bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2023–09–17
39 papers selected by
Christian Frezza, Universität zu Köln
  1. Tumor microenvironmental nutrients, cellular responses, and cancer.
  2. The pro-oncogenic protein IF1 does not contribute to the Warburg effect and is not regulated by PKA in cancer cells.
  3. Serine starvation silences estrogen receptor signaling through histone hypoacetylation.
  4. Fumarate hydratase (FH) and cancer: a paradigm of oncometabolism.
  5. Mitochondrial degradation: Mitophagy and beyond.
  6. An integrated single-cell islet atlas in health and disease.
  7. Mitochondrial GTP metabolism controls reproductive aging in C. elegans.
  8. The Role of Stroma in Cancer Metabolism.
  9. Screening in serum-derived medium reveals differential response to compounds targeting metabolism.
  10. Alternative to lysosomal degradation: mitochondrial removal via EVs.
  11. Stress granules and hormetic adaptation of cancer.
  12. Using light to drive energy transduction in metazoan aging.
  13. Fully accessible fitness landscape of oncogene-negative lung adenocarcinoma.
  14. Cold-stimulated brown adipose tissue activation is related to changes in serum metabolites relevant to NAD+ metabolism in humans.
  15. Codependencies of mTORC1 signaling and endolysosomal actin structures.
  16. Metabolic and chemical architecture of the mammalian circadian clock.
  17. Metabolic heterogeneity of tissue-resident macrophages in homeostasis and during helminth infection.
  18. Dynamic lipidome alterations associated with human health, disease and ageing.
  19. TFEB and TFE3 control glucose homeostasis by regulating insulin gene expression.
  20. Continuous sensing of nutrients and growth factors by the mTORC1-TFEB axis.
  21. TGF-β signaling in health and disease.
  22. Molecular pathway of mitochondrial preprotein import through the TOM-TIM23 supercomplex.
  23. Seasonal light hours modulate peripheral clocks and energy metabolism in mice.
  24. How and why does metabolism scale with body mass?
  25. Outer mitochondrial membrane E3 Ub ligase MARCH5 controls mitochondrial steps in peroxisome biogenesis.
  26. An interview with Lydia Finley.
  27. Stem cells provide clues to why vertebrae attract tumour cells.
  28. Modular pooled discovery of synthetic knockin sequences to program durable cell therapies.
  29. TNFα increases the degradation of pyruvate dehydrogenase kinase 4 by the Lon protease to support proinflammatory genes.
  30. A nucleotide diphosphate kinase mediates tethering between mitochondria prior to fusion.
  31. Global impact of somatic structural variation on the cancer proteome.
  32. Gut microbes and the liver circadian clock partition glucose and lipid metabolism.
  33. The Batten disease gene product CLN5 is the lysosomal bis(monoacylglycero)phosphate synthase.
  34. Mitochondrial membrane potential acts as a retrograde signal to regulate cell cycle progression.
  35. Geroprotective interventions converge on gene expression programs of reduced inflammation and restored fatty acid metabolism.
  36. Death-seq identifies regulators of cell death and senolytic therapies.
  37. Nrf2 depletion in the context of loss-of-function Keap1 leads to mitolysosome accumulation.
  38. The evolution of aging and lifespan.
  39. Mathematical reconstruction of the metabolic network in an in-vitro multiple myeloma model.
  1. Cell Chem Biol. 2023 Sep 01. pii: S2451-9456(23)00281-7. [Epub ahead of print]
    Tumor microenvironmental nutrients, cellular responses, and cancer.
    Graham P Lobel, Yanqing Jiang, M Celeste Simon.
      Over the last two decades, the rapidly expanding field of tumor metabolism has enhanced our knowledge of the impact of nutrient availability on metabolic reprogramming in cancer. Apart from established roles in cancer cells themselves, various nutrients, metabolic enzymes, and stress responses are key to the activities of tumor microenvironmental immune, fibroblastic, endothelial, and other cell types that support malignant transformation. In this article, we review our current understanding of how nutrient availability affects metabolic pathways and responses in both cancer and "stromal" cells, by dissecting major examples and their regulation of cellular activity. Understanding the relationship of nutrient availability to cellular behaviors in the tumor ecosystem will broaden the horizon of exploiting novel therapeutic vulnerabilities in cancer.
    Keywords:  Cancer metabolism; cancer therapeutics; cancer-associated fibroblasts; immune cell metabolism; nutrient exchange; stress responses; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.chembiol.2023.08.011
  2. Biochim Biophys Acta Mol Basis Dis. 2023 Sep 07. pii: S0925-4439(23)00245-4. [Epub ahead of print] 166879
    The pro-oncogenic protein IF1 does not contribute to the Warburg effect and is not regulated by PKA in cancer cells.
    Gianluca Sgarbi, Riccardo Righetti, Valentina Del Dotto, Silvia Grillini, Valentina Giorgio, Alessandra Baracca, Giancarlo Solaini.
      The endogenous inhibitor of mitochondrial F1Fo-ATPase (ATP synthase), IF1, has been shown to exert pro-oncogenic actions, including reprogramming of cellular energy metabolism (Warburg effect). The latter action of IF1 has been reported to be hampered by its PKA-dependent phosphorylation, but both reprogramming of metabolism and PKA-dependent phosphorylation are intensely debated. To clarify these critical issues, we prepared stably IF1-silenced clones and compared their bioenergetics with that of the three parental IF1-expressing cancer cell lines. All functional parameters: respiration rate, ATP synthesis rate (OXPHOS), and mitochondrial membrane potential were similar in IF1-silenced and control cells, clearly indicating that IF1 cannot inhibit the ATP synthase in cancer cells when the enzyme works physiologically. Furthermore, all cell types exposed to PKA modulators and energized with NAD+-dependent substrates or succinate showed similar OXPHOS rate regardless of the presence or absence of IF1. Therefore, our results rule out that IF1 action is modulated by its PKA-dependent phosphorylated/dephosphorylated state. Notably, cells exposed to a negative PKA modulator and energized with NAD+-dependent substrates showed a significant decrease of the OXPHOS rate matching previously reported inactivation of complex I. Overall, this study definitively demonstrates that IF1 inhibits neither mitochondrial ATP synthase nor OXPHOS in normoxic cancer cells and does not contribute to the Warburg effect. Thus, currently the protection of cancer cells from severe hypoxia/anoxia and apoptosis remain the only unquestionable actions of IF1 as pro-oncogenic factors that may be exploited to develop therapeutic approaches.
    Keywords:  ATP synthase; Bioenergetics; Cancer metabolism; IF(1); Mitochondria; Warburg effect
    DOI:  https://doi.org/10.1016/j.bbadis.2023.166879
  3. Proc Natl Acad Sci U S A. 2023 Sep 19. 120(38): e2302489120
    Serine starvation silences estrogen receptor signaling through histone hypoacetylation.
    Albert M Li, Bo He, Dimitris Karagiannis, Yang Li, Haowen Jiang, Preethi Srinivasan, Yaniel Ramirez, Meng-Ning Zhou, Christina Curtis, Joshua J Gruber, Chao Lu, Erinn B Rankin, Jiangbin Ye.
      Loss of estrogen receptor (ER) pathway activity promotes breast cancer progression, yet how this occurs remains poorly understood. Here, we show that serine starvation, a metabolic stress often found in breast cancer, represses estrogen receptor alpha (ERα) signaling by reprogramming glucose metabolism and epigenetics. Using isotope tracing and time-resolved metabolomic analyses, we demonstrate that serine is required to maintain glucose flux through glycolysis and the TCA cycle to support acetyl-CoA generation for histone acetylation. Consequently, limiting serine depletes histone H3 lysine 27 acetylation (H3K27ac), particularly at the promoter region of ER pathway genes including the gene encoding ERα, ESR1. Mechanistically, serine starvation impairs acetyl-CoA-dependent gene expression by inhibiting the entry of glycolytic carbon into the TCA cycle and down-regulating the mitochondrial citrate exporter SLC25A1, a critical enzyme in the production of nucleocytosolic acetyl-CoA from glucose. Consistent with this model, total H3K27ac and ERα expression are suppressed by SLC25A1 inhibition and restored by acetate, an alternate source of acetyl-CoA, in serine-free conditions. We thus uncover an unexpected role for serine in sustaining ER signaling through the regulation of acetyl-CoA metabolism.
    Keywords:  SLC25A1; breast cancer; estrogen receptor; histone acetylation; serine metabolism
    DOI:  https://doi.org/10.1073/pnas.2302489120
  4. Br J Cancer. 2023 Sep 09.
    Fumarate hydratase (FH) and cancer: a paradigm of oncometabolism.
    Lorea Valcarcel-Jimenez, Christian Frezza.
      Fumarate hydratase (FH) is an enzyme of the Tricarboxylic Acid (TCA) cycle whose mutations lead to hereditary and sporadic forms of cancer. Although more than twenty years have passed since its discovery as the leading cause of the cancer syndrome Hereditary leiomyomatosis and Renal Cell Carcinoma (HLRCC), it is still unclear how the loss of FH causes cancer in a tissue-specific manner and with such aggressive behaviour. It has been shown that FH loss, via the accumulation of FH substrate fumarate, activates a series of oncogenic cascades whose contribution to transformation is still under investigation. In this review, we will summarise these recent findings in an integrated fashion and put forward the case that understanding the biology of FH and how its mutations promote transformation will be vital to establish novel paradigms of oncometabolism.
    DOI:  https://doi.org/10.1038/s41416-023-02412-w
  5. Mol Cell. 2023 Sep 07. pii: S1097-2765(23)00656-1. [Epub ahead of print]
    Mitochondrial degradation: Mitophagy and beyond.
    Louise Uoselis, Thanh Ngoc Nguyen, Michael Lazarou.
      Mitochondria are central hubs of cellular metabolism that also play key roles in signaling and disease. It is therefore fundamentally important that mitochondrial quality and activity are tightly regulated. Mitochondrial degradation pathways contribute to quality control of mitochondrial networks and can also regulate the metabolic profile of mitochondria to ensure cellular homeostasis. Here, we cover the many and varied ways in which cells degrade or remove their unwanted mitochondria, ranging from mitophagy to mitochondrial extrusion. The molecular signals driving these varied pathways are discussed, including the cellular and physiological contexts under which the different degradation pathways are engaged.
    Keywords:  MDV; PINK1; Parkin; degradation; mitochondria; mitochondrial quality control; mitophagy; proteasome; selective autophagy; ubiquitin
    DOI:  https://doi.org/10.1016/j.molcel.2023.08.021
  6. Nat Metab. 2023 Sep 12.
    An integrated single-cell islet atlas in health and disease.
      
    DOI:  https://doi.org/10.1038/s42255-023-00884-x
  7. Dev Cell. 2023 Sep 07. pii: S1534-5807(23)00435-5. [Epub ahead of print]
    Mitochondrial GTP metabolism controls reproductive aging in C. elegans.
    Yi-Tang Lee, Marzia Savini, Tao Chen, Jin Yang, Qian Zhao, Lang Ding, Shihong Max Gao, Mumine Senturk, Jessica N Sowa, Jue D Wang, Meng C Wang.
      Healthy mitochondria are critical for reproduction. During aging, both reproductive fitness and mitochondrial homeostasis decline. Mitochondrial metabolism and dynamics are key factors in supporting mitochondrial homeostasis. However, how they are coupled to control reproductive health remains unclear. We report that mitochondrial GTP (mtGTP) metabolism acts through mitochondrial dynamics factors to regulate reproductive aging. We discovered that germline-only inactivation of GTP- but not ATP-specific succinyl-CoA synthetase (SCS) promotes reproductive longevity in Caenorhabditis elegans. We further identified an age-associated increase in mitochondrial clustering surrounding oocyte nuclei, which is attenuated by GTP-specific SCS inactivation. Germline-only induction of mitochondrial fission factors sufficiently promotes mitochondrial dispersion and reproductive longevity. Moreover, we discovered that bacterial inputs affect mtGTP levels and dynamics factors to modulate reproductive aging. These results demonstrate the significance of mtGTP metabolism in regulating oocyte mitochondrial homeostasis and reproductive longevity and identify mitochondrial fission induction as an effective strategy to improve reproductive health.
    Keywords:  GTP metabolism; bacteria-host interaction; gene-environment interaction; mitochondrial distribution; mitochondrial dynamics; oocyte quality control; reproductive aging; succinyl-CoA synthetase; vitamin B12
    DOI:  https://doi.org/10.1016/j.devcel.2023.08.019
  8. Cold Spring Harb Perspect Med. 2023 Sep 11. pii: a041540. [Epub ahead of print]
    The Role of Stroma in Cancer Metabolism.
    Alec C Kimmelman, Mara H Sherman.
      The altered metabolism of tumor cells is a well-known hallmark of cancer and is driven by multiple factors such as mutations in oncogenes and tumor suppressor genes, the origin of the tissue where the tumor arises, and the microenvironment of the tumor. These metabolic changes support the growth of cancer cells by providing energy and the necessary building blocks to sustain proliferation. Targeting these metabolic alterations therapeutically is a potential strategy to treat cancer, but it is challenging due to the metabolic plasticity of tumors. Cancer cells have developed ways to scavenge nutrients through autophagy and macropinocytosis and can also form metabolic networks with stromal cells in the tumor microenvironment. Understanding the role of the tumor microenvironment in tumor metabolism is crucial for effective therapeutic targeting. This review will discuss tumor metabolism and the contribution of the stroma in supporting tumor growth through metabolic interactions.
    DOI:  https://doi.org/10.1101/cshperspect.a041540
  9. Cell Chem Biol. 2023 Aug 31. pii: S2451-9456(23)00279-9. [Epub ahead of print]
    Screening in serum-derived medium reveals differential response to compounds targeting metabolism.
    Keene L Abbott, Ahmed Ali, Dominick Casalena, Brian T Do, Raphael Ferreira, Jaime H Cheah, Christian K Soule, Amy Deik, Tenzin Kunchok, Daniel R Schmidt, Steffen Renner, Sophie E Honeder, Michelle Wu, Sze Ham Chan, Tenzin Tseyang, Andrew T Stoltzfus, Sarah L J Michel, Daniel Greaves, Peggy P Hsu, Christopher W Ng, Chelsea J Zhang, Ali Farsidjani, Johnathan R Kent, Maria Lucia L Madariaga, Iva Monique T Gramatikov, Nicholas J Matheson, Caroline A Lewis, Clary B Clish, Matthew G Rees, Jennifer A Roth, Lesley Mathews Griner, Alexander Muir, Douglas S Auld, Matthew G Vander Heiden.
      A challenge for screening new anticancer drugs is that efficacy in cell culture models is not always predictive of efficacy in patients. One limitation of standard cell culture is a reliance on non-physiological nutrient levels, which can influence cell metabolism and drug sensitivity. A general assessment of how physiological nutrients affect cancer cell response to small molecule therapies is lacking. To address this, we developed a serum-derived culture medium that supports the proliferation of diverse cancer cell lines and is amenable to high-throughput screening. We screened several small molecule libraries and found that compounds targeting metabolic enzymes were differentially effective in standard compared to serum-derived medium. We exploited the differences in nutrient levels between each medium to understand why medium conditions affected the response of cells to some compounds, illustrating how this approach can be used to screen potential therapeutics and understand how their efficacy is modified by available nutrients.
    Keywords:  Cancer cell metabolism; Culture media; Drug sensitivity; High-throughput screening; Nutrient environment; Phenotypic drug screening; Physiologic media
    DOI:  https://doi.org/10.1016/j.chembiol.2023.08.007
  10. Nat Rev Mol Cell Biol. 2023 Sep 11.
    Alternative to lysosomal degradation: mitochondrial removal via EVs.
    Paulina Strzyz.
      
    DOI:  https://doi.org/10.1038/s41580-023-00660-5
  11. Trends Cancer. 2023 Sep 11. pii: S2405-8033(23)00165-6. [Epub ahead of print]
    Stress granules and hormetic adaptation of cancer.
    Alexandra Redding, Elda Grabocka.
      Cell stress is inherent to cancer and a key driver of tumorigenesis. Recent studies have proposed that cell stress promotes tumorigenesis through non-membranous organelles known as stress granules (SGs). While the biology of SGs is an emerging field, all studies to date point to the enhanced ability of cancer cells to form SGs compared with normal cells, a heightened dependence on SGs for survival under adverse conditions and for chemotherapy resistance, and the dependence of tumors on SGs for growth. Why cancer cells become dependent on SGs and how SGs promote tumorigenesis remain to be elucidated. Here, we attempt to provide a framework for answering these questions by framing SGs as a hormetic response to tumor-associated stress stimuli.
    Keywords:  cell fitness; hormesis; stress adaptation; stress granules; tumor-associated stress stimuli
    DOI:  https://doi.org/10.1016/j.trecan.2023.08.005
  12. Trends Biochem Sci. 2023 Sep 11. pii: S0968-0004(23)00213-X. [Epub ahead of print]
    Using light to drive energy transduction in metazoan aging.
    Vaibhav Tiwary, Anne-Marie Galow, Andrew P Wojtovich, Shahaf Peleg.
      Mitochondrial dysfunction is a central hallmark of aging and energy transduction is a promising target for longevity interventions. New research suggests that interventions in how energy is transduced could benefit healthy longevity. Here, we propose using light as an alternative energy source to fuel mitochondria and increase metazoan lifespan.
    Keywords:  bioenergetics; lifespan; metabolism; mitochondria; optogenetics; proton pump
    DOI:  https://doi.org/10.1016/j.tibs.2023.08.010
  13. Proc Natl Acad Sci U S A. 2023 Sep 19. 120(38): e2303224120
    Fully accessible fitness landscape of oncogene-negative lung adenocarcinoma.
    Maryam Yousefi, Laura Andrejka, Márton Szamecz, Monte M Winslow, Dmitri A Petrov, Gábor Boross.
      Cancer genomes are almost invariably complex with genomic alterations cooperating during each step of carcinogenesis. In cancers that lack a single dominant oncogene mutation, cooperation between the inactivation of multiple tumor suppressor genes can drive tumor initiation and growth. Here, we shed light on how the sequential acquisition of genomic alterations generates oncogene-negative lung tumors. We couple tumor barcoding with combinatorial and multiplexed somatic genome editing to characterize the fitness landscapes of three tumor suppressor genes NF1, RASA1, and PTEN, the inactivation of which jointly drives oncogene-negative lung adenocarcinoma initiation and growth. The fitness landscape was surprisingly accessible, with each additional mutation leading to growth advantage. Furthermore, the fitness landscapes remained fully accessible across backgrounds with the inactivation of additional tumor suppressor genes. These results suggest that while predicting cancer evolution will be challenging, acquiring the multiple alterations that drive the growth of oncogene-negative tumors can be facilitated by the lack of constraints on mutational order.
    Keywords:  cancer evolution; fitness landscapes; mouse models; quantitative
    DOI:  https://doi.org/10.1073/pnas.2303224120
  14. Cell Rep. 2023 Sep 13. pii: S2211-1247(23)01143-9. [Epub ahead of print]42(9): 113131
    Cold-stimulated brown adipose tissue activation is related to changes in serum metabolites relevant to NAD+ metabolism in humans.
    Mueez U-Din, Vanessa D de Mello, Marjo Tuomainen, Juho Raiko, Tarja Niemi, Tobias Fromme, Anton Klåvus, Nadine Gautier, Kimmo Haimilahti, Marko Lehtonen, Karsten Kristiansen, John W Newman, Kirsi H Pietiläinen, Jussi Pihlajamäki, Ez-Zoubir Amri, Martin Klingenspor, Pirjo Nuutila, Eija Pirinen, Kati Hanhineva, Kirsi A Virtanen.
      Cold-induced brown adipose tissue (BAT) activation is considered to improve metabolic health. In murine BAT, cold increases the fundamental molecule for mitochondrial function, nicotinamide adenine dinucleotide (NAD+), but limited knowledge of NAD+ metabolism during cold in human BAT metabolism exists. We show that cold increases the serum metabolites of the NAD+ salvage pathway (nicotinamide and 1-methylnicotinamide) in humans. Additionally, individuals with cold-stimulated BAT activation have decreased levels of metabolites from the de novo NAD+ biosynthesis pathway (tryptophan, kynurenine). Serum nicotinamide correlates positively with cold-stimulated BAT activation, whereas tryptophan and kynurenine correlate negatively. Furthermore, the expression of genes involved in NAD+ biosynthesis in BAT is related to markers of metabolic health. Our data indicate that cold increases serum tryptophan conversion to nicotinamide to be further utilized by BAT. We conclude that NAD+ metabolism is activated upon cold in humans and is probably regulated in a coordinated fashion by several tissues.
    Keywords:  BAT; CP: Metabolism; NAD(+); cold exposure; human brown adipose tissue; nicotinamide; tryptophan
    DOI:  https://doi.org/10.1016/j.celrep.2023.113131
  15. Sci Adv. 2023 Sep 15. 9(37): eadd9084
    Codependencies of mTORC1 signaling and endolysosomal actin structures.
    Amulya Priya, Sandra Antoine-Bally, Anne-Sophie Macé, Pedro Monteiro, Valentin Sabatet, David Remy, Florent Dingli, Damarys Loew, Constantinos Demetriades, Alexis M Gautreau, Philippe Chavrier.
      The mechanistic target of rapamycin complex 1 (mTORC1) is part of the amino acid sensing machinery that becomes activated on the endolysosomal surface in response to nutrient cues. Branched actin generated by WASH and Arp2/3 complexes defines endolysosomal microdomains. Here, we find mTORC1 components in close proximity to endolysosomal actin microdomains. We investigated for interactors of the mTORC1 lysosomal tether, RAGC, by proteomics and identified multiple actin filament capping proteins and their modulators. Perturbation of RAGC function affected the size of endolysosomal actin, consistent with a regulation of actin filament capping by RAGC. Reciprocally, the pharmacological inhibition of actin polymerization or alteration of endolysosomal actin obtained upon silencing of WASH or Arp2/3 complexes impaired mTORC1 activity. Mechanistically, we show that actin is required for proper association of RAGC and mTOR with endolysosomes. This study reveals an unprecedented interplay between actin and mTORC1 signaling on the endolysosomal system.
    DOI:  https://doi.org/10.1126/sciadv.add9084
  16. Cell Chem Biol. 2023 Sep 08. pii: S2451-9456(23)00286-6. [Epub ahead of print]
    Metabolic and chemical architecture of the mammalian circadian clock.
    Isara Laothamatas, Emil Sjulstok Rasmussen, Carla B Green, Joseph S Takahashi.
      Circadian rhythms are endogenous periodic biological processes that occur on a daily timescale. These rhythms are generated by a transcriptional/translational feedback loop that consists of the CLOCK-BMAL1 heterodimeric transcriptional activator complex and the PER1/2-CRY1/2-CK1δ/ε repressive complex. The output pathways of this molecular feedback loop generate circadian rhythmicity in various biological processes. Among these, metabolism is a primary regulatory target of the circadian clock which can also feedback to modulate clock function. This intertwined relationship between circadian rhythms and metabolism makes circadian clock components promising therapeutic targets. Despite this, pharmacological therapeutics that target the circadian clock are relatively rare. In this review, we hope to stimulate interest in chemical chronobiology by providing a comprehensive background on the molecular mechanism of mammalian circadian rhythms and their connection to metabolism, highlighting important studies in the chemical approach to circadian research, and offering our perspectives on future developments in the field.
    Keywords:  chronobiology; circadian rhythms; drug discovery; high-throughput screening; metabolism
    DOI:  https://doi.org/10.1016/j.chembiol.2023.08.014
  17. Nat Commun. 2023 Sep 12. 14(1): 5627
    Metabolic heterogeneity of tissue-resident macrophages in homeostasis and during helminth infection.
    Graham A Heieis, Thiago A Patente, Luís Almeida, Frank Vrieling, Tamar Tak, Georgia Perona-Wright, Rick M Maizels, Rinke Stienstra, Bart Everts.
      Tissue-resident macrophage populations constitute a mosaic of phenotypes, yet how their metabolic states link to the range of phenotypes and functions in vivo is still poorly defined. Here, using high-dimensional spectral flow cytometry, we observe distinct metabolic profiles between different organs and functionally link acetyl CoA carboxylase activity to efferocytotic capacity. Additionally, differences in metabolism are evident within populations from a specific site, corresponding to relative stages of macrophage maturity. Immune perturbation with intestinal helminth infection increases alternative activation and metabolic rewiring of monocyte-derived macrophage populations, while resident TIM4+ intestinal macrophages remain immunologically and metabolically hyporesponsive. Similar metabolic signatures in alternatively-activated macrophages are seen from different tissues using additional helminth models, but to different magnitudes, indicating further tissue-specific contributions to metabolic states. Thus, our high-dimensional, flow-based metabolic analyses indicates complex metabolic heterogeneity and dynamics of tissue-resident macrophage populations at homeostasis and during helminth infection.
    DOI:  https://doi.org/10.1038/s41467-023-41353-z
  18. Nat Metab. 2023 Sep 11.
    Dynamic lipidome alterations associated with human health, disease and ageing.
    Daniel Hornburg, Si Wu, Mahdi Moqri, Xin Zhou, Kevin Contrepois, Nasim Bararpour, Gavin M Traber, Baolong Su, Ahmed A Metwally, Monica Avina, Wenyu Zhou, Jessalyn M Ubellacker, Tejaswini Mishra, Sophia Miryam Schüssler-Fiorenza Rose, Paula B Kavathas, Kevin J Williams, Michael P Snyder.
      Lipids can be of endogenous or exogenous origin and affect diverse biological functions, including cell membrane maintenance, energy management and cellular signalling. Here, we report >800 lipid species, many of which are associated with health-to-disease transitions in diabetes, ageing and inflammation, as well as cytokine-lipidome networks. We performed comprehensive longitudinal lipidomic profiling and analysed >1,500 plasma samples from 112 participants followed for up to 9 years (average 3.2 years) to define the distinct physiological roles of complex lipid subclasses, including large and small triacylglycerols, ester- and ether-linked phosphatidylethanolamines, lysophosphatidylcholines, lysophosphatidylethanolamines, cholesterol esters and ceramides. Our findings reveal dynamic changes in the plasma lipidome during respiratory viral infection, insulin resistance and ageing, suggesting that lipids may have roles in immune homoeostasis and inflammation regulation. Individuals with insulin resistance exhibit disturbed immune homoeostasis, altered associations between lipids and clinical markers, and accelerated changes in specific lipid subclasses during ageing. Our dataset based on longitudinal deep lipidome profiling offers insights into personalized ageing, metabolic health and inflammation, potentially guiding future monitoring and intervention strategies.
    DOI:  https://doi.org/10.1038/s42255-023-00880-1
  19. EMBO J. 2023 Sep 15. e113928
    TFEB and TFE3 control glucose homeostasis by regulating insulin gene expression.
    Adrien Pasquier, Nunzia Pastore, Luca D'Orsi, Rita Colonna, Alessandra Esposito, Veronica Maffia, Rossella De Cegli, Margherita Mutarelli, Susanna Ambrosio, Gennaro Tufano, Antonio Grimaldi, Marcella Cesana, Davide Cacchiarelli, Nathalie Delalleau, Gennaro Napolitano, Andrea Ballabio.
      To fulfill their function, pancreatic beta cells require precise nutrient-sensing mechanisms that control insulin production. Transcription factor EB (TFEB) and its homolog TFE3 have emerged as crucial regulators of the adaptive response of cell metabolism to environmental cues. Here, we show that TFEB and TFE3 regulate beta-cell function and insulin gene expression in response to variations in nutrient availability. We found that nutrient deprivation in beta cells promoted TFEB/TFE3 activation, which resulted in suppression of insulin gene expression. TFEB overexpression was sufficient to inhibit insulin transcription, whereas beta cells depleted of both TFEB and TFE3 failed to suppress insulin gene expression in response to amino acid deprivation. Interestingly, ChIP-seq analysis showed binding of TFEB to super-enhancer regions that regulate insulin transcription. Conditional, beta-cell-specific, Tfeb-overexpressing, and Tfeb/Tfe3 double-KO mice showed severe alteration of insulin transcription, secretion, and glucose tolerance, indicating that TFEB and TFE3 are important physiological mediators of pancreatic function. Our findings reveal a nutrient-controlled transcriptional mechanism that regulates insulin production, thus playing a key role in glucose homeostasis at both cellular and organismal levels.
    Keywords:  TFEB; beta cells; glucose homeostasis; insulin; mTORC1
    DOI:  https://doi.org/10.15252/embj.2023113928
  20. Elife. 2023 Sep 12. pii: e74903. [Epub ahead of print]12
    Continuous sensing of nutrients and growth factors by the mTORC1-TFEB axis.
    Breanne Sparta, Nont Kosaisawe, Michael Pargett, Madhura Patankar, Nicholaus DeCuzzi, John G Albeck.
      mTORC1 senses nutrients and growth factors and phosphorylates downstream targets, including the transcription factor TFEB, to coordinate metabolic supply and demand. These functions position mTORC1 as a central controller of cellular homeostasis, but the behavior of this system in individual cells has not been well characterized. Here, we provide measurements necessary to refine quantitative models for mTORC1 as a metabolic controller. We developed a series of fluorescent protein-TFEB fusions and a multiplexed immunofluorescence approach to investigate how combinations of stimuli jointly regulate mTORC1 signaling at the single-cell level. Live imaging of individual MCF10A cells confirmed that mTORC1-TFEB signaling responds continuously to individual, sequential, or simultaneous treatment with amino acids and the growth factor insulin. Under physiologically relevant concentrations of amino acids, we observe correlated fluctuations in TFEB, AMPK, and AKT signaling that indicate continuous activity adjustments to nutrient availability. Using partial least squares regression modeling, we show that these continuous gradations are connected to protein synthesis rate via a distributed network of mTORC1 effectors, providing quantitative support for the qualitative model of mTORC1 as a homeostatic controller and clarifying its functional behavior within individual cells.
    Keywords:  cell biology; computational biology; human; systems biology
    DOI:  https://doi.org/10.7554/eLife.74903
  21. Cell. 2023 Sep 14. pii: S0092-8674(23)00851-6. [Epub ahead of print]186(19): 4007-4037
    TGF-β signaling in health and disease.
    Joan Massagué, Dean Sheppard.
      The TGF-β regulatory system plays crucial roles in the preservation of organismal integrity. TGF-β signaling controls metazoan embryo development, tissue homeostasis, and injury repair through coordinated effects on cell proliferation, phenotypic plasticity, migration, metabolic adaptation, and immune surveillance of multiple cell types in shared ecosystems. Defects of TGF-β signaling, particularly in epithelial cells, tissue fibroblasts, and immune cells, disrupt immune tolerance, promote inflammation, underlie the pathogenesis of fibrosis and cancer, and contribute to the resistance of these diseases to treatment. Here, we review how TGF-β coordinates multicellular response programs in health and disease and how this knowledge can be leveraged to develop treatments for diseases of the TGF-β system.
    DOI:  https://doi.org/10.1016/j.cell.2023.07.036
  22. Nat Struct Mol Biol. 2023 Sep 11.
    Molecular pathway of mitochondrial preprotein import through the TOM-TIM23 supercomplex.
    Xueyin Zhou, Yuqi Yang, Guopeng Wang, Shanshan Wang, Dongjie Sun, Xiaomin Ou, Yuke Lian, Long Li.
      Over half of mitochondrial proteins are imported from the cytosol via the pre-sequence pathway, controlled by the TOM complex in the outer membrane and the TIM23 complex in the inner membrane. The mechanisms through which proteins are translocated via the TOM and TIM23 complexes remain unclear. Here we report the assembly of the active TOM-TIM23 supercomplex of Saccharomyces cerevisiae with translocating polypeptide substrates. Electron cryo-microscopy analyses reveal that the polypeptide substrates pass the TOM complex through the center of a Tom40 subunit, interacting with a glutamine-rich region. Structural and biochemical analyses show that the TIM23 complex contains a heterotrimer of the subunits Tim23, Tim17 and Mgr2. The polypeptide substrates are shielded from lipids by Mgr2 and Tim17, which creates a translocation pathway characterized by a negatively charged entrance and a central hydrophobic region. These findings reveal an unexpected pre-sequence pathway through the TOM-TIM23 supercomplex spanning the double membranes of mitochondria.
    DOI:  https://doi.org/10.1038/s41594-023-01103-7
  23. Cell Metab. 2023 Sep 01. pii: S1550-4131(23)00300-5. [Epub ahead of print]
    Seasonal light hours modulate peripheral clocks and energy metabolism in mice.
    Lewin Small, Leonidas S Lundell, Jo Iversen, Amy M Ehrlich, Morten Dall, Astrid L Basse, Emilie Dalbram, Ann N Hansen, Jonas T Treebak, Romain Barrès, Juleen R Zierath.
      Except for latitudes close to the equator, seasonal variation in light hours can change dramatically between summer and winter. Yet investigations into the interplay between energy metabolism and circadian rhythms typically use a 12 h light:12 h dark photoperiod corresponding to the light duration at the equator. We hypothesized that altering the seasonal photoperiod affects both the rhythmicity of peripheral tissue clocks and energy homeostasis. Mice were housed at photoperiods representing either light hours in summer, winter, or the equinox. Mice housed at a winter photoperiod exhibited an increase in the amplitude of rhythmic lipid metabolism and a modest reduction in fat mass and liver triglyceride content. Comparing melatonin-proficient and -deficient mice, the effect of seasonal light on energy metabolism was largely driven by differences in the rhythmicity of food intake and not melatonin. Together, these data indicate that seasonal light impacts energy metabolism by modulating the timing of eating.
    Keywords:  circadian biology; energy homeostasis; glucose metabolism; hormones; integrative physiology; obesity; transcriptomics
    DOI:  https://doi.org/10.1016/j.cmet.2023.08.005
  24. Physiology (Bethesda). 2023 Sep 12.
    How and why does metabolism scale with body mass?
    Craig R White, Dustin J Marshall.
      Most explanations for the relationship between body size and metabolism invoke physical constraints: such explanations are evolutionarily inert, limiting their predictive capacity. Contemporary approaches to metabolic rate and life history lack the pluralism of foundational work. Here, we call for re-forging of the lost links between optimisation approaches and physiology.
    Keywords:  Optimisation; constraint; life history; metabolic rate; scaling
    DOI:  https://doi.org/10.1152/physiol.00015.2023
  25. bioRxiv. 2023 Sep 01. pii: 2023.08.31.555756. [Epub ahead of print]
    Outer mitochondrial membrane E3 Ub ligase MARCH5 controls mitochondrial steps in peroxisome biogenesis.
    Nicolas Verhoeven, Yumiko Oshima, Etienne Cartier, Albert Neutzner, Liron Boyman, Mariusz Karbowski.
      Peroxisome de novo biogenesis requires yet unidentified mitochondrial proteins. We report that the outer mitochondrial membrane (OMM)-associated E3 Ub ligase MARCH5 is vital for generating mitochondria-derived pre-peroxisomes. MARCH5 knockout results in accumulation of immature peroxisomes and lower expression of various peroxisomal proteins. Upon fatty acid-induced peroxisomal biogenesis, MARCH5 redistributes to newly formed peroxisomes; the peroxisomal biogenesis under these conditions is inhibited in MARCH5 knockout cells. MARCH5 activity-deficient mutants are stalled on peroxisomes and induce accumulation of peroxisomes containing high levels of the OMM protein Tom20 (mitochondria-derived pre-peroxisomes). Furthermore, depletion of peroxisome biogenesis factor Pex14 leads to the formation of MARCH5- and Tom20-positive peroxisomes, while no peroxisomes are detected in Pex14/MARCH5 dko cells. Reexpression of WT, but not MARCH5 mutants, restores Tom20-positive pre-peroxisomes in Pex14/MARCH5 dko cells. Thus, MARCH5 acts upstream of Pex14 in mitochondrial steps of peroxisome biogenesis. Our data validate the hybrid, mitochondria-dependent model of peroxisome biogenesis and reveal that MARCH5 is an essential mitochondrial protein in this process.
    Summary: The authors found that mitochondrial E3 Ub ligase MARCH5 controls the formation of mitochondria-derived pre-peroxisomes. The data support the hybrid, mitochondria-dependent model of peroxisome biogenesis and reveal that MARCH5 is an essential mitochondrial protein in this process.
    DOI:  https://doi.org/10.1101/2023.08.31.555756
  26. Development. 2023 Oct 15. pii: dev202317. [Epub ahead of print]150(20):
    An interview with Lydia Finley.
      Lydia Finley is an Associate Professor at the Memorial Sloan Kettering Cancer Center, New York, USA. Her research focuses on the metabolic programming of embryonic stem cells and how metabolism regulates and drives cell fate decisions. Lydia is a Guest Editor of this Development Special Issue on Metabolic and Nutritional Control of Development and Regeneration. We caught up with Lydia over Zoom to discover more about her research, her views on developmental metabolism and her roles and aims as Guest Editor.
    DOI:  https://doi.org/10.1242/dev.202317
  27. Nature. 2023 Sep 13.
    Stem cells provide clues to why vertebrae attract tumour cells.
    Geert Carmeliet.
      
    Keywords:  Cancer; Medical research; Stem cells
    DOI:  https://doi.org/10.1038/d41586-023-02768-2
  28. Cell. 2023 Sep 14. pii: S0092-8674(23)00902-9. [Epub ahead of print]186(19): 4216-4234.e33
    Modular pooled discovery of synthetic knockin sequences to program durable cell therapies.
    Franziska Blaeschke, Yan Yi Chen, Ryan Apathy, Bence Daniel, Andy Y Chen, Peixin Amy Chen, Katalin Sandor, Wenxi Zhang, Zhongmei Li, Cody T Mowery, Tori N Yamamoto, William A Nyberg, Angela To, Ruby Yu, Raymund Bueno, Min Cheol Kim, Ralf Schmidt, Daniel B Goodman, Tobias Feuchtinger, Justin Eyquem, Chun Jimmie Ye, Julia Carnevale, Ansuman T Satpathy, Eric Shifrut, Theodore L Roth, Alexander Marson.
      Chronic stimulation can cause T cell dysfunction and limit the efficacy of cellular immunotherapies. Improved methods are required to compare large numbers of synthetic knockin (KI) sequences to reprogram cell functions. Here, we developed modular pooled KI screening (ModPoKI), an adaptable platform for modular construction of DNA KI libraries using barcoded multicistronic adaptors. We built two ModPoKI libraries of 100 transcription factors (TFs) and 129 natural and synthetic surface receptors (SRs). Over 30 ModPoKI screens across human TCR- and CAR-T cells in diverse conditions identified a transcription factor AP4 (TFAP4) construct that enhanced fitness of chronically stimulated CAR-T cells and anti-cancer function in vitro and in vivo. ModPoKI's modularity allowed us to generate an ∼10,000-member library of TF combinations. Non-viral KI of a combined BATF-TFAP4 polycistronic construct enhanced fitness. Overexpressed BATF and TFAP4 co-occupy and regulate key gene targets to reprogram T cell function. ModPoKI facilitates the discovery of complex gene constructs to program cellular functions.
    Keywords:  CRISPR; chimeric antigen receptor; chronic stimulation; human T cells; immunotherapy; knockins; pooled screens; synthetic surface receptor; transcription factor
    DOI:  https://doi.org/10.1016/j.cell.2023.08.013
  29. Proc Natl Acad Sci U S A. 2023 Sep 19. 120(38): e2218150120
    TNFα increases the degradation of pyruvate dehydrogenase kinase 4 by the Lon protease to support proinflammatory genes.
    Nabil E Boutagy, Joseph W Fowler, Kariona A Grabinska, Rebecca Cardone, Qiushi Sun, Kyla R Vazquez, Michael B Whalen, Xiaolong Zhu, Raja Chakraborty, Kathleen A Martin, Michael Simons, Casey E Romanoski, Richard G Kibbey, William C Sessa.
      The endothelium is a major target of the proinflammatory cytokine, tumor necrosis factor alpha (TNFα). Exposure of endothelial cells (EC) to proinflammatory stimuli leads to an increase in mitochondrial metabolism; however, the function and regulation of elevated mitochondrial metabolism in EC in response to proinflammatory cytokines remain unclear. Studies using high-resolution metabolomics and 13C-glucose and 13C-glutamine labeling flux techniques showed that pyruvate dehydrogenase activity (PDH) and oxidative tricarboxylic acid cycle (TCA) flux are elevated in human umbilical vein ECs in response to overnight (16 h) treatment with TNFα (10 ng/mL). Mechanistic studies indicated that TNFα mediated these metabolic changes via mitochondrial-specific protein degradation of pyruvate dehydrogenase kinase 4 (PDK4, inhibitor of PDH) by the Lon protease via an NF-κB-dependent mechanism. Using RNA sequencing following siRNA-mediated knockdown of the catalytically active subunit of PDH, PDHE1α (PDHA1 gene), we show that PDH flux controls the transcription of approximately one-third of the genes that are up-regulated by TNFα stimulation. Notably, TNFα-induced PDH flux regulates a unique signature of proinflammatory mediators (cytokines and chemokines) but not inducible adhesion molecules. Metabolomics and ChIP sequencing for acetylated modification on lysine 27 of histone 3 (H3K27ac) showed that TNFα-induced PDH flux promotes histone acetylation of specific gene loci via citrate accumulation and ATP-citrate lyase-mediated generation of acetyl CoA. Together, these results uncover a mechanism by which TNFα signaling increases oxidative TCA flux of glucose to support TNFα-induced gene transcription through extramitochondrial acetyl CoA generation and histone acetylation.
    Keywords:  TNF; endothelium; gene expression; inflammation; vascular
    DOI:  https://doi.org/10.1073/pnas.2218150120
  30. J Cell Biol. 2023 Oct 02. pii: e202309037. [Epub ahead of print]222(10):
    A nucleotide diphosphate kinase mediates tethering between mitochondria prior to fusion.
    Arisa Ikeda, Miho Iijima, Hiromi Sesaki.
      Mitochondrial fusion plays an important role in both their structure and function. In this issue, Su et al. (2023. J. Cell Biol.https://doi.org/10.1083/jcb.202301091) report that a nucleoside diphosphate kinase, NME3, facilitates mitochondrial tethering prior to fusion through its direct membrane-binding and hexamerization but not its kinase activity.
    DOI:  https://doi.org/10.1083/jcb.202309037
  31. Nat Commun. 2023 Sep 13. 14(1): 5637
    Global impact of somatic structural variation on the cancer proteome.
    Fengju Chen, Yiqun Zhang, Darshan S Chandrashekar, Sooryanarayana Varambally, Chad J Creighton.
      Both proteome and transcriptome data can help assess the relevance of non-coding somatic mutations in cancer. Here, we combine mass spectrometry-based proteomics data with whole genome sequencing data across 1307 human tumors spanning various tissues to determine the extent somatic structural variant (SV) breakpoint patterns impact protein expression of nearby genes. We find that about 25% of the hundreds of genes with SV-associated cis-regulatory alterations at the mRNA level are similarly associated at the protein level. SVs associated with enhancer hijacking, retrotransposon translocation, altered DNA methylation, or fusion transcripts are implicated in protein over-expression. SVs combined with altered protein levels considerably extend the numbers of patients with tumors somatically altered for critical pathways. We catalog both SV breakpoint patterns involving patient survival and genes with nearby SV breakpoints associated with increased cell dependency in cancer cell lines. Pan-cancer proteogenomics identifies targetable non-coding alterations, by virtue of the associated deregulated genes.
    DOI:  https://doi.org/10.1038/s41467-023-41374-8
  32. J Clin Invest. 2023 Sep 15. pii: e162515. [Epub ahead of print]133(18):
    Gut microbes and the liver circadian clock partition glucose and lipid metabolism.
    Katya Frazier, Sumeed Manzoor, Katherine Carroll, Orlando DeLeon, Sawako Miyoshi, Jun Miyoshi, Marissa St George, Alan Tan, Evan A Chrisler, Mariko Izumo, Joseph S Takahashi, Mrinalini C Rao, Vanessa A Leone, Eugene B Chang.
      Circadian rhythms govern glucose homeostasis, and their dysregulation leads to complex metabolic diseases. Gut microbes exhibit diurnal rhythms that influence host circadian networks and metabolic processes, yet underlying mechanisms remain elusive. Here, we showed hierarchical, bidirectional communication among the liver circadian clock, gut microbes, and glucose homeostasis in mice. To assess this relationship, we utilized mice with liver-specific deletion of the core circadian clock gene Bmal1 via Albumin-cre maintained in either conventional or germ-free housing conditions. The liver clock, but not the forebrain clock, required gut microbes to drive glucose clearance and gluconeogenesis. Liver clock dysfunctionality expanded proportions and abundances of oscillating microbial features by 2-fold relative to that in controls. The liver clock was the primary driver of differential and rhythmic hepatic expression of glucose and fatty acid metabolic pathways. Absent the liver clock, gut microbes provided secondary cues that dampened these rhythms, resulting in reduced lipid fuel utilization relative to carbohydrates. All together, the liver clock transduced signals from gut microbes that were necessary for regulating glucose and lipid metabolism and meeting energy demands over 24 hours.
    Keywords:  Fatty acid oxidation; Gluconeogenesis; Metabolism; Mouse models
    DOI:  https://doi.org/10.1172/JCI162515
  33. Science. 2023 Sep 15. 381(6663): 1182-1189
    The Batten disease gene product CLN5 is the lysosomal bis(monoacylglycero)phosphate synthase.
    Uche N Medoh, Andy Hims, Julie Y Chen, Ali Ghoochani, Kwamina Nyame, Wentao Dong, Monther Abu-Remaileh.
      Lysosomes critically rely on bis(monoacylglycero)phosphate (BMP) to stimulate lipid catabolism, cholesterol homeostasis, and lysosomal function. Alterations in BMP levels in monogenic and complex neurodegeneration suggest an essential function in human health. However, the site and mechanism responsible for BMP synthesis have been subject to debate for decades. Here, we report that the Batten disease gene product CLN5 is the elusive BMP synthase (BMPS). BMPS-deficient cells exhibited a massive accumulation of the BMP synthesis precursor lysophosphatidylglycerol (LPG), depletion of BMP species, and dysfunctional lipid metabolism. Mechanistically, we found that BMPS mediated synthesis through an energy-independent base exchange reaction between two LPG molecules with increased activity on BMP-laden vesicles. Our study elucidates BMP biosynthesis and reveals an anabolic function of late endosomes/lysosomes.
    DOI:  https://doi.org/10.1126/science.adg9288
  34. Life Sci Alliance. 2023 Dec;pii: e202302091. [Epub ahead of print]6(12):
    Mitochondrial membrane potential acts as a retrograde signal to regulate cell cycle progression.
    Choco Michael Gorospe, Gustavo Carvalho, Alicia Herrera Curbelo, Lisa Marchhart, Isabela C Mendes, Katarzyna Niedźwiecka, Paulina H Wanrooij.
      Mitochondria are central to numerous metabolic pathways whereby mitochondrial dysfunction has a profound impact and can manifest in disease. The consequences of mitochondrial dysfunction can be ameliorated by adaptive responses that rely on crosstalk from the mitochondria to the rest of the cell. Such mito-cellular signalling slows cell cycle progression in mitochondrial DNA-deficient (ρ0) Saccharomyces cerevisiae cells, but the initial trigger of the response has not been thoroughly studied. Here, we show that decreased mitochondrial membrane potential (ΔΨm) acts as the initial signal of mitochondrial stress that delays G1-to-S phase transition in both ρ0 and control cells containing mtDNA. Accordingly, experimentally increasing ΔΨm was sufficient to restore timely cell cycle progression in ρ0 cells. In contrast, cellular levels of oxidative stress did not correlate with the G1-to-S delay. Restored G1-to-S transition in ρ0 cells with a recovered ΔΨm is likely attributable to larger cell size, whereas the timing of G1/S transcription remained delayed. The identification of ΔΨm as a regulator of cell cycle progression may have implications for disease states involving mitochondrial dysfunction.
    DOI:  https://doi.org/10.26508/lsa.202302091
  35. Geroscience. 2023 Sep 12.
    Geroprotective interventions converge on gene expression programs of reduced inflammation and restored fatty acid metabolism.
    Tomer Landsberger, Ido Amit, Uri Alon.
      Understanding the mechanisms of geroprotective interventions is central to aging research. We compare four prominent interventions: senolysis, caloric restriction, in vivo partial reprogramming, and heterochronic parabiosis. Using published mice transcriptomic data, we juxtapose these interventions against normal aging. We find a gene expression program common to all four interventions, in which inflammation is reduced and several metabolic processes, especially fatty acid metabolism, are increased. Normal aging exhibits the inverse of this signature across multiple organs and tissues. A similar inverse signature arises in three chronic inflammation disease models in a non-aging context, suggesting that the shift in metabolism occurs downstream of inflammation. Chronic inflammation is also shown to accelerate transcriptomic age. We conclude that a core mechanism of geroprotective interventions acts through the reduction of inflammation with downstream effects that restore fatty acid metabolism. This supports the notion of directly targeting genes associated with these pathways to mitigate age-related deterioration.
    Keywords:  Aging; Geroprotective interventions; Inflammation; Longevity; Rejuvenation; Transcriptomics
    DOI:  https://doi.org/10.1007/s11357-023-00915-1
  36. Cell Metab. 2023 Sep 05. pii: S1550-4131(23)00303-0. [Epub ahead of print]
    Death-seq identifies regulators of cell death and senolytic therapies.
    Alex Colville, Jie-Yu Liu, Cristina Rodriguez-Mateo, Samantha Thomas, Heather D Ishak, Ronghao Zhou, Julian D D Klein, David W Morgens, Armon Goshayeshi, Jayesh S Salvi, David Yao, Kaitlyn Spees, Scott J Dixon, Chun Liu, June-Wha Rhee, Celine Lai, Joseph C Wu, Michael C Bassik, Thomas A Rando.
      Selectively ablating damaged cells is an evolving therapeutic approach for age-related disease. Current methods for genome-wide screens to identify genes whose deletion might promote the death of damaged or senescent cells are generally underpowered because of the short timescales of cell death as well as the difficulty of scaling non-dividing cells. Here, we establish "Death-seq," a positive-selection CRISPR screen optimized to identify enhancers and mechanisms of cell death. Our screens identified synergistic enhancers of cell death induced by the known senolytic ABT-263. The screen also identified inducers of cell death and senescent cell clearance in models of age-related diseases by a related compound, ABT-199, which alone is not senolytic but exhibits less toxicity than ABT-263. Death-seq enables the systematic screening of cell death pathways to uