foundation for all cellular functions. During persistent infections, in adapted pathogenic bacteria metabolism functions radically differently compared with more naïve strains. Whether this is simply a necessary accommodation to the persistence phenotype or if metabolism plays a direct role in achieving persistence in the host is still unclear. Here, we characterize a convergent shift in metabolic function(s) linked with the persistence phenotype during Pseudomonas aeruginosa colonization in the airways of people with cystic fibrosis. We show that clinically relevant mutations in the key metabolic enzyme, pyruvate dehydrogenase, lead to a host-specialized metabolism together with a lower virulence and immune response recruitment. These changes in infection phenotype are mediated by impaired type III secretion system activity and by secretion of the antioxidant metabolite, pyruvate, respectively. Our results show how metabolic adaptations directly impinge on persistence and pathogenicity in this organism.
    DOI:  https://doi.org/10.1371/journal.pbio.3002781
  26. PLoS Biol. 2024 Aug;22(8): e3002723
    Somatic nuclear mitochondrial DNA insertions are prevalent in the human brain and accumulate over time in fibroblasts.
    Weichen Zhou, Kalpita R Karan, Wenjin Gu, Hans-Ulrich Klein, Gabriel Sturm, Philip L De Jager, David A Bennett, Michio Hirano, Martin Picard, Ryan E Mills.
      The transfer of mitochondrial DNA into the nuclear genomes of eukaryotes (Numts) has been linked to lifespan in nonhuman species and recently demonstrated to occur in rare instances from one human generation to the next. Here, we investigated numtogenesis dynamics in humans in 2 ways. First, we quantified Numts in 1,187 postmortem brain and blood samples from different individuals. Compared to circulating immune cells (n = 389), postmitotic brain tissue (n = 798) contained more Numts, consistent with their potential somatic accumulation. Within brain samples, we observed a 5.5-fold enrichment of somatic Numt insertions in the dorsolateral prefrontal cortex (DLPFC) compared to cerebellum samples, suggesting that brain Numts arose spontaneously during development or across the lifespan. Moreover, an increase in the number of brain Numts was linked to earlier mortality. The brains of individuals with no cognitive impairment (NCI) who died at younger ages carried approximately 2 more Numts per decade of life lost than those who lived longer. Second, we tested the dynamic transfer of Numts using a repeated-measures whole-genome sequencing design in a human fibroblast model that recapitulates several molecular hallmarks of aging. These longitudinal experiments revealed a gradual accumulation of 1 Numt every ~13 days. Numtogenesis was independent of large-scale genomic instability and unlikely driven by cell clonality. Targeted pharmacological perturbations including chronic glucocorticoid signaling or impairing mitochondrial oxidative phosphorylation (OxPhos) only modestly increased the rate of numtogenesis, whereas patient-derived SURF1-mutant cells exhibiting mtDNA instability accumulated Numts 4.7-fold faster than healthy donors. Combined, our data document spontaneous numtogenesis in human cells and demonstrate an association between brain cortical somatic Numts and human lifespan. These findings open the possibility that mito-nuclear horizontal gene transfer among human postmitotic tissues produces functionally relevant human Numts over timescales shorter than previously assumed.
    DOI:  https://doi.org/10.1371/journal.pbio.3002723
  27. Sci Immunol. 2024 Aug 23. 9(98): eadn2717
    PPARβ/δ-orchestrated metabolic reprogramming supports the formation and maintenance of memory CD8+ T cells.
    Alessio Bevilacqua, Fabien Franco, Ya-Ting Lu, Nabil Rahiman, Kung-Chi Kao, Yu-Ming Chuang, Yanan Zhu, Werner Held, Xin Xie, Kristin C Gunsalus, Zhengtao Xiao, Shih-Yu Chen, Ping-Chih Ho.
      The formation of memory T cells is a fundamental feature of adaptative immunity, allowing the establishment of long-term protection against pathogens. Although emerging evidence suggests that metabolic reprogramming is crucial for memory T cell differentiation and survival, the underlying mechanisms that drive metabolic rewiring in memory T cells remain unclear. Here, we found that up-regulation of the nuclear receptor peroxisome proliferator-activated receptor β/δ (PPARβ/δ) instructs the metabolic reprogramming that occurs during the establishment of central memory CD8+ T cells. PPARβ/δ-regulated changes included suppression of aerobic glycolysis and enhancement of oxidative metabolism and fatty acid oxidation. Mechanistically, exposure to interleukin-15 and expression of T cell factor 1 facilitated activation of the PPARβ/δ pathway, counteracting apoptosis induced by antigen clearance and metabolic stress. Together, our findings indicate that PPARβ/δ is a master metabolic regulator orchestrating a metabolic switch that may be favorable for T cell longevity.
    DOI:  https://doi.org/10.1126/sciimmunol.adn2717
  28. Nat Commun. 2024 Aug 21. 15(1): 7181
    A class I PI3K signalling network regulates primary cilia disassembly in normal physiology and disease.
    Sarah E Conduit, Wayne Pearce, Amandeep Bhamra, Benoit Bilanges, Laura Bozal-Basterra, Lazaros C Foukas, Mathias Cobbaut, Sandra D Castillo, Mohammad Amin Danesh, Mahreen Adil, Arkaitz Carracedo, Mariona Graupera, Neil Q McDonald, Peter J Parker, Pedro R Cutillas, Silvia Surinova, Bart Vanhaesebroeck.
      Primary cilia are antenna-like organelles which sense extracellular cues and act as signalling hubs. Cilia dysfunction causes a heterogeneous group of disorders known as ciliopathy syndromes affecting most organs. Cilia disassembly, the process by which cells lose their cilium, is poorly understood but frequently observed in disease and upon cell transformation. Here, we uncover a role for the PI3Kα signalling enzyme in cilia disassembly. Genetic PI3Kα-hyperactivation, as observed in PIK3CA-related overgrowth spectrum (PROS) and cancer, induced a ciliopathy-like phenotype during mouse development. Mechanistically, PI3Kα and PI3Kβ produce the PIP3 lipid at the cilia transition zone upon disassembly stimulation. PI3Kα activation initiates cilia disassembly through a kinase signalling axis via the PDK1/PKCι kinases, the CEP170 centrosomal protein and the KIF2A microtubule-depolymerising kinesin. Our data suggest diseases caused by PI3Kα-activation may be considered 'Disorders with Ciliary Contributions', a recently-defined subset of ciliopathies in which some, but not all, of the clinical manifestations result from cilia dysfunction.
    DOI:  https://doi.org/10.1038/s41467-024-51354-1
  29. Nature. 2024 Aug 22.
    Can ageing be stopped? A biologist explains.
    Benjamin Thompson.
      
    Keywords:  Ageing; Cancer; Public health
    DOI:  https://doi.org/10.1038/d41586-024-02713-x
  30. Nat Commun. 2024 Aug 21. 15(1): 7121
    The effects of ENDOG on lipid metabolism may be tissue-dependent and may not require its translocation from mitochondria.
    Marta Llovera, Leonor Gouveia, Antonio Zorzano, Daniel Sanchis.
      
    DOI:  https://doi.org/10.1038/s41467-024-51447-x
  31. Nature. 2024 Aug 21.
    Short-term post-fast refeeding enhances intestinal stemness via polyamines.
    Shinya Imada, Saleh Khawaled, Heaji Shin, Sven W Meckelmann, Charles A Whittaker, Renan Oliveira Corrêa, Chiara Alquati, Yixin Lu, Guodong Tie, Dikshant Pradhan, Gizem Calibasi-Kocal, Luiza Martins Nascentes Melo, Gabriele Allies, Jonas Rösler, Pia Wittenhofer, Jonathan Krystkiewicz, Oliver J Schmitz, Jatin Roper, Marco Aurelio Ramirez Vinolo, Luigi Ricciardiello, Evan C Lien, Matthew G Vander Heiden, Ramesh A Shivdasani, Chia-Wei Cheng, Alpaslan Tasdogan, Ömer H Yilmaz.
      For over a century, fasting regimens have improved health, lifespan and tissue regeneration in diverse organisms, including humans1-6. However, how fasting and post-fast refeeding affect adult stem cells and tumour formation has yet to be explored in depth. Here we demonstrate that post-fast refeeding increases intestinal stem cell (ISC) proliferation and tumour formation; post-fast refeeding augments the regenerative capacity of Lgr5+ ISCs, and loss of the tumour suppressor gene Apc in post-fast-refed ISCs leads to a higher tumour incidence in the small intestine and colon than in the fasted or ad libitum-fed states, demonstrating that post-fast refeeding is a distinct state. Mechanistically, we discovered that robust mTORC1 induction in post-fast-refed ISCs increases protein synthesis via polyamine metabolism to drive these changes, as inhibition of mTORC1, polyamine metabolite production or protein synthesis abrogates the regenerative or tumorigenic effects of post-fast refeeding. Given our findings, fast-refeeding cycles must be carefully considered and tested when planning diet-based strategies for regeneration without increasing cancer risk, as post-fast refeeding leads to a burst in stem-cell-driven regeneration and tumorigenicity.
    DOI:  https://doi.org/10.1038/s41586-024-07840-z
  32. Plant J. 2024 Aug 23.
    Coordinated metabolic adaptation of Arabidopsis thaliana to high light.
    Gerd Ulrich Balcke, Khabat Vahabi, Jonas Giese, Iris Finkemeier, Alain Tissier.
      
    Keywords:  acclimation; anaplerosis; excess light; malate valve; metabolism; metabolomics; photosystem; regulation; stress; transcriptomics; vacuole
    DOI:  https://doi.org/10.1111/tpj.16992
  33. Nat Cell Biol. 2024 Aug 22.
    The Rubicon-WIPI axis regulates exosome biogenesis during ageing.
    Kyosuke Yanagawa, Akiko Kuma, Maho Hamasaki, Shunbun Kita, Tadashi Yamamuro, Kohei Nishino, Shuhei Nakamura, Hiroko Omori, Tatsuya Kaminishi, Satoshi Oikawa, Yoshio Kato, Ryuya Edahiro, Ryosuke Kawagoe, Takako Taniguchi, Yoko Tanaka, Takayuki Shima, Keisuke Tabata, Miki Iwatani, Nao Bekku, Rikinari Hanayama, Yukinori Okada, Takayuki Akimoto, Hidetaka Kosako, Akiko Takahashi, Iichiro Shimomura, Yasushi Sakata, Tamotsu Yoshimori.
      Cells release intraluminal vesicles in multivesicular bodies as exosomes to communicate with other cells. Although recent studies suggest an intimate link between exosome biogenesis and autophagy, the detailed mechanism is not fully understood. Here we employed comprehensive RNA interference screening for autophagy-related factors and discovered that Rubicon, a negative regulator of autophagy, is essential for exosome release. Rubicon recruits WIPI2d to endosomes to promote exosome biogenesis. Interactome analysis of WIPI2d identified the ESCRT components that are required for intraluminal vesicle formation. Notably, we found that Rubicon is required for an age-dependent increase of exosome release in mice. In addition, small RNA sequencing of serum exosomes revealed that Rubicon determines the fate of exosomal microRNAs associated with cellular senescence and longevity pathways. Taken together, our current results suggest that the Rubicon-WIPI axis functions as a key regulator of exosome biogenesis and is responsible for age-dependent changes in exosome quantity and quality.
    DOI:  https://doi.org/10.1038/s41556-024-01481-0
  34. Redox Biol. 2024 Jul 28. pii: S2213-2317(24)00267-2. [Epub ahead of print]76 103289
    Transcriptional Isoforms of NAD+ kinase regulate oxidative stress resistance and melanoma metastasis.
    Graciela Cascio, Kelsey N Aguirre, Kellsey P Church, Riley O Hughes, Leona A Nease, Ines Delclaux, Hannah J Davis, Elena Piskounova.
