bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2023–10–22
forty-one papers selected by
Christian Frezza, Universität zu Köln
  1. Dissecting the cellular states and fates of shed mouse intestinal cells.
  2. Cancer Metabolism under Limiting Oxygen Conditions.
  3. mtFociCounter for automated single-cell mitochondrial nucleoid quantification and reproducible foci analysis.
  4. Long-term super-resolution inner mitochondrial membrane imaging with a lipid probe.
  5. Contact sites between host organelles and pathogens: boon or bane?
  6. Monitoring metabolic changes during the menstrual cycle.
  7. Aspirin reprogrammes colorectal cancer cell metabolism and sensitises to glutaminase inhibition.
  8. Dietary fructose-mediated adipocyte metabolism drives antitumor CD8+ T cell responses.
  9. Aspartyl-tRNA synthetase 2 orchestrates iron-sulfur metabolism in hematopoietic stem cells via fine-tuning alternative RNA splicing.
  10. FDX1 is required for the biogenesis of mitochondrial cytochrome c oxidase in mammalian cells.
  11. Nutritional and metabolic control of germ cell fate through O-GlcNAc regulation.
  12. On a sugar high: Role of O-GlcNAcylation in Cancer.
  13. Mitochondria-lysosome-related organelles mediate mitochondrial clearance during cellular dedifferentiation.
  14. An intact pituitary vasopressin system is critical for building a robust circadian clock in the suprachiasmatic nucleus.
  15. A guide to studying mitochondria transfer.
  16. Identification of hyperoxidized PRDX3 as a ferroptosis marker reveals ferroptotic damage in chronic liver diseases.
  17. Control of mitochondrial dynamics by a fusogenic lipid.
  18. Female advantage in neoadjuvant pancreatic cancer therapy: is it down to macrophages?
  19. Mitochondrial metabolism in Drosophila macrophage-like cells regulates body growth via modulation of cytokine and insulin signaling.
  20. MANF stimulates autophagy and restores mitochondrial homeostasis to treat autosomal dominant tubulointerstitial kidney disease in mice.
  21. The metabolic control theory: Its development and its application to mitochondrial oxidative phosphorylation.
  22. The cycle that sculpted evolution.
  23. Chromatin compartmentalization regulates the response to DNA damage.
  24. Dormant tumors circumvent tumor-specific adaptive immunity by establishing a Treg-dominated niche via DKK3.
  25. Polyamine metabolism controls B-to-Z DNA transition to orchestrate DNA sensor cGAS activity.
  26. TCA cycle tailoring facilitates optimal growth of proton-pumping NADH dehydrogenase-dependent Escherichia coli.
  27. Metabolic stratification of human breast tumors reveal subtypes of clinical and therapeutic relevance.
  28. Molecular mechanism of glutaminase activation through filamentation and the role of filaments in mitophagy protection.
  29. AI rapidly diagnoses brain tumours during surgery.
  30. Roles of NAD+ in Health and Aging.
  31. TERRA R-loops connect and protect sister telomeres in mitosis.
  32. Single-cell and spatial analyses reveal a tradeoff between murine mammary proliferation and lineage programs associated with endocrine cues.
  33. MAO-SiR is a tool for visualizing the inner workings of mitochondria.
  34. StarD7 deficiency switches on glycolysis and promotes mitophagy flux in C2C12 myoblasts.
  35. O-GlcNAcylation at the center of antitumor immunity.
  36. Exploiting O-GlcNAc transferase promiscuity to dissect site-specific O-GlcNAcylation.
  37. Lactylation of METTL16 promotes cuproptosis via m6A-modification on FDX1 mRNA in gastric cancer.
  38. Delineating a role for methionine metabolism in colorectal cancer.
  39. O-GlcNAcylation regulates neurofilament-light assembly and function and is perturbed by Charcot-Marie-Tooth disease mutations.
  40. Evolutionary dynamics of whole-body regeneration across planarian flatworms.
  41. PAICS ubiquitination recruits UBAP2 to trigger phase separation for purinosome assembly.
  1. Nat Metab. 2023 Oct 20.
    Dissecting the cellular states and fates of shed mouse intestinal cells.
      
    DOI:  https://doi.org/10.1038/s42255-023-00907-7
  2. Cold Spring Harb Perspect Med. 2023 Oct 17. pii: a041542. [Epub ahead of print]
    Cancer Metabolism under Limiting Oxygen Conditions.
    Laura C Kim, Nicholas P Lesner, M Celeste Simon.
      Molecular oxygen (O2) is essential for cellular bioenergetics and numerous biochemical reactions necessary for life. Solid tumors outgrow the native blood supply and diffusion limits of O2, and therefore must engage hypoxia response pathways that evolved to withstand acute periods of low O2 Hypoxia activates coordinated gene expression programs, primarily through hypoxia inducible factors (HIFs), to support survival. Many of these changes involve metabolic rewiring such as increasing glycolysis to support ATP generation while suppressing mitochondrial metabolism. Since low O2 is often coupled with nutrient stress in the tumor microenvironment, other responses to hypoxia include activation of nutrient uptake pathways, metabolite scavenging, and regulation of stress and growth signaling cascades. Continued development of models that better recapitulate tumors and their microenvironments will lead to greater understanding of oxygen-dependent metabolic reprogramming and lead to more effective cancer therapies.
    DOI:  https://doi.org/10.1101/cshperspect.a041542
  3. Nucleic Acids Res. 2023 Oct 18. pii: gkad864. [Epub ahead of print]
    mtFociCounter for automated single-cell mitochondrial nucleoid quantification and reproducible foci analysis.
    Timo Rey, Luis Carlos Tábara, Julien Prudent, Michal Minczuk.
      Mitochondrial DNA (mtDNA) encodes the core subunits for OXPHOS, essential in near-all eukaryotes. Packed into distinct foci (nucleoids) inside mitochondria, the number of mtDNA copies differs between cell-types and is affected in several human diseases. Currently, common protocols estimate per-cell mtDNA-molecule numbers by sequencing or qPCR from bulk samples. However, this does not allow insight into cell-to-cell heterogeneity and can mask phenotypical sub-populations. Here, we present mtFociCounter, a single-cell image analysis tool for reproducible quantification of nucleoids and other foci. mtFociCounter is a light-weight, open-source freeware and overcomes current limitations to reproducible single-cell analysis of mitochondrial foci. We demonstrate its use by analysing 2165 single fibroblasts, and observe a large cell-to-cell heterogeneity in nucleoid numbers. In addition, mtFociCounter quantifies mitochondrial content and our results show good correlation (R = 0.90) between nucleoid number and mitochondrial area, and we find nucleoid density is less variable than nucleoid numbers in wild-type cells. Finally, we demonstrate mtFociCounter readily detects differences in foci-numbers upon sample treatment, and applies to Mitochondrial RNA Granules and superresolution microscopy. mtFociCounter provides a versatile solution to reproducibly quantify cellular foci in single cells and our results highlight the importance of accounting for cell-to-cell variance and mitochondrial context in mitochondrial foci analysis.
    DOI:  https://doi.org/10.1093/nar/gkad864
  4. Nat Chem Biol. 2023 Oct 19.
    Long-term super-resolution inner mitochondrial membrane imaging with a lipid probe.
    Shuai Zheng, Neville Dadina, Deepto Mozumdar, Lauren Lesiak, Kayli N Martinez, Evan W Miller, Alanna Schepartz.
      The inner mitochondrial membrane (IMM) generates power to drive cell function, and its dynamics control mitochondrial health and cellular homeostasis. Here, we describe the cell-permeant, lipid-like small molecule MAO-N3 and use it to assemble high-density environmentally sensitive (HIDE) probes that selectively label and image the IMM in live cells and multiple cell states. MAO-N3 pairs with strain-promoted azide-alkyne click chemistry-reactive fluorophores to support HIDE imaging using confocal, structured illumination, single-molecule localization and stimulated emission depletion microscopy, all with significantly improved resistance to photobleaching. These probes generate images with excellent spatial and temporal resolution, require no genetic manipulations, are non-toxic in model cell lines and primary cardiomyocytes (even under conditions that amplify the effects of mitochondrial toxins) and can visualize mitochondrial dynamics for 12.5 h. This probe will enable comprehensive studies of IMM dynamics with high temporal and spatial resolution.
    DOI:  https://doi.org/10.1038/s41589-023-01450-y
  5. mSphere. 2023 Oct 18. e0044823
    Contact sites between host organelles and pathogens: boon or bane?
    Chahat Mehra, Lena Pernas.
      A microbe and its host are in constant communication. An emerging platform for direct communication is the membrane contact sites that form between several pathogens and host organelles. Here, we review our progress on the molecular mechanisms underlying contact sites between host mitochondria and the human parasite Toxoplasma gondii. We discuss open questions regarding their function during infection as well as those formed between the host endoplasmic reticulum and Toxoplasma.
    Keywords:  Toxoplasma gondii; endoplasmic reticulum; membrane; membrane contact sites; mitochondria; pathogens
    DOI:  https://doi.org/10.1128/msphere.00448-23
  6. Nat Med. 2023 Oct 17.
    Monitoring metabolic changes during the menstrual cycle.
    Sonia Muliyil.
      
    Keywords:  Brain; Metabolism
    DOI:  https://doi.org/10.1038/d41591-023-00090-y
  7. Cancer Metab. 2023 Oct 19. 11(1): 18
    Aspirin reprogrammes colorectal cancer cell metabolism and sensitises to glutaminase inhibition.
    Amy K Holt, Arafath K Najumudeen, Tracey J Collard, Hao Li, Laura M Millett, Ashley J Hoskin, Danny N Legge, Eleanor M H Mortensson, Dustin J Flanagan, Nicholas Jones, Madhu Kollareddy, Penny Timms, Matthew D Hitchings, James Cronin, Owen J Sansom, Ann C Williams, Emma E Vincent.
       BACKGROUND: To support proliferation and survival within a challenging microenvironment, cancer cells must reprogramme their metabolism. As such, targeting cancer cell metabolism is a promising therapeutic avenue. However, identifying tractable nodes of metabolic vulnerability in cancer cells is challenging due to their metabolic plasticity. Identification of effective treatment combinations to counter this is an active area of research. Aspirin has a well-established role in cancer prevention, particularly in colorectal cancer (CRC), although the mechanisms are not fully understood.
    METHODS: We generated a model to investigate the impact of long-term (52 weeks) aspirin exposure on CRC cells, which has allowed us comprehensively characterise the metabolic impact of long-term aspirin exposure (2-4mM for 52 weeks) using proteomics, Seahorse Extracellular Flux Analysis and Stable Isotope Labelling (SIL). Using this information, we were able to identify nodes of metabolic vulnerability for further targeting, investigating the impact of combining aspirin with metabolic inhibitors in vitro and in vivo.
    RESULTS: We show that aspirin regulates several enzymes and transporters of central carbon metabolism and results in a reduction in glutaminolysis and a concomitant increase in glucose metabolism, demonstrating reprogramming of nutrient utilisation. We show that aspirin causes likely compensatory changes that render the cells sensitive to the glutaminase 1 (GLS1) inhibitor-CB-839. Of note given the clinical interest, treatment with CB-839 alone had little effect on CRC cell growth or survival. However, in combination with aspirin, CB-839 inhibited CRC cell proliferation and induced apoptosis in vitro and, importantly, reduced crypt proliferation in Apcfl/fl mice in vivo.
    CONCLUSIONS: Together, these results show that aspirin leads to significant metabolic reprogramming in colorectal cancer cells and raises the possibility that aspirin could significantly increase the efficacy of metabolic cancer therapies in CRC.
    Keywords:  Aspirin; CB-839; Colorectal cancer; Glutaminase; Metabolic reprogramming; Metabolism
    DOI:  https://doi.org/10.1186/s40170-023-00318-y
  8. Cell Metab. 2023 Oct 15. pii: S1550-4131(23)00367-4. [Epub ahead of print]
    Dietary fructose-mediated adipocyte metabolism drives antitumor CD8+ T cell responses.
    Yuerong Zhang, Xiaoyan Yu, Rujuan Bao, Haiyan Huang, Chuanjia Gu, Qianming Lv, Qiaoqiao Han, Xian Du, Xu-Yun Zhao, Youqiong Ye, Ren Zhao, Jiayuan Sun, Qiang Zou.
      Fructose consumption is associated with tumor growth and metastasis in mice, yet its impact on antitumor immune responses remains unclear. Here, we show that dietary fructose modulates adipocyte metabolism to enhance antitumor CD8+ T cell immune responses and control tumor growth. Transcriptional profiling of tumor-infiltrating CD8+ T cells reveals that dietary fructose mediates attenuated transition of CD8+ T cells to terminal exhaustion, leading to a superior antitumor efficacy. High-fructose feeding initiates adipocyte-derived leptin production in an mTORC1-dependent manner, thereby triggering leptin-boosted antitumor CD8+ T cell responses. Importantly, high plasma leptin levels are correlated with elevated plasma fructose concentrations and improved antitumor CD8+ T cell responses in patients with lung cancer. Our study characterizes a critical role for dietary fructose in shaping adipocyte metabolism to prime antitumor CD8+ T cell responses and highlights that the fructose-leptin axis may be harnessed for cancer immunotherapy.
    Keywords:  adipocyte metabolism; antitumor CD8(+) T cell responses; dietary fructose; mTORC1
    DOI:  https://doi.org/10.1016/j.cmet.2023.09.011
  9. Cell Rep. 2023 Oct 13. pii: S2211-1247(23)01276-7. [Epub ahead of print]42(10): 113264
    Aspartyl-tRNA synthetase 2 orchestrates iron-sulfur metabolism in hematopoietic stem cells via fine-tuning alternative RNA splicing.
    Xuan Gu, Kailing Li, Meng Zhang, Yandan Chen, Jingchao Zhou, Chunxu Yao, Yong Zang, Jiefeng He, Jun Wan, Bin Guo.
      Aspartyl-tRNA synthetase 2 (Dars2) is involved in the regulation of mitochondrial protein synthesis and tissue-specific mitochondrial unfolded protein response (UPRmt). The role of Dars2 in the self-renewal and differentiation of hematopoietic stem cells (HSCs) is unknown. Here, we show that knockout (KO) of Dars2 significantly impairs the maintenance of hematopoietic stem and progenitor cells (HSPCs) without involving its tRNA synthetase activity. Dars2 KO results in significantly reduced expression of Srsf2/3/6 and impairs multiple events of mRNA alternative splicing (AS). Dars2 directly localizes to Srsf3-labeled spliceosomes in HSPCs and regulates the stability of Srsf3. Dars2-deficient HSPCs exhibit aberrant AS of mTOR and Slc22a17. Dars2 KO greatly suppresses the levels of labile ferrous iron and iron-sulfur cluster-containing proteins, which dampens mitochondrial metabolic activity and DNA damage repair pathways in HSPCs. Our study reveals that Dars2 plays a crucial role in the iron-sulfur metabolism and maintenance of HSPCs by modulating RNA splicing.
