bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2024–06–30
fifty-one papers selected by
Christian Frezza, Universität zu Köln
  1. HIF-2α expression and metabolic signaling require ACSS2 in clear cell renal cell carcinoma.
  2. Raman micro-spectroscopy reveals the spatial distribution of fumarate in cells and tissues.
  3. CHCHD4 regulates the expression of mitochondrial genes that are essential for tumour cell growth.
  4. ATF4 and mTOR regulate metabolic reprogramming in TGF-β-treated lung fibroblasts.
  5. The catalytic activity of methyltransferase METTL15 is dispensable for its role in mitochondrial ribosome biogenesis.
  6. Ferroptosis in health and disease.
  7. Mitochondrial One-Carbon Metabolism and Alzheimer's Disease.
  8. Implications of mitochondrial membrane potential gradients on signaling and ATP production analyzed by correlative multi-parameter microscopy.
  9. TERT activation targets DNA methylation and multiple aging hallmarks.
  10. Human mitochondrial carriers of the SLC25 family function as monomers exchanging substrates with a ping-pong kinetic mechanism.
  11. Lactate transported by MCT1 plays an active role in promoting mitochondrial biogenesis and enhancing TCA flux in skeletal muscle.
  12. The extracellular matrix integrates mitochondrial homeostasis.
  13. Knockout Mouse Studies Show That Mitochondrial CLPP Peptidase and CLPX Unfoldase Act in Matrix Condensates near IMM, as Fast Stress Response in Protein Assemblies for Transcript Processing, Translation, and Heme Production.
  14. Multi-State Gene Cluster Switches Determine the Adaptive Mitochondrial And Metabolic Landscape of Breast Cancer.
  15. NPY-mediated synaptic plasticity in the extended amygdala prioritizes feeding during starvation.
  16. ACAT1 suppresses clear cell renal cell carcinoma progression by AMPK mediated fatty acid metabolism.
  17. Ferroptosis-like cell death promotes and prolongs inflammation in Drosophila.
  18. N-terminal cysteine acetylation and oxidation patterns may define protein stability.
  19. Fluorescence Lifetime Super-Resolution Imaging Unveil the Dynamic Relationship between Mitochondrial Membrane Potential and Cristae Structure Using the Förster Resonance Energy Transfer Strategy.
  20. Immune evasion impacts the landscape of driver genes during cancer evolution.
  21. Historic obstacles and emerging opportunities in the field of developmental metabolism - lessons from Heidelberg.
  22. FADS1/2 control lipid metabolism and ferroptosis susceptibility in triple-negative breast cancer.
  23. METTL3-mediated chromatin contacts promote stress granule phase separation through metabolic reprogramming during senescence.
  24. Unraveling CRP/cAMP-Mediated Metabolic Regulation In Escherichia coli Persister Cells.
  25. An aggregated mitochondrial distribution in preimplantation embryos disrupts nuclear morphology, function, and developmental potential.
  26. Mitochondrial DNA Instability Supersedes Parkin Mutations in Driving Mitochondrial Proteomic Alterations and Functional Deficits in Polg Mutator Mice.
  27. Interplay between mTOR and Purine Metabolism Enzymes and Its Relevant Role in Cancer.
  28. Aged mice regain youthful muscles thanks to a compound that acts on the genes.
  29. Developmental and tissue-specific roles of mammalian centrosomes.
  30. Intra-organ cell specific mitochondrial quantitative interactomics.
  31. Oxylipins and metabolites from pyroptotic cells act as promoters of tissue repair.
  32. Endothelial Drp1 Couples VEGF-induced Redox Signaling with Glycolysis Through Cysteine Oxidation to Drive Angiogenesis.
  33. Autophagic signaling promotes systems-wide remodeling in skeletal muscle upon oncometabolic stress by D2-HG.
  34. Integrated multi-omic analyses uncover the effects of aging on cell-type regulation in glucose-responsive tissues.
  35. The MICOS Complex Regulates Mitochondrial Structure and Oxidative Stress During Age-Dependent Structural Deficits in the Kidney.
  36. Histone oxidation as a new mechanism of metabolic control over gene expression.
  37. An intermediate Rb-E2F activity state safeguards proliferation commitment.
  38. Single-cell transcriptional profiling of clear cell renal cell carcinoma reveals a tumor-associated endothelial tip cell phenotype.
  39. Metabolic channeling of lipids via the contact zones between different organelles.
  40. Roles of the oncometabolite enantiomers of 2-hydroxyglutarate and their metabolism by diverse dehydrogenases.
  41. One-carbon metabolism shapes T cell immunity in cancer.
  42. A commensal-derived sugar protects against metabolic disease.
  43. PELI2 is a negative regulator of STING signaling that is dynamically repressed during viral infection.
  44. Microglial-derived C1q integrates into neuronal ribonucleoprotein complexes and impacts protein homeostasis in the aging brain.
  45. Genome-scale exon perturbation screens uncover exons critical for cell fitness.
  46. Cancer Cell Small Molecule Secretome Induces the Immune Checkpoint NKG2A and Dysfunction of Human CD8+ T Cells.
  47. Sequence-specific dynamic DNA bending explains mitochondrial TFAM's dual role in DNA packaging and transcription initiation.
  48. The ENCODE mouse postnatal developmental time course identifies regulatory programs of cell types and cell states.
  49. Type I conventional dendritic cells facilitate immunotherapy in pancreatic cancer.
  50. A metabolic redox relay supports ER proinsulin export in pancreatic islet β-cells.
  51. Immunometabolism in atherosclerosis: a new understanding of an old disease.
  1. J Clin Invest. 2024 Jun 17. pii: e164249. [Epub ahead of print]134(12):
    HIF-2α expression and metabolic signaling require ACSS2 in clear cell renal cell carcinoma.
    Zachary A Bacigalupa, Emily N Arner, Logan M Vlach, Melissa M Wolf, Whitney A Brown, Evan S Krystofiak, Xiang Ye, Rachel A Hongo, Madelyn Landis, Edith K Amason, Kathryn E Beckermann, W Kimryn Rathmell, Jeffrey C Rathmell.
      Clear cell renal cell carcinoma (ccRCC) is an aggressive cancer driven by VHL loss and aberrant HIF-2α signaling. Identifying means to regulate HIF-2α thus has potential therapeutic benefit. Acetyl-CoA synthetase 2 (ACSS2) converts acetate to acetyl-CoA and is associated with poor patient prognosis in ccRCC. Here we tested the effects of ACSS2 on HIF-2α and cancer cell metabolism and growth in ccRCC models and clinical samples. ACSS2 inhibition reduced HIF-2α levels and suppressed ccRCC cell line growth in vitro, in vivo, and in cultures of primary ccRCC patient tumors. This treatment reduced glycolytic signaling, cholesterol metabolism, and mitochondrial integrity, all of which are consistent with loss of HIF-2α. Mechanistically, ACSS2 inhibition decreased chromatin accessibility and HIF-2α expression and stability. While HIF-2α protein levels are widely regulated through pVHL-dependent proteolytic degradation, we identify a potential pVHL-independent pathway of degradation via the E3 ligase MUL1. We show that MUL1 can directly interact with HIF-2α and that overexpression of MUL1 decreased HIF-2α levels in a manner partially dependent on ACSS2. These findings identify multiple mechanisms to regulate HIF-2α stability and ACSS2 inhibition as a strategy to complement HIF-2α-targeted therapies and deplete pathogenically stabilized HIF-2α.
    Keywords:  Cancer; Cell biology; Hypoxia; Metabolism; Molecular biology
    DOI:  https://doi.org/10.1172/JCI164249
  2. Nat Commun. 2024 Jun 25. 15(1): 5386
    Raman micro-spectroscopy reveals the spatial distribution of fumarate in cells and tissues.
    Marlous Kamp, Jakub Surmacki, Marc Segarra Mondejar, Tim Young, Karolina Chrabaszcz, Fadwa Joud, Vincent Zecchini, Alyson Speed, Christian Frezza, Sarah E Bohndiek.
      Aberrantly accumulated metabolites elicit intra- and inter-cellular pro-oncogenic cascades, yet current measurement methods require sample perturbation/disruption and lack spatio-temporal resolution, limiting our ability to fully characterize their function and distribution. Here, we show that Raman spectroscopy (RS) can directly detect fumarate in living cells in vivo and animal tissues ex vivo, and that RS can distinguish between Fumarate hydratase (Fh1)-deficient and Fh1-proficient cells based on fumarate concentration. Moreover, RS reveals the spatial compartmentalization of fumarate within cellular organelles in Fh1-deficient cells: consistent with disruptive methods, we observe the highest fumarate concentration (37 ± 19 mM) in mitochondria, where the TCA cycle operates, followed by the cytoplasm (24 ± 13 mM) and then the nucleus (9 ± 6 mM). Finally, we apply RS to tissues from an inducible mouse model of FH loss in the kidney, demonstrating RS can classify FH status. These results suggest RS could be adopted as a valuable tool for small molecule metabolic imaging, enabling in situ non-destructive evaluation of fumarate compartmentalization.
    DOI:  https://doi.org/10.1038/s41467-024-49403-w
  3. Biochim Biophys Acta Mol Basis Dis. 2024 Jun 21. pii: S0925-4439(24)00271-0. [Epub ahead of print] 167282
    CHCHD4 regulates the expression of mitochondrial genes that are essential for tumour cell growth.
    Luke W Thomas, Jenna M Stephen, Margaret Ashcroft.
      CHCHD4 (MIA40) is a central component of the mitochondrial disulfide relay system (DRS), is essential and evolutionarily conserved. Previously, we have shown CHCHD4 to be a critical regulator of tumour cell growth. Here, we use genome-wide CRISPR/Cas9 and SILAC proteomic analyses to delineate mechanisms of CHCHD4 essentiality in cancer. We identify a short-list of common essential genes/proteins associated with CHCHD4 essentiality in tumour cells, which includes subunits of complex I that are known DRS substrates, and genes/proteins involved in key metabolic pathways. Our study highlights a range of nuclear encoded mitochondrial genes essential for CHCHD4-regulated tumour cell growth.
    Keywords:  CHCHD4; CRISPR/Cas9 genome-wide deletion screen; Gene essentiality; Mitochondria; Proteomics; SILAC analysis
    DOI:  https://doi.org/10.1016/j.bbadis.2024.167282
  4. bioRxiv. 2024 Jun 13. pii: 2024.06.12.598694. [Epub ahead of print]
    ATF4 and mTOR regulate metabolic reprogramming in TGF-β-treated lung fibroblasts.
    Kun Woo D Shin, M Volkan Atalay, Rengul Cetin-Atalay, Erin M O'Leary, Mariel E Glass, Jennifer C Houpy Szafran, Parker S Woods, Angelo Y Meliton, Obada R Shamaa, Yufeng Tian, Gökhan M Mutlu, Robert B Hamanaka.
      Idiopathic pulmonary fibrosis is a fatal disease characterized by the TGF-β-dependent activation of lung fibroblasts, leading to excessive deposition of collagen proteins and progressive replacement of healthy lung with scar tissue. We and others have shown that fibroblast activation is supported by metabolic reprogramming, including the upregulation of the de novo synthesis of glycine, the most abundant amino acid found in collagen protein. How fibroblast metabolic reprogramming is regulated downstream of TGF-β is incompletely understood. We and others have shown that TGF-β-mediated activation of the Mechanistic Target of Rapamycin Complex 1 (mTORC1) and downstream upregulation of Activating Transcription Factor 4 (ATF4) promote increased expression of the enzymes required for de novo glycine synthesis; however, whether mTOR and ATF4 regulate other metabolic pathways in lung fibroblasts has not been explored. Here, we used RNA sequencing to determine how both ATF4 and mTOR regulate gene expression in human lung fibroblasts following TGF-β. We found that ATF4 primarily regulates enzymes and transporters involved in amino acid homeostasis as well as aminoacyl-tRNA synthetases. mTOR inhibition resulted not only in the loss of ATF4 target gene expression, but also in the reduced expression of glycolytic enzymes and mitochondrial electron transport chain subunits. Analysis of TGF-β-induced changes in cellular metabolite levels confirmed that ATF4 regulates amino acid homeostasis in lung fibroblasts while mTOR also regulates glycolytic and TCA cycle metabolites. We further analyzed publicly available single cell RNAseq data sets and found increased expression of ATF4 and mTOR metabolic targets in pathologic fibroblast populations from the lungs of IPF patients. Our results provide insight into the mechanisms of metabolic reprogramming in lung fibroblasts and highlight novel ATF4 and mTOR-dependent pathways that may be targeted to inhibit fibrotic processes.