      Metastasizing cancer cells encounter a multitude of stresses throughout the metastatic cascade. Oxidative stress is known to be a major barrier for metastatic colonization, such that metastasizing cancer cells must rewire their metabolic pathways to increase their antioxidant capacity. NADPH is essential for regeneration of cellular antioxidants and several NADPH-regenerating pathways have been shown to play a role in metastasis. We have found that metastatic melanoma cells have increased levels of both NADPH and NADP+ suggesting increased de novo biosynthesis of NADP+. De novo biosynthesis of NADP+ occurs through a single enzymatic reaction catalyzed by NAD+ kinase (NADK). Here we show that different NADK isoforms are differentially expressed in metastatic melanoma cells, with Isoform 3 being specifically upregulated in metastasis. We find that Isoform 3 is more potent in expanding the NADP(H) pools, increasing oxidative stress resistance and promoting metastatic colonization compared to Isoform 1. We have found that Isoform 3 is transcriptionally upregulated by oxidative stress through the action of NRF2. Together, our work presents a previously uncharacterized role of NADK isoforms in oxidative stress resistance and metastasis and suggests that NADK Isoform 3 is a potential therapeutic target in metastatic disease.
    Keywords:  Antioxidants; Metastasis; NADK; NADP(+); Oxidative stress
    DOI:  https://doi.org/10.1016/j.redox.2024.103289
  35. Cell Rep. 2024 Aug 18. pii: S2211-1247(24)00982-3. [Epub ahead of print]43(8): 114632
    Aerobic glycolysis but not GLS1-dependent glutamine metabolism is critical for anti-tumor immunity and response to checkpoint inhibition.
    Patrick M Gubser, Sharanya Wijesinghe, Leonie Heyden, Sarah S Gabriel, David P de Souza, Christoph Hess, Malcolm M McConville, Daniel T Utzschneider, Axel Kallies.
      Tumor cells undergo uncontrolled proliferation driven by enhanced anabolic metabolism including glycolysis and glutaminolysis. Targeting these pathways to inhibit cancer growth is a strategy for cancer treatment. Critically, however, tumor-responsive T cells share metabolic features with cancer cells, making them susceptible to these treatments as well. Here, we assess the impact on anti-tumor T cell immunity and T cell exhaustion by genetic ablation of lactate dehydrogenase A (LDHA) and glutaminase1 (GLS1), key enzymes in aerobic glycolysis and glutaminolysis. Loss of LDHA severely impairs expansion of T cells in response to tumors and chronic infection. In contrast, T cells lacking GLS1 can compensate for impaired glutaminolysis by engaging alternative pathways, including upregulation of asparagine synthetase, and thus efficiently respond to tumor challenge and chronic infection as well as immune checkpoint blockade. Targeting GLS1-dependent glutaminolysis, but not aerobic glycolysis, may therefore be a successful strategy in cancer treatment, particularly in combination with immunotherapy.
    Keywords:  CP: Cancer; CP: Metabolism; GLS1; LDHA; Tpex
    DOI:  https://doi.org/10.1016/j.celrep.2024.114632
  36. Cell Rep. 2024 Aug 17. pii: S2211-1247(24)00983-5. [Epub ahead of print]43(8): 114633
    A CLIC1 network coordinates matrix stiffness and the Warburg effect to promote tumor growth in pancreatic cancer.
    Jia-Hao Zheng, Yu-Heng Zhu, Jian Yang, Pei-Xuan Ji, Rui-Kang Zhao, Zong-Hao Duan, Hong-Fei Yao, Qin-Yuan Jia, Yi-Fan Yin, Li-Peng Hu, Qing Li, Shu-Heng Jiang, Yan-Miao Huo, Wei Liu, Yong-Wei Sun, De-Jun Liu.
      Pancreatic ductal adenocarcinoma (PDAC) features substantial matrix stiffening and reprogrammed glucose metabolism, particularly the Warburg effect. However, the complex interplay between these traits and their impact on tumor advancement remains inadequately explored. Here, we integrated clinical, cellular, and bioinformatics approaches to explore the connection between matrix stiffness and the Warburg effect in PDAC, identifying CLIC1 as a key mediator. Elevated CLIC1 expression, induced by matrix stiffness through Wnt/β-catenin/TCF4 signaling, signifies poorer prognostic outcomes in PDAC. Functionally, CLIC1 serves as a catalyst for glycolytic metabolism, propelling tumor proliferation. Mechanistically, CLIC1 fortifies HIF1α stability by curbing hydroxylation via reactive oxygen species (ROS). Collectively, PDAC cells elevate CLIC1 levels in a matrix-stiffness-responsive manner, bolstering the Warburg effect to drive tumor growth via ROS/HIF1α signaling. Our insights highlight opportunities for targeted therapies that concurrently address matrix properties and metabolic rewiring, with CLIC1 emerging as a promising intervention point.
    Keywords:  CP: Cancer; CP: Metabolism; chloride intracellular channel 1; extracellular matrix stiffness; pancreatic ductal adenocarcinoma; the Warburg effect
    DOI:  https://doi.org/10.1016/j.celrep.2024.114633
  37. Sci Adv. 2024 Aug 23. 10(34): eadn6016
    Phosphoglycerate kinase is a central leverage point in Parkinson's disease-driven neuronal metabolic deficits.
    Alexandros C Kokotos, Aldana M Antoniazzi, Santiago R Unda, Myung Soo Ko, Daehun Park, David Eliezer, Michael G Kaplitt, Pietro De Camilli, Timothy A Ryan.
      Although certain drivers of familial Parkinson's disease (PD) compromise mitochondrial integrity, whether metabolic deficits underly other idiopathic or genetic origins of PD is unclear. Here, we demonstrate that phosphoglycerate kinase 1 (PGK1), a gene in the PARK12 susceptibility locus, is rate limiting in neuronal glycolysis and that modestly increasing PGK1 expression boosts neuronal adenosine 5'-triphosphate production kinetics that is sufficient to suppress PARK20-driven synaptic dysfunction. We found that this activity enhancement depends on the molecular chaperone PARK7/DJ-1, whose loss of function significantly disrupts axonal bioenergetics. In vivo, viral expression of PGK1 confers protection of striatal dopamine axons against metabolic lesions. These data support the notion that bioenergetic deficits may underpin PD-associated pathologies and point to improving neuronal adenosine 5'-triphosphate production kinetics as a promising path forward in PD therapeutics.
    DOI:  https://doi.org/10.1126/sciadv.adn6016
  38. Nat Commun. 2024 Aug 20. 15(1): 7132
    Mdm2 requires Sprouty4 to regulate focal adhesion formation and metastasis independent of p53.
    Rafaela Muniz de Queiroz, Gizem Efe, Asja Guzman, Naoko Hashimoto, Yusuke Kawashima, Tomoaki Tanaka, Anil K Rustgi, Carol Prives.
      Although the E3 ligase Mdm2 and its homologue and binding partner MdmX are the major regulators of the p53 tumor suppressor protein, it is now evident that Mdm2 and MdmX have multiple functions that do not involve p53. As one example, it is known that Mdm2 can regulate cell migration, although mechanistic insight into this function is still lacking. Here we show in cells lacking p53 expression that knockdown of Mdm2 or MdmX, as well as pharmacological inhibition of the Mdm2/MdmX complex, not only reduces cell migration and invasion, but also impairs cell spreading and focal adhesion formation. In addition, Mdm2 knockdown decreases metastasis in vivo. Interestingly, Mdm2 downregulates the expression of Sprouty4, which is required for the Mdm2 mediated effects on cell migration, focal adhesion formation and metastasis. Further, our findings indicate that Mdm2 dampening of Sprouty4 is a prerequisite for maintaining RhoA levels in the cancer cells that we have studied. Taken together we describe a molecular mechanism whereby the Mdm2/MdmX complex through Sprouty4 regulates cellular processes leading to increase metastatic capability independently of p53.
    DOI:  https://doi.org/10.1038/s41467-024-51488-2
  39. J Biol Chem. 2024 Aug 20. pii: S0021-9258(24)02198-7. [Epub ahead of print] 107697
    Cell fate simulation reveals cancer cell features in the tumor microenvironment.
    Sachiko Sato, Ann Rancourt, Masahiko S Satoh.
      To elucidate the dynamic evolution of cancer cell characteristics within the tumor microenvironment (TME), we developed an integrative approach combining single-cell tracking, cell fate simulation, and three-dimensional (3D) TME modeling. We began our investigation by analyzing the spatiotemporal behavior of individual cancer cells in cultured pancreatic (MiaPaCa2) and cervical (HeLa) cancer cell lines, with a focus on the α2-6 sialic acid (α2-6Sia) modification on glycans, which is associated with cell stemness. Our findings revealed that MiaPaCa2 cells exhibited significantly higher levels of α2-6Sia modification, correlating with enhanced reproductive capabilities, whereas HeLa cells showed less prevalence of this modification. To accommodate the in vivo variability of α2-6Sia levels, we employed a cell fate simulation algorithm that digitally generates cell populations based on our observed data while varying the level of sialylation, thereby simulating cell growth patterns. Subsequently, we performed a 3D TME simulation with these deduced cell populations, considering the microenvironment that could impact cancer cell growth. Immune cell landscape information derived from 193 cervical and 172 pancreatic cancer cases was used to estimate the degree of the positive or negative impact. Our analysis suggests that the deduced cells generated based on the characteristics of MiaPaCa2 cells are less influenced by the immune cell landscape within the TME compared to those of HeLa cells, highlighting that the fate of cancer cells is shaped by both the surrounding immune landscape and the intrinsic characteristics of the cancer cells.
    Keywords:  3-dimensional tumor microenvironment simulation; Sambucus nigra lectin; Single-cell tracking; cancer cell heterogeneity; cancer cell lines; cell fate simulation; cervical cancer; live cell imaging; pancreatic cancer; stemness; tumor microenvironment; α2-6 sialic acid modification on glycans
    DOI:  https://doi.org/10.1016/j.jbc.2024.107697
  40. Cell Mol Life Sci. 2024 Aug 19. 81(1): 357
    SLC30A9: an evolutionarily conserved mitochondrial zinc transporter essential for mammalian early embryonic development.
    Jing Ge, Huihui Li, Xin Liang, Bing Zhou.
      SLC30A9 (ZnT9) is a mitochondria-resident zinc transporter. Mutations in SLC30A9 have been reported in human patients with a novel cerebro-renal syndrome. Here, we show that ZnT9 is an evolutionarily highly conserved protein, with many regions extremely preserved among evolutionarily distant organisms. In Drosophila melanogaster (the fly), ZnT9 (ZnT49B) knockdown results in acutely impaired movement and drastic mitochondrial deformation. Severe Drosophila ZnT9 (dZnT9) reduction and ZnT9-null mutant flies are pupal lethal. The phenotype of dZnT9 knockdown can be partially rescued by mouse ZnT9 expression or zinc chelator TPEN, indicating the defect of dZnT9 loss is indeed a result of zinc dyshomeostasis. Interestingly, in the mouse, germline loss of Znt9 produces even more extreme phenotypes: the mutant embryos exhibit midgestational lethality with severe development abnormalities. Targeted mutagenesis of Znt9 in the mouse brain leads to serious dwarfism and physical incapacitation, followed by death shortly. Strikingly, the GH/IGF-1 signals are almost non-existent in these tissue-specific knockout mice, consistent with the medical finding in some human patients with severe mitochondrial deficiecny. ZnT9 mutations cause mitochondrial zinc dyshomeostasis, and we demonstrate mechanistically that mitochondrial zinc elevation quickly and potently inhibits the activities of respiration complexes. These results reveal the critical role of ZnT9 and mitochondrial zinc homeostasis in mammalian development. Based on our functional analyses, we finally discussed the possible nature of the so far identified human SLC30A9 mutations.
    Keywords:  CG8632; Electron transport chain; GH/IGF; ZnT49B; ZnT9
    DOI:  https://doi.org/10.1007/s00018-024-05377-y
  41. Nature. 2024 Aug 21.
    The periosteum provides a stromal defence against cancer invasion into the bone.