    Keywords:  CP: Metabolism; CP: Stem cell research
    DOI:  https://doi.org/10.1016/j.celrep.2023.113264
  10. J Mol Biol. 2023 Oct 17. pii: S0022-2836(23)00428-X. [Epub ahead of print] 168317
    FDX1 is required for the biogenesis of mitochondrial cytochrome c oxidase in mammalian cells.
    Mohammad Zulkifli, Adriana U Okonkwo, Vishal M Gohil.
      Ferredoxins (FDXs) are evolutionarily conserved iron-sulfur (Fe-S) proteins that function as electron transfer proteins in diverse metabolic pathways. Mammalian mitochondria contain two ferredoxins, FDX1 and FDX2, which share a high degree of structural similarity but exhibit different functionalities. Previous studies have established the unique role of FDX2 in the biogenesis of Fe-S clusters; however, FDX1 seems to have multiple targets in vivo, some of which are only recently emerging. Using CRISPR-Cas9-based loss-of-function studies in rat cardiomyocyte cell line, we demonstrate an essential requirement of FDX1 in mitochondrial respiration and energy production. We attribute reduced mitochondrial respiration to a specific decrease in the abundance and assembly of cytochrome c oxidase (CcO), a mitochondrial heme-copper oxidase and the terminal enzyme of the mitochondrial respiratory chain. FDX1 knockout cells have reduced levels of copper and heme a/a3, factors that are essential for the maturation of the CcO enzyme complex. Copper supplementation failed to rescue CcO biogenesis, but overexpression of heme a synthase, COX15, partially rescued COX1 abundance in FDX1 knockouts. This finding links FDX1 function to heme a biosynthesis, and places it upstream of COX15 in CcO biogenesis like its ancestral yeast homolog. Taken together, our work has identified FDX1 as a critical CcO biogenesis factor in mammalian cells.
    Keywords:  COX1; Copper; Heme a; Mitochondria; respiration
    DOI:  https://doi.org/10.1016/j.jmb.2023.168317
  11. EMBO Rep. 2023 Oct 16. e56845
    Nutritional and metabolic control of germ cell fate through O-GlcNAc regulation.
    Yohei Hayashi, Yukiko Tando, Yumi Ito-Matsuoka, Kaho Ikuta, Asuka Takehara, Katsutaro Morino, Hiroshi Maegawa, Yasuhisa Matsui.
      Fate determination of primordial germ cells (PGCs) is regulated in a multi-layered manner, involving signaling pathways, epigenetic mechanisms, and transcriptional control. Chemical modification of macromolecules, including epigenetics, is expected to be closely related with metabolic mechanisms but the detailed molecular machinery linking these two layers remains poorly understood. Here, we show that the hexosamine biosynthetic pathway controls PGC fate determination via O-linked β-N-acetylglucosamine (O-GlcNAc) modification. Consistent with this model, reduction of carbohydrate metabolism via a maternal ketogenic diet that decreases O-GlcNAcylation levels causes repression of PGC formation in vivo. Moreover, maternal ketogenic diet intake until mid-gestation affects the number of ovarian germ cells in newborn pups. Taken together, we show that nutritional and metabolic mechanisms play a previously unappreciated role in PGC fate determination.
    Keywords:  O-GlcNAcylation; germ cells; glucose metabolism; ketogenic diet; maternal nutrition
    DOI:  https://doi.org/10.15252/embr.202356845
  12. J Biol Chem. 2023 Oct 12. pii: S0021-9258(23)02372-4. [Epub ahead of print] 105344
    On a sugar high: Role of O-GlcNAcylation in Cancer.
    Giang Le Minh, Emily M Esquea, Riley G Young, Jessie Huang, Mauricio J Reginato.
      Recent advances in the understanding of the molecular mechanisms underlying cancer progression have led to the development of novel therapeutic targeting strategies. Aberrant glycosylation patterns and their implication in cancer have gained increasing attention as potential targets due to the critical role of glycosylation in regulating tumor-specific pathways that contribute to cancer cell survival, proliferation, and progression. A special type of glycosylation that has been gaining momentum in cancer research is the modification of nuclear, cytoplasmic, and mitochondrial proteins, termed O-GlcNAcylation. This protein modification is catalyzed by an enzyme called O-GlcNAc transferase (OGT), which uses the final product of the Hexosamine Biosynthetic Pathway (HBP) to connect altered nutrient availability to changes in cellular signaling that contribute to multiple aspects of tumor progression. Both O-GlcNAc and its enzyme OGT are highly elevated in cancer and fulfill the crucial role in regulating many hallmarks of cancer. In this review, we present and discuss the latest findings elucidating the involvement of OGT and O-GlcNAc in cancer.
    Keywords:  O-GlcNAc; OGT; cancer; hexosamine; metabolism; metastasis
    DOI:  https://doi.org/10.1016/j.jbc.2023.105344
  13. Cell Rep. 2023 Oct 19. pii: S2211-1247(23)01303-7. [Epub ahead of print]42(10): 113291
    Mitochondria-lysosome-related organelles mediate mitochondrial clearance during cellular dedifferentiation.
    Xiaowen Ma, Sharon Manley, Hui Qian, Yuan Li, Chen Zhang, Kevin Li, Benjamin Ding, Fengli Guo, Allen Chen, Xing Zhang, Meilian Liu, Meihua Hao, Benjamin Kugler, E Matthew Morris, John Thyfault, Ling Yang, Hiromi Sesaki, Hong-Min Ni, Heidi McBride, Wen-Xing Ding.
      Dysfunctional mitochondria are removed via multiple pathways, such as mitophagy, a selective autophagy process. Here, we identify an intracellular hybrid mitochondria-lysosome organelle (termed the mitochondria-lysosome-related organelle [MLRO]), which regulates mitochondrial homeostasis independent of canonical mitophagy during hepatocyte dedifferentiation. The MLRO is an electron-dense organelle that has either a single or double membrane with both mitochondria and lysosome markers. Mechanistically, the MLRO is likely formed from the fusion of mitochondria-derived vesicles (MDVs) with lysosomes through a PARKIN-, ATG5-, and DRP1-independent process, which is negatively regulated by transcription factor EB (TFEB) and associated with mitochondrial protein degradation and hepatocyte dedifferentiation. The MLRO, which is galectin-3 positive, is reminiscent of damaged lysosome and could be cleared by overexpression of TFEB, resulting in attenuation of hepatocyte dedifferentiation. Together, results from this study suggest that the MLRO may act as an alternative mechanism for mitochondrial quality control independent of canonical autophagy/mitophagy involved in cell dedifferentiation.
    Keywords:  ATG5; CP: Cell biology; DRP1; autophagy; hepatocytes; lysosome; mitophagy
    DOI:  https://doi.org/10.1016/j.celrep.2023.113291
  14. Proc Natl Acad Sci U S A. 2023 Oct 24. 120(43): e2308489120
    An intact pituitary vasopressin system is critical for building a robust circadian clock in the suprachiasmatic nucleus.
    Yoshiaki Yamaguchi, Yota Maekawa, Kyohei Kabashima, Takanobu Mizuno, Motomi Tainaka, Toru Suzuki, Kumiko Dojo, Takeichiro Tominaga, Sayaka Kuroiwa, Satoru Masubuchi, Masao Doi, Keiko Tominaga, Kazuto Kobayashi, Satoshi Yamagata, Keiichi Itoi, Manabu Abe, William J Schwartz, Kenji Sakimura, Hitoshi Okamura.
      The circadian clock is a biological timekeeping system that oscillates with a circa-24-h period, reset by environmental timing cues, especially light, to the 24-h day-night cycle. In mammals, a "central" clock in the hypothalamic suprachiasmatic nucleus (SCN) synchronizes "peripheral" clocks throughout the body to regulate behavior, metabolism, and physiology. A key feature of the clock's oscillation is resistance to abrupt perturbations, but the mechanisms underlying such robustness are not well understood. Here, we probe clock robustness to unexpected photic perturbation by measuring the speed of reentrainment of the murine locomotor rhythm after an abrupt advance of the light-dark cycle. Using an intersectional genetic approach, we implicate a critical role for arginine vasopressin pathways, both central within the SCN and peripheral from the anterior pituitary.
    Keywords:  circadian clock; pituitary; suprachiasmatic nucleus; vasopressin
    DOI:  https://doi.org/10.1073/pnas.2308489120
  15. Nat Cell Biol. 2023 Oct 18.
    A guide to studying mitochondria transfer.
    Snigdha Tiash, Jonathan Robert Brestoff, Clair Crewe.
      
    DOI:  https://doi.org/10.1038/s41556-023-01246-1
  16. Mol Cell. 2023 Oct 17. pii: S1097-2765(23)00752-9. [Epub ahead of print]
    Identification of hyperoxidized PRDX3 as a ferroptosis marker reveals ferroptotic damage in chronic liver diseases.
    Shaojie Cui, Anchal Ghai, Yaqin Deng, Shili Li, Ruihui Zhang, Christopher Egbulefu, Guosheng Liang, Samuel Achilefu, Jin Ye.
      Ferroptosis, a regulated cell death pathway driven by accumulation of phospholipid peroxides, has been challenging to identify in physiological conditions owing to the lack of a specific marker. Here, we identify hyperoxidized peroxiredoxin 3 (PRDX3) as a marker for ferroptosis both in vitro and in vivo. During ferroptosis, mitochondrial lipid peroxides trigger PRDX3 hyperoxidation, a posttranslational modification that converts a Cys thiol to sulfinic or sulfonic acid. Once hyperoxidized, PRDX3 translocates from mitochondria to plasma membranes, where it inhibits cystine uptake, thereby causing ferroptosis. Applying hyperoxidized PRDX3 as a marker, we determined that ferroptosis is responsible for death of hepatocytes in mouse models of both alcoholic and nonalcoholic fatty liver diseases, the most prevalent chronic liver disorders. Our study highlights the importance of ferroptosis in pathophysiological conditions and opens the possibility to treat these liver diseases with drugs that inhibit ferroptosis.
    Keywords:  AFLD; NAFLD; PRDX3; cell death marker; ferroptosis; hyperoxidation
    DOI:  https://doi.org/10.1016/j.molcel.2023.09.025
  17. Trends Cell Biol. 2023 Oct 17. pii: S0962-8924(23)00210-6. [Epub ahead of print]
    Control of mitochondrial dynamics by a fusogenic lipid.
    Zheng Yang, David C Chan.
      Mitochondrial fusion enables cooperation between the mitochondrial population and is critical for mitochondrial function. Phosphatidic acid (PA) on the mitochondrial surface has a key role in mitochondrial fusion. A recent study by Su et al. shows that the nucleoside diphosphate (NDP) kinase NME3 recognizes PA and mediates its effects on mitochondrial dynamics.
    Keywords:  membrane fusion; mitochondria; organelle; phospholipid
    DOI:  https://doi.org/10.1016/j.tcb.2023.10.006
  18. Gut. 2023 Oct 09. pii: gutjnl-2023-330830. [Epub ahead of print]
    Female advantage in neoadjuvant pancreatic cancer therapy: is it down to macrophages?
    Patrick Michl, Laura Roth.
      
    Keywords:  CHEMOTHERAPY; MACROPHAGES; PANCREATIC CANCER
    DOI:  https://doi.org/10.1136/gutjnl-2023-330830
  19. Biol Open. 2023 Oct 13. pii: bio.059968. [Epub ahead of print]
    Mitochondrial metabolism in Drosophila macrophage-like cells regulates body growth via modulation of cytokine and insulin signaling.
    Shrivani Sriskanthadevan-Pirahas, Abdul Qadeer Tinwala, Michael J Turingan, Shahoon Khan, Savraj S Grewal.
      Macrophages play critical roles in regulating and maintaining tissue and whole-body metabolism in normal and disease states. While the cell-cell signaling pathways that underlie these functions are becoming clear, less is known about how alterations in macrophage metabolism influence their roles as regulators of systemic physiology. Here, we investigate this by examining Drosophila macrophage-like cells called hemocytes. We used knockdown of TFAM, a mitochondrial genome transcription factor, to reduce mitochondrial OxPhos activity specifically in larval hemocytes. We find that this reduction in hemocyte OxPhos leads to a decrease in larval growth and body size. These effects are associated with a suppression of systemic insulin, the main endocrine stimulator of body growth. We also find that TFAM knockdown leads to decreased hemocyte JNK signaling and decreased expression of the TNF alpha homolog, Eiger in hemocytes. Furthermore, we show that genetic knockdown of hemocyte JNK signaling or Eiger expression mimics the effects of TFAM knockdown and leads to a non-autonomous suppression of body size without altering hemocyte numbers. Our data suggest that modulation of hemocyte mitochondrial metabolism can determine their non-autonomous effects on organismal growth by altering cytokine and systemic insulin signaling. Given that nutrient availability can control mitochondrial metabolism, our findings may explain how macrophages function as nutrient-responsive regulators of tissue and whole-body physiology and homeostasis.
    Keywords:   Drosophila ; Cytokine TNF-α/Eiger; Hemocytes; Insulin signaling; JNK signaling; Metabolism; Mitochondria; OxPhos; Systemic growth; TFAM
    DOI:  https://doi.org/10.1242/bio.059968
  20. Nat Commun. 2023 Oct 14. 14(1): 6493
    MANF stimulates autophagy and restores mitochondrial homeostasis to treat autosomal dominant tubulointerstitial kidney disease in mice.
    Yeawon Kim, Chuang Li, Chenjian Gu, Yili Fang, Eric Tycksen, Anuradhika Puri, Terri A Pietka, Jothilingam Sivapackiam, Kendrah Kidd, Sun-Ji Park, Bryce G Johnson, Stanislav Kmoch, Jeremy S Duffield, Anthony J Bleyer, Meredith E Jackrel, Fumihiko Urano, Vijay Sharma, Maria Lindahl, Ying Maggie Chen.
      Misfolded protein aggregates may cause toxic proteinopathy, including autosomal dominant tubulointerstitial kidney disease due to uromodulin mutations (ADTKD-UMOD), a leading hereditary kidney disease. There are no targeted therapies. In our generated mouse model recapitulating human ADTKD-UMOD carrying a leading UMOD mutation, we show that autophagy/mitophagy and mitochondrial biogenesis are impaired, leading to cGAS-STING activation and tubular injury. Moreover, we demonstrate that inducible tubular overexpression of mesencephalic astrocyte-derived neurotrophic factor (MANF), a secreted endoplasmic reticulum protein, after the onset of disease stimulates autophagy/mitophagy, clears mutant UMOD, and promotes mitochondrial biogenesis through p-AMPK enhancement, thus protecting kidney function in our ADTKD mouse model. Conversely, genetic ablation of MANF in the mutant thick ascending limb tubular cells worsens autophagy suppression and kidney fibrosis. Together, we have discovered MANF as a biotherapeutic protein and elucidated previously unknown mechanisms of MANF in the regulation of organelle homeostasis, which may have broad therapeutic applications to treat various proteinopathies.
    DOI:  https://doi.org/10.1038/s41467-023-42154-0
  21. Biosystems. 2023 Oct 12. pii: S0303-2647(23)00213-7. [Epub ahead of print] 105038
    The metabolic control theory: Its development and its application to mitochondrial oxidative phosphorylation.
    Jean-Pierre Mazat.
      Metabolic Control Theory (MCT) and Metabolic Control Analysis (MCA) are the two sides, theoretical and experimental, of the measurement of the sensitivity of metabolic networks in the vicinity of a steady state. We will describe the birth and the development of this theory from the first analyses of linear pathways up to a global mathematical theory applicable to any metabolic network. We will describe how the theory, given the global nature of mitochondrial oxidative phosphorylation, solved the problem of what controls mitochondrial ATP synthesis and then how it led to a better understanding of the differential tissue expression of human mitochondrial pathologies and of the heteroplasmy of mitochondrial DNA, leading to the concept of the threshold effect.
    Keywords:  Metabolic control analysis; Metabolic control theory; Mitochondrial diseases; Oxidative phoshorylation
    DOI:  https://doi.org/10.1016/j.biosystems.2023.105038
  22. Nat Rev Chem. 2023 Oct 18.
    The cycle that sculpted evolution.
    Markus Ralser.
      
    DOI:  https://doi.org/10.1038/s41570-023-00545-3
  23. Nature. 2023 Oct 18.
    Chromatin compartmentalization regulates the response to DNA damage.
    Coline Arnould, Vincent Rocher, Florian Saur, Aldo S Bader, Fernando Muzzopappa, Sarah Collins, Emma Lesage, Benjamin Le Bozec, Nadine Puget, Thomas Clouaire, Thomas Mangeat, Raphael Mourad, Nadav Ahituv, Daan Noordermeer, Fabian Erdel, Martin Bushell, Aline Marnef, Gaëlle Legube.
      The DNA damage response is essential to safeguard genome integrity. Although the contribution of chromatin in DNA repair has been investigated1,2, the contribution of chromosome folding to these processes remains unclear3. Here we report that, after the production of double-stranded breaks (DSBs) in mammalian cells, ATM drives the formation of a new chromatin compartment (D compartment) through the clustering of damaged topologically associating domains, decorated with γH2AX and 53BP1. This compartment forms by a mechanism that is consistent with polymer-polymer phase separation rather than liquid-liquid phase separation. The D compartment arises mostly in G1 phase, is independent of cohesin and is enhanced after pharmacological inhibition of DNA-dependent protein kinase (DNA-PK) or R-loop accumulation. Importantly, R-loop-enriched DNA-damage-responsive genes physically localize to the D compartment, and this contributes to their optimal activation, providing a function for DSB clustering in the DNA damage response. However, DSB-induced chromosome reorganization comes at the expense of an increased rate of translocations, also observed in cancer genomes. Overall, we characterize how DSB-induced compartmentalization orchestrates the DNA damage response and highlight the critical impact of chromosome architecture in genomic instability.
    DOI:  https://doi.org/10.1038/s41586-023-06635-y
  24. JCI Insight. 2023 Oct 17. pii: e174458. [Epub ahead of print]
    Dormant tumors circumvent tumor-specific adaptive immunity by establishing a Treg-dominated niche via DKK3.
    Timothy N Trotter, Carina E Dagotto, Delila Serra, Tao Wang, Xiao Yang, Chaitanya R Acharya, Junping Wei, Gangjun Lei, Herbert Kim Lyerly, Zachary C Hartman.
      Approximately 30% of breast cancer survivors deemed 'free of disease' will experience locoregional or metastatic recurrence even up to 30 years post initial diagnosis, yet how residual/dormant tumor cells escape immunity elicited by the primary tumor remains unclear. We demonstrate that intrinsically dormant tumor cells are indeed recognized and lysed by antigen-specific T cells in vitro and elicit robust immune responses in vivo. However, despite close proximity to CD8+ killer T cells, dormant tumor cells themselves support early accumulation of protective FoxP3+ T regulatory cells (Tregs), which can be targeted to reduce tumor burden. These intrinsically dormant tumor cells maintain a hybrid epithelial/mesenchymal state which is associated with immune dysfunction, and we find the tumor-derived stem/basal gene Dickkopf WNT Signaling Pathway Inhibitor 3 (DKK3) is critical for Treg inhibition of CD8+ T cells. We also demonstrate that DKK3 promotes immune-mediated progression of proliferative tumors and is significantly associated with poor survival and immune suppression in human breast cancers. Together, these findings reveal that latent tumors can use fundamental mechanisms of tolerance to alter the T cell microenvironment and subvert immune detection. Thus, targeting these pathways, such as DKK3, may help render dormant tumors susceptible to immunotherapies.
    Keywords:  Breast cancer; Cancer immunotherapy; Immunology; Oncology
    DOI:  https://doi.org/10.1172/jci.insight.174458
  25. Immunity. 2023 Oct 08. pii: S1074-7613(23)00417-X. [Epub ahead of print]
    Polyamine metabolism controls B-to-Z DNA transition to orchestrate DNA sensor cGAS activity.
    Chunyuan Zhao, Yunjin Ma, Minghui Zhang, Xiaoyan Gao, Wenbo Liang, Ying Qin, Yue Fu, Mutian Jia, Hui Song, Chengjiang Gao, Wei Zhao.
      Cyclic guanosine monophosphate (GMP)-AMP (cGAMP) synthase (cGAS) is a universal double-stranded DNA (dsDNA) sensor that recognizes foreign and self-DNA in the cytoplasm and initiates innate immune responses and has been implicated in various infectious and non-infectious contexts. cGAS binds to the backbone of dsDNA and generates the second messenger, cGAMP, which activates the stimulator of interferon genes (STING). Here, we show that the endogenous polyamines spermine and spermidine attenuated cGAS activity and innate immune responses. Mechanistically, spermine and spermidine induced the transition of B-form DNA to Z-form DNA (Z-DNA), thereby decreasing its binding affinity with cGAS. Spermidine/spermine N1-acetyltransferase 1 (SAT1), the rate-limiting enzyme in polyamine catabolism that decreases the cellular concentrations of spermine and spermidine, enhanced cGAS activation by inhibiting cellular Z-DNA accumulation; SAT1 deficiency promoted herpes simplex virus 1 (HSV-1) replication in vivo. The results indicate that spermine and spermidine induce dsDNA to adopt the Z-form conformation and that SAT1-mediated polyamine metabolism orchestrates cGAS activity.
    Keywords:  B-DNA; Z-DNA; cGAS; innate immunity; polyamine metabolism; spermidine; spermine; type I IFNs
    DOI:  https://doi.org/10.1016/j.immuni.2023.09.012
  26. Microbiol Spectr. 2023 Oct 19. e0222523
    TCA cycle tailoring facilitates optimal growth of proton-pumping NADH dehydrogenase-dependent Escherichia coli.
    Nikita Goel, Stuti Srivastav, Arjun Patel, Akshay Shirsath, Tushar Ranjan Panda, Malay Patra, Adam M Feist, Amitesh Anand.