    DOI:  https://doi.org/10.1101/2024.06.12.598694
  5. RNA Biol. 2024 Jan;21(1): 23-30
    The catalytic activity of methyltransferase METTL15 is dispensable for its role in mitochondrial ribosome biogenesis.
    Christian D Mutti, Lindsey Van Haute, Michal Minczuk.
      Ribosomes are large macromolecular complexes composed of both proteins and RNA, that require a plethora of factors and post-transcriptional modifications for their biogenesis. In human mitochondria, the ribosomal RNA is post-transcriptionally modified at ten sites. The N4-methylcytidine (m4C) methyltransferase, METTL15, modifies the 12S rRNA of the small subunit at position C1486. The enzyme is essential for mitochondrial protein synthesis and assembly of the mitoribosome small subunit, as shown here and by previous studies. Here, we demonstrate that the m4C modification is not required for small subunit biogenesis, indicating that the chaperone-like activity of the METTL15 protein itself is an essential component for mitoribosome biogenesis.
    Keywords:  Mitochondrial ribosome; chaperone; epitranscriptomics; methyltransferase; mitochondria; ribosomal RNA
    DOI:  https://doi.org/10.1080/15476286.2024.2369374
  6. Redox Biol. 2024 May 30. pii: S2213-2317(24)00189-7. [Epub ahead of print]75 103211
    Ferroptosis in health and disease.
    Carsten Berndt, Hamed Alborzinia, Vera Skafar Amen, Scott Ayton, Uladzimir Barayeu, Alexander Bartelt, Hülya Bayir, Christina M Bebber, Kivanc Birsoy, Jan P Böttcher, Simone Brabletz, Thomas Brabletz, Ashley R Brown, Bernhard Brüne, Giorgia Bulli, Alix Bruneau, Quan Chen, Gina M DeNicola, Tobias P Dick, Ayelén Distéfano, Scott J Dixon, Jan B Engler, Julia Esser-von Bieren, Maria Fedorova, José Pedro Friedmann Angeli, Manuel A Friese, Dominic C Fuhrmann, Ana J García-Sáez, Karolina Garbowicz, Magdalena Götz, Wei Gu, Linda Hammerich, Behrouz Hassannia, Xuejun Jiang, Aicha Jeridi, Yun Pyo Kang, Valerian E Kagan, David B Konrad, Stefan Kotschi, Peng Lei, Marlène Le Tertre, Sima Lev, Deguang Liang, Andreas Linkermann, Carolin Lohr, Svenja Lorenz, Tom Luedde, Axel Methner, Bernhard Michalke, Anna V Milton, Junxia Min, Eikan Mishima, Sebastian Müller, Hozumi Motohashi, Martina U Muckenthaler, Shohei Murakami, James A Olzmann, Gabriela Pagnussat, Zijan Pan, Thales Papagiannakopoulos, Lohans Pedrera Puentes, Derek A Pratt, Bettina Proneth, Lukas Ramsauer, Raphael Rodriguez, Yoshiro Saito, Felix Schmidt, Carina Schmitt, Almut Schulze, Annemarie Schwab, Anna Schwantes, Mariluz Soula, Benedikt Spitzlberger, Brent R Stockwell, Leonie Thewes, Oliver Thorn-Seshold, Shinya Toyokuni, Wulf Tonnus, Andreas Trumpp, Peter Vandenabeele, Tom Vanden Berghe, Vivek Venkataramani, Felix C E Vogel, Silvia von Karstedt, Fudi Wang, Frank Westermann, Chantal Wientjens, Christoph Wilhelm, Michele Wölk, Katherine Wu, Xin Yang, Fan Yu, Yilong Zou, Marcus Conrad.
      Ferroptosis is a pervasive non-apoptotic form of cell death highly relevant in various degenerative diseases and malignancies. The hallmark of ferroptosis is uncontrolled and overwhelming peroxidation of polyunsaturated fatty acids contained in membrane phospholipids, which eventually leads to rupture of the plasma membrane. Ferroptosis is unique in that it is essentially a spontaneous, uncatalyzed chemical process based on perturbed iron and redox homeostasis contributing to the cell death process, but that it is nonetheless modulated by many metabolic nodes that impinge on the cells' susceptibility to ferroptosis. Among the various nodes affecting ferroptosis sensitivity, several have emerged as promising candidates for pharmacological intervention, rendering ferroptosis-related proteins attractive targets for the treatment of numerous currently incurable diseases. Herein, the current members of a Germany-wide research consortium focusing on ferroptosis research, as well as key external experts in ferroptosis who have made seminal contributions to this rapidly growing and exciting field of research, have gathered to provide a comprehensive, state-of-the-art review on ferroptosis. Specific topics include: basic mechanisms, in vivo relevance, specialized methodologies, chemical and pharmacological tools, and the potential contribution of ferroptosis to disease etiopathology and progression. We hope that this article will not only provide established scientists and newcomers to the field with an overview of the multiple facets of ferroptosis, but also encourage additional efforts to characterize further molecular pathways modulating ferroptosis, with the ultimate goal to develop novel pharmacotherapies to tackle the various diseases associated with - or caused by - ferroptosis.
    Keywords:  Cancer; Cell death; Iron; Ischemia/reperfusion; Lipid peroxidation; Neurodegeneration
    DOI:  https://doi.org/10.1016/j.redox.2024.103211
  7. Int J Mol Sci. 2024 Jun 07. pii: 6302. [Epub ahead of print]25(12):
    Mitochondrial One-Carbon Metabolism and Alzheimer's Disease.
    Yizhou Yu, L Miguel Martins.
      Mitochondrial one-carbon metabolism provides carbon units to several pathways, including nucleic acid synthesis, mitochondrial metabolism, amino acid metabolism, and methylation reactions. Late-onset Alzheimer's disease is the most common age-related neurodegenerative disease, characterised by impaired energy metabolism, and is potentially linked to mitochondrial bioenergetics. Here, we discuss the intersection between the molecular pathways linked to both mitochondrial one-carbon metabolism and Alzheimer's disease. We propose that enhancing one-carbon metabolism could promote the metabolic processes that help brain cells cope with Alzheimer's disease-related injuries. We also highlight potential therapeutic avenues to leverage one-carbon metabolism to delay Alzheimer's disease pathology.
    Keywords:  Alzheimer’s disease; folate; mitochondria; one-carbon metabolism
    DOI:  https://doi.org/10.3390/ijms25126302
  8. Sci Rep. 2024 06 26. 14(1): 14784
    Implications of mitochondrial membrane potential gradients on signaling and ATP production analyzed by correlative multi-parameter microscopy.
    Benjamin Gottschalk, Zhanat Koshenov, Roland Malli, Wolfgang F Graier.
      The complex architecture and biochemistry of the inner mitochondrial membrane generate ultra-structures with different phospholipid and protein compositions, shapes, characteristics, and functions. The crista junction (CJ) serves as an important barrier separating the cristae (CM) and inner boundary membranes (IBM). Thereby CJ regulates the movement of ions and ensures distinct electrical potentials across the cristae (ΔΨC) and inner boundary (ΔΨIBM) membranes. We have developed a robust and flexible approach to visualize the CJ permeability with super-resolution microscopy as a readout of local mitochondrial membrane potential (ΔΨmito) fluctuations. This method involves analyzing the distribution of TMRM fluorescence intensity in a model that is restricted to the mitochondrial geometry. We show that mitochondrial Ca2+ elevation hyperpolarizes the CM most likely caused by Ca2+ sensitive increase of mitochondrial tricarboxylic acid cycle (TCA) and subsequent oxidative phosphorylation (OXPHOS) activity in the cristae. Dynamic multi-parameter correlation measurements of spatial mitochondrial membrane potential gradients, ATP levels, and mitochondrial morphometrics revealed a CJ-based membrane potential overflow valve mechanism protecting the mitochondrial integrity during excessive cristae hyperpolarization.
    Keywords:  Correlative microscopy; Cristae junctions; Membrane potential gradient; Mitochondria; Mitochondrial membranes
    DOI:  https://doi.org/10.1038/s41598-024-65595-z
  9. Cell. 2024 Jun 21. pii: S0092-8674(24)00592-0. [Epub ahead of print]
    TERT activation targets DNA methylation and multiple aging hallmarks.
    Hong Seok Shim, Jonathan Iaconelli, Xiaoying Shang, Jiexi Li, Zheng D Lan, Shan Jiang, Kayla Nutsch, Brittney A Beyer, Luke L Lairson, Adam T Boutin, Michael J Bollong, Peter G Schultz, Ronald A DePinho.
      Insufficient telomerase activity, stemming from low telomerase reverse transcriptase (TERT) gene transcription, contributes to telomere dysfunction and aging pathologies. Besides its traditional function in telomere synthesis, TERT acts as a transcriptional co-regulator of genes pivotal in aging and age-associated diseases. Here, we report the identification of a TERT activator compound (TAC) that upregulates TERT transcription via the MEK/ERK/AP-1 cascade. In primary human cells and naturally aged mice, TAC-induced elevation of TERT levels promotes telomere synthesis, blunts tissue aging hallmarks with reduced cellular senescence and inflammatory cytokines, and silences p16INK4a expression via upregulation of DNMT3B-mediated promoter hypermethylation. In the brain, TAC alleviates neuroinflammation, increases neurotrophic factors, stimulates adult neurogenesis, and preserves cognitive function without evident toxicity, including cancer risk. Together, these findings underscore TERT's critical role in aging processes and provide preclinical proof of concept for physiological TERT activation as a strategy to mitigate multiple aging hallmarks and associated pathologies.
    Keywords:  adult neurogenesis; cognition; epigenetics; inflammation; p16(INK4a); senescence; telomerase; telomere
    DOI:  https://doi.org/10.1016/j.cell.2024.05.048
  10. EMBO J. 2024 Jun 27.
    Human mitochondrial carriers of the SLC25 family function as monomers exchanging substrates with a ping-pong kinetic mechanism.
    Camila Cimadamore-Werthein, Martin S King, Denis Lacabanne, Eva Pyrihová, Stephany Jaiquel Baron, Edmund Rs Kunji.
      Members of the SLC25 mitochondrial carrier family link cytosolic and mitochondrial metabolism and support cellular maintenance and growth by transporting compounds across the mitochondrial inner membrane. Their monomeric or dimeric state and kinetic mechanism have been a matter of long-standing debate. It is believed by some that they exist as homodimers and transport substrates with a sequential kinetic mechanism, forming a ternary complex where both exchanged substrates are bound simultaneously. Some studies, in contrast, have provided evidence indicating that the mitochondrial ADP/ATP carrier (SLC25A4) functions as a monomer, has a single substrate binding site, and operates with a ping-pong kinetic mechanism, whereby ADP is imported before ATP is exported. Here we reanalyze the oligomeric state and kinetic properties of the human mitochondrial citrate carrier (SLC25A1), dicarboxylate carrier (SLC25A10), oxoglutarate carrier (SLC25A11), and aspartate/glutamate carrier (SLC25A13), all previously reported to be dimers with a sequential kinetic mechanism. We demonstrate that they are monomers, except for dimeric SLC25A13, and operate with a ping-pong kinetic mechanism in which the substrate import and export steps occur consecutively. These observations are consistent with a common transport mechanism, based on a functional monomer, in which a single central substrate-binding site is alternately accessible.
