bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2024‒02‒18
forty-four papers selected by
Christian Frezza, Universität zu Köln
  1. SLC25A39 links mitochondrial GSH sensing with iron metabolism.
  2. Cysteine induces mitochondrial reductive stress in glioblastoma through hydrogen peroxide production.
  3. The cell biology of ferroptosis.
  4. SLC25A51 decouples the mitochondrial NAD+/NADH ratio to control proliferation of AML cells.
  5. Selenium reduction of ubiquinone via SQOR suppresses ferroptosis.
  6. Decoding Serine Metabolism: Unveiling Novel Pathways for Evolving Cancer Therapies.
  7. Mitochondrial S-adenosylmethionine deficiency induces mitochondrial unfolded protein response and extends lifespan in Caenorhabditis elegans.
  8. Mitochondrial haplotype and mito-nuclear matching drive somatic mutation and selection throughout ageing.
  9. The HRI branch of the integrated stress response selectively triggers mitophagy.
  10. Phospholipids with two polyunsaturated fatty acyl tails promote ferroptosis.
  11. Selenium abandons selenoproteins to inhibit ferroptosis rapidly.
  12. Nutrient-dependent regulation of a stable intron modulates germline mitochondrial quality control.
  13. VHL suppresses autophagy and tumor growth through PHD1-dependent Beclin1 hydroxylation.
  14. A Berlin-sided retrospective of the origins of metabolic control theory.
  15. Multimodal mass spectrometry imaging identifies cell-type-specific metabolic and lipidomic variation in the mammalian liver.
  16. A mechanism of lysosomal calcium entry.
  17. Targeting de novo lipogenesis to mitigate kidney disease.
  18. Cisplatin drives mitochondrial dysregulation in sensory hair cells.
  19. Single-nucleoid architecture reveals heterogeneous packaging of mitochondrial DNA.
  20. COQ4 is required for the oxidative decarboxylation of the C1 carbon of coenzyme Q in eukaryotic cells.
  21. STING licensing of type I dendritic cells potentiates antitumor immunity.
  22. Pan-cancer proteogenomics characterization of tumor immunity.
  23. Mutant p53 protects triple-negative breast adenocarcinomas from ferroptosis in vivo.
  24. Structural basis for regulated assembly of the mitochondrial fission GTPase Drp1.
  25. Renal aging and mitochondrial quality control.
  26. Genetic determinants of micronucleus formation in vivo.
  27. Adaptive inhibition of CGAS signaling by TREX1.
  28. BRD4-mediated epigenetic regulation of endoplasmic reticulum-mitochondria contact sites is governed by the mitochondrial complex III.
  29. Hijacking of nucleotide biosynthesis and deamidation-mediated glycolysis by an oncogenic herpesvirus.
  30. Emerging mechanistic understanding of cilia function in cellular signalling.
  31. GLUT1-mediated glucose import in B cells is critical for anaplerotic balance and humoral immunity.
  32. Transcellular Barriers to Glucose Delivery in the Body.
  33. Cone photoreceptor phosphodiesterase PDE6H inhibition regulates cancer cell growth and metabolism, replicating the dark retina response.
  34. Hypoxia-inducible factor induces cysteine dioxygenase and promotes cysteine homeostasis in Caenorhabditis elegans.
  35. Proline restores mitochondrial function and reverses aging hallmarks in senescent cells.
  36. Next-Generation Genetically Encoded Fluorescent Biosensors Illuminate Cell Signaling and Metabolism.
  37. The proteome is a terminal electron acceptor.
  38. Efferocytosis reprograms the tumor microenvironment to promote pancreatic cancer liver metastasis.
  39. Loss of mitochondrial pyruvate carrier 1 supports proline-dependent proliferation and collagen biosynthesis in ovarian cancer.
  40. Adipose Treg cells in charge of metabolism.
  41. Beyond genetics: driving cancer with the tumour microenvironment behind the wheel.
  42. Validation of biomarkers of aging.
  43. Deposition of onco-histone H3.3-G34W leads to DNA repair deficiency and activates cGAS/STING-mediated immune responses.
  44. Adipocyte p53 coordinates the response to intermittent fasting by regulating adipose tissue immune cell landscape.
  1. Mol Cell. 2024 Feb 15. pii: S1097-2765(23)01083-3. [Epub ahead of print]84(4): 616-618
    SLC25A39 links mitochondrial GSH sensing with iron metabolism.
    Xiong Chen, Boyi Gan.
      Two recent studies by Liu et al.1 in Science and Shi et al.2 in this issue of Molecular Cell identify a mitochondrial GSH-sensing mechanism that couples SLC25A39-mediated GSH import to iron metabolism, advancing our understanding of nutrient sensing within organelles.
    DOI:  https://doi.org/10.1016/j.molcel.2023.12.037
  2. Proc Natl Acad Sci U S A. 2024 Feb 20. 121(8): e2317343121
    Cysteine induces mitochondrial reductive stress in glioblastoma through hydrogen peroxide production.
    Evan K Noch, Laura Palma, Isaiah Yim, Nayah Bullen, Daniel Barnett, Alexander Walsh, Bhavneet Bhinder, Elisa Benedetti, Jan Krumsiek, Justin Gurvitch, Sumaiyah Khwaja, Daphne Atlas, Olivier Elemento, Lewis C Cantley.
      Glucose and amino acid metabolism are critical for glioblastoma (GBM) growth, but little is known about the specific metabolic alterations in GBM that are targetable with FDA-approved compounds. To investigate tumor metabolism signatures unique to GBM, we interrogated The Cancer Genome Atlas for alterations in glucose and amino acid signatures in GBM relative to other human cancers and found that GBM exhibits the highest levels of cysteine and methionine pathway gene expression of 32 human cancers. Treatment of patient-derived GBM cells with the FDA-approved single cysteine compound N-acetylcysteine (NAC) reduced GBM cell growth and mitochondrial oxygen consumption, which was worsened by glucose starvation. Normal brain cells and other cancer cells showed no response to NAC. Mechanistic experiments revealed that cysteine compounds induce rapid mitochondrial H2O2 production and reductive stress in GBM cells, an effect blocked by oxidized glutathione, thioredoxin, and redox enzyme overexpression. From analysis of the clinical proteomic tumor analysis consortium (CPTAC) database, we found that GBM cells exhibit lower expression of mitochondrial redox enzymes than four other cancers whose proteomic data are available in CPTAC. Knockdown of mitochondrial thioredoxin-2 in lung cancer cells induced NAC susceptibility, indicating the importance of mitochondrial redox enzyme expression in mitigating reductive stress. Intraperitoneal treatment of mice bearing orthotopic GBM xenografts with a two-cysteine peptide induced H2O2 in brain tumors in vivo. These findings indicate that GBM is uniquely susceptible to NAC-driven reductive stress and could synergize with glucose-lowering treatments for GBM.
    Keywords:  cysteine; glioblastoma; hydrogen peroxide; mitochondrial metabolism; reductive stress
    DOI:  https://doi.org/10.1073/pnas.2317343121
  3. Nat Rev Mol Cell Biol. 2024 Feb 16.
    The cell biology of ferroptosis.
    Scott J Dixon, James A Olzmann.
      Ferroptosis is a non-apoptotic cell death mechanism characterized by iron-dependent membrane lipid peroxidation. Here, we review what is known about the cellular mechanisms mediating the execution and regulation of ferroptosis. We first consider how the accumulation of membrane lipid peroxides leads to the execution of ferroptosis by altering ion transport across the plasma membrane. We then discuss how metabolites and enzymes that are distributed in different compartments and organelles throughout the cell can regulate sensitivity to ferroptosis by impinging upon iron, lipid and redox metabolism. Indeed, metabolic pathways that reside in the mitochondria, endoplasmic reticulum, lipid droplets, peroxisomes and other organelles all contribute to the regulation of ferroptosis sensitivity. We note how the regulation of ferroptosis sensitivity by these different organelles and pathways seems to vary between different cells and death-inducing conditions. We also highlight transcriptional master regulators that integrate the functions of different pathways and organelles to modulate ferroptosis sensitivity globally. Throughout this Review, we highlight open questions and areas in which progress is needed to better understand the cell biology of ferroptosis.
    DOI:  https://doi.org/10.1038/s41580-024-00703-5
  4. Cell Metab. 2024 Feb 13. pii: S1550-4131(24)00013-5. [Epub ahead of print]
    SLC25A51 decouples the mitochondrial NAD+/NADH ratio to control proliferation of AML cells.
    Mu-Jie Lu, Jonathan Busquets, Valeria Impedovo, Crystal N Wilson, Hsin-Ru Chan, Yu-Tai Chang, William Matsui, Stefano Tiziani, Xiaolu A Cambronne.