      The bacterial lifestyle is plastic, requiring transcriptional, translational, and metabolic tailoring for survival. These dynamic cellular processes are energy intensive; therefore, flexible energetics is requisite for adaptive plasticity. An intricate network of complementary and supplementary pathways exists in bacterial energy metabolism. There are two main entry points for electrons in the aerobic electron transport system, NADH dehydrogenase (NDH) and succinate dehydrogenase (SDH), receiving electrons from NADH and succinate, respectively. Aerobic bacterial phyla have a non-proton-pumping NADH dehydrogenase, which is often the primary dehydrogenase under aerobiosis. Here, we report adaptive changes supporting growth restoration in an Escherichia coli strain lacking the primary dehydrogenase. Growth optimization is achieved by reducing the activity of succinate dehydrogenase, and thus we demonstrate a physiological discord between proton-pumping NADH dehydrogenase and succinate dehydrogenase in supporting growth. Beyond the fundamental understanding of the bioenergetic network, identifying this compensatory feature provides impetus to rational antimicrobial combinations for targeting the non-proton-pumping dehydrogenase. IMPORTANCE Energy generation pathways are a potential avenue for the development of novel antibiotics. However, bacteria possess remarkable resilience due to the compensatory pathways, which presents a challenge in this direction. NADH, the primary reducing equivalent, can transfer electrons to two distinct types of NADH dehydrogenases. Type I NADH dehydrogenase is an enzyme complex comprising multiple subunits and can generate proton motive force (PMF). Type II NADH dehydrogenase does not pump protons but plays a crucial role in maintaining the turnover of NAD+. To study the adaptive rewiring of energy metabolism, we evolved an Escherichia coli mutant lacking type II NADH dehydrogenase. We discovered that by modifying the flux through the tricarboxylic acid (TCA) cycle, E. coli could mitigate the growth impairment observed in the absence of type II NADH dehydrogenase. This research provides valuable insights into the intricate mechanisms employed by bacteria to compensate for disruptions in energy metabolism.
    Keywords:  adaptive laboratory evolution; bioenergetics; electron transport; metabolism
    DOI:  https://doi.org/10.1128/spectrum.02225-23
  27. iScience. 2023 Oct 20. 26(10): 108059
    Metabolic stratification of human breast tumors reveal subtypes of clinical and therapeutic relevance.
    Mohammad A Iqbal, Shumaila Siddiqui, Kirk Smith, Prithvi Singh, Bhupender Kumar, Salem Chouaib, Sriram Chandrasekaran.
      Extensive metabolic heterogeneity in breast cancers has limited the deployment of metabolic therapies. To enable patient stratification, we studied the metabolic landscape in breast cancers (∼3000 patients combined) and identified three subtypes with increasing degrees of metabolic deregulation. Subtype M1 was found to be dependent on bile-acid biosynthesis, whereas M2 showed reliance on methionine pathway, and M3 engaged fatty-acid, nucleotide, and glucose metabolism. The extent of metabolic alterations correlated strongly with tumor aggressiveness and patient outcome. This pattern was reproducible in independent datasets and using in vivo tumor metabolite data. Using machine-learning, we identified robust and generalizable signatures of metabolic subtypes in tumors and cell lines. Experimental inhibition of metabolic pathways in cell lines representing metabolic subtypes revealed subtype-specific sensitivity, therapeutically relevant drugs, and promising combination therapies. Taken together, metabolic stratification of breast cancers can thus aid in predicting patient outcome and designing precision therapies.
    Keywords:  Medical informatics; cancer; computational bioinformatics
    DOI:  https://doi.org/10.1016/j.isci.2023.108059
  28. Nat Struct Mol Biol. 2023 Oct 19.
    Molecular mechanism of glutaminase activation through filamentation and the role of filaments in mitophagy protection.
    Douglas Adamoski, Marilia Meira Dias, Jose Edwin Neciosup Quesñay, Zhengyi Yang, Ievgeniia Zagoriy, Anna M Steyer, Camila Tanimoto Rodrigues, Alliny Cristiny da Silva Bastos, Bianca Novaes da Silva, Renna Karoline Eloi Costa, Flávia Mayumi Odahara de Abreu, Zeyaul Islam, Alexandre Cassago, Marin Gerard van Heel, Sílvio Roberto Consonni, Simone Mattei, Julia Mahamid, Rodrigo Villares Portugal, Andre Luis Berteli Ambrosio, Sandra Martha Gomes Dias.
      Glutaminase (GLS), which deaminates glutamine to form glutamate, is a mitochondrial tetrameric protein complex. Although inorganic phosphate (Pi) is known to promote GLS filamentation and activation, the molecular basis of this mechanism is unknown. Here we aimed to determine the molecular mechanism of Pi-induced mouse GLS filamentation and its impact on mitochondrial physiology. Single-particle cryogenic electron microscopy revealed an allosteric mechanism in which Pi binding at the tetramer interface and the activation loop is coupled to direct nucleophile activation at the active site. The active conformation is prone to enzyme filamentation. Notably, human GLS filaments form inside tubulated mitochondria following glutamine withdrawal, as shown by in situ cryo-electron tomography of cells thinned by cryo-focused ion beam milling. Mitochondria with GLS filaments exhibit increased protection from mitophagy. We reveal roles of filamentous GLS in mitochondrial morphology and recycling.
    DOI:  https://doi.org/10.1038/s41594-023-01118-0
  29. Nature. 2023 Oct 17.
    AI rapidly diagnoses brain tumours during surgery.
    Lissa C Baird.
      
    Keywords:  Cancer; Medical research
    DOI:  https://doi.org/10.1038/d41586-023-03072-9
  30. Cold Spring Harb Perspect Med. 2023 Oct 17. pii: a041193. [Epub ahead of print]
    Roles of NAD+ in Health and Aging.
    Sofie Lautrup, Yujun Hou, Evandro F Fang, Vilhelm A Bohr.
      NAD+, the essential metabolite involved in multiple reactions such as the regulation of cellular metabolism, energy production, DNA repair, mitophagy and autophagy, inflammation, and neuronal function, has been the subject of intense research in the field of aging and disease over the last decade. NAD+ levels decline with aging and in some age-related diseases, and reduction in NAD+ affects all the hallmarks of aging. Here, we present an overview of the discovery of NAD+, the cellular pathways of producing and consuming NAD+, and discuss how imbalances in the production rate and cellular request of NAD+ likely contribute to aging and age-related diseases including neurodegeneration. Preclinical studies have revealed great potential for NAD+ precursors in promotion of healthy aging and improvement of neurodegeneration. This has led to the initiation of several clinical trials with NAD+ precursors to treat accelerated aging, age-associated dysfunctions, and diseases including Alzheimer's and Parkinson's. NAD supplementation has great future potential clinically, and these studies will also provide insight into the mechanisms of aging.
    DOI:  https://doi.org/10.1101/cshperspect.a041193
  31. Cell Rep. 2023 Oct 14. pii: S2211-1247(23)01247-0. [Epub ahead of print]42(10): 113235
    TERRA R-loops connect and protect sister telomeres in mitosis.
    Samantha Sze, Amit Bhardwaj, Priyanka Fnu, Kameron Azarm, Rachel Mund, Katherine Ring, Susan Smith.
      Resolution of cohesion between sister telomeres in human cells depends on TRF1-mediated recruitment of the polyADP-ribosyltransferase tankyrase to telomeres. In human aged cells, due to insufficient recruitment of TRF1/tankyrase to shortened telomeres, sisters remain cohered in mitosis. This persistent cohesion plays a protective role, but the mechanism by which sisters remain cohered is not well understood. Here we show that telomere repeat-containing RNA (TERRA) holds sister telomeres together through RNA-DNA hybrid (R-loop) structures. We show that a tankyrase-interacting partner, the RNA-binding protein C19orf43, is required for repression of TERRA R-loops. Persistent telomere cohesion in C19orf43-depleted cells is counteracted by RNaseH1, confirming that RNA-DNA hybrids hold sisters together. Consistent with a protective role for persistent telomere cohesion, depletion of C19orf43 in aged cells reduces DNA damage and delays replicative senescence. We propose that the inherent inability of shortened telomeres to recruit R-loop-repressing machinery permits a controlled onset of senescence.
    Keywords:  C19orf43; CP: Molecular biology; R-Loops; RNA-DNA hybrids; RNaseH; TERRA; TRF1; cohesion; senescence; tankyrase; telomeres
    DOI:  https://doi.org/10.1016/j.celrep.2023.113235
  32. Cell Rep. 2023 Oct 17. pii: S2211-1247(23)01305-0. [Epub ahead of print]42(10): 113293
    Single-cell and spatial analyses reveal a tradeoff between murine mammary proliferation and lineage programs associated with endocrine cues.
    G Kenneth Gray, Nomeda Girnius, Hendrik J Kuiken, Aylin Z Henstridge, Joan S Brugge.
      Although distinct epithelial cell types have been distinguished in glandular tissues such as the mammary gland, the extent of heterogeneity within each cell type and the degree of endocrine control of this diversity across development are incompletely understood. By combining mass cytometry and cyclic immunofluorescence, we define a rich array of murine mammary epithelial cell subtypes associated with puberty, the estrous cycle, and sex. These subtypes are differentially proliferative and spatially segregate distinctly in adult versus pubescent glands. Further, we identify systematic suppression of lineage programs at the protein and RNA levels as a common feature of mammary epithelial expansion during puberty, the estrous cycle, and gestation and uncover a pervasive enrichment of ribosomal protein genes in luminal cells elicited specifically during progesterone-dominant expansionary periods. Collectively, these data expand our knowledge of murine mammary epithelial heterogeneity and connect endocrine-driven epithelial expansion with lineage suppression.
    Keywords:  CP: Cancer; CP: Developmental biology; cell heterogeneity; cyclic immunofluorescence; mammary gland; mass cytometry; puberty
    DOI:  https://doi.org/10.1016/j.celrep.2023.113293
  33. Nat Chem Biol. 2023 Oct 20.
    MAO-SiR is a tool for visualizing the inner workings of mitochondria.
      
    DOI:  https://doi.org/10.1038/s41589-023-01451-x
  34. FEBS J. 2023 Oct 16.
    StarD7 deficiency switches on glycolysis and promotes mitophagy flux in C2C12 myoblasts.
    María L Rojas, Juan Pablo Muñoz, Jésica Flores-Martín, Paula Sànchez-Fernàndez-de-Landa, Mariano Cruz Del Puerto, Susana Genti-Raimondi, Antonio Zorzano.
      StarD7 is a member of the START protein family required for phosphatidylcholine delivery to the mitochondria, thus key to maintain mitochondrial structure. Its deficiency has been associated with an impairment of cellular processes, such as proliferation and migration, and it has also been reported that it is needed in myogenic differentiation. Here, we show that StarD7 deficiency in C2C12 muscle cells results in the accumulation of abnormal mitochondria, a reduced number of mitochondria per cell area and increased glycolysis. In addition, StarD7-deficient cells undergo an increase in mitochondria-ER contact sites, reduced connexin 43 expression, and disturbances in lipid handling, evidenced by lipid droplet accumulation and decreased levels in phosphatidylserine synthase 1 and 2 expression. Interestingly, StarD7-deficient cells showed alterations in mitophagy markers. We observed accumulation of LC3B-II and BNIP3 proteins in mitochondria-enriched fractions and accumulation of autophagolysosomal and lysosomal vesicles in StarD7-deficient cells. Furthermore, live-cell imaging experiments of StarD7 knockdown cells expressing mitochondria-targeted mKeima indicated an enhanced mitochondria delivery into lysosomes. Importantly, StarD7 reconstitution in StarD7-deficient cells restores LC3B-II expression in mitochondria-enriched fractions at similar levels to those observed in control cells. Collectively, these findings suggest that StarD7-deficient C2C12 myoblasts are associated with altered cristae structure, disturbances in neutral lipid accumulation, glucose metabolism, and increased mitophagy flux. The alterations mentioned above allow for the maintenance of mitochondrial function.
    Keywords:  StarD7; cristae morphology; lipid droplet; mitophagy
    DOI:  https://doi.org/10.1111/febs.16979
  35. Curr Opin Biotechnol. 2023 Oct 18. pii: S0958-1669(23)00119-2. [Epub ahead of print]84 103009
    O-GlcNAcylation at the center of antitumor immunity.
    Graham A Heieis, Bart Everts.
      The post-translational modification known as O-GlcNAcylation is a highly dysregulated process in tumors, and a key contributor to malignant transformation. In contrast, after three decades since its discovery, very little has been revealed about this process in the immune system. With the prospect of targeting O-GlcNAcylation as tumor therapy, greater understanding of how it regulates immune responses in the context of the tumor microenvironment will be needed. Here, we discuss recent discoveries from which a picture is emerging that O-GlcNAcylation, in either tumors or in immune cells, could negatively impact overall antitumor immune responses. We propose that interference with O-GlcNAcylation thus holds promise for cancer treatment from both perspectives.
    DOI:  https://doi.org/10.1016/j.copbio.2023.103009
  36. Glycobiology. 2023 Oct 19. pii: cwad086. [Epub ahead of print]
    Exploiting O-GlcNAc transferase promiscuity to dissect site-specific O-GlcNAcylation.
    Conor W Mitchell, Sergio Galan Bartual, Andrew T Ferenbach, Carsten Scavenius, Daan M F van Aalten.
      Protein O-GlcNAcylation is an evolutionary conserved post-translational modification catalysed by the nucleocytoplasmic O-GlcNAc transferase (OGT) and reversed by O-GlcNAcase (OGA). How site-specific O-GlcNAcylation modulates a diverse range of cellular processes is largely unknown. A limiting factor in studying this is the lack of accessible techniques capable of producing homogeneously O-GlcNAcylated proteins, in high yield, for in vitro studies. Here, we exploit the tolerance of OGT for cysteine instead of serine, combined with a co-expressed OGA to achieve site-specific, highly homogeneous mono-glycosylation. Applying this to DDX3X, TAB1, and CK2α, we demonstrate that near-homogeneous mono-S-GlcNAcylation of these proteins promotes DDX3X and CK2α solubility and enables production of mono-S-GlcNAcylated TAB1 crystals, albeit with limited diffraction. Taken together, this work provides a new approach for functional dissection of protein O-GlcNAcylation.
    Keywords:  O-GlcNAc; O-GlcNAc transferase; S-GlcNAc; methodology
    DOI:  https://doi.org/10.1093/glycob/cwad086
  37. Nat Commun. 2023 Oct 20. 14(1): 6523
    Lactylation of METTL16 promotes cuproptosis via m6A-modification on FDX1 mRNA in gastric cancer.
    Lianhui Sun, Yuan Zhang, Boyu Yang, Sijun Sun, Pengshan Zhang, Zai Luo, Tingting Feng, Zelin Cui, Ting Zhu, Yuming Li, Zhengjun Qiu, Guangjian Fan, Chen Huang.
      Cuproptosis, caused by excessively high copper concentrations, is urgently exploited as a potential cancer therapeutic. However, the mechanisms underlying the initiation, propagation, and ultimate execution of cuproptosis in tumors remain unknown. Here, we show that copper content is significantly elevated in gastric cancer (GC), especially in malignant tumors. Screening reveals that METTL16, an atypical methyltransferase, is a critical mediator of cuproptosis through the m6A modification on FDX1 mRNA. Furthermore, copper stress promotes METTL16 lactylation at site K229 followed by cuproptosis. The process of METTL16 lactylation is inhibited by SIRT2. Elevated METTL16 lactylation significantly improves the therapeutic efficacy of the copper ionophore- elesclomol. Combining elesclomol with AGK2, a SIRT2-specific inhibitor, induce cuproptosis in gastric tumors in vitro and in vivo. These results reveal the significance of non-histone protein METTL16 lactylation on cuproptosis in tumors. Given the high copper and lactate concentrations in GC, cuproptosis induction becomes a promising therapeutic strategy for GC.
    DOI:  https://doi.org/10.1038/s41467-023-42025-8
  38. Cancer Res. 2023 Oct 17.
    Delineating a role for methionine metabolism in colorectal cancer.
    Shiyu Liu, Jason W Locasale.
      Advances in mass spectrometry allow for broader applications of metabolomics in research and clinical applications. In a recent issue of Nature Metabolism, Voorde and colleagues utilized metabolite profiling to investigate the metabolism of colorectal cancer (CRC) in mouse models, organoids and patients. This study underscores the utility of metabolomics in distinguishing CRC, offering potential for its use in precision medicine. It also revealed a pivotal role for adenosylhomocysteinase in the methionine cycle and highlighted its potential as a therapeutic target.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-23-3169
  39. Nat Commun. 2023 Oct 17. 14(1): 6558
    O-GlcNAcylation regulates neurofilament-light assembly and function and is perturbed by Charcot-Marie-Tooth disease mutations.
    Duc T Huynh, Kalina N Tsolova, Abigail J Watson, Sai Kwan Khal, Jordan R Green, Di Li, Jimin Hu, Erik J Soderblom, Jen-Tsan Chi, Chantell S Evans, Michael Boyce.
      The neurofilament (NF) cytoskeleton is critical for neuronal morphology and function. In particular, the neurofilament-light (NF-L) subunit is required for NF assembly in vivo and is mutated in subtypes of Charcot-Marie-Tooth (CMT) disease. NFs are highly dynamic, and the regulation of NF assembly state is incompletely understood. Here, we demonstrate that human NF-L is modified in a nutrient-sensitive manner by O-linked-β-N-acetylglucosamine (O-GlcNAc), a ubiquitous form of intracellular glycosylation. We identify five NF-L O-GlcNAc sites and show that they regulate NF assembly state. NF-L engages in O-GlcNAc-mediated protein-protein interactions with itself and with the NF component α-internexin, implying that O-GlcNAc may be a general regulator of NF architecture. We further show that NF-L O-GlcNAcylation is required for normal organelle trafficking in primary neurons. Finally, several CMT-causative NF-L mutants exhibit perturbed O-GlcNAc levels and resist the effects of O-GlcNAcylation on NF assembly state, suggesting a potential link between dysregulated O-GlcNAcylation and pathological NF aggregation. Our results demonstrate that site-specific glycosylation regulates NF-L assembly and function, and aberrant NF O-GlcNAcylation may contribute to CMT and other neurodegenerative disorders.
    DOI:  https://doi.org/10.1038/s41467-023-42227-0
  40. Nat Ecol Evol. 2023 Oct 19.
    Evolutionary dynamics of whole-body regeneration across planarian flatworms.
    Miquel Vila-Farré, Andrei Rozanski, Mario Ivanković, James Cleland, Jeremias N Brand, Felix Thalen, Markus A Grohme, Stephanie von Kannen, Alexandra L Grosbusch, Hanh T-K Vu, Carlos E Prieto, Fernando Carbayo, Bernhard Egger, Christoph Bleidorn, John E J Rasko, Jochen C Rink.
      Regenerative abilities vary dramatically across animals. Even amongst planarian flatworms, well-known for complete regeneration from tiny body fragments, some species have restricted regeneration abilities while others are almost entirely regeneration incompetent. Here, we assemble a diverse live collection of 40 planarian species to probe the evolution of head regeneration in the group. Combining quantification of species-specific head-regeneration abilities with a comprehensive transcriptome-based phylogeny reconstruction, we show multiple independent transitions between robust whole-body regeneration and restricted regeneration in freshwater species. RNA-mediated genetic interference inhibition of canonical Wnt signalling in RNA-mediated genetic interference-sensitive species bypassed all head-regeneration defects, suggesting that the Wnt pathway is linked to the emergence of planarian regeneration defects. Our finding that Wnt signalling has multiple roles in the reproductive system of the model species Schmidtea mediterranea raises the possibility that a trade-off between egg-laying, asexual reproduction by fission/regeneration and Wnt signalling drives regenerative trait evolution. Although quantitative comparisons of Wnt signalling levels, yolk content and reproductive strategy across our species collection remained inconclusive, they revealed divergent Wnt signalling roles in the reproductive system of planarians. Altogether, our study establishes planarians as a model taxon for comparative regeneration research and presents a framework for the mechanistic evolution of regenerative abilities.
    DOI:  https://doi.org/10.1038/s41559-023-02221-7
  41. Mol Cell. 2023 Oct 10. pii: S1097-2765(23)00755-4. [Epub ahead of print]
    PAICS ubiquitination recruits UBAP2 to trigger phase separation for purinosome assembly.
    Ming-Chieh Chou, Yi-Hsuan Wang, Fei-Yun Chen, Chun-Ying Kung, Kuen-Phon Wu, Jean-Cheng Kuo, Shu-Jou Chan, Mei-Ling Cheng, Chih-Yu Lin, Yu-Chi Chou, Meng-Chiao Ho, Steven Firestine, Jie-Rong Huang, Ruey-Hwa Chen.
      Purinosomes serve as metabolons to enhance de novo purine synthesis (DNPS) efficiency through compartmentalizing DNPS enzymes during stressed conditions. However, the mechanism underpinning purinosome assembly and its pathophysiological functions remains elusive. Here, we show that K6-polyubiquitination of the DNPS enzyme phosphoribosylaminoimidazole carboxylase and phosphoribosylaminoimidazolesuccinocarboxamide synthetase (PAICS) by cullin-5/ankyrin repeat and SOCS box containing 11 (Cul5/ASB11)-based ubiquitin ligase plays a driving role in purinosome assembly. Upon several purinosome-inducing cues, ASB11 is upregulated by relieving the H3K9me3/HP1α-mediated transcriptional silencing, thus stimulating PAICS polyubiquitination. The polyubiquitinated PAICS recruits ubiquitin-associated protein 2 (UBAP2), a ubiquitin-binding protein with multiple stretches of intrinsically disordered regions, thereby inducing phase separation to trigger purinosome assembly for enhancing DNPS pathway flux. In human melanoma, ASB11 is highly expressed to facilitate a constitutive purinosome formation to which melanoma cells are addicted for supporting their proliferation, viability, and tumorigenesis in a xenograft model. Our study identifies a driving mechanism for purinosome assembly in response to cellular stresses and uncovers the impact of purinosome formation on human malignancies.
    Keywords:  Cullin-RING ubiquitin ligase; biomolecular condensates; de novo purine synthesis; liquid-liquid phase separation; metabolon; purinosome; ubiquitination
    DOI:  https://doi.org/10.1016/j.molcel.2023.09.028
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