    Keywords:  Bioenergetics; Kinetic Analysis; Mitochondria; SLC25 Mitochondrial Carrier Family; Transport
    DOI:  https://doi.org/10.1038/s44318-024-00150-0
  11. Sci Adv. 2024 Jun 28. 10(26): eadn4508
    Lactate transported by MCT1 plays an active role in promoting mitochondrial biogenesis and enhancing TCA flux in skeletal muscle.
    Lingling Zhang, Chenhao Xin, Shuo Wang, Shixuan Zhuo, Jing Zhu, Zi Li, Yuyi Liu, Lifeng Yang, Yan Chen.
      Once considered as a "metabolic waste," lactate is now recognized as a major fuel for tricarboxylic acid (TCA) cycle. Our metabolic flux analysis reveals that skeletal muscle mainly uses lactate to fuel TCA cycle. Lactate is transported through the cell membrane via monocarboxylate transporters (MCTs) in which MCT1 is highly expressed in the muscle. We analyzed how MCT1 affects muscle functions using mice with specific deletion of MCT1 in skeletal muscle. MCT1 deletion enhances running performance, increases oxidative fibers while decreasing glycolytic fibers, and enhances flux of glucose to TCA cycle. MCT1 deficiency increases the expression of mitochondrial proteins, augments cell respiration rate, and elevates mitochondrial activity in the muscle. Mechanistically, the protein level of PGC-1α, a master regulator of mitochondrial biogenesis, is elevated upon loss of MCT1 via increases in cellular NAD+ level and SIRT1 activity. Collectively, these results demonstrate that MCT1-mediated lactate shuttle plays a key role in regulating muscle functions by modulating mitochondrial biogenesis and TCA flux.
    DOI:  https://doi.org/10.1126/sciadv.adn4508
  12. Cell. 2024 Jun 24. pii: S0092-8674(24)00638-X. [Epub ahead of print]
    The extracellular matrix integrates mitochondrial homeostasis.
    Hanlin Zhang, C Kimberly Tsui, Gilberto Garcia, Larry K Joe, Haolun Wu, Ayane Maruichi, Wudi Fan, Sentibel Pandovski, Peter H Yoon, Brant M Webster, Jenni Durieux, Phillip A Frankino, Ryo Higuchi-Sanabria, Andrew Dillin.
      Cellular homeostasis is intricately influenced by stimuli from the microenvironment, including signaling molecules, metabolites, and pathogens. Functioning as a signaling hub within the cell, mitochondria integrate information from various intracellular compartments to regulate cellular signaling and metabolism. Multiple studies have shown that mitochondria may respond to various extracellular signaling events. However, it is less clear how changes in the extracellular matrix (ECM) can impact mitochondrial homeostasis to regulate animal physiology. We find that ECM remodeling alters mitochondrial homeostasis in an evolutionarily conserved manner. Mechanistically, ECM remodeling triggers a TGF-β response to induce mitochondrial fission and the unfolded protein response of the mitochondria (UPRMT). At the organismal level, ECM remodeling promotes defense of animals against pathogens through enhanced mitochondrial stress responses. We postulate that this ECM-mitochondria crosstalk represents an ancient immune pathway, which detects infection- or mechanical-stress-induced ECM damage, thereby initiating adaptive mitochondria-based immune and metabolic responses.
    Keywords:  TGF-β; TMEM2; extracellular matrix; hyaluronan; immunity; mitochondria
    DOI:  https://doi.org/10.1016/j.cell.2024.05.057
  13. Genes (Basel). 2024 May 27. pii: 694. [Epub ahead of print]15(6):
    Knockout Mouse Studies Show That Mitochondrial CLPP Peptidase and CLPX Unfoldase Act in Matrix Condensates near IMM, as Fast Stress Response in Protein Assemblies for Transcript Processing, Translation, and Heme Production.
    Jana Key, Suzana Gispert, Georg Auburger.
      LONP1 is the principal AAA+ unfoldase and bulk protease in the mitochondrial matrix, so its deletion causes embryonic lethality. The AAA+ unfoldase CLPX and the peptidase CLPP also act in the matrix, especially during stress periods, but their substrates are poorly defined. Mammalian CLPP deletion triggers infertility, deafness, growth retardation, and cGAS-STING-activated cytosolic innate immunity. CLPX mutations impair heme biosynthesis and heavy metal homeostasis. CLPP and CLPX are conserved from bacteria to humans, despite their secondary role in proteolysis. Based on recent proteomic-metabolomic evidence from knockout mice and patient cells, we propose that CLPP acts on phase-separated ribonucleoprotein granules and CLPX on multi-enzyme condensates as first-aid systems near the inner mitochondrial membrane. Trimming within assemblies, CLPP rescues stalled processes in mitoribosomes, mitochondrial RNA granules and nucleoids, and the D-foci-mediated degradation of toxic double-stranded mtRNA/mtDNA. Unfolding multi-enzyme condensates, CLPX maximizes PLP-dependent delta-transamination and rescues malformed nascent peptides. Overall, their actions occur in granules with multivalent or hydrophobic interactions, separated from the aqueous phase. Thus, the role of CLPXP in the matrix is compartment-selective, as other mitochondrial peptidases: MPPs at precursor import pores, m-AAA and i-AAA at either IMM face, PARL within the IMM, and OMA1/HTRA2 in the intermembrane space.
    Keywords:  ALAS; GFM1; ISC; OAT; PNPT1; Perrault syndrome type 3 (PRLTS3); RNA-G4; VWA8; iron toxicity; pyridoxal-5′-phosphate
    DOI:  https://doi.org/10.3390/genes15060694
  14. Cancer Res. 2024 Jun 26.
    Multi-State Gene Cluster Switches Determine the Adaptive Mitochondrial And Metabolic Landscape of Breast Cancer.
    Michela Menegollo, Robert B Bentham, Tiago Henriques, Seow Qi Ng, Ziyu Ren, Clarinde Esculier, Sia Agarwal, Emily T Y Tong, Clement Lo, Sanjana Ilangovan, Zorka Szabadkai, Matteo Suman, Neill Patani, Avinash Ghanate, Kevin Bryson, Robert C Stein, Mariia Yuneva, Gyorgy Szabadkai.
      Adaptive metabolic switches are proposed to underlie conversions between cellular states during normal development as well as in cancer evolution. Metabolic adaptations represent important therapeutic targets in tumors, highlighting the need to characterize the full spectrum, characteristics, and regulation of the metabolic switches. To investigate the hypothesis that metabolic switches associated with specific metabolic states can be recognized by locating large alternating gene expression patterns, we developed a method to identify interspersed gene sets by massive correlated biclustering (MCbiclust) and to predict their metabolic wiring. Testing the method on breast cancer transcriptome datasets revealed a series of gene sets with switch-like behavior that could be used to predict mitochondrial content, metabolic activity, and central carbon flux in tumors. The predictions were experimentally validated by bioenergetic profiling and metabolic flux analysis of 13C-labelled substrates. The metabolic switch positions also distinguished between cellular states, correlating with tumor pathology, prognosis, and chemosensitivity. The method is applicable to any large and heterogeneous transcriptome dataset to discover metabolic and associated pathophysiological states.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-23-3172
  15. Nat Commun. 2024 Jun 27. 15(1): 5439
    NPY-mediated synaptic plasticity in the extended amygdala prioritizes feeding during starvation.
    Stephan Dodt, Noah V Widdershooven, Marie-Luise Dreisow, Lisa Weiher, Lukas Steuernagel, F Thomas Wunderlich, Jens C Brüning, Henning Fenselau.
      Efficient control of feeding behavior requires the coordinated adjustment of complex motivational and affective neurocircuits. Neuropeptides from energy-sensing hypothalamic neurons are potent feeding modulators, but how these endogenous signals shape relevant circuits remains unclear. Here, we examine how the orexigenic neuropeptide Y (NPY) adapts GABAergic inputs to the bed nucleus of the stria terminalis (BNST). We find that fasting increases synaptic connectivity between agouti-related peptide (AgRP)-expressing 'hunger' and BNST neurons, a circuit that promotes feeding. In contrast, GABAergic input from the central amygdala (CeA), an extended amygdala circuit that decreases feeding, is reduced. Activating NPY-expressing AgRP neurons evokes these synaptic adaptations, which are absent in NPY-deficient mice. Moreover, fasting diminishes the ability of CeA projections in the BNST to suppress food intake, and NPY-deficient mice fail to decrease anxiety in order to promote feeding. Thus, AgRP neurons drive input-specific synaptic plasticity, enabling a selective shift in hunger and anxiety signaling during starvation through NPY.
    DOI:  https://doi.org/10.1038/s41467-024-49766-0
  16. Transl Oncol. 2024 Jun 22. pii: S1936-5233(24)00170-0. [Epub ahead of print]47 102043
    ACAT1 suppresses clear cell renal cell carcinoma progression by AMPK mediated fatty acid metabolism.
    Ming Zheng, Shenghu Zhang, Jiajie Zhou, Ming Lin, Yixiang Liao.
      Renal cell carcinoma (RCC) stands as a prevalent malignancy within urological pathology, exhibiting a noteworthy escalation in its incidence. Despite being a mitochondrial enzyme, the precise role of Acetyl-CoA Acetyltransferase 1 (ACAT1) in RCC remains elusive. In this investigation, we employed bioinformatics methodologies to assess the expression patterns and prognostic significance across various RCC subtypes, encompassing clear cell renal cell carcinoma (ccRCC), papillary cell carcinoma, and chromophobe cell carcinoma. Our findings unveil a close correlation between ACAT1 expression and the prognostic implications specifically within ccRCC. Through both in vitro and in vivo overexpression studies, we delineated the functional and mechanistic facets of ACAT1 in impeding the progression of ccRCC. Our results unequivocally demonstrated that ACAT1 overexpression markedly curtailed proliferation, invasion, and metastasis of ccRCC cells in both in vivo models and cell cultures. Mechanistically, ACAT1's inhibitory effect on the AMPK signaling pathway orchestrated a regulatory role in modulating fatty acid metabolism, thereby effectively restraining the advancement of ccRCC. Collectively, our findings underscore ACAT1 as a pivotal tumor suppressor, instrumental in curtailing the proliferation, migration, and invasion of ccRCC by governing fatty acid metabolism through the AMPK signaling pathway. These insights posit ACAT1 as a potential predictive biomarker and therapeutic target warranting further exploration in RCC management.
    Keywords:  Acetyl-CoA Acetyltransferase 1; Clear cell renal cell carcinoma; Fatty acid metabolism; Progression
    DOI:  https://doi.org/10.1016/j.tranon.2024.102043
  17. Nat Cell Biol. 2024 Jun 25.
    Ferroptosis-like cell death promotes and prolongs inflammation in Drosophila.
    Andrew J Davidson, Rosalind Heron, Jyotirekha Das, Michael Overholtzer, Will Wood.
      Ferroptosis is a distinct form of necrotic cell death caused by overwhelming lipid peroxidation, and emerging evidence indicates a major contribution to organ damage in multiple pathologies. However, ferroptosis has not yet been visualized in vivo due to a lack of specific probes, which has severely limited the study of how the immune system interacts with ferroptotic cells and how this process contributes to inflammation. Consequently, whether ferroptosis has a physiological role has remained a key outstanding question. Here we identify a distinct, ferroptotic-like, necrotic cell death occurring in vivo during wounding of the Drosophila embryo using live imaging. We further demonstrate that macrophages rapidly engage these necrotic cells within the embryo but struggle to engulf them, leading to prolonged, frustrated phagocytosis and frequent corpse disintegration. Conversely, suppression of the ferroptotic programme during wounding delays macrophage recruitment to the injury site, pointing to conflicting roles for ferroptosis during inflammation in vivo.
    DOI:  https://doi.org/10.1038/s41556-024-01450-7
  18. Nat Commun. 2024 Jun 25. 15(1): 5360
    N-terminal cysteine acetylation and oxidation patterns may define protein stability.
    Karen C Heathcote, Thomas P Keeley, Matti Myllykoski, Malin Lundekvam, Nina McTiernan, Salma Akter, Norma Masson, Peter J Ratcliffe, Thomas Arnesen, Emily Flashman.
      Oxygen homeostasis is maintained in plants and animals by O2-sensing enzymes initiating adaptive responses to low O2 (hypoxia). Recently, the O2-sensitive enzyme ADO was shown to initiate degradation of target proteins RGS4/5 and IL32 via the Cysteine/Arginine N-degron pathway. ADO functions by catalysing oxidation of N-terminal cysteine residues, but despite multiple proteins in the human proteome having an N-terminal cysteine, other endogenous ADO substrates have not yet been identified. This could be because alternative modifications of N-terminal cysteine residues, including acetylation, prevent ADO-catalysed oxidation. Here we investigate the relationship between ADO-catalysed oxidation and NatA-catalysed acetylation of a broad range of protein sequences with N-terminal cysteines. We present evidence that human NatA catalyses N-terminal cysteine acetylation in vitro and in vivo. We then show that sequences downstream of the N-terminal cysteine dictate whether this residue is oxidised or acetylated, with ADO preferring basic and aromatic amino acids and NatA preferring acidic or polar residues. In vitro, the two modifications appear to be mutually exclusive, suggesting that distinct pools of N-terminal cysteine proteins may be acetylated or oxidised. These results reveal the sequence determinants that contribute to N-terminal cysteine protein modifications, with implications for O2-dependent protein stability and the hypoxic response.
    DOI:  https://doi.org/10.1038/s41467-024-49489-2
  19. Anal Chem. 2024 Jun 26.
    Fluorescence Lifetime Super-Resolution Imaging Unveil the Dynamic Relationship between Mitochondrial Membrane Potential and Cristae Structure Using the Förster Resonance Energy Transfer Strategy.
    Fei Peng, Xiangnan Ai, Jing Sun, Xichuan Ge, Meiqi Li, Peng Xi, Baoxiang Gao.
      Mitochondrial cristae, invaginations of the inner mitochondrial membrane (IMM) into the matrix, are the main site for the generation of ATP via oxidative phosphorylation, and mitochondrial membrane potential (MMP). Synchronous study of the dynamic relationship between cristae and MMP is very important for further understanding of mitochondrial function. Due to the lack of suitable IMM probes and imaging techniques, the dynamic relationship between MMP and cristae structure alterations remains poorly understood. We designed a pair of FRET-based molecular probes, with the donor (OR-LA) being rhodamine modified with mitochondrial coenzyme lipoic acid and the acceptor (SiR-BA) being silicon-rhodamine modified with a butyl chain, for simultaneous dynamic monitoring of mitochondrial cristae structure and MMP. The FRET process of the molecular pair in mitochondria is regulated by MMP, enabling more precise visualization of MMP through fluorescence intensity ratio and fluorescence lifetime. By combining FRET with FLIM super-resolution imaging technology, we achieved simultaneous dynamic monitoring of mitochondrial cristae structure and MMP, revealing that during the decline of MMP, there is a progression involving cristae dilation, fragmentation, mitochondrial vacuolization, and eventual rupture. Significantly, we successfully observed that the rapid decrease in MMP at the site of mitochondrial membrane rupture may be a critical factor in mitochondrial fragmentation. These data collectively reveal the dynamic relationship between cristae structural alterations and MMP decline, laying a foundation for further investigation into cellular energy regulation mechanisms and therapeutic strategies for mitochondria-related diseases.
    DOI:  https://doi.org/10.1021/acs.analchem.4c01905
  20. Genome Biol. 2024 Jun 26. 25(1): 168
    Immune evasion impacts the landscape of driver genes during cancer evolution.
    Lucie Gourmet, Andrea Sottoriva, Simon Walker-Samuel, Maria Secrier, Luis Zapata.
       BACKGROUND: Carcinogenesis is driven by interactions between genetic mutations and the local tumor microenvironment. Recent research has identified hundreds of cancer driver genes; however, these studies often include a mixture of different molecular subtypes and ecological niches and ignore the impact of the immune system.
    RESULTS: In this study, we compare the landscape of driver genes in tumors that escaped the immune system (escape +) versus those that did not (escape -). We analyze 9896 primary tumors from The Cancer Genome Atlas using the ratio of non-synonymous to synonymous mutations (dN/dS) and find 85 driver genes, including 27 and 16 novel genes, in escape - and escape + tumors, respectively. The dN/dS of driver genes in immune escaped tumors is significantly lower and closer to neutrality than in non-escaped tumors, suggesting selection buffering in driver genes fueled by immune escape. Additionally, we find that immune evasion leads to more mutated sites, a diverse array of mutational signatures and is linked to tumor prognosis.
    CONCLUSIONS: Our findings highlight the need for improved patient stratification to identify new therapeutic targets for cancer treatment.
    Keywords:  Cancer Evolution; Cancer Hallmarks; Immunogenomics; immune evasion; natural selection
    DOI:  https://doi.org/10.1186/s13059-024-03302-x
  21. Development. 2024 Jun 15. pii: dev202937. [Epub ahead of print]151(12):
    Historic obstacles and emerging opportunities in the field of developmental metabolism - lessons from Heidelberg.
    Alexandra M Garfinkel, Efe Ilker, Hidenobu Miyazawa, Kathrin Schmeisser, Jason M Tennessen.
      The field of developmental metabolism is experiencing a technological revolution that is opening entirely new fields of inquiry. Advances in metabolomics, small-molecule sensors, single-cell RNA sequencing and computational modeling present new opportunities for exploring cell-specific and tissue-specific metabolic networks, interorgan metabolic communication, and gene-by-metabolite interactions in time and space. Together, these advances not only present a means by which developmental biologists can tackle questions that have challenged the field for centuries, but also present young scientists with opportunities to define new areas of inquiry. These emerging frontiers of developmental metabolism were at the center of a highly interactive 2023 EMBO workshop 'Developmental metabolism: flows of energy, matter, and information'. Here, we summarize key discussions from this forum, emphasizing modern developmental biology's challenges and opportunities.
    Keywords:  Developmental metabolism; FRET sensors; Metabolic diseases; Metabolic set-points; Spatial metabolomics; Theoretical modeling
    DOI:  https://doi.org/10.1242/dev.202937
  22. EMBO Mol Med. 2024 Jun 26.
    FADS1/2 control lipid metabolism and ferroptosis susceptibility in triple-negative breast cancer.
    Nicla Lorito, Angela Subbiani, Alfredo Smiriglia, Marina Bacci, Francesca Bonechi, Laura Tronci, Elisabetta Romano, Alessia Corrado, Dario Livio Longo, Marta Iozzo, Luigi Ippolito, Giuseppina Comito, Elisa Giannoni, Icro Meattini, Alexandra Avgustinova, Paola Chiarugi, Angela Bachi, Andrea Morandi.
      Triple-negative breast cancer (TNBC) has limited therapeutic options, is highly metastatic and characterized by early recurrence. Lipid metabolism is generally deregulated in TNBC and might reveal vulnerabilities to be targeted or used as biomarkers with clinical value. Ferroptosis is a type of cell death caused by iron-dependent lipid peroxidation which is facilitated by the presence of polyunsaturated fatty acids (PUFA). Here we identify fatty acid desaturases 1 and 2 (FADS1/2), which are responsible for PUFA biosynthesis, to be highly expressed in a subset of TNBC with a poorer prognosis. Lipidomic analysis, coupled with functional metabolic assays, showed that FADS1/2 high-expressing TNBC are susceptible to ferroptosis-inducing agents and that targeting FADS1/2 by both genetic interference and pharmacological approach renders those tumors ferroptosis-resistant while unbalancing PUFA/MUFA ratio by the supplementation of exogenous PUFA sensitizes resistant tumors to ferroptosis induction. Last, inhibiting lipid droplet (LD) formation and turnover suppresses the buffering capacity of LD and potentiates iron-dependent cell death. These findings have been validated in vitro and in vivo in mouse- and human-derived clinically relevant models and in a retrospective cohort of TNBC patients.
    Keywords:  Desaturases; Ferroptosis; Lipid Droplets; Lipid Metabolism; Polyunsaturated Fatty Acids
    DOI:  https://doi.org/10.1038/s44321-024-00090-6
  23. Nat Commun. 2024 Jun 26. 15(1): 5410
    METTL3-mediated chromatin contacts promote stress granule phase separation through metabolic reprogramming during senescence.
    Chen Wang, Hideki Tanizawa, Connor Hill, Aaron Havas, Qiang Zhang, Liping Liao, Xue Hao, Xue Lei, Lu Wang, Hao Nie, Yuan Qi, Bin Tian, Alessandro Gardini, Andrew V Kossenkov, Aaron Goldman, Shelley L Berger, Ken-Ichi Noma, Peter D Adams, Rugang Zhang.
      METTL3 is the catalytic subunit of the methyltransferase complex, which mediates m6A modification to regulate gene expression. In addition, METTL3 regulates transcription in an enzymatic activity-independent manner by driving changes in high-order chromatin structure. However, how these functions of the methyltransferase complex are coordinated remains unknown. Here we show that the methyltransferase complex coordinates its enzymatic activity-dependent and independent functions to regulate cellular senescence, a state of stable cell growth arrest. Specifically, METTL3-mediated chromatin loops induce Hexokinase 2 expression through the three-dimensional chromatin organization during senescence. Elevated Hexokinase 2 expression subsequently promotes liquid-liquid phase separation, manifesting as stress granule phase separation, by driving metabolic reprogramming. This correlates with an impairment of translation of cell-cycle related mRNAs harboring polymethylated m6A sites. In summary, our results report a coordination of m6A-dependent and -independent function of the methyltransferase complex in regulating senescence through phase separation driven by metabolic reprogramming.
    DOI:  https://doi.org/10.1038/s41467-024-49745-5
  24. bioRxiv. 2024 Jun 10. pii: 2024.06.10.598332. [Epub ahead of print]
    Unraveling CRP/cAMP-Mediated Metabolic Regulation In Escherichia coli Persister Cells.
    Han G Ngo, Sayed Golam Mohiuddin, Aina Ananda, Mehmet A Orman.
      A substantial gap persists in our comprehension of how bacterial metabolism undergoes rewiring during the transition to a persistent state. Also, it remains unclear which metabolic mechanisms become indispensable for persister cell survival. To address these questions, we directed our efforts towards persister cells in Escherichia coli that emerge during the late stationary phase. These cells have been recognized for their exceptional resilience and are commonly believed to be in a dormant state. Our results demonstrate that the global metabolic regulator Crp/cAMP redirects the metabolism of these antibiotic-tolerant cells from anabolism to oxidative phosphorylation. Although our data indicates that persisters exhibit a reduced metabolic rate compared to rapidly growing exponential-phase cells, their survival still relies on energy metabolism. Extensive genomic-level analyses of metabolomics, proteomics, and single-gene deletions consistently emphasize the critical role of energy metabolism, specifically the tricarboxylic acid (TCA) cycle, electron transport chain (ETC), and ATP synthase, in sustaining the viability of persisters. Altogether, this study provides much-needed clarification regarding the role of energy metabolism in antibiotic tolerance and highlights the importance of using a multipronged approach at the genomic level to obtain a broader picture of the metabolic state of persister cells.
    DOI:  https://doi.org/10.1101/2024.06.10.598332
  25. Proc Natl Acad Sci U S A. 2024 Jul 02. 121(27): e2317316121
    An aggregated mitochondrial distribution in preimplantation embryos disrupts nuclear morphology, function, and developmental potential.
    In-Won Lee, Abbas Pirpour Tazehkand, Zi-Yi Sha, Deepak Adhikari, John Carroll.
      A dispersed cytoplasmic distribution of mitochondria is a hallmark of normal cellular organization. Here, we have utilized the expression of exogenous Trak2 in mouse oocytes and embryos to disrupt the dispersed distribution of mitochondria by driving them into a large cytoplasmic aggregate. Our findings reveal that aggregated mitochondria have minimal impact on asymmetric meiotic cell divisions of the oocyte. In contrast, aggregated mitochondria during the first mitotic division result in daughter cells with unequal sizes and increased micronuclei. Further, in two-cell embryos, microtubule-mediated centering properties of the mitochondrial aggregate prevent nuclear centration, distort nuclear shape, and inhibit DNA synthesis and the onset of embryonic transcription. These findings demonstrate the motor protein-mediated distribution of mitochondria throughout the cytoplasm is highly regulated and is an essential feature of cytoplasmic organization to ensure optimal cell function.
    Keywords:  Meiosis; Mitosis; Nuclear morphology; TRAK2; mitochondrial aggregation
    DOI:  https://doi.org/10.1073/pnas.2317316121
  26. Int J Mol Sci. 2024 Jun 11. pii: 6441. [Epub ahead of print]25(12):
    Mitochondrial DNA Instability Supersedes Parkin Mutations in Driving Mitochondrial Proteomic Alterations and Functional Deficits in Polg Mutator Mice.
    Andrew J Trease, Steven Totusek, Eliezer Z Lichter, Kelly L Stauch, Howard S Fox.
      Mitochondrial quality control is essential in mitochondrial function. To examine the importance of Parkin-dependent mechanisms in mitochondrial quality control, we assessed the impact of modulating Parkin on proteome flux and mitochondrial function in a context of reduced mtDNA fidelity. To accomplish this, we crossed either the Parkin knockout mouse or ParkinW402A knock-in mouse lines to the Polg mitochondrial mutator line to generate homozygous double mutants. In vivo longitudinal isotopic metabolic labeling was followed by isolation of liver mitochondria and synaptic terminals from the brain, which are rich in mitochondria. Mass spectrometry and bioenergetics analysis were assessed. We demonstrate that slower mitochondrial protein turnover is associated with loss of mtDNA fidelity in liver mitochondria but not synaptic terminals, and bioenergetic function in both tissues is impaired. Pathway analysis revealed loss of mtDNA fidelity is associated with disturbances of key metabolic pathways, consistent with its association with metabolic disorders and neurodegeneration. Furthermore, we find that loss of Parkin leads to exacerbation of Polg-driven proteomic consequences, though it may be bioenergetically protective in tissues exhibiting rapid mitochondrial turnover. Finally, we provide evidence that, surprisingly, dis-autoinhibition of Parkin (ParkinW402A) functionally resembles Parkin knockout and fails to rescue deleterious Polg-driven effects. Our study accomplishes three main outcomes: (1) it supports recent studies suggesting that Parkin dependence is low in response to an increased mtDNA mutational load, (2) it provides evidence of a potential protective role of Parkin insufficiency, and (3) it draws into question the therapeutic attractiveness of enhancing Parkin function.
    Keywords:  Parkin; Parkinson’s disease; aging; metabolism; mitochondria; mitophagy
    DOI:  https://doi.org/10.3390/ijms25126441
  27. Int J Mol Sci. 2024 Jun 19. pii: 6735. [Epub ahead of print]25(12):
    Interplay between mTOR and Purine Metabolism Enzymes and Its Relevant Role in Cancer.
    Simone Allegrini, Marcella Camici, Mercedes Garcia-Gil, Rossana Pesi, Maria Grazia Tozzi.
      Tumor cells reprogram their metabolism to meet the increased demand for nucleotides and other molecules necessary for growth and proliferation. In fact, cancer cells are characterized by an increased "de novo" synthesis of purine nucleotides. Therefore, it is not surprising that specific enzymes of purine metabolism are the targets of drugs as antineoplastic agents, and a better knowledge of the mechanisms underlying their regulation would be of great help in finding new therapeutic approaches. The mammalian target of the rapamycin (mTOR) signaling pathway, which is often activated in cancer cells, promotes anabolic processes and is a major regulator of cell growth and division. Among the numerous effects exerted by mTOR, noteworthy is its empowerment of the "de novo" synthesis of nucleotides, accomplished by supporting the formation of purinosomes, and by increasing the availability of necessary precursors, such as one-carbon formyl group, bicarbonate and 5-phosphoribosyl-1-pyrophosphate. In this review, we highlight the connection between purine and mitochondrial metabolism, and the bidirectional relation between mTOR signaling and purine synthesis pathways.
    Keywords:  AKT; c-Myc; cancer; cell survival; mTOR; mitochondria; one-carbon metabolism; proliferation; purine metabolism; purinosome
    DOI:  https://doi.org/10.3390/ijms25126735
  28. Nature. 2024 Jun 26.
    Aged mice regain youthful muscles thanks to a compound that acts on the genes.
      
    Keywords:  Ageing
    DOI:  https://doi.org/10.1038/d41586-024-02100-6
  29. FEBS J. 2024 Jun 27.
    Developmental and tissue-specific roles of mammalian centrosomes.
    Charlotte Meyer-Gerards, Hisham Bazzi.
      Centrosomes are dominant microtubule organizing centers in animal cells with a pair of centrioles at their core. They template cilia during interphase and help organize the mitotic spindle for a more efficient cell division. Here, we review the roles of centrosomes in the early developing mouse and during organ formation. Mammalian cells respond to centrosome loss-of-function by activating the mitotic surveillance pathway, a timing mechanism that, when a defined mitotic duration is exceeded, leads to p53-dependent cell death in the descendants. Mouse embryos without centrioles are highly susceptible to this pathway and undergo embryonic arrest at mid-gestation. The complete loss of the centriolar core results in earlier and more severe phenotypes than that of other centrosomal proteins. Finally, different developing tissues possess varying thresholds and mount graded responses to the loss of centrioles that go beyond the germ layer of origin.
    Keywords:  53BP1; USP28; cell division; centriole; mitotic surveillance pathway; mouse; p53
    DOI:  https://doi.org/10.1111/febs.17212
  30. bioRxiv. 2024 Jun 12. pii: 2024.06.10.598354. [Epub ahead of print]
    Intra-organ cell specific mitochondrial quantitative interactomics.
    A A Bakhtina, M D Campbell, B D Sibley, M Sanchez-Contreras, M T Sweetwyne, J E Bruce.
      Almost every organ consists of many cell types, each with its unique functions. Proteomes of these cell types are thus unique too. But it is reasonable to assume that interactome (inter and intra molecular interactions of proteins) are also distinct since protein interactions are what ultimately carry out the function. Podocytes and tubules are two cell types within kidney with vastly different functions: podocytes envelop the blood vessels in the glomerulus and act as filters while tubules are located downstream of the glomerulus and are responsible for reabsorption of important nutrients. It has been long known that for tubules mitochondria plays an important role as they require a lot of energy to carry out their functions. In podocytes, however, it has been assumed that mitochondria might not matter as much in both normal physiology and pathology 1 . Here we have applied quantitative cross-linking mass spectrometry to compare mitochondrial interactomes of tubules and podocytes using a transgenic mitochondrial tagging strategy to immunoprecipitate cell-specific mitochondria directly from whole kidney. We have uncovered that mitochondrial proteomes of these cell types are quite similar, although still showing unique features that correspond to known functions, such as high energy production through TCA cycle in tubules and requirements for detoxification in podocytes which are on the frontline of filtration where they encounter toxic compounds and therefore, as a non-renewing cell type they must have ways to protect themselves from cellular toxicity. But we gained much deeper insight with the interactomics data. We were able to find pathways differentially regulated in podocytes and tubules based on changing cross-link levels and not just protein levels. Among these pathways are betaine metabolism, lysine degradation, and many others. We have also demonstrated how quantitative interactomics could be used to detect different activity levels of an enzyme even when protein abundances of it are the same between cell types. We have validated this finding with an orthogonal activity assay. Overall, this work presents a new view of mitochondrial biology for two important, but functionally distinct, cell types within the mouse kidney showing both similarities and unique features. This data can continue to be explored to find new aspects of mitochondrial biology, especially in podocytes, where mitochondria has been understudied. In the future this methodology can also be applied to other organs to uncover differences in the function of cell types.
    DOI:  https://doi.org/10.1101/2024.06.10.598354
  31. Nature. 2024 Jun 26.
    Oxylipins and metabolites from pyroptotic cells act as promoters of tissue repair.
    Parul Mehrotra, Sophia Maschalidi, Laura Boeckaerts, Christian Maueröder, Rochelle Tixeira, Jonathan Pinney, Javier Burgoa Cardás, Vladimir Sukhov, Yunus Incik, Christopher J Anderson, Bing Hu, Burcu N Keçeli, Amanda Goncalves, Lieselotte Vande Walle, Nina Van Opdenbosch, Alexey Sergushichev, Esther Hoste, Umang Jain, Mohamed Lamkanfi, Kodi S Ravichandran.
      Pyroptosis is a lytic cell death mode that helps limit the spread of infections and is also linked to pathology in sterile inflammatory diseases and autoimmune diseases1-4. During pyroptosis, inflammasome activation and the engagement of caspase-1 lead to cell death, along with the maturation and secretion of the inflammatory cytokine interleukin-1β (IL-1β). The dominant effect of IL-1β in promoting tissue inflammation has clouded the potential influence of other factors released from pyroptotic cells. Here, using a system in which macrophages are induced to undergo pyroptosis without IL-1β or IL-1α release (denoted Pyro-1), we identify unexpected beneficial effects of the Pyro-1 secretome. First, we noted that the Pyro-1 supernatants upregulated gene signatures linked to migration, cellular proliferation and wound healing. Consistent with this gene signature, Pyro-1 supernatants boosted migration of primary fibroblasts and macrophages, and promoted faster wound closure in vitro and improved tissue repair in vivo. In mechanistic studies, lipidomics and metabolomics of the Pyro-1 supernatants identified the presence of both oxylipins and metabolites, linking them to pro-wound-healing effects. Focusing specifically on the oxylipin prostaglandin E2 (PGE2), we find that its synthesis is induced de novo during pyroptosis, downstream of caspase-1 activation and cyclooxygenase-2 activity; further, PGE2 synthesis occurs late in pyroptosis, with its release dependent on gasdermin D pores opened during pyroptosis. As for the pyroptotic metabolites, they link to immune cell infiltration into the wounds, and polarization to CD301+ macrophages. Collectively, these data advance the concept that the pyroptotic secretome possesses oxylipins and metabolites with tissue repair properties that may be harnessed therapeutically.
    DOI:  https://doi.org/10.1038/s41586-024-07585-9
  32. bioRxiv. 2024 Jun 16. pii: 2024.06.15.599174. [Epub ahead of print]
    Endothelial Drp1 Couples VEGF-induced Redox Signaling with Glycolysis Through Cysteine Oxidation to Drive Angiogenesis.
    Sheela Nagarkoti, Young-Mee Kim, Archita Das, Dipankar Ash, Eric A Vitriol, Tracy-Ann Read, Varadarajan Sudhahar, Md Selim Hossain, Shikha Yadav, Malgorzata McMenamin, Stephanie Kelley, Rudolf Lucas, David Stepp, Eric J Belin de Chantemele, Ruth B Caldwell, David Jr Fulton, Tohru Fukai, Masuko Ushio-Fukai.
      Angiogenesis plays a vital role for postnatal development and tissue repair following ischemia. Reactive oxygen species (ROS) generated by NADPH oxidases (NOXes) and mitochondria act as signaling molecules that promote angiogenesis in endothelial cells (ECs) which mainly relies on aerobic glycolysis for ATP production. However, the connections linking redox signaling with glycolysis are not well understood. The GTPase Drp1 is a member of the dynamin superfamily that moves from cytosol to mitochondria through posttranslational modifications to induce mitochondrial fission. The role of Drp1 in ROS-dependent VEGF signaling and angiogenesis in ECs has not been previously described. Here, we identify an unexpected function of endothelial Drp1 as a redox sensor, transmitting VEGF-induced H 2 O 2 signals to enhance glycolysis and angiogenesis. Loss of Drp1 expression in ECs inhibited VEGF-induced angiogenic responses. Mechanistically, VEGF rapidly induced the NOX4-dependent sulfenylation (CysOH) of Drp1 on Cys 644 , promoting disulfide bond formation with the metabolic kinase AMPK and subsequent sulfenylation of AMPK at Cys 299 / 304 via the mitochondrial fission-mitoROS axis. This cysteine oxidation of AMPK, in turn, enhanced glycolysis and angiogenesis. In vivo , mice with EC-specific Drp1 deficiency or CRISPR/Cas9-engineered "redox-dead" (Cys to Ala) Drp1 knock-in mutations exhibited impaired retinal angiogenesis and post-ischemic neovascularization. Our findings uncover a novel role for endothelial Drp1 in linking VEGF-induced mitochondrial redox signaling to glycolysis through a cysteine oxidation-mediated Drp1-AMPK redox relay, driving both developmental and reparative angiogenesis.
    DOI:  https://doi.org/10.1101/2024.06.15.599174
  33. Mol Metab. 2024 Jun 20. pii: S2212-8778(24)00100-5. [Epub ahead of print] 101969
    Autophagic signaling promotes systems-wide remodeling in skeletal muscle upon oncometabolic stress by D2-HG.
    Yaqi Gao, Kyoungmin Kim, Heidi Vitrac, Rebecca L Salazar, Benjamin D Gould, Daniel Soedkamp, Weston Spivia, Koen Raedschelders, An Q Dinh, Anna G Guzman, Lin Tan, Stavros Azinas, David J R Taylor, Walter Schiffer, Daniel McNavish, Helen B Burks, Roberta A Gottlieb, Philip L Lorenzi, Blake M Hanson, Jennifer E Van Eyk, Heinrich Taegtmeyer, Anja Karlstaedt.
       OBJECTIVES: Cachexia is a metabolic disorder and comorbidity with cancer and heart failure. The syndrome impacts more than thirty million people worldwide, accounting for 20% of all cancer deaths. In acute myeloid leukemia, somatic mutations of the metabolic enzyme isocitrate dehydrogenase 1 and 2 cause the production of the oncometabolite D2-hydroxyglutarate (D2-HG). Increased production of D2-HG is associated with heart and skeletal muscle atrophy, but the mechanistic links between metabolic and proteomic remodeling remain poorly understood. Therefore, we assessed how oncometabolic stress by D2-HG activates autophagy and drives skeletal muscle loss.
    METHODS: We quantified genomic, metabolomic, and proteomic changes in cultured skeletal muscle cells and mouse models of IDH-mutant leukemia using RNA sequencing, mass spectrometry, and computational modeling.
    RESULTS: D2-HG impairs NADH redox homeostasis in myotubes. Increased NAD+ levels drive activation of nuclear deacetylase Sirt1, which causes deacetylation and activation of LC3, a key regulator of autophagy. Using LC3 mutants, we confirm that deacetylation of LC3 by Sirt1 shifts its distribution from the nucleus into the cytosol, where it can undergo lipidation at pre-autophagic membranes. Sirt1 silencing or p300 overexpression attenuated autophagy activation in myotubes. In vivo, we identified increased muscle atrophy and reduced grip strength in response to D2-HG in male vs. female mice. In male mice, glycolytic intermediates accumulated, and protein expression of oxidative phosphorylation machinery was reduced. In contrast, female animals upregulated the same proteins, attenuating the phenotype in vivo. Network modeling and machine learning algorithms allowed us to identify candidate proteins essential for regulating oncometabolic adaptation in mouse skeletal muscle.
    CONCLUSIONS: Our multi-omics approach exposes new metabolic vulnerabilities in response to D2-HG in skeletal muscle and provides a conceptual framework for identifying therapeutic targets in cachexia.
    Keywords:  Autophagy; Cachexia; Oncometabolism; Systems Biology
    DOI:  https://doi.org/10.1016/j.molmet.2024.101969
  34. Aging Cell. 2024 Jun 26. e14199
    Integrated multi-omic analyses uncover the effects of aging on cell-type regulation in glucose-responsive tissues.
    Peng Xu, Yimeng Kong, Nicholette D Palmer, Maggie C Y Ng, Bin Zhang, Swapan K Das.
      Aging significantly influences cellular activity and metabolism in glucose-responsive tissues, yet a comprehensive evaluation of the impacts of aging and associated cell-type responses has been lacking. This study integrates transcriptomic, methylomic, single-cell RNA sequencing, and metabolomic data to investigate aging-related regulations in adipose and muscle tissues. Through coexpression network analysis of the adipose tissue, we identified aging-associated network modules specific to certain cell types, including adipocytes and immune cells. Aging upregulates the metabolic functions of lysosomes and downregulates the branched-chain amino acids (BCAAs) degradation pathway. Additionally, aging-associated changes in cell proportions, methylation profiles, and single-cell expressions were observed in the adipose. In the muscle tissue, aging was found to repress the metabolic processes of glycolysis and oxidative phosphorylation, along with reduced gene activity of fast-twitch type II muscle fibers. Metabolomic profiling linked aging-related alterations in plasma metabolites to gene expression in glucose-responsive tissues, particularly in tRNA modifications, BCAA metabolism, and sex hormone signaling. Together, our multi-omic analyses provide a comprehensive understanding of the impacts of aging on glucose-responsive tissues and identify potential plasma biomarkers for these effects.
    Keywords:  adipose; aging; cell‐type; metabolite; multi‐omic; muscle; network
    DOI:  https://doi.org/10.1111/acel.14199
  35. bioRxiv. 2024 Jun 12. pii: 2024.06.09.598108. [Epub ahead of print]
    The MICOS Complex Regulates Mitochondrial Structure and Oxidative Stress During Age-Dependent Structural Deficits in the Kidney.
    Zer Vue, Praveena Prasad, Han Le, Kit Neikirk, Chanel Harris, Edgar Garza-Lopez, Eric Wang, Alexandria Murphy, Brenita Jenkins, Larry Vang, Estevão Scudese, Bryanna Shao, Ashlesha Kadam, Jianqiang Shao, Andrea G Marshall, Amber Crabtree, Benjamin Kirk, Alice Koh, Genesis Wilson, Ashton Oliver, Taylor Rodman, Kinuthia Kabugi, Ho-Jin Koh, Quinton Smith, Elma Zaganjor, Celestine N Wanjalla, Chandravanu Dash, Chantell Evans, Mark A Phillips, David Hubert, Olujimi Ajijola, Aaron Whiteside, Young Do Koo, André Kinder, Mert Demirci, Claude F Albritton, Nelson Wandira, Sydney Jamison, Taseer Ahmed, Mohammad Saleem, Dhanendra Tomar, Clintoria R Williams, Mariya T Sweetwyne, Sandra A Murray, Anthonya Cooper, Annet Kirabo, Pooja Jadiya, Anita Quintana, Prasanna Katti, Dao Fu Dai, Melanie R McReynolds, Antentor Hinton.
      The kidney filters nutrient waste and bodily fluids from the bloodstream, in addition to secondary functions of metabolism and hormone secretion, requiring an astonishing amount of energy to maintain its functions. In kidney cells, mitochondria produce adenosine triphosphate (ATP) and help maintain kidney function. Due to aging, the efficiency of kidney functions begins to decrease. Dysfunction in mitochondria and cristae, the inner folds of mitochondria, is a hallmark of aging. Therefore, age-related kidney function decline could be due to changes in mitochondrial ultrastructure, increased reactive oxygen species (ROS), and subsequent alterations in metabolism and lipid composition. We sought to understand if there is altered mitochondrial ultrastructure, as marked by 3D morphological changes, across time in tubular kidney cells. Serial block facing-scanning electron microscope (SBF-SEM) and manual segmentation using the Amira software were used to visualize murine kidney samples during the aging process at 3 months (young) and 2 years (old). We found that 2-year mitochondria are more fragmented, compared to the 3-month, with many uniquely shaped mitochondria observed across aging, concomitant with shifts in ROS, metabolomics, and lipid homeostasis. Furthermore, we show that the mitochondrial contact site and cristae organizing system (MICOS) complex is impaired in the kidney due to aging. Disruption of the MICOS complex shows altered mitochondrial calcium uptake and calcium retention capacity, as well as generation of oxidative stress. We found significant, detrimental structural changes to aged kidney tubule mitochondria suggesting a potential mechanism underlying why kidney diseases occur more readily with age. We hypothesize that disruption in the MICOS complex further exacerbates mitochondrial dysfunction, creating a vicious cycle of mitochondrial degradation and oxidative stress, thus impacting kidney health.
    Translational Statement: Due to aging, the efficiency of kidney functions begins to decrease and the risk of kidney diseases may increase, but specific regulators of mitochondrial age-related changes are poorly explained. This study demonstrates the MICOS complex may be a target for mitigating age-related changes in mitochondria. The MICOS complex can be associated with oxidative stress and calcium dysregulation, which also arise in many kidney pathologies.
    DOI:  https://doi.org/10.1101/2024.06.09.598108
  36. Trends Genet. 2024 Jun 22. pii: S0168-9525(24)00134-3. [Epub ahead of print]
    Histone oxidation as a new mechanism of metabolic control over gene expression.
    Benjamin N Gantner, Flavio R Palma, Cezar Kayzuka, Riccardo Lacchini, Daniel R Foltz, Vadim Backman, Neil Kelleher, Ali Shilatifard, Marcelo G Bonini.
      The emergence of aerobic respiration created unprecedented bioenergetic advantages, while imposing the need to protect critical genetic information from reactive byproducts of oxidative metabolism (i.e., reactive oxygen species, ROS). The evolution of histone proteins fulfilled the need to shield DNA from these potentially damaging toxins, while providing the means to compact and structure massive eukaryotic genomes. To date, several metabolism-linked histone post-translational modifications (PTMs) have been shown to regulate chromatin structure and gene expression. However, whether and how PTMs enacted by metabolically produced ROS regulate adaptive chromatin remodeling remain relatively unexplored. Here, we review novel mechanistic insights into the interactions of ROS with histones and their consequences for the control of gene expression regulation, cellular plasticity, and behavior.
    Keywords:  ROS; chromatin structure; cysteine oxidation; epigenetics; histone oxidation; histones
    DOI:  https://doi.org/10.1016/j.tig.2024.05.012
  37. Nature. 2024 Jun 26.
    An intermediate Rb-E2F activity state safeguards proliferation commitment.
    Yumi Konagaya, David Rosenthal, Nalin Ratnayeke, Yilin Fan, Tobias Meyer.
      Tissue repair, immune defence and cancer progression rely on a vital cellular decision between quiescence and proliferation1,2. Mammalian cells proliferate by triggering a positive feedback mechanism3,4. The transcription factor E2F activates cyclin-dependent kinase 2 (CDK2), which in turn phosphorylates and inactivates the E2F inhibitor protein retinoblastoma (Rb). This action further increases E2F activity to express genes needed for proliferation. Given that positive feedback can inadvertently amplify small signals, understanding how cells keep this positive feedback in check remains a puzzle. Here we measured E2F and CDK2 signal changes in single cells and found that the positive feedback mechanism engages only late in G1 phase. Cells spend variable and often extended times in a reversible state of intermediate E2F activity before committing to proliferate. This intermediate E2F activity is proportional to the amount of phosphorylation of a conserved T373 residue in Rb that is mediated by CDK2 or CDK4/CDK6. Such T373-phosphorylated Rb remains bound on chromatin but dissociates from it once Rb is hyperphosphorylated at many sites, which fully activates E2F. The preferential initial phosphorylation of T373 can be explained by its relatively slower rate of dephosphorylation. Together, our study identifies a primed state of intermediate E2F activation whereby cells sense external and internal signals and decide whether to reverse and exit to quiescence or trigger the positive feedback mechanism that initiates cell proliferation.
    DOI:  https://doi.org/10.1038/s41586-024-07554-2
  38. Commun Biol. 2024 Jun 28. 7(1): 780
    Single-cell transcriptional profiling of clear cell renal cell carcinoma reveals a tumor-associated endothelial tip cell phenotype.
    Justina Zvirblyte, Juozas Nainys, Simonas Juzenas, Karolis Goda, Raimonda Kubiliute, Darius Dasevicius, Marius Kincius, Albertas Ulys, Sonata Jarmalaite, Linas Mazutis.
      Clear cell renal cell carcinoma (ccRCC) is the most prevalent form of renal cancer, accounting for over 75% of cases. The asymptomatic nature of the disease contributes to late-stage diagnoses and poor survival. Highly vascularized and immune infiltrated microenvironment are prominent features of ccRCC, yet the interplay between vasculature and immune cells, disease progression and response to therapy remains poorly understood. Using droplet-based single-cell RNA sequencing we profile 50,236 transcriptomes from paired tumor and healthy adjacent kidney tissues. Our analysis reveals significant heterogeneity and inter-patient variability of the tumor microenvironment. Notably, we discover a previously uncharacterized vasculature subpopulation associated with epithelial-mesenchymal transition. The cell-cell communication analysis reveals multiple modes of immunosuppressive interactions within the tumor microenvironment, including clinically relevant interactions between tumor vasculature and stromal cells with immune cells. The upregulation of the genes involved in these interactions is associated with worse survival in the TCGA KIRC cohort. Our findings demonstrate the role of tumor vasculature and stromal cell populations in shaping the ccRCC microenvironment and uncover a subpopulation of cells within the tumor vasculature that is associated with an angiogenic phenotype.
    DOI:  https://doi.org/10.1038/s42003-024-06478-x
  39. Bioessays. 2024 Jun 27. e2400045
    Metabolic channeling of lipids via the contact zones between different organelles.
    Kentaro Hanada.
      Various lipid transfer proteins (LTPs) mediate the inter-organelle transport of lipids. By working at membrane contact zones between donor and acceptor organelles, LTPs achieve rapid and accurate inter-organelle transfer of lipids. This article will describe the emerging paradigm that the action of LTPs at organelle contact zones generates metabolic channeling events in lipid metabolism, mainly referring to how ceramide synthesized in the endoplasmic reticulum is preferentially metabolized to sphingomyelin in the distal Golgi region, how cholesterol and phospholipids receive specific metabolic reactions in mitochondria, and how the hijacking of host LTPs by intracellular pathogens may generate new channeling-like events. In addition, the article will discuss how the function of LTPs is regulated, exemplified by a few representative LTP systems, and will briefly touch on experiments that will be necessary to establish the paradigm that LTP-mediated inter-organelle transport of lipids is one of the mechanisms of compartmentalization-based metabolic channeling events.
    Keywords:  cholesterol; compartmentalization; lipid transfer proteins; metabolic channeling; organelle contact; sphingolipids
    DOI:  https://doi.org/10.1002/bies.202400045
  40. Essays Biochem. 2024 Jun 26. pii: EBC20230077. [Epub ahead of print]
    Roles of the oncometabolite enantiomers of 2-hydroxyglutarate and their metabolism by diverse dehydrogenases.
    Ivelitza Garcia, Kathleen Cornely, Celeste N Peterson, Melanie B Berkmen.
      2-Hydroxyglutarate (2HG) is an oncometabolite that can contribute to tumor progression. Two enantiomer forms, L-2HG and D-2HG, arise from independent pathways starting from the precursor α-ketoglutarate (αKG). L-2HG production occurs through the promiscuous activities of malate dehydrogenase (MDH) and lactate dehydrogenase (LDH) under acidic and/or hypoxic conditions. D-2HG frequently accumulates by gain-of-function mutations in the genes encoding two isoforms of isocitrate dehydrogenase (IDH1 and IDH2). Cognate metabolite repair enzymes, L- and D-2-hydroxyglutarate dehydrogenases, oxidize the enantiomers and cause abnormally high 2HG accumulation and disease when mutated. Elevated levels of either oncometabolite affect redox homeostasis, metabolism, and immune system functioning. Moreover, the oncometabolites inhibit several α-ketoglutarate-dependent dioxygenases resulting in epigenetic changes such as DNA and histone hypermethylation as well as deficiencies in DNA repair. L-2HG, and D-2HG in some cases, inhibit degradation of hypoxia-inducible factor (HIF1α), a transcription factor that alters gene expression to adapt to hypoxic conditions, favoring tumorigenesis. Patients with the rare disease 2-hydroxyglutaric aciduria (2HGA) have exceedingly high levels of 2HG, which is neurotoxic, causing developmental delays and brain abnormalities. D-2HG also has specific effects on collagen production and NADPH pools. Recently, D-2HG has been targeted in new chemotherapies aimed at disrupting the gain-of-function IDH1 and IDH2 mutants, resulting in successful clinical trials for several cancers.
    Keywords:  2-hydroxygluratate; isocitrate dehydrogenase; lactate dehydrogenase; malate dehydrogenase; oncometabolite
    DOI:  https://doi.org/10.1042/EBC20230077
  41. Trends Endocrinol Metab. 2024 Jun 25. pii: S1043-2760(24)00160-7. [Epub ahead of print]
    One-carbon metabolism shapes T cell immunity in cancer.
    Yajing Qiu, Ermei Xie, Haipeng Xu, Hongcheng Cheng, Guideng Li.
      One-carbon metabolism (1CM), comprising folate metabolism and methionine metabolism, serves as an important mechanism for cellular energy provision and the production of vital signaling molecules, including single-carbon moieties. Its regulation is instrumental in sustaining the proliferation of cancer cells and facilitating metastasis; in addition, recent research has shed light on its impact on the efficacy of T cell-mediated immunotherapy. In this review, we consolidate current insights into how 1CM affects T cell activation, differentiation, and functionality. Furthermore, we delve into the strategies for modulating 1CM in both T cells and tumor cells to enhance the efficacy of adoptively transferred T cells, overcome metabolic challenges in the tumor microenvironment (TME), and maximize the benefits of T cell-mediated immunotherapy.
    Keywords:  One-carbon metabolism; T cell fate; T cell-mediated immunotherapy; folate cycle; methionine cycle
    DOI:  https://doi.org/10.1016/j.tem.2024.05.010
  42. bioRxiv. 2024 Jun 12. pii: 2024.06.12.598703. [Epub ahead of print]
    A commensal-derived sugar protects against metabolic disease.
    Chin Yee Tan, Danting Jiang, Barbara S Theriot, Meghana V Rao, Neeraj K Surana.
      Obesity is a worsening global epidemic that is regulated by the microbiota through unknown bacterial factors. We discovered a human-derived commensal bacterium, Clostridium immunis , that protects against metabolic disease by secreting a phosphocholine-modified exopolysaccharide. Genetic interruption of the phosphocholine biosynthesis locus ( licABC ) results in a functionally inactive exopolysaccharide, which demonstrates the critical requirement for this phosphocholine moiety. This C. immunis exopolysaccharide acts via group 3 innate lymphoid cells and modulating IL-22 levels, which results in a reduction in serum triglycerides, body weight, and visceral adiposity. Importantly, phosphocholine biosynthesis genes are less abundant in humans with obesity or hypertriglyceridemia, findings that suggest the role of bacterial phosphocholine is conserved across mice and humans. These results define a bacterial molecule-and its key structural motif-that regulates host metabolism. More broadly, they highlight how small molecules, such as phosphocholine, may help fine-tune microbiome- immune-metabolism interactions.
    DOI:  https://doi.org/10.1101/2024.06.12.598703
  43. Mol Cell. 2024 Jun 19. pii: S1097-2765(24)00479-9. [Epub ahead of print]
    PELI2 is a negative regulator of STING signaling that is dynamically repressed during viral infection.
    Christopher Ritchie, Lingyin Li.
      The innate immune cGAS-STING pathway is activated by cytosolic double-stranded DNA (dsDNA), a ubiquitous danger signal, to produce interferon, a potent anti-viral and anti-cancer cytokine. However, STING activation must be tightly controlled because aberrant interferon production leads to debilitating interferonopathies. Here, we discover PELI2 as a crucial negative regulator of STING. Mechanistically, PELI2 inhibits the transcription factor IRF3 by binding to phosphorylated Thr354 and Thr356 on the C-terminal tail of STING, leading to ubiquitination and inhibition of the kinase TBK1. PELI2 sets a threshold for STING activation that tolerates low levels of cytosolic dsDNA, such as that caused by silenced TREX1, RNASEH2B, BRCA1, or SETX. When this threshold is reached, such as during viral infection, STING-induced interferon production temporarily downregulates PELI2, creating a positive feedback loop allowing a robust immune response. Lupus patients have insufficient PELI2 levels and high basal interferon production, suggesting that PELI2 dysregulation may drive the onset of lupus and other interferonopathies.
    Keywords:  E3 ubiquitin ligase; FHA domain; PELI2; STING regulation; autoimmunity; dsDNA sensing; immunotransmitter; innate immunity; type I interferon; viral infection
    DOI:  https://doi.org/10.1016/j.molcel.2024.06.001
  44. Cell. 2024 Jun 24. pii: S0092-8674(24)00639-1. [Epub ahead of print]
    Microglial-derived C1q integrates into neuronal ribonucleoprotein complexes and impacts protein homeostasis in the aging brain.
    Nicole Scott-Hewitt, Matthew Mahoney, Youtong Huang, Nils Korte, T Yvanka de Soysa, Daniel K Wilton, Emily Knorr, Kevin Mastro, Allison Chang, Allison Zhang, David Melville, Monica Schenone, Christina Hartigan, Beth Stevens.
      Neuroimmune interactions mediate intercellular communication and underlie critical brain functions. Microglia, CNS-resident macrophages, modulate the brain through direct physical interactions and the secretion of molecules. One such secreted factor, the complement protein C1q, contributes to complement-mediated synapse elimination in both developmental and disease models, yet brain C1q protein levels increase significantly throughout aging. Here, we report that C1q interacts with neuronal ribonucleoprotein (RNP) complexes in an age-dependent manner. Purified C1q protein undergoes RNA-dependent liquid-liquid phase separation (LLPS) in vitro, and the interaction of C1q with neuronal RNP complexes in vivo is dependent on RNA and endocytosis. Mice lacking C1q have age-specific alterations in neuronal protein synthesis in vivo and impaired fear memory extinction. Together, our findings reveal a biophysical property of C1q that underlies RNA- and age-dependent neuronal interactions and demonstrate a role of C1q in critical intracellular neuronal processes.