      SLC25A51 selectively imports oxidized NAD+ into the mitochondrial matrix and is required for sustaining cell respiration. We observed elevated expression of SLC25A51 that correlated with poorer outcomes in patients with acute myeloid leukemia (AML), and we sought to determine the role SLC25A51 may serve in this disease. We found that lowering SLC25A51 levels led to increased apoptosis and prolonged survival in orthotopic xenograft models. Metabolic flux analyses indicated that depletion of SLC25A51 shunted flux away from mitochondrial oxidative pathways, notably without increased glycolytic flux. Depletion of SLC25A51 combined with 5-azacytidine treatment limits expansion of AML cells in vivo. Together, the data indicate that AML cells upregulate SLC25A51 to decouple mitochondrial NAD+/NADH for a proliferative advantage by supporting oxidative reactions from a variety of fuels. Thus, SLC25A51 represents a critical regulator that can be exploited by cancer cells and may be a vulnerability for refractory AML.
    Keywords:  AML; MCART1; SLC25A51; glutamine utilization; oxidative mitochondria; tumor metabolism
    DOI:  https://doi.org/10.1016/j.cmet.2024.01.013
  5. Nat Metab. 2024 Feb 13.
    Selenium reduction of ubiquinone via SQOR suppresses ferroptosis.
    Namgyu Lee, Sung Jin Park, Mike Lange, Tenzin Tseyang, Mihir B Doshi, Tae Yong Kim, Yoseb Song, Dong In Kim, Paul L Greer, James A Olzmann, Jessica B Spinelli, Dohoon Kim.
      The canonical biological function of selenium is in the production of selenocysteine residues of selenoproteins, and this forms the basis for its role as an essential antioxidant and cytoprotective micronutrient. Here we demonstrate that, via its metabolic intermediate hydrogen selenide, selenium reduces ubiquinone in the mitochondria through catalysis by sulfide quinone oxidoreductase. Through this mechanism, selenium rapidly protects against lipid peroxidation and ferroptosis in a timescale that precedes selenoprotein production, doing so even when selenoprotein production has been eliminated. Our findings identify a regulatory mechanism against ferroptosis that implicates sulfide quinone oxidoreductase and expands our understanding of selenium in biology.
    DOI:  https://doi.org/10.1038/s42255-024-00974-4
  6. Cancer Res. 2024 Feb 16.
    Decoding Serine Metabolism: Unveiling Novel Pathways for Evolving Cancer Therapies.
    Aristotle Lau, John Blenis, Guillermo Burgos-Barragan.
      Serine metabolism plays a pivotal role in cancer, making it an appealing therapeutic target. Two recent studies published in Nature Metabolism and Science Translational Medicine uncovered novel players and therapeutic opportunities within this crucial metabolic pathway. Papalazarou and colleagues employed genetic tools coupled with metabolomics and high-throughput imaging to identify and characterize membrane transporters involved in serine uptake and mitochondrial import in colorectal cancer. Notably, they showed that dual inhibition of these transporters in combination with impaired serine biosynthesis reduced tumor growth in xenograft models. In a parallel study, Zhang and colleagues identified isocitrate dehydrogenase I (IDH1) as a novel regulator of serine biosynthesis in non-small cell lung cancer (NSCLC). Through extensive mechanistic studies, they demonstrated that IDH1 enhances the expression of the key enzymes phosphoglycerate dehydrogenase (PHGDH) and phosphoserine aminotransferase 1 (PSAT1) via a non-canonical function independent of its enzymatic activity. Strikingly, pharmacological disruption of this novel function of IDH1 not only diminished tumor growth but also enhanced the anticancer efficacy of dietary serine restriction in mouse models of lung cancer. Together, these studies advance our mechanistic understanding of how cancer cells fulfill their serine requirements and reveal innovative therapeutic avenues to deprive tumors of this vital nutrient.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-0541
  7. Aging Cell. 2024 Feb 15. e14103
    Mitochondrial S-adenosylmethionine deficiency induces mitochondrial unfolded protein response and extends lifespan in Caenorhabditis elegans.
    Tse Yu Chen, Feng-Yung Wang, Pin-Jung Lee, Ao-Lin Hsu, Tsui-Ting Ching.
      S-adenosylmethionine (SAM), generated from methionine and ATP by S-adenosyl methionine synthetase (SAMS), is the universal methyl group donor required for numerous cellular methylation reactions. In Caenorhabditis elegans, silencing sams-1, the major isoform of SAMS, genetically or via dietary restriction induces a robust mitochondrial unfolded protein response (UPRmt ) and lifespan extension. In this study, we found that depleting SAMS-1 markedly decreases mitochondrial SAM levels. Moreover, RNAi knockdown of SLC-25A26, a carrier protein responsible for transporting SAM from the cytoplasm into the mitochondria, significantly lowers the mitochondrial SAM levels and activates UPRmt , suggesting that the UPRmt induced by sams-1 mutations might result from disrupted mitochondrial SAM homeostasis. Through a genetic screen, we then identified a putative mitochondrial tRNA methyltransferase TRMT-10C.2 as a major downstream effector of SAMS-1 to regulate UPRmt and longevity. As disruption of mitochondrial tRNA methylation likely leads to impaired mitochondrial tRNA maturation and consequently reduced mitochondrial translation, our findings suggest that depleting mitochondrial SAM level might trigger UPRmt via attenuating protein translation in the mitochondria. Together, this study has revealed a potential mechanism by which SAMS-1 regulates UPRmt and longevity.
    Keywords:  S-adenosyl methionine; UPRmt; longevity; mitochondrial tRNA methyltransferase
    DOI:  https://doi.org/10.1111/acel.14103
  8. Nat Ecol Evol. 2024 Feb 15.
    Mitochondrial haplotype and mito-nuclear matching drive somatic mutation and selection throughout ageing.
    Isabel M Serrano, Misa Hirose, Charles C Valentine, Sharon Roesner, Elizabeth Schmidt, Gabriel Pratt, Lindsey Williams, Jesse Salk, Saleh Ibrahim, Peter H Sudmant.
      Mitochondrial genomes co-evolve with the nuclear genome over evolutionary timescales and are shaped by selection in the female germline. Here we investigate how mismatching between nuclear and mitochondrial ancestry impacts the somatic evolution of the mitochondrial genome in different tissues throughout ageing. We used ultrasensitive duplex sequencing to profile ~2.5 million mitochondrial genomes across five mitochondrial haplotypes and three tissues in young and aged mice, cataloguing ~1.2 million mitochondrial somatic and ultralow-frequency inherited mutations, of which 81,097 are unique. We identify haplotype-specific mutational patterns and several mutational hotspots, including at the light strand origin of replication, which consistently exhibits the highest mutation frequency. We show that rodents exhibit a distinct mitochondrial somatic mutational spectrum compared with primates with a surfeit of reactive oxygen species-associated G > T/C > A mutations, and that somatic mutations in protein-coding genes exhibit signatures of negative selection. Lastly, we identify an extensive enrichment in somatic reversion mutations that 're-align' mito-nuclear ancestry within an organism's lifespan. Together, our findings demonstrate that mitochondrial genomes are a dynamically evolving subcellular population shaped by somatic mutation and selection throughout organismal lifetimes.
    DOI:  https://doi.org/10.1038/s41559-024-02338-3
  9. Mol Cell. 2024 Feb 06. pii: S1097-2765(24)00052-2. [Epub ahead of print]
    The HRI branch of the integrated stress response selectively triggers mitophagy.
    Yogaditya Chakrabarty, Zheng Yang, Hsiuchen Chen, David C Chan.
      To maintain mitochondrial homeostasis, damaged or excessive mitochondria are culled in coordination with the physiological state of the cell. The integrated stress response (ISR) is a signaling network that recognizes diverse cellular stresses, including mitochondrial dysfunction. Because the four ISR branches converge to common outputs, it is unclear whether mitochondrial stress detected by this network can regulate mitophagy, the autophagic degradation of mitochondria. Using a whole-genome screen, we show that the heme-regulated inhibitor (HRI) branch of the ISR selectively induces mitophagy. Activation of the HRI branch results in mitochondrial localization of phosphorylated eukaryotic initiation factor 2, which we show is sufficient to induce mitophagy. The HRI mitophagy pathway operates in parallel with the mitophagy pathway controlled by the Parkinson's disease related genes PINK1 and PARKIN and is mechanistically distinct. Therefore, HRI repurposes machinery that is normally used for translational initiation to trigger mitophagy in response to mitochondrial damage.
    Keywords:  autophagy; integrated stress response; iron metabolism; mitochondria; mitophagy; organelle quality control
    DOI:  https://doi.org/10.1016/j.molcel.2024.01.016
  10. Cell. 2024 Feb 08. pii: S0092-8674(24)00067-9. [Epub ahead of print]
    Phospholipids with two polyunsaturated fatty acyl tails promote ferroptosis.
    Baiyu Qiu, Fereshteh Zandkarimi, Carla T Bezjian, Eduard Reznik, Rajesh Kumar Soni, Wei Gu, Xuejun Jiang, Brent R Stockwell.
      Phospholipids containing a single polyunsaturated fatty acyl tail (PL-PUFA1s) are considered the driving force behind ferroptosis, whereas phospholipids with diacyl-PUFA tails (PL-PUFA2s) have been rarely characterized. Dietary lipids modulate ferroptosis, but the mechanisms governing lipid metabolism and ferroptosis sensitivity are not well understood. Our research revealed a significant accumulation of diacyl-PUFA phosphatidylcholines (PC-PUFA2s) following fatty acid or phospholipid treatments, correlating with cancer cell sensitivity to ferroptosis. Depletion of PC-PUFA2s occurred in aging and Huntington's disease brain tissue, linking it to ferroptosis. Notably, PC-PUFA2s interacted with the mitochondrial electron transport chain, generating reactive oxygen species (ROS) for initiating lipid peroxidation. Mitochondria-targeted antioxidants protected cells from PC-PUFA2-induced mitochondrial ROS (mtROS), lipid peroxidation, and cell death. These findings reveal a critical role for PC-PUFA2s in controlling mitochondria homeostasis and ferroptosis in various contexts and explain the ferroptosis-modulating mechanisms of free fatty acids. PC-PUFA2s may serve as diagnostic and therapeutic targets for modulating ferroptosis.
    Keywords:  PUFA; ROS; complex I; diacyl-PUFA phosphatidylcholine; electron transport chain; ferroptosis; lipids; mitochondria; phospholipid; polyunsaturated fatty acid
    DOI:  https://doi.org/10.1016/j.cell.2024.01.030
  11. Nat Metab. 2024 Feb 13.
    Selenium abandons selenoproteins to inhibit ferroptosis rapidly.
    Ian G Chambers, Rajiv R Ratan.
      
    DOI:  https://doi.org/10.1038/s42255-024-00980-6
  12. Nat Commun. 2024 Feb 10. 15(1): 1252
    Nutrient-dependent regulation of a stable intron modulates germline mitochondrial quality control.
    Annabel Qi En Ng, Seow Neng Chan, Jun Wei Pek.
      Mitochondria are inherited exclusively from the mothers and are required for the proper development of embryos. Hence, germline mitochondrial quality is highly regulated during oogenesis to ensure oocyte viability. How nutrient availability influences germline mitochondrial quality control is unclear. Here we find that fasting leads to the accumulation of mitochondrial clumps and oogenesis arrest in Drosophila. Fasting induces the downregulation of the DIP1-Clueless pathway, leading to an increase in the expression of a stable intronic sequence RNA called sisR-1. Mechanistically, sisR-1 localizes to the mitochondrial clumps to inhibit the poly-ubiquitination of the outer mitochondrial protein Porin/VDAC1, thereby suppressing p62-mediated mitophagy. Alleviation of the fasting-induced high sisR-1 levels by either sisR-1 RNAi or refeeding leads to mitophagy, the resumption of oogenesis and an improvement in oocyte quality. Thus, our study provides a possible mechanism by which fasting can improve oocyte quality by modulating the mitochondrial quality control pathway. Of note, we uncover that the sisR-1 response also regulates mitochondrial clumping and oogenesis during protein deprivation, heat shock and aging, suggesting a broader role for this mechanism in germline mitochondrial quality control.
    DOI:  https://doi.org/10.1038/s41467-024-45651-y
  13. EMBO J. 2024 Feb 15.
    VHL suppresses autophagy and tumor growth through PHD1-dependent Beclin1 hydroxylation.
    Zheng Wang, Meisi Yan, Leiguang Ye, Qimin Zhou, Yuran Duan, Hongfei Jiang, Lei Wang, Yuan Ouyang, Huahe Zhang, Yuli Shen, Guimei Ji, Xiaohan Chen, Qi Tian, Liwei Xiao, Qingang Wu, Ying Meng, Guijun Liu, Leina Ma, Bo Lei, Zhimin Lu, Daqian Xu.
      The Von Hippel-Lindau (VHL) protein, which is frequently mutated in clear-cell renal cell carcinoma (ccRCC), is a master regulator of hypoxia-inducible factor (HIF) that is involved in oxidative stresses. However, whether VHL possesses HIF-independent tumor-suppressing activity remains largely unclear. Here, we demonstrate that VHL suppresses nutrient stress-induced autophagy, and its deficiency in sporadic ccRCC specimens is linked to substantially elevated levels of autophagy and correlates with poorer patient prognosis. Mechanistically, VHL directly binds to the autophagy regulator Beclin1, after its PHD1-mediated hydroxylation on Pro54. This binding inhibits the association of Beclin1-VPS34 complexes with ATG14L, thereby inhibiting autophagy initiation in response to nutrient deficiency. Expression of non-hydroxylatable Beclin1 P54A abrogates VHL-mediated autophagy inhibition and significantly reduces the tumor-suppressing effect of VHL. In addition, Beclin1 P54-OH levels are inversely correlated with autophagy levels in wild-type VHL-expressing human ccRCC specimens, and with poor patient prognosis. Furthermore, combined treatment of VHL-deficient mouse tumors with autophagy inhibitors and HIF2α inhibitors suppresses tumor growth. These findings reveal an unexpected mechanism by which VHL suppresses tumor growth, and suggest a potential treatment for ccRCC through combined inhibition of both autophagy and HIF2α.
    Keywords:  Autophagy; Beclin1; Hydroxylation; VHL; ccRCC
    DOI:  https://doi.org/10.1038/s44318-024-00051-2
  14. Interface Focus. 2024 Feb 15. 14(1): 20230024
    A Berlin-sided retrospective of the origins of metabolic control theory.
    Tom A Rapoport.
      Metabolic control theory (MCA) is celebrating its 50th anniversary. The theory introduced quantitative terms that describe the importance of an enzyme for the regulation of the overall flux and of metabolite concentrations. MCA was developed independently by two groups. The Berlin group included Reinhart Heinrich, Tom A. Rapoport and Samuel M. Rapoport, and the Edinburgh group Henrik Kacser and James A. Burns. Here, I provide a brief reminiscence from the perspective of the Berlin group.
    Keywords:  Berlin; metabolic control theory; metabolism; origins; retrospective; sided
    DOI:  https://doi.org/10.1098/rsfs.2023.0024
  15. Dev Cell. 2024 Feb 12. pii: S1534-5807(24)00045-5. [Epub ahead of print]
    Multimodal mass spectrometry imaging identifies cell-type-specific metabolic and lipidomic variation in the mammalian liver.
    Hua Tian, Presha Rajbhandari, Jay Tarolli, Aubrianna M Decker, Taruna V Neelakantan, Tina Angerer, Fereshteh Zandkarimi, Helen Remotti, Gilles Frache, Nicholas Winograd, Brent R Stockwell.
      Spatial single-cell omics provides a readout of biochemical processes. It is challenging to capture the transient lipidome/metabolome from cells in a native tissue environment. We employed water gas cluster ion beam secondary ion mass spectrometry imaging ([H2O]n>28K-GCIB-SIMS) at ≤3 μm resolution using a cryogenic imaging workflow. This allowed multiple biomolecular imaging modes on the near-native-state liver at single-cell resolution. Our workflow utilizes desorption electrospray ionization (DESI) to build a reference map of metabolic heterogeneity and zonation across liver functional units at tissue level. Cryogenic dual-SIMS integrated metabolomics, lipidomics, and proteomics in the same liver lobules at single-cell level, characterizing the cellular landscape and metabolic states in different cell types. Lipids and metabolites classified liver metabolic zones, cell types and subtypes, highlighting the power of spatial multi-omics at high spatial resolution for understanding celluar and biomolecular organizations in the mammalian liver.
    Keywords:  (H(2)O)(n>28K)-GCIB-SIMS; DESI; MSI; desorption electrospray ionization; liver heterogeneity; mass spectrometry imaging; metabolism; single cell; spatial omics; water gas cluster ion beam secondary ion mass spectrometry imaging
    DOI:  https://doi.org/10.1016/j.devcel.2024.01.025
  16. Sci Adv. 2024 Feb 16. 10(7): eadk2317
    A mechanism of lysosomal calcium entry.
    Matthew Zajac, Sourajit Mukherjee, Palapuravan Anees, Daphne Oettinger, Katharine Henn, Jainaha Srikumar, Junyi Zou, Anand Saminathan, Yamuna Krishnan.
      Lysosomal calcium (Ca2+) release is critical to cell signaling and is mediated by well-known lysosomal Ca2+ channels. Yet, how lysosomes refill their Ca2+ remains hitherto undescribed. Here, from an RNA interference screen in Caenorhabditis elegans, we identify an evolutionarily conserved gene, lci-1, that facilitates lysosomal Ca2+ entry in C. elegans and mammalian cells. We found that its human homolog TMEM165, previously designated as a Ca2+/H+ exchanger, imports Ca2+ pH dependently into lysosomes. Using two-ion mapping and electrophysiology, we show that TMEM165, hereafter referred to as human LCI, acts as a proton-activated, lysosomal Ca2+ importer. Defects in lysosomal Ca2+ channels cause several neurodegenerative diseases, and knowledge of lysosomal Ca2+ importers may provide previously unidentified avenues to explore the physiology of Ca2+ channels.
    DOI:  https://doi.org/10.1126/sciadv.adk2317
  17. J Clin Invest. 2024 Feb 15. pii: e178125. [Epub ahead of print]134(4):
    Targeting de novo lipogenesis to mitigate kidney disease.
    Haikuo Li, Benjamin D Humphreys.
      Ten percent of the population worldwide suffers from chronic kidney disease (CKD), but the mechanisms driving CKD pathology are incompletely understood. While dysregulated lipid metabolism is one hallmark of CKD, the pathogenesis of cellular lipid accumulation remains unclear. In this issue of the JCI, Mukhi et al. Identify acyl-CoA synthetase short-chain family 2 (ACSS2) as a disease risk gene and demonstrate a role for ACSS2 in de novo lipogenesis (DNL). Notably, genetic or pharmacological inhibition of DNL protected against kidney disease progression in mice. These findings warrant evaluation of DNL inhibition with respect to efficacy and safety in people with CKD.
    DOI:  https://doi.org/10.1172/JCI178125
  18. bioRxiv. 2024 Jan 30. pii: 2024.01.29.577846. [Epub ahead of print]
    Cisplatin drives mitochondrial dysregulation in sensory hair cells.
    David S Lee, Angela Schrader, Jiaoxia Zou, Wee Han Ang, Mark E Warchol, Lavinia Sheets.
      Cisplatin is a commonly used chemotherapy that causes permanent hearing loss by injuring cochlear hair cells. The underlying mechanisms that drive hair cell loss remain unknown, but mitochondria have emerged as potential mediators of cisplatin ototoxicity. Direct observation of changes in hair cell mitochondrial function are challenging because the mammalian inner ear is optically inaccessible. Here, we perform live in vivo imaging of hair cells within the zebrafish lateral-line organ to evaluate the role of mitochondria in cisplatin ototoxicity. Using a genetically encoded biosensor that measures cumulative mitochondrial activity in hair cells, we demonstrate that greater redox history increases susceptibility to cisplatin. Next, we conduct time-lapse imaging of individual hair cells to understand dynamic changes in mitochondrial homeostasis. We observe spikes in mitochondrial calcium and cytosolic calcium immediately prior to hair cell death. Furthermore, we use a mitochondrially-localized probe that fluoresces in the presence of cisplatin to show that cisplatin accumulates in hair cell mitochondria. Lastly, we demonstrate that this accumulation occurs before mitochondrial dysregulation, Caspase-3 activation, and ultimately, hair cell death. Our findings provide additional evidence that suggest mitochondria are integral to cisplatin ototoxicity and cisplatin directly targets hair cell mitochondria.
    DOI:  https://doi.org/10.1101/2024.01.29.577846
  19. Nat Struct Mol Biol. 2024 Feb 12.
    Single-nucleoid architecture reveals heterogeneous packaging of mitochondrial DNA.
    R Stefan Isaac, Thomas W Tullius, Katja G Hansen, Danilo Dubocanin, Mary Couvillion, Andrew B Stergachis, L Stirling Churchman.
      Cellular metabolism relies on the regulation and maintenance of mitochondrial DNA (mtDNA). Hundreds to thousands of copies of mtDNA exist in each cell, yet because mitochondria lack histones or other machinery important for nuclear genome compaction, it remains unresolved how mtDNA is packaged into individual nucleoids. In this study, we used long-read single-molecule accessibility mapping to measure the compaction of individual full-length mtDNA molecules at near single-nucleotide resolution. We found that, unlike the nuclear genome, human mtDNA largely undergoes all-or-none global compaction, with most nucleoids existing in an inaccessible, inactive state. Highly accessible mitochondrial nucleoids are co-occupied by transcription and replication components and selectively form a triple-stranded displacement loop structure. In addition, we showed that the primary nucleoid-associated protein TFAM directly modulates the fraction of inaccessible nucleoids both in vivo and in vitro, acting consistently with a nucleation-and-spreading mechanism to coat and compact mitochondrial nucleoids. Together, these findings reveal the primary architecture of mtDNA packaging and regulation in human cells.
    DOI:  https://doi.org/10.1038/s41594-024-01225-6
  20. Mol Cell. 2024 Jan 24. pii: S1097-2765(24)00004-2. [Epub ahead of print]
    COQ4 is required for the oxidative decarboxylation of the C1 carbon of coenzyme Q in eukaryotic cells.
    Ludovic Pelosi, Laura Morbiato, Arthur Burgardt, Fiorella Tonello, Abigail K Bartlett, Rachel M Guerra, Katayoun Kazemzadeh Ferizhendi, Maria Andrea Desbats, Bérengère Rascalou, Marco Marchi, Luis Vázquez-Fonseca, Caterina Agosto, Giuseppe Zanotti, Morgane Roger-Margueritat, María Alcázar-Fabra, Laura García-Corzo, Ana Sánchez-Cuesta, Plácido Navas, Gloria Brea-Calvo, Eva Trevisson, Volker F Wendisch, David J Pagliarini, Leonardo Salviati, Fabien Pierrel.
      Coenzyme Q (CoQ) is a redox lipid that fulfills critical functions in cellular bioenergetics and homeostasis. CoQ is synthesized by a multi-step pathway that involves several COQ proteins. Two steps of the eukaryotic pathway, the decarboxylation and hydroxylation of position C1, have remained uncharacterized. Here, we provide evidence that these two reactions occur in a single oxidative decarboxylation step catalyzed by COQ4. We demonstrate that COQ4 complements an Escherichia coli strain deficient for C1 decarboxylation and hydroxylation and that COQ4 displays oxidative decarboxylation activity in the non-CoQ producer Corynebacterium glutamicum. Overall, our results substantiate that COQ4 contributes to CoQ biosynthesis, not only via its previously proposed structural role but also via the oxidative decarboxylation of CoQ precursors. These findings fill a major gap in the knowledge of eukaryotic CoQ biosynthesis and shed light on the pathophysiology of human primary CoQ deficiency due to COQ4 mutations.
    Keywords:  COQ4; Corynebacterium; coenzyme Q; coenzyme Q biosynthesis; coenzyme Q deficiency; mitochondria; oxidative decarboxylation; respiratory chain
    DOI:  https://doi.org/10.1016/j.molcel.2024.01.003
  21. Sci Immunol. 2024 Feb 16. 9(92): eadj3945
    STING licensing of type I dendritic cells potentiates antitumor immunity.
    Jian Wang, Suxin Li, Maggie Wang, Xu Wang, Shuqing Chen, Zhichen Sun, Xiubao Ren, Gang Huang, Baran D Sumer, Nan Yan, Yang-Xin Fu, Jinming Gao.
      Stimulator of interferon genes (STING) is an immune adaptor protein that senses cyclic GMP-AMP in response to self or microbial cytosolic DNA as a danger signal. STING is ubiquitously expressed in diverse cell populations, including cancer cells, with distinct cellular functions, such as activation of type I interferons, autophagy induction, or triggering apoptosis. It is not well understood whether and which subsets of immune cells, stromal cells, or cancer cells are particularly important for STING-mediated antitumor immunity. Here, using a polymeric STING-activating nanoparticle (PolySTING) with a shock-and-lock dual activation mechanism, we show that conventional type 1 dendritic cells (cDC1s) are essential for STING-mediated rejection of multiple established and metastatic murine tumors. STING status in the host but not in the cancer cells (Tmem173-/-) is important for antitumor efficacy. Specific depletion of cDC1 (Batf3-/-) or STING deficiency in cDC1 (XCR1creSTINGfl/fl) abolished PolySTING efficacy, whereas depletion of other myeloid cells had little effect. Adoptive transfer of wild-type cDC1 in Batf3-/- mice restored antitumor efficacy, whereas transfer of cDC1 with STING or IRF3 deficiency failed to rescue. PolySTING induced a specific chemokine signature in wild-type but not Batf3-/- mice. Multiplexed immunohistochemistry analysis of STING-activating cDC1s in resected tumors correlates with patient survival. Furthermore, STING-cDC1 signature was increased after neoadjuvant pembrolizumab therapy in patients with non-small cell lung cancer. Therefore, we have defined that a subset of myeloid cells is essential for STING-mediated antitumor immunity with associated biomarkers for prognosis.
    DOI:  https://doi.org/10.1126/sciimmunol.adj3945
  22. Cell. 2024 Feb 12. pii: S0092-8674(24)00064-3. [Epub ahead of print]
    Pan-cancer proteogenomics characterization of tumor immunity.
    Clinical Proteomic Tumor Analysis Consortium
      Despite the successes of immunotherapy in cancer treatment over recent decades, less than <10%-20% cancer cases have demonstrated durable responses from immune checkpoint blockade. To enhance the efficacy of immunotherapies, combination therapies suppressing multiple immune evasion mechanisms are increasingly contemplated. To better understand immune cell surveillance and diverse immune evasion responses in tumor tissues, we comprehensively characterized the immune landscape of more than 1,000 tumors across ten different cancers using CPTAC pan-cancer proteogenomic data. We identified seven distinct immune subtypes based on integrative learning of cell type compositions and pathway activities. We then thoroughly categorized unique genomic, epigenetic, transcriptomic, and proteomic changes associated with each subtype. Further leveraging the deep phosphoproteomic data, we studied kinase activities in different immune subtypes, which revealed potential subtype-specific therapeutic targets. Insights from this work will facilitate the development of future immunotherapy strategies and enhance precision targeting with existing agents.
    Keywords:  histopathology; immune subtype; immunotherapy; kinase activity; multiomic deconvolution; proteogenomics; tumor immunity
    DOI:  https://doi.org/10.1016/j.cell.2024.01.027
  23. Sci Adv. 2024 Feb 16. 10(7): eadk1835
    Mutant p53 protects triple-negative breast adenocarcinomas from ferroptosis in vivo.
    Denada Dibra, Shunbin Xiong, Sydney M Moyer, Adel K El-Naggar, Yuan Qi, Xiaoping Su, Elisabeth K Kong, Anil Korkut, Guillermina Lozano.
      The TP53 tumor suppressor gene is mutated early in most of the patients with triple-negative breast cancer (TNBC). The most frequent TP53 alterations are missense mutations that contribute to tumor aggressiveness. Here, we used an autochthonous somatic TNBC mouse model, in which mutant p53 can be toggled on and off genetically while leaving the tumor microenvironment intact and wild-type for p53 to identify physiological dependencies on mutant p53. In TNBCs that develop in this model, deletion of two different hotspot p53R172H and p53R245W mutants triggers ferroptosis in vivo, a cell death mechanism involving iron-dependent lipid peroxidation. Mutant p53 protects cells from ferroptosis inducers, and ferroptosis inhibitors reverse the effects of mutant p53 loss in vivo. Single-cell transcriptomic data revealed that mutant p53 protects cells from undergoing ferroptosis through NRF2-dependent regulation of Mgst3 and Prdx6, which encode two glutathione-dependent peroxidases that detoxify lipid peroxides. Thus, mutant p53 protects TNBCs from ferroptotic death.
    DOI:  https://doi.org/10.1126/sciadv.adk1835
  24. Nat Commun. 2024 Feb 13. 15(1): 1328
    Structural basis for regulated assembly of the mitochondrial fission GTPase Drp1.
    Kristy Rochon, Brianna L Bauer, Nathaniel A Roethler, Yuli Buckley, Chih-Chia Su, Wei Huang, Rajesh Ramachandran, Maria S K Stoll, Edward W Yu, Derek J Taylor, Jason A Mears.
      Mitochondrial fission is a critical cellular event to maintain organelle function. This multistep process is initiated by the enhanced recruitment and oligomerization of dynamin-related protein 1 (Drp1) at the surface of mitochondria. As such, Drp1 is essential for inducing mitochondrial division in mammalian cells, and homologous proteins are found in all eukaryotes. As a member of the dynamin superfamily of proteins (DSPs), controlled Drp1 self-assembly into large helical polymers stimulates its GTPase activity to promote membrane constriction. Still, little is known about the mechanisms that regulate correct spatial and temporal assembly of the fission machinery. Here we present a cryo-EM structure of a full-length Drp1 dimer in an auto-inhibited state. This dimer reveals two key conformational rearrangements that must be unlocked through intramolecular rearrangements to achieve the assembly-competent state observed in previous structures. This structural insight provides understanding into the mechanism for regulated self-assembly of the mitochondrial fission machinery.
    DOI:  https://doi.org/10.1038/s41467-024-45524-4
  25. Biogerontology. 2024 Feb 13.
    Renal aging and mitochondrial quality control.
    Xiuli Guo, Jiao Wang, Yinjie Wu, Xinwang Zhu, Li Xu.
      Mitochondria are dynamic organelles that participate in different cellular process that control metabolism, cell division, and survival, and the kidney is one of the most metabolically active organs that contains abundant mitochondria. Perturbations in mitochondrial homeostasis in the kidney can accelerate kidney aging, and maintaining mitochondrial homeostasis can effectively delay aging in the kidney. Kidney aging is a degenerative process linked to detrimental processes. The significance of aberrant mitochondrial homeostasis in renal aging has received increasing attention. However, the contribution of mitochondrial quality control (MQC) to renal aging has not been reviewed in detail. Here, we generalize the current factors contributing to renal aging, review the alterations in MQC during renal injury and aging, and analyze the relationship between mitochondria and intrinsic renal cells. We also introduce MQC in the context of renal aging, and discuss the study of mitochondria in the intrinsic cells of the kidney, which is the innovation of our paper. In addition, during kidney injury and repair, the specific functions and regulatory mechanisms of MQC systems in resident and circulating cell types remain unclear. Currently, most of the studies we reviewed are based on animal and cellular models, the relationship between renal tissue aging and mitochondria has not been adequately investigated in clinical studies, and there is still a long way to go.
    Keywords:  Aging; Mitochondrial dysfunction; Mitochondrial quality control; Renal intrinsic cells
    DOI:  https://doi.org/10.1007/s10522-023-10091-6
  26. Nature. 2024 Feb 14.
    Genetic determinants of micronucleus formation in vivo.
    Sanger Mouse Genetics Project
      Genomic instability arising from defective responses to DNA damage1 or mitotic chromosomal imbalances2 can lead to the sequestration of DNA in aberrant extranuclear structures called micronuclei (MN). Although MN are a hallmark of ageing and diseases associated with genomic instability, the catalogue of genetic players that regulate the generation of MN remains to be determined. Here we analyse 997 mouse mutant lines, revealing 145 genes whose loss significantly increases (n = 71) or decreases (n = 74) MN formation, including many genes whose orthologues are linked to human disease. We found that mice null for Dscc1, which showed the most significant increase in MN, also displayed a range of phenotypes characteristic of patients with cohesinopathy disorders. After validating the DSCC1-associated MN instability phenotype in human cells, we used genome-wide CRISPR-Cas9 screening to define synthetic lethal and synthetic rescue interactors. We found that the loss of SIRT1 can rescue phenotypes associated with DSCC1 loss in a manner paralleling restoration of protein acetylation of SMC3. Our study reveals factors involved in maintaining genomic stability and shows how this information can be used to identify mechanisms that are relevant to human disease biology1.
    DOI:  https://doi.org/10.1038/s41586-023-07009-0
  27. Trends Cancer. 2024 Feb 13. pii: S2405-8033(24)00027-X. [Epub ahead of print]
    Adaptive inhibition of CGAS signaling by TREX1.
    María Cecilia Lira, Claire Vanpouille-Box, Lorenzo Galluzzi.
      Mammalian cells react to the accumulation of double-stranded (ds)DNA in the cytosol by secreting antiviral and proinflammatory cytokines, notably type I interferon (IFN). Recent data reported by Tani et al. demonstrate that overactivation of this pathway is prevented by an adaptive feedback mechanism elicited by type I IFN receptors and executed by the exonuclease three prime repair exonuclease 1 (TREX1).
    Keywords:  NK cells; PD-1; STAT1; STING1; autophagy; immune checkpoint inhibitors
    DOI:  https://doi.org/10.1016/j.trecan.2024.02.001
  28. bioRxiv. 2024 Feb 04. pii: 2024.02.02.578646. [Epub ahead of print]
    BRD4-mediated epigenetic regulation of endoplasmic reticulum-mitochondria contact sites is governed by the mitochondrial complex III.
    Brandon Chen, Theophilus M Lynn-Nguyen, Pankaj Jadhav, Benjamin S Halligan, Nicholas J Rossiter, Rachel M Guerra, Sergei Koshkin, Imhoi Koo, Pietro Morlacchi, David A Hanna, Jason Lin, Ruma Banerjee, David J Pagliarini, Andrew D Patterson, Shyamal Mosalaganti, Jonathan Z Sexton, Tito Calì, Costas A Lyssiotis, Yatrik M Shah.