    Kazutaka Nakamura, Masayuki Tsukasaki, Takaaki Tsunematsu, Minglu Yan, Yutaro Ando, Nam Cong-Nhat Huynh, Kyoko Hashimoto, Qiao Gou, Ryunosuke Muro, Ayumi Itabashi, Takahiro Iguchi, Kazuo Okamoto, Takashi Nakamura, Kenta Nakano, Tadashi Okamura, Tomoya Ueno, Kosei Ito, Naozumi Ishimaru, Kazuto Hoshi, Hiroshi Takayanagi.
      The periosteum is the layer of cells that covers nearly the entire surface of every bone. Upon infection, injury or malignancy the bone surface undergoes new growth-the periosteal reaction-but the mechanism and physiological role of this process remain unknown1,2. Here we show that the periosteal reaction protects against cancer invasion into the bone. Histological analyses of human lesions of head and neck squamous cell carcinomas (HNSCCs) show that periosteal thickening occurs in proximity to the tumour. We developed a genetically dissectible mouse model of HNSCC and demonstrate that inducible depletion of periosteal cells accelerates cancerous invasion of the bone. Single-cell RNA sequencing reveals that expression of the gene encoding the protease inhibitor TIMP1 is markedly increased in the periosteum at the pre-invasive stage. This increase is due to upregulation of HIF1α expression in the tumour microenvironment, and increased TIMP1 inactivates matrix-degrading proteases, promoting periosteal thickening to inhibit cancer invasion. Genetic deletion of Timp1 impairs periosteal expansion, exacerbating bone invasion and decreasing survival in tumour-bearing mice. Together, these data show that the periosteal reaction may act as a functional stromal barrier against tumour progression, representing a unique example of tissue immunity mediated by stromal cells.
    DOI:  https://doi.org/10.1038/s41586-024-07822-1
  42. Cell Syst. 2024 Aug 21. pii: S2405-4712(24)00206-0. [Epub ahead of print]15(8): 738-752.e5
    Enhanced cellular longevity arising from environmental fluctuations.
    Yuting Liu, Zhen Zhou, Hetian Su, Songlin Wu, Gavin Ni, Alex Zhang, Lev S Tsimring, Jeff Hasty, Nan Hao.
      Cellular longevity is regulated by both genetic and environmental factors. However, the interactions of these factors in the context of aging remain largely unclear. Here, we formulate a mathematical model for dynamic glucose modulation of a core gene circuit in yeast aging, which not only guided the design of pro-longevity interventions but also revealed the theoretical principles underlying these interventions. We introduce the dynamical systems theory to capture two general means for promoting longevity-the creation of a stable fixed point in the "healthy" state of the cell and the "dynamic stabilization" of the system around this healthy state through environmental oscillations. Guided by the model, we investigate how both of these can be experimentally realized by dynamically modulating environmental glucose levels. The results establish a paradigm for theoretically analyzing the trajectories and perturbations of aging that can be generalized to aging processes in diverse cell types and organisms.
    Keywords:  aging; caloric restriction; computational modeling; dynamical systems theory; longevity; metabolism; quantitative biology; single-cell imaging; systems biology; time-lapse microscopy
    DOI:  https://doi.org/10.1016/j.cels.2024.07.007
  43. Proc Natl Acad Sci U S A. 2024 Aug 27. 121(35): e2402697121
    Circadian and environmental signal integration in a natural population of Arabidopsis.
    Haruki Nishio, Dora L Cano-Ramirez, Tomoaki Muranaka, Luíza Lane de Barros Dantas, Mie N Honjo, Jiro Sugisaka, Hiroshi Kudoh, Antony N Dodd.
      Plants sense and respond to environmental cues during 24 h fluctuations in their environment. This requires the integration of internal cues such as circadian timing with environmental cues such as light and temperature to elicit cellular responses through signal transduction. However, the integration and transduction of circadian and environmental signals by plants growing in natural environments remains poorly understood. To gain insights into 24 h dynamics of environmental signaling in nature, we performed a field study of signal transduction from the nucleus to chloroplasts in a natural population of Arabidopsis halleri. Using several modeling approaches to interpret the data, we identified that the circadian clock and temperature are key regulators of this pathway under natural conditions. We identified potential time-delay steps between pathway components, and diel fluctuations in the response of the pathway to temperature cues that are reminiscent of the process of circadian gating. We found that our modeling framework can be extended to other signaling pathways that undergo diel oscillations and respond to environmental cues. This approach of combining studies of gene expression in the field with modeling allowed us to identify the dynamic integration and transduction of environmental cues, in plant cells, under naturally fluctuating diel cycles.
    Keywords:  circadian rhythms; field biology; signal transduction; state-space modeling
    DOI:  https://doi.org/10.1073/pnas.2402697121
  44. Cells Dev. 2024 Aug 14. pii: S2667-2901(24)00072-X. [Epub ahead of print] 203964
    Of criminals and cancer: The importance of social bonds and innate morality on cellular societies.
    Anuraag Bukkuri, Frederick R Adler.
      The current dogma in cancer biology contends that cancer is an identity problem: mutations in a cell's DNA cause it to "go rogue" and proliferate out of control. However, this largely ignores the role of cell-cell interaction and fails to explain phenomena such as cancer reversion, the existence of cancers without mutations, and foreign-body carcinogenesis. In this proof-of-concept paper, we draw on criminology to propose that cancer may alternatively be conceptualized as a relational problem: Although a cell's genetics is essential, the influence of its interaction with other cells is equally important in determining its phenotype. We create a simple agent-based network model of interactions among normal and cancer cells to demonstrate this idea. We find that both high mutation rates and low levels of connectivity among cells can promote oncogenesis. Viewing cancer as a breakdown in communication networks among cells in a tissue complements the gene-centric paradigm nicely and provides a novel perspective for understanding and treating cancer.
    Keywords:  Cancer evolution; Cancer reversion; Cancer, corruption, and criminology; Foreign-body carcinogenesis; Somatic mutation theory
    DOI:  https://doi.org/10.1016/j.cdev.2024.203964
  45. Oncogene. 2024 Aug 18.
    Jumonji histone demethylases are therapeutic targets in small cell lung cancer.
    Aiden Nguyen, Clarissa G Nuñez, Tram Anh Tran, Luc Girard, Michael Peyton, Rodrigo Catalan, Cristina Guerena, Kimberley Avila, Benjamin J Drapkin, Raghav Chandra, John D Minna, Elisabeth D Martinez.
      Small cell lung cancer (SCLC) is a recalcitrant cancer of neuroendocrine (NE) origin. Changes in therapeutic approaches against SCLC have been lacking over the decades. Here, we use preclinical models to identify a new therapeutic vulnerability in SCLC consisting of the targetable Jumonji lysine demethylase (KDM) family. We show that Jumonji demethylase inhibitors block malignant growth and that etoposide-resistant SCLC cell lines are particularly sensitive to Jumonji inhibition. Mechanistically, small molecule-mediated inhibition of Jumonji KDMs activates endoplasmic reticulum (ER) stress genes, upregulates ER stress signaling, and triggers apoptotic cell death. Furthermore, Jumonji inhibitors decrease protein levels of SCLC NE markers INSM1 and Secretogranin-3 and of driver transcription factors ASCL1 and NEUROD1. Genetic knockdown of KDM4A, a Jumonji demethylase highly expressed in SCLC and a known regulator of ER stress genes, induces ER stress response genes, decreases INSM1, Secretogranin-3, and NEUROD1 and inhibits proliferation of SCLC in vitro and in vivo. Lastly, we demonstrate that two different small molecule Jumonji KDM inhibitors (pan-inhibitor JIB-04 and KDM4 inhibitor SD70) block the growth of SCLC tumor xenografts in vivo. Our study highlights the translational potential of Jumonji KDM inhibitors against SCLC, a clinically feasible approach in light of recently opened clinical trials evaluating this drug class, and establishes KDM4A as a relevant target across SCLC subtypes.
    DOI:  https://doi.org/10.1038/s41388-024-03125-x
  46. Int Immunol. 2024 Aug 23. pii: dxae051. [Epub ahead of print]
    Spatial diversity of in vivo tissue immunity.
    Yu Miyamoto, Masaru Ishii.
      The immune system exhibits spatial diversity in in vivo tissues. Immune cells are strategically distributed within tissues to maintain the organ integrity. Advanced technologies such as intravital imaging and spatial transcriptomics have revealed the spatial heterogeneity of immune cell distribution and function within organs such as the liver, kidney, intestine, and lung. In addition, these technologies visualize nutrient and oxygen environments across tissues. Recent spatial analyses have suggested that a functional immune niche is determined by interactions between immune and non-immune cells in an appropriate nutrient and oxygen environment. Understanding the spatial communication between immune cells, environment, and surrounding non-immune cells is crucial for developing strategies to control immune responses and effectively manage inflammatory diseases.
    Keywords:  Intravital imaging; Spatial transcriptomics; Tissue immunology
    DOI:  https://doi.org/10.1093/intimm/dxae051
  47. Nat Cell Biol. 2024 Aug 22.
    Exosome regulation by Rubicon in ageing.
    Yan Zhen, Harald Stenmark.
      
    DOI:  https://doi.org/10.1038/s41556-024-01482-z
  48. iScience. 2024 Aug 16. 27(8): 110529
    Multimodal analysis unveils tumor microenvironment heterogeneity linked to immune activity and evasion.
    Óscar Lapuente-Santana, Gregor Sturm, Joan Kant, Markus Ausserhofer, Constantin Zackl, Maria Zopoglou, Nicholas McGranahan, Dietmar Rieder, Zlatko Trajanoski, Noel Filipe da Cunha Carvalho de Miranda, Federica Eduati, Francesca Finotello.
      The cellular and molecular heterogeneity of tumors is a major obstacle to cancer immunotherapy. Here, we use a systems biology approach to derive a signature of the main sources of heterogeneity in the tumor microenvironment (TME) from lung cancer transcriptomics. We demonstrate that this signature, which we called iHet, is conserved in different cancers and associated with antitumor immunity. Through analysis of single-cell and spatial transcriptomics data, we trace back the cellular origin of the variability explaining the iHet signature. Finally, we demonstrate that iHet has predictive value for cancer immunotherapy, which can be further improved by disentangling three major determinants of anticancer immune responses: activity of immune cells, immune infiltration or exclusion, and cancer-cell foreignness. This work shows how transcriptomics data can be integrated to derive a holistic representation of the phenotypic heterogeneity of the TME and to predict its unfolding and fate during immunotherapy with immune checkpoint blockers.
    Keywords:  cancer; cancer systems biology; immunology; systems biology; transcriptomics
    DOI:  https://doi.org/10.1016/j.isci.2024.110529
  49. Cell. 2024 Aug 14. pii: S0092-8674(24)00832-8. [Epub ahead of print]
    A genetic basis for sex differences in Xp11 translocation renal cell carcinoma.
    Mingkee Achom, Ananthan Sadagopan, Chunyang Bao, Fiona McBride, Jiao Li, Prathyusha Konda, Richard W Tourdot, Qingru Xu, Maria Nakhoul, Daniel S Gallant, Usman Ali Ahmed, Jillian O'Toole, Dory Freeman, Gwo-Shu Mary Lee, Jonathan L Hecht, Eric C Kauffman, David J Einstein, Toni K Choueiri, Cheng-Zhong Zhang, Srinivas R Viswanathan.
      Xp11 translocation renal cell carcinoma (tRCC) is a rare, female-predominant cancer driven by a fusion between the transcription factor binding to IGHM enhancer 3 (TFE3) gene on chromosome Xp11.2 and a partner gene on either chromosome X (chrX) or an autosome. It remains unknown what types of rearrangements underlie TFE3 fusions, whether fusions can arise from both the active (chrXa) and inactive X (chrXi) chromosomes, and whether TFE3 fusions from chrXi translocations account for the female predominance of tRCC. To address these questions, we performed haplotype-specific analyses of chrX rearrangements in tRCC whole genomes. We show that TFE3 fusions universally arise as reciprocal translocations and that oncogenic TFE3 fusions can arise from chrXi:autosomal translocations. Female-specific chrXi:autosomal translocations result in a 2:1 female-to-male ratio of TFE3 fusions involving autosomal partner genes and account for the female predominance of tRCC. Our results highlight how X chromosome genetics constrains somatic chrX alterations and underlies cancer sex differences.
    Keywords:  MITF; TFE3; X chromosome; X inactivation; XIST; cancer genomics; cancer sex bias; gene fusions; kidney cancer; renal cell carcinoma; tRCC; translocation renal cell carcinoma
    DOI:  https://doi.org/10.1016/j.cell.2024.07.038
  50. J Mol Cell Cardiol. 2024 Aug 21. pii: S0022-2828(24)00135-4. [Epub ahead of print]195 103-109
    Metabolic cycles: A unifying concept for energy transfer in the heart.
    Mitchell Beito, Heinrich Taegtmeyer.
      It is still debated whether changes in metabolic flux are cause or consequence of contractile dysfunction in non-ischemic heart disease. We have previously proposed a model of cardiac metabolism grounded in a series of six moiety-conserved, interconnected cycles. In view of a recent interest to augment oxygen availability in heart failure through iron supplementation, we integrated this intervention in terms of moiety conservation. Examining published work from both human and murine models, we argue this strategy restores a mitochondrial cycle of energy transfer by enhancing mitochondrial pyruvate carrier (MPC) expression and providing pyruvate as a substrate for carboxylation and anaplerosis. Metabolomic data from failing heart muscle reveal elevated pyruvate levels with a concomitant decrease in the levels of Krebs cycle intermediates. Additionally, MPC is downregulated in the same failing hearts, as well as under hypoxic conditions. MPC expression increases upon mechanical unloading in the failing human heart, as does contractile function. We note that MPC deficiency also alters expression of enzymes involved in pyruvate carboxylation and decarboxylation, increases intermediates of biosynthetic pathways, and eventually leads to cardiac hypertrophy and dilated cardiomyopathy. Collectively, we propose that an unbroken chain of moiety-conserved cycles facilitates energy transfer in the heart. We refer to the transport and subsequent carboxylation of pyruvate in the mitochondrial matrix as an example and a proposed target for metabolic support to reverse impaired contractile function.
    Keywords:  Cardiac metabolism; Energy transfer; Heart failure; Metabolic cycles
    DOI:  https://doi.org/10.1016/j.yjmcc.2024.08.002
  51. EMBO J. 2024 Aug 19.
    Mouse models to investigate in situ cell fate decisions induced by p53.
    Elizabeth Lieschke, Annabella F Thomas, Andrew Kueh, Georgia K Atkin-Smith, Pedro L Baldoni, John E La Marca, Savannah Young, Allan Shuai Huang, Aisling M Ross, Lauren Whelan, Deeksha Kaloni, Lin Tai, Gordon K Smyth, Marco J Herold, Edwin D Hawkins, Andreas Strasser, Gemma L Kelly.
      Investigating how transcription factors control complex cellular processes requires tools that enable responses to be visualised at the single-cell level and their cell fate to be followed over time. For example, the tumour suppressor p53 (also called TP53 in humans and TRP53 in mice) can initiate diverse cellular responses by transcriptional activation of its target genes: Puma to induce apoptotic cell death and p21 to induce cell cycle arrest/cell senescence. However, it is not known how these processes are regulated and initiated in different cell types. Also, the context-dependent interaction partners and binding loci of p53 remain largely elusive. To be able to examine these questions, we here developed knock-in mice expressing triple-FLAG-tagged p53 to facilitate p53 pull-down and two p53 response reporter mice, knocking tdTomato and GFP into the Puma/Bbc3 and p21 gene loci, respectively. By crossing these reporter mice into a p53-deficient background, we show that the new reporters reliably inform on p53-dependent and p53-independent initiation of both apoptotic or cell cycle arrest/senescence programs, respectively, in vitro and in vivo.
    Keywords:  Apoptosis; Cancer; Cell Cycle Arrest; Reporter Mice; p53/TRP53/TP53
    DOI:  https://doi.org/10.1038/s44318-024-00189-z
  52. Neuron. 2024 Aug 13. pii: S0896-6273(24)00539-7. [Epub ahead of print]
    Negative feedback control of hypothalamic feeding circuits by the taste of food.
    Tara J Aitken, Zhengya Liu, Truong Ly, Sarah Shehata, Nilla Sivakumar, Naymalis La Santa Medina, Lindsay A Gray, Jingkun Zhang, Naz Dundar, Chris Barnes, Zachary A Knight.
      The rewarding taste of food is critical for motivating animals to eat, but whether taste has a parallel function in promoting meal termination is not well understood. Here, we show that hunger-promoting agouti-related peptide (AgRP) neurons are rapidly inhibited during each bout of ingestion by a signal linked to the taste of food. Blocking these transient dips in activity via closed-loop optogenetic stimulation increases food intake by selectively delaying the onset of satiety. We show that upstream leptin-receptor-expressing neurons in the dorsomedial hypothalamus (DMHLepR) are tuned to respond to sweet or fatty tastes and exhibit time-locked activation during feeding that is the mirror image of downstream AgRP cells. These findings reveal an unexpected role for taste in the negative feedback control of ingestion. They also reveal a mechanism by which AgRP neurons, which are the primary cells that drive hunger, are able to influence the moment-by-moment dynamics of food consumption.
    Keywords:  arcuate nucleus; feeding; gustatory; hunger; hypothalamus; leptin receptor; microendoscopy; photometry; taste
    DOI:  https://doi.org/10.1016/j.neuron.2024.07.017
  53. Proc Natl Acad Sci U S A. 2024 Aug 27. 121(35): e2408322121
    A circadian clock output functions independently of phyB to sustain daytime PIF3 degradation.
    Wei Liu, Harper Lowrey, Anxu Xu, Chun Chung Leung, Christopher Adamchek, Jiangman He, Juan Du, Meng Chen, Joshua M Gendron.
      The circadian clock is an endogenous oscillator, and its importance lies in its ability to impart rhythmicity on downstream biological processes, or outputs. Our knowledge of output regulation, however, is often limited to an understanding of transcriptional connections between the clock and outputs. For instance, the clock is linked to plant growth through the gating of photoreceptors via rhythmic transcription of the nodal growth regulators, PHYTOCHROME-INTERACTING FACTORs (PIFs), but the clock's role in PIF protein stability is less clear. Here, we identified a clock-regulated, F-box type E3 ubiquitin ligase, CLOCK-REGULATED F-BOX WITH A LONG HYPOCOTYL 1 (CFH1), that specifically interacts with and degrades PIF3 during the daytime. Additionally, genetic evidence indicates that CFH1 functions primarily in monochromatic red light, yet CFH1 confers PIF3 degradation independent of the prominent red-light photoreceptor phytochrome B (phyB). This work reveals a clock-mediated growth regulation mechanism in which circadian expression of CFH1 promotes sustained, daytime PIF3 degradation in parallel with phyB signaling.
    Keywords:  PIF3; circadian clock; photomorphogenesis; post-translational modification; red light signaling
    DOI:  https://doi.org/10.1073/pnas.2408322121
  54. Cell Metab. 2024 Aug 12. pii: S1550-4131(24)00290-0. [Epub ahead of print]
    Acetate enables metabolic fitness and cognitive performance during sleep disruption.
    Qinqin He, Liwei Ji, Yanyan Wang, Yarong Zhang, Haiyan Wang, Junyan Wang, Qing Zhu, Maodi Xie, Wei Ou, Jun Liu, Kuo Tang, Kening Lu, Qingmei Liu, Jian Zhou, Rui Zhao, Xintian Cai, Nanfang Li, Yang Cao, Tao Li.
      Sleep is essential for overall health, and its disruption is linked to increased risks of metabolic, cognitive, and cardiovascular dysfunctions; however, the molecular mechanisms remain poorly understood. This study investigated how sleep disturbances contribute to metabolic imbalance and cognition impairment using a chronic sleep fragmentation (SF) mouse model. SF mice exhibited impaired cognition, glucose metabolism, and insulin sensitivity compared with controls. We identified increased acetate levels in hypothalamic astrocytes as a defensive response in SF mice. Through acetate infusion or astrocyte-specific Acss1 deletion to elevate acetate levels, we observed mitigated metabolic and cognitive impairments in SF mice. Mechanistically, acetate binds and activates pyruvate carboxylase, thereby restoring glycolysis and the tricarboxylic acid cycle. Among individuals most commonly affected by SF, patients with obstructive sleep apnea exhibited elevated acetate levels when coupled with type 2 diabetes. Our study uncovers the protective effect of acetate against sleep-induced metabolic and cognitive impairments.
    Keywords:  acetate; astrocyte; cognitive performance; glucose homeostasis; hypothalamus; pyruvate carboxylase; sleep disruption
    DOI:  https://doi.org/10.1016/j.cmet.2024.07.019
  55. Nat Commun. 2024 Aug 22. 15(1): 7238
    Enhanced metabolic entanglement emerges during the evolution of an interkingdom microbial community.
    Giovanni Scarinci, Jan-Luca Ariens, Georgia Angelidou, Sebastian Schmidt, Timo Glatter, Nicole Paczia, Victor Sourjik.
      While different stages of mutualism can be observed in natural communities, the dynamics and mechanisms underlying the gradual erosion of independence of the initially autonomous organisms are not yet fully understood. In this study, by conducting the laboratory evolution on an engineered microbial community, we reproduce and molecularly track the stepwise progression towards enhanced partner entanglement. We observe that the evolution of the community both strengthens the existing metabolic interactions and leads to the emergence of de novo interdependence between partners for nitrogen metabolism, which is a common feature of natural symbiotic interactions. Selection for enhanced metabolic entanglement during the community evolution repeatedly occurred indirectly, via pleiotropies and trade-offs within cellular regulatory networks, and with no evidence of group selection. The indirect positive selection of metabolic dependencies between microbial community members, which results from the direct selection of other coupled traits in the same regulatory network, may therefore be a common but underappreciated driving force guiding the evolution of natural mutualistic communities.
    DOI:  https://doi.org/10.1038/s41467-024-51702-1
  56. Nature. 2024 Aug 21.
    Cells poised to divide can delay their commitment to proliferate.
      
    Keywords:  Cancer; Cell biology
    DOI:  https://doi.org/10.1038/d41586-024-02640-x
  57. PLoS Biol. 2024 Aug;22(8): e3002756
    A somatic view of the genomic impact of mitochondrial endosymbiosis.
    Rose M Doss, Martin W Breuss.
      The endosymbiosis of mitochondrial ancestors resulted in the transfer of genetic material on an evolutionary scale for eukaryotic species. A new study in PLOS Biology expands this to the genome of somatic cells within individuals and highlights its correlation with aging and disease.
    DOI:  https://doi.org/10.1371/journal.pbio.3002756
  58. Nature. 2024 Aug;632(8026): 729-730
    Forever young: what science can and can't tell us about cheating ageing.
    Jan H J Hoeijmakers.
      
    Keywords:  Ageing; Genetics; Genomics; Medical research
    DOI:  https://doi.org/10.1038/d41586-024-02677-y
  59. J Phys Chem B. 2024 Aug 21.
    Oxidative Phosphorylation Does Not Violate the Second Law of Thermodynamics.
    Todd P Silverstein.
      In a recent series of papers, James W. Lee reported that mitochondrial oxidative phosphorylation violates the second law of thermodynamics and that it is allowed to do so because it is a "Type-B" process that features lateral and longitudinal membrane asymmetry. We show here that these contentions are based on problematic interpretations of the literature. More reliable values of ΔGredox and ΔGATP synthesis show that the second law is not violated. More recent reports on the structures of the redox-driven proton pumps (Complexes I, III, and IV) suggest that longitudinal membrane asymmetry does not exist. Finally, Lee's predictions for the concentration of protons localized at the P-side surface of the bioenergetic membrane are likely to be much too high due to several errors; thus, his predicted high values of ΔpHsurface that violate the second law are likely to be wrong. There is currently no strong experimental or theoretical evidence to support the contention that oxidative phosphorylation violates the second law of thermodynamics.
    DOI:  https://doi.org/10.1021/acs.jpcb.4c03047
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