    Keywords:  C1q; RNA granule; RNA-binding protein; complement; liquid-liquid phase separation; microglia; neuroimmune; neuronal translation; polysome; ribonucleoprotein complex
    DOI:  https://doi.org/10.1016/j.cell.2024.05.058
  45. Mol Cell. 2024 Jun 18. pii: S1097-2765(24)00447-7. [Epub ahead of print]
    Genome-scale exon perturbation screens uncover exons critical for cell fitness.
    Mei-Sheng Xiao, Arun Prasath Damodaran, Bandana Kumari, Ethan Dickson, Kun Xing, Tyler A On, Nikhil Parab, Helen E King, Alexendar R Perez, Wilfried M Guiblet, Gerard Duncan, Anney Che, Raj Chari, Thorkell Andresson, Joana A Vidigal, Robert J Weatheritt, Michael Aregger, Thomas Gonatopoulos-Pournatzis.
      CRISPR-Cas technology has transformed functional genomics, yet understanding of how individual exons differentially shape cellular phenotypes remains limited. Here, we optimized and conducted massively parallel exon deletion and splice-site mutation screens in human cell lines to identify exons that regulate cellular fitness. Fitness-promoting exons are prevalent in essential and highly expressed genes and commonly overlap with protein domains and interaction interfaces. Conversely, fitness-suppressing exons are enriched in nonessential genes, exhibiting lower inclusion levels, and overlap with intrinsically disordered regions and disease-associated mutations. In-depth mechanistic investigation of the screen-hit TAF5 alternative exon-8 revealed that its inclusion is required for assembly of the TFIID general transcription initiation complex, thereby regulating global gene expression output. Collectively, our orthogonal exon perturbation screens established a comprehensive repository of phenotypically important exons and uncovered regulatory mechanisms governing cellular fitness and gene expression.
    Keywords:  CRISPR screen; Cas12a; TAF5; TFIID; alternative splicing; base editor; cell fitness exons; exon deletion; exon perturbation; functional genomics
    DOI:  https://doi.org/10.1016/j.molcel.2024.05.024
  46. Immunohorizons. 2024 Jun 01. 8(6): 464-477
    Cancer Cell Small Molecule Secretome Induces the Immune Checkpoint NKG2A and Dysfunction of Human CD8+ T Cells.
    Gabriel J Rodriguez-Garcia, Diana K Graves, Muhammad B Mirza, Kamran Idrees, Young J Kim, Michael J Korrer, Jeffrey C Rathmell.
      PD-1 blockade has been approved for head and neck squamous cell carcinoma (HNSCC) patients. However, many HNSCC patients do not respond to this treatment, and other tumor microenvironmental factors may promote resistance to PD-1 blockade. We previously identified increased expression of the inhibitory receptor NKG2A on CD8+ T cells in HNSCC tumors compared with T cells in matching PBMC samples. Mechanisms that promote NKG2A expression and the role of NKG2A on human T cells in the tumor microenvironment, however, are uncertain. In this study, we show that tumor-conditioned media (TCM) of HNSCC cancer cell lines or ascites fluid from colorectal carcinoma patients is sufficient to induce the expression of NKG2A and other inhibitory receptors on activated CD8+ T cells isolated from PBMCs of healthy donors. Boiling or small molecular mass cutoff filtering did not eliminate the effect of TCM, suggesting that a small molecule promotes NKG2A. T cell activation in TCM decreased the basal and maximal mitochondrial respiration to metabolically restrain CD8+ T cells. Functionally, T cell activation in TCM reduced CD8+ T cell cytotoxicity as shown by lower production of cytokines, granzyme B, and perforin. Furthermore, TCM prevented CD8+ T cells from killing cancer cells in response to an anti-CD19/anti-CD3 bispecific T cell engager. Thus, a small secreted molecule from HNSCC cells can induce NKG2A expression and promote T cell dysfunction. Our findings may lead to targets for novel cancer therapies or biomarkers for NKG2A blockade response and provide a model to study T cell dysfunction and impaired metabolism.
    DOI:  https://doi.org/10.4049/immunohorizons.2400046
  47. Nat Commun. 2024 Jun 27. 15(1): 5446
    Sequence-specific dynamic DNA bending explains mitochondrial TFAM's dual role in DNA packaging and transcription initiation.
    Hyun Huh, Jiayu Shen, Yogeeshwar Ajjugal, Aparna Ramachandran, Smita S Patel, Sang-Hyuk Lee.
      Mitochondrial transcription factor A (TFAM) employs DNA bending to package mitochondrial DNA (mtDNA) into nucleoids and recruit mitochondrial RNA polymerase (POLRMT) at specific promoter sites, light strand promoter (LSP) and heavy strand promoter (HSP). Herein, we characterize the conformational dynamics of TFAM on promoter and non-promoter sequences using single-molecule fluorescence resonance energy transfer (smFRET) and single-molecule protein-induced fluorescence enhancement (smPIFE) methods. The DNA-TFAM complexes dynamically transition between partially and fully bent DNA conformational states. The bending/unbending transition rates and bending stability are DNA sequence-dependent-LSP forms the most stable fully bent complex and the non-specific sequence the least, which correlates with the lifetimes and affinities of TFAM with these DNA sequences. By quantifying the dynamic nature of the DNA-TFAM complexes, our study provides insights into how TFAM acts as a multifunctional protein through the DNA bending states to achieve sequence specificity and fidelity in mitochondrial transcription while performing mtDNA packaging.
    DOI:  https://doi.org/10.1038/s41467-024-49728-6
  48. bioRxiv. 2024 Jun 14. pii: 2024.06.12.598567. [Epub ahead of print]
    The ENCODE mouse postnatal developmental time course identifies regulatory programs of cell types and cell states.
    Elisabeth Rebboah, Narges Rezaie, Brian A Williams, Annika K Weimer, Minyi Shi, Xinqiong Yang, Heidi Yahan Liang, Louise A Dionne, Fairlie Reese, Diane Trout, Jennifer Jou, Ingrid Youngworth, Laura Reinholdt, Samuel Morabito, Michael P Snyder, Barbara J Wold, Ali Mortazavi.
      Postnatal genomic regulation significantly influences tissue and organ maturation but is under-studied relative to existing genomic catalogs of adult tissues or prenatal development in mouse. The ENCODE4 consortium generated the first comprehensive single-nucleus resource of postnatal regulatory events across a diverse set of mouse tissues. The collection spans seven postnatal time points, mirroring human development from childhood to adulthood, and encompasses five core tissues. We identified 30 cell types, further subdivided into 69 subtypes and cell states across adrenal gland, left cerebral cortex, hippocampus, heart, and gastrocnemius muscle. Our annotations cover both known and novel cell differentiation dynamics ranging from early hippocampal neurogenesis to a new sex-specific adrenal gland population during puberty. We used an ensemble Latent Dirichlet Allocation strategy with a curated vocabulary of 2,701 regulatory genes to identify regulatory "topics," each of which is a gene vector, linked to cell type differentiation, subtype specialization, and transitions between cell states. We find recurrent regulatory topics in tissue-resident macrophages, neural cell types, endothelial cells across multiple tissues, and cycling cells of the adrenal gland and heart. Cell-type-specific topics are enriched in transcription factors and microRNA host genes, while chromatin regulators dominate mitosis topics. Corresponding chromatin accessibility data reveal dynamic and sex-specific regulatory elements, with enriched motifs matching transcription factors in regulatory topics. Together, these analyses identify both tissue-specific and common regulatory programs in postnatal development across multiple tissues through the lens of the factors regulating transcription.
    DOI:  https://doi.org/10.1101/2024.06.12.598567
  49. Science. 2024 Jun 28. 384(6703): eadh4567
    Type I conventional dendritic cells facilitate immunotherapy in pancreatic cancer.
    Krishnan K Mahadevan, Allison M Dyevoich, Yang Chen, Bingrui Li, Hikaru Sugimoto, Amari M Sockwell, Kathleen M McAndrews, Lakshmi Kavitha Sthanam, Huamin Wang, Shabnam Shalapour, Stephanie S Watowich, Raghu Kalluri.
      Inflammation and tissue damage associated with pancreatitis can precede or occur concurrently with pancreatic ductal adenocarcinoma (PDAC). We demonstrate that in PDAC coupled with pancreatitis (ptPDAC), antigen-presenting type I conventional dendritic cells (cDC1s) are specifically activated. Immune checkpoint blockade therapy (iCBT) leads to cytotoxic CD8+ T cell activation and elimination of ptPDAC with restoration of life span even upon PDAC rechallenge. Using PDAC antigen-loaded cDC1s as a vaccine, immunotherapy-resistant PDAC was rendered sensitive to iCBT with elimination of tumors. cDC1 vaccination coupled with iCBT identified specific CDR3 sequences in the tumor-infiltrating CD8+ T cells with potential therapeutic importance. This study identifies a fundamental difference in the immune microenvironment in PDAC concurrent with, or without, pancreatitis and provides a rationale for combining cDC1 vaccination with iCBT as a potential treatment option.
    DOI:  https://doi.org/10.1126/science.adh4567
  50. JCI Insight. 2024 Jun 27. pii: e178725. [Epub ahead of print]
    A metabolic redox relay supports ER proinsulin export in pancreatic islet β-cells.
    Kristen E Rohli, Nicole J Stubbe, Emily M Walker, Gemma L Pearson, Scott A Soleimanpour, Samuel B Stephens.
      Endoplasmic reticulum (ER) stress and proinsulin misfolding are heralded as contributing factors to β-cell dysfunction in Type 2 diabetes (T2D), yet how ER function becomes compromised is not well understood. Recent data identifies altered ER redox homeostasis as a critical mechanism that contributes to insulin granule loss in diabetes. Hyperoxidation of the ER delays proinsulin export and limits the proinsulin supply available for insulin granule formation. In this report, we identified glucose metabolism as a critical determinant in the redox homeostasis of the ER. Using multiple β-cell models, we showed that loss of mitochondrial function or inhibition of cellular metabolism elicited ER hyperoxidation and delayed ER proinsulin export. Our data further demonstrated that β-cell ER redox homeostasis was supported by the metabolic supply of reductive redox donors. We showed that limiting NADPH and thioredoxin flux delayed ER proinsulin export, whereas Txnip suppression restored ER redox and proinsulin trafficking. Taken together, we propose that β-cell ER redox homeostasis is buffered by cellular redox donor cycles, which are maintained through active glucose metabolism.
    Keywords:  Beta cells; Cell biology; Endocrinology; Insulin; Protein traffic
    DOI:  https://doi.org/10.1172/jci.insight.178725
  51. Trends Biochem Sci. 2024 Jun 26. pii: S0968-0004(24)00146-4. [Epub ahead of print]
    Immunometabolism in atherosclerosis: a new understanding of an old disease.
    Michelangelo Certo, Mahsa Rahimzadeh, Claudio Mauro.
      Atherosclerosis, a chronic inflammatory condition, remains a leading cause of death globally, necessitating innovative approaches to target pro-atherogenic pathways. Recent advancements in the field of immunometabolism have highlighted the crucial interplay between metabolic pathways and immune cell function in atherogenic milieus. Macrophages and T cells undergo dynamic metabolic reprogramming to meet the demands of activation and differentiation, influencing plaque progression. Furthermore, metabolic intermediates intricately regulate immune cell responses and atherosclerosis development. Understanding the metabolic control of immune responses in atherosclerosis, known as athero-immunometabolism, offers new avenues for preventive and therapeutic interventions. This review elucidates the emerging intricate interplay between metabolism and immunity in atherosclerosis, underscoring the significance of metabolic enzymes and metabolites as key regulators of disease pathogenesis and therapeutic targets.
    Keywords:  chronic inflammatory disease; immune response; metabolic pathways; metabolic reprogramming; metabolites; therapeutic targets
    DOI:  https://doi.org/10.1016/j.tibs.2024.06.003
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