      Inter-organellar communication is critical for cellular metabolic homeostasis. One of the most abundant inter-organellar interactions are those at the endoplasmic reticulum and mitochondria contact sites (ERMCS). However, a detailed understanding of the mechanisms governing ERMCS regulation and their roles in cellular metabolism are limited by a lack of tools that permit temporal induction and reversal. Through unbiased screening approaches, we identified fedratinib, an FDA-approved drug, that dramatically increases ERMCS abundance by inhibiting the epigenetic modifier BRD4. Fedratinib rapidly and reversibly modulates mitochondrial and ER morphology and alters metabolic homeostasis. Moreover, ERMCS modulation depends on mitochondria electron transport chain complex III function. Comparison of fedratinib activity to other reported inducers of ERMCS revealed common mechanisms of induction and function, providing clarity and union to a growing body of experimental observations. In total, our results uncovered a novel epigenetic signaling pathway and an endogenous metabolic regulator that connects ERMCS and cellular metabolism.
    DOI:  https://doi.org/10.1101/2024.02.02.578646
  29. Nat Commun. 2024 Feb 16. 15(1): 1442
    Hijacking of nucleotide biosynthesis and deamidation-mediated glycolysis by an oncogenic herpesvirus.
    Quanyuan Wan, Leah Tavakoli, Ting-Yu Wang, Andrew J Tucker, Ruiting Zhou, Qizhi Liu, Shu Feng, Dongwon Choi, Zhiheng He, Michaela U Gack, Jun Zhao.
      Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi's sarcoma (KS) and multiple types of B cell malignancies. Emerging evidence demonstrates that KSHV reprograms host-cell central carbon metabolic pathways, which contributes to viral persistence and tumorigenesis. However, the mechanisms underlying KSHV-mediated metabolic reprogramming remain poorly understood. Carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, and dihydroorotase (CAD) is a key enzyme of the de novo pyrimidine synthesis, and was recently identified to deamidate the NF-κB subunit RelA to promote aerobic glycolysis and cell proliferation. Here we report that KSHV infection exploits CAD for nucleotide synthesis and glycolysis. Mechanistically, KSHV vCyclin binds to and hijacks cyclin-dependent kinase CDK6 to phosphorylate Ser-1900 on CAD, thereby activating CAD-mediated pyrimidine synthesis and RelA-deamidation-mediated glycolytic reprogramming. Correspondingly, genetic depletion or pharmacological inhibition of CDK6 and CAD potently impeded KSHV lytic replication and thwarted tumorigenesis of primary effusion lymphoma (PEL) cells in vitro and in vivo. Altogether, our work defines a viral metabolic reprogramming mechanism underpinning KSHV oncogenesis, which may spur the development of new strategies to treat KSHV-associated malignancies and other diseases.
    DOI:  https://doi.org/10.1038/s41467-024-45852-5
  30. Nat Rev Mol Cell Biol. 2024 Feb 16.
    Emerging mechanistic understanding of cilia function in cellular signalling.
    Keren I Hilgendorf, Benjamin R Myers, Jeremy F Reiter.
      Primary cilia are solitary, immotile sensory organelles present on most cells in the body that participate broadly in human health, physiology and disease. Cilia generate a unique environment for signal transduction with tight control of protein, lipid and second messenger concentrations within a relatively small compartment, enabling reception, transmission and integration of biological information. In this Review, we discuss how cilia function as signalling hubs in cell-cell communication using three signalling pathways as examples: ciliary G-protein-coupled receptors (GPCRs), the Hedgehog (Hh) pathway and polycystin ion channels. We review how defects in these ciliary signalling pathways lead to a heterogeneous group of conditions known as 'ciliopathies', including metabolic syndromes, birth defects and polycystic kidney disease. Emerging understanding of these pathways' transduction mechanisms reveals common themes between these cilia-based signalling pathways that may apply to other pathways as well. These mechanistic insights reveal how cilia orchestrate normal and pathophysiological signalling outputs broadly throughout human biology.
    DOI:  https://doi.org/10.1038/s41580-023-00698-5
  31. Cell Rep. 2024 Feb 08. pii: S2211-1247(24)00067-6. [Epub ahead of print]43(2): 113739
    GLUT1-mediated glucose import in B cells is critical for anaplerotic balance and humoral immunity.
    Theresa E H Bierling, Amelie Gumann, Shannon R Ottmann, Sebastian R Schulz, Leonie Weckwerth, Jana Thomas, Arne Gessner, Magdalena Wichert, Frederic Kuwert, Franziska Rost, Manuela Hauke, Tatjana Freudenreich, Dirk Mielenz, Hans-Martin Jäck, Katharina Pracht.
      Glucose uptake increases during B cell activation and antibody-secreting cell (ASC) differentiation, but conflicting findings prevent a clear metabolic profile at different stages of B cell activation. Deletion of the glucose transporter type 1 (GLUT1) gene in mature B cells (GLUT1-cKO) results in normal B cell development, but it reduces germinal center B cells and ASCs. GLUT1-cKO mice show decreased antigen-specific antibody titers after vaccination. In vitro, GLUT1-deficient B cells show impaired activation, whereas established plasmablasts abolish glycolysis, relying on mitochondrial activity and fatty acids. Transcriptomics and metabolomics reveal an altered anaplerotic balance in GLUT1-deficient ASCs. Despite attempts to compensate for glucose deprivation by increasing mitochondrial mass and gene expression associated with glycolysis, the tricarboxylic acid cycle, and hexosamine synthesis, GLUT1-deficient ASCs lack the metabolites for energy production and mitochondrial respiration, limiting protein synthesis. We identify GLUT1 as a critical metabolic player defining the germinal center response and humoral immunity.
    Keywords:  CP: Immunology; CP: Metabolism; GLUT1; adaptive immune response; antibody-secreting cell; glucose transporter type 1; glycolysis; metabolism; mitochondrial respiration; plasma cell; plasmablast
    DOI:  https://doi.org/10.1016/j.celrep.2024.113739
  32. Annu Rev Physiol. 2024 Feb 12. 86 149-173
    Transcellular Barriers to Glucose Delivery in the Body.
    Amira Klip, Katrien De Bock, Philip J Bilan, Erik A Richter.
      Glucose is the universal fuel of most mammalian cells, and it is largely replenished through dietary intake. Glucose availability to tissues is paramount for the maintenance of homeostatic energetics and, hence, supply should match demand by the consuming organs. In its journey through the body, glucose encounters cellular barriers for transit at the levels of the absorbing intestinal epithelial wall, the renal epithelium mediating glucose reabsorption, and the tight capillary endothelia (especially in the brain). Glucose transiting through these cellular barriers must escape degradation to ensure optimal glucose delivery to the bloodstream or tissues. The liver, which stores glycogen and generates glucose de novo, must similarly be able to release it intact to the circulation. We present the most up-to-date knowledge on glucose handling by the gut, liver, brain endothelium, and kidney, and discuss underlying molecular mechanisms and open questions. Diseases associated with defects in glucose delivery and homeostasis are also briefly addressed. We propose that the universal problem of sparing glucose from catabolism in favor of translocation across the barriers posed by epithelia and endothelia is resolved through common mechanisms involving glucose transfer to the endoplasmic reticulum, from where glucose exits the cells via unconventional cellular mechanisms.
    Keywords:  GLUT; SLGT; endothelium; epithelium; glucose; glucose-6-phosphatase
    DOI:  https://doi.org/10.1146/annurev-physiol-042022-031657
  33. Cancer Metab. 2024 Feb 13. 12(1): 5
    Cone photoreceptor phosphodiesterase PDE6H inhibition regulates cancer cell growth and metabolism, replicating the dark retina response.
    Ceren Yalaz, Esther Bridges, Nasullah K Alham, Christos E Zois, Jianzhou Chen, Karim Bensaad, Ana Miar, Elisabete Pires, Ruth J Muschel, James S O McCullagh, Adrian L Harris.
      BACKGROUND: PDE6H encodes PDE6γ', the inhibitory subunit of the cGMP-specific phosphodiesterase 6 in cone photoreceptors. Inhibition of PDE6, which has been widely studied for its role in light transduction, increases cGMP levels. The purpose of this study is to characterise the role of PDE6H in cancer cell growth.METHODS: From an siRNA screen for 487 genes involved in metabolism, PDE6H was identified as a controller of cell cycle progression in HCT116 cells. Role of PDE6H in cancer cell growth and metabolism was studied through the effects of its depletion on levels of cell cycle controllers, mTOR effectors, metabolite levels, and metabolic energy assays. Effect of PDE6H deletion on tumour growth was also studied in a xenograft model.
    RESULTS: PDE6H knockout resulted in an increase of intracellular cGMP levels, as well as changes to the levels of nucleotides and key energy metabolism intermediates. PDE6H knockdown induced G1 cell cycle arrest and cell death and reduced mTORC1 signalling in cancer cell lines. Both knockdown and knockout of PDE6H resulted in the suppression of mitochondrial function. HCT116 xenografts revealed that PDE6H deletion, as well as treatment with the PDE5/6 inhibitor sildenafil, slowed down tumour growth and improved survival, while sildenafil treatment did not have an additive effect on slowing the growth of PDE6γ'-deficient tumours.
    CONCLUSIONS: Our results indicate that the changes in cGMP and purine pools, as well as mitochondrial function which is observed upon PDE6γ' depletion, are independent of the PKG pathway. We show that in HCT116, PDE6H deletion replicates many effects of the dark retina response and identify PDE6H as a new target in preventing cancer cell proliferation and tumour growth.
    DOI:  https://doi.org/10.1186/s40170-023-00326-y
  34. Elife. 2024 Feb 13. pii: RP89173. [Epub ahead of print]12
    Hypoxia-inducible factor induces cysteine dioxygenase and promotes cysteine homeostasis in Caenorhabditis elegans.
    Kurt Warnhoff, Sushila Bhattacharya, Jennifer Snoozy, Peter C Breen, Gary Ruvkun.
      Dedicated genetic pathways regulate cysteine homeostasis. For example, high levels of cysteine activate cysteine dioxygenase, a key enzyme in cysteine catabolism in most animal and many fungal species. The mechanism by which cysteine dioxygenase is regulated is largely unknown. In an unbiased genetic screen for mutations that activate cysteine dioxygenase (cdo-1) in the nematode Caenorhabditis elegans, we isolated loss-of-function mutations in rhy-1 and egl-9, which encode proteins that negatively regulate the stability or activity of the oxygen-sensing hypoxia inducible transcription factor (hif-1). EGL-9 and HIF-1 are core members of the conserved eukaryotic hypoxia response. However, we demonstrate that the mechanism of HIF-1-mediated induction of cdo-1 is largely independent of EGL-9 prolyl hydroxylase activity and the von Hippel-Lindau E3 ubiquitin ligase, the classical hypoxia signaling pathway components. We demonstrate that C. elegans cdo-1 is transcriptionally activated by high levels of cysteine and hif-1. hif-1-dependent activation of cdo-1 occurs downstream of an H2S-sensing pathway that includes rhy-1, cysl-1, and egl-9. cdo-1 transcription is primarily activated in the hypodermis where it is also sufficient to drive sulfur amino acid metabolism. Thus, the regulation of cdo-1 by hif-1 reveals a negative feedback loop that maintains cysteine homeostasis. High levels of cysteine stimulate the production of an H2S signal. H2S then acts through the rhy-1/cysl-1/egl-9 signaling pathway to increase HIF-1-mediated transcription of cdo-1, promoting degradation of cysteine via CDO-1.
    Keywords:  C. elegans; Cysteine; genetics; genomics; hypoxia; metabolism
    DOI:  https://doi.org/10.7554/eLife.89173
  35. Cell Rep. 2024 Feb 12. pii: S2211-1247(24)00066-4. [Epub ahead of print]43(2): 113738
    Proline restores mitochondrial function and reverses aging hallmarks in senescent cells.
    Debanik Choudhury, Na Rong, Hamsa Vardini Senthil Kumar, Sydney Swedick, Ronel Z Samuel, Pihu Mehrotra, John Toftegaard, Nika Rajabian, Ramkumar Thiyagarajan, Ashis K Podder, Yulun Wu, Shahryar Shahini, Kenneth L Seldeen, Bruce Troen, Pedro Lei, Stelios T Andreadis.
      Mitochondrial dysfunction is a hallmark of cellular senescence, with the loss of mitochondrial function identified as a potential causal factor contributing to senescence-associated decline in cellular functions. Our recent findings revealed that ectopic expression of the pluripotency transcription factor NANOG rejuvenates dysfunctional mitochondria of senescent cells by rewiring metabolic pathways. In this study, we report that NANOG restores the expression of key enzymes, PYCR1 and PYCR2, in the proline biosynthesis pathway. Additionally, senescent mesenchymal stem cells manifest severe mitochondrial respiratory impairment, which is alleviated through proline supplementation. Proline induces mitophagy by activating AMP-activated protein kinase α and upregulating Parkin expression, enhancing mitochondrial clearance and ultimately restoring cell metabolism. Notably, proline treatment also mitigates several aging hallmarks, including DNA damage, senescence-associated β-galactosidase, inflammatory cytokine expressions, and impaired myogenic differentiation capacity. Overall, this study highlights the role of proline in mitophagy and its potential in reversing senescence-associated mitochondrial dysfunction and aging hallmarks.
    Keywords:  AMPKα; CP: Cell biology; CP: Metabolism; Parkin; aging; amino acid; autophagy; mitochondria; mitophagy; proline; senescence
    DOI:  https://doi.org/10.1016/j.celrep.2024.113738
  36. Annu Rev Biophys. 2024 Feb 12.
    Next-Generation Genetically Encoded Fluorescent Biosensors Illuminate Cell Signaling and Metabolism.
    Michelle S Frei, Sohum Mehta, Jin Zhang.
      Genetically encoded fluorescent biosensors have revolutionized the study of cell signaling and metabolism, as they allow for live-cell measurements with high spatiotemporal resolution. This success has spurred the development of tailor-made biosensors that enable the study of dynamic phenomena on different timescales and length scales. In this review, we discuss different approaches to enhancing and developing new biosensors. We summarize the technologies used to gain structural insights into biosensor design and comment on useful screening technologies. Furthermore, we give an overview of different applications where biosensors have led to key advances over recent years. Finally, we give our perspective on where future work is bound to make a large impact. Expected final online publication date for the Annual Review of Biophysics, Volume 53 is May 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
    DOI:  https://doi.org/10.1146/annurev-biophys-030722-021359
  37. bioRxiv. 2024 Feb 01. pii: 2024.01.31.578293. [Epub ahead of print]
    The proteome is a terminal electron acceptor.
    Avi I Flamholz, Akshit Goyal, Woodward W Fischer, Dianne K Newman, Rob Phillips.
      Microbial metabolism is impressively flexible, enabling growth even when available nutrients differ greatly from biomass in redox state. E. coli , for example, rearranges its physiology to grow on reduced and oxidized carbon sources through several forms of fermentation and respiration. To understand the limits on and evolutionary consequences of metabolic flexibility, we developed a mathematical model coupling redox chemistry with principles of cellular resource allocation. Our integrated model clarifies key phenomena, including demonstrating that autotrophs grow slower than heterotrophs because of constraints imposed by intracellular production of reduced carbon. Our model further indicates that growth is improved by adapting the redox state of biomass to nutrients, revealing an unexpected mode of evolution where proteins accumulate mutations benefiting organismal redox balance.One sentence summary: Microbial proteins adapt their composition on physiological and evolutionary timescales to ensure organismal redox balance.
    DOI:  https://doi.org/10.1101/2024.01.31.578293
  38. Nat Cancer. 2024 Feb 14.
    Efferocytosis reprograms the tumor microenvironment to promote pancreatic cancer liver metastasis.
    Yuliana Astuti, Meirion Raymant, Valeria Quaranta, Kim Clarke, Maidinaimu Abudula, Olivia Smith, Gaia Bellomo, Vatshala Chandran-Gorner, Craig Nourse, Christopher Halloran, Paula Ghaneh, Daniel Palmer, Robert P Jones, Fiona Campbell, Jeffrey W Pollard, Jennifer P Morton, Ainhoa Mielgo, Michael C Schmid.
      Pancreatic ductal adenocarcinoma is a highly metastatic disease and macrophages support liver metastases. Efferocytosis, or engulfment of apoptotic cells by macrophages, is an essential process in tissue homeostasis and wound healing, but its role in metastasis is less well understood. Here, we found that the colonization of the hepatic metastatic site is accompanied by low-grade tissue injury and that efferocytosis-mediated clearance of parenchymal dead cells promotes macrophage reprogramming and liver metastasis. Mechanistically, progranulin expression in macrophages is necessary for efficient efferocytosis by controlling lysosomal acidification via cystic fibrosis transmembrane conductance regulator and the degradation of lysosomal cargo, resulting in LXRα/RXRα-mediated macrophage conversion and upregulation of arginase 1. Pharmacological blockade of efferocytosis or macrophage-specific genetic depletion of progranulin impairs macrophage conversion, improves CD8+ T cell functions, and reduces liver metastasis. Our findings reveal how hard-wired functions of macrophages in tissue repair contribute to liver metastasis and identify potential targets for prevention of pancreatic ductal adenocarcinoma liver metastasis.
    DOI:  https://doi.org/10.1038/s43018-024-00731-2
  39. Mol Metab. 2024 Feb 12. pii: S2212-8778(24)00031-0. [Epub ahead of print] 101900
    Loss of mitochondrial pyruvate carrier 1 supports proline-dependent proliferation and collagen biosynthesis in ovarian cancer.
    M R Farook, Z Croxford, S Morgan, A D Horlock, A Holt, A Rees, B J Jenkins, C Tse, E Stanton, D M Davies, C A Thornton, N Jones, I M Sheldon, E E Vincent, J G Cronin.
      The pyruvate transporter MPC1 (mitochondrial pyruvate carrier 1) acts as a tumour-suppressor, loss of which correlates with a pro-tumorigenic phenotype and poor survival in several tumour types. In high-grade serous ovarian cancers (HGSOC), patients display copy number loss of MPC1 in around 78% of cases and reduced MPC1 mRNA expression. To explore the metabolic effect of reduced expression, we demonstrate that depleting MPC1 in HGSOC cell lines drives expression of key proline biosynthetic genes; PYCR1, PYCR2 and PYCR3, and biosynthesis of proline. We show that altered proline metabolism underpins cancer cell proliferation, reactive oxygen species (ROS) production, and type I and type VI collagen formation in ovarian cancer cells. Furthermore, exploring The Cancer Genome Atlas, we discovered the PYCR3 isozyme to be highly expressed in a third of HGSOC patients, which was associated with more aggressive disease and diagnosis at a younger age. Taken together, our study highlights that targeting proline metabolism is a potential therapeutic avenue for the treatment of HGSOC.
    DOI:  https://doi.org/10.1016/j.molmet.2024.101900
  40. Nat Immunol. 2024 Feb 14.
    Adipose Treg cells in charge of metabolism.
    Melanie Grusdat, Dirk Brenner.
      
    DOI:  https://doi.org/10.1038/s41590-024-01762-8
  41. Nat Rev Cancer. 2024 Feb 12.
    Beyond genetics: driving cancer with the tumour microenvironment behind the wheel.
    Shaopeng Yuan, Jorge Almagro, Elaine Fuchs.
      Cancer has long been viewed as a genetic disease of cumulative mutations. This notion is fuelled by studies showing that ageing tissues are often riddled with clones of complex oncogenic backgrounds coexisting in seeming harmony with their normal tissue counterparts. Equally puzzling, however, is how cancer cells harbouring high mutational burden contribute to normal, tumour-free mice when allowed to develop within the confines of healthy embryos. Conversely, recent evidence suggests that adult tissue cells expressing only one or a few oncogenes can, in some contexts, generate tumours exhibiting many of the features of a malignant, invasive cancer. These disparate observations are difficult to reconcile without invoking environmental cues triggering epigenetic changes that can either dampen or drive malignant transformation. In this Review, we focus on how certain oncogenes can launch a two-way dialogue of miscommunication between a stem cell and its environment that can rewire downstream events non-genetically and skew the morphogenetic course of the tissue. We review the cells and molecules of and the physical forces acting in the resulting tumour microenvironments that can profoundly affect the behaviours of transformed cells. Finally, we discuss possible explanations for the remarkable diversity in the relative importance of mutational burden versus tumour microenvironment and its clinical relevance.
    DOI:  https://doi.org/10.1038/s41568-023-00660-9
  42. Nat Med. 2024 Feb 14.
    Validation of biomarkers of aging.
    Mahdi Moqri, Chiara Herzog, Jesse R Poganik, Kejun Ying, Jamie N Justice, Daniel W Belsky, Albert T Higgins-Chen, Brian H Chen, Alan A Cohen, Georg Fuellen, Sara Hägg, Riccardo E Marioni, Martin Widschwendter, Kristen Fortney, Peter O Fedichev, Alex Zhavoronkov, Nir Barzilai, Jessica Lasky-Su, Douglas P Kiel, Brian K Kennedy, Steven Cummings, P Eline Slagboom, Eric Verdin, Andrea B Maier, Vittorio Sebastiano, Michael P Snyder, Vadim N Gladyshev, Steve Horvath, Luigi Ferrucci.
      The search for biomarkers that quantify biological aging (particularly 'omic'-based biomarkers) has intensified in recent years. Such biomarkers could predict aging-related outcomes and could serve as surrogate endpoints for the evaluation of interventions promoting healthy aging and longevity. However, no consensus exists on how biomarkers of aging should be validated before their translation to the clinic. Here, we review current efforts to evaluate the predictive validity of omic biomarkers of aging in population studies, discuss challenges in comparability and generalizability and provide recommendations to facilitate future validation of biomarkers of aging. Finally, we discuss how systematic validation can accelerate clinical translation of biomarkers of aging and their use in gerotherapeutic clinical trials.
    DOI:  https://doi.org/10.1038/s41591-023-02784-9
  43. Int J Cancer. 2024 Feb 14.
    Deposition of onco-histone H3.3-G34W leads to DNA repair deficiency and activates cGAS/STING-mediated immune responses.
    Daniela Mancarella, Henrik Ellinghaus, Gianluca Sigismondo, Olivera Veselinov, Alexander Kühn, Ashish Goyal, Mark Hartmann, Jörg Fellenberg, Jeroen Krijgsveld, Christoph Plass, Odilia Popanda, Peter Schmezer, Ali Bakr.
      Mutations in histone H3.3-encoding genes causing mutant histone tails are associated with specific cancers such as pediatric glioblastomas (H3.3-G34R/V) and giant cell tumor of the bone (H3.3-G34W). The mechanisms by which these mutations promote malignancy are not completely understood. Here we show that cells expressing H3.3-G34W exhibit DNA double-strand breaks (DSBs) repair defects and increased cellular sensitivity to ionizing radiation (IR). Mechanistically, H3.3-G34W can be deposited to damaged chromatin, but in contrast to wild-type H3.3, does not interact with non-homologous end-joining (NHEJ) key effectors KU70/80 and XRCC4 leading to NHEJ deficiency. Together with defective cell cycle checkpoints reported previously, this DNA repair deficiency in H3.3-G34W cells led to accumulation of micronuclei and cytosolic DNA following IR, which subsequently led to activation of the cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) pathway, thereby inducing release of immune-stimulatory cytokines. These findings suggest a potential for radiotherapy for tumors expressing H3.3-G34W, which can be further improved by combination with STING agonists to induce immune-mediated therapeutic efficacy.
    Keywords:  DNA repair; H3.3-G34W; cGAS/STING-mediated immune responses; radiation
    DOI:  https://doi.org/10.1002/ijc.34883
  44. Nat Commun. 2024 Feb 15. 15(1): 1391
    Adipocyte p53 coordinates the response to intermittent fasting by regulating adipose tissue immune cell landscape.
    Isabel Reinisch, Helene Michenthaler, Alba Sulaj, Elisabeth Moyschewitz, Jelena Krstic, Markus Galhuber, Ruonan Xu, Zina Riahi, Tongtong Wang, Nemanja Vujic, Melina Amor, Riccardo Zenezini Chiozzi, Martin Wabitsch, Dagmar Kolb, Anastasia Georgiadi, Lisa Glawitsch, Ellen Heitzer, Tim J Schulz, Michael Schupp, Wenfei Sun, Hua Dong, Adhideb Ghosh, Anne Hoffmann, Dagmar Kratky, Laura C Hinte, Ferdinand von Meyenn, Albert J R Heck, Matthias Blüher, Stephan Herzig, Christian Wolfrum, Andreas Prokesch.
      In obesity, sustained adipose tissue (AT) inflammation constitutes a cellular memory that limits the effectiveness of weight loss interventions. Yet, the impact of fasting regimens on the regulation of AT immune infiltration is still elusive. Here we show that intermittent fasting (IF) exacerbates the lipid-associated macrophage (LAM) inflammatory phenotype of visceral AT in obese mice. Importantly, this increase in LAM abundance is strongly p53 dependent and partly mediated by p53-driven adipocyte apoptosis. Adipocyte-specific deletion of p53 prevents LAM accumulation during IF, increases the catabolic state of adipocytes, and enhances systemic metabolic flexibility and insulin sensitivity. Finally, in cohorts of obese/diabetic patients, we describe a p53 polymorphism that links to efficacy of a fasting-mimicking diet and that the expression of p53 and TREM2 in AT negatively correlates with maintaining weight loss after bariatric surgery. Overall, our results demonstrate that p53 signalling in adipocytes dictates LAM accumulation in AT under IF and modulates fasting effectiveness in mice and humans.
    DOI:  https://doi.org/10.1038/s41467-024-45724-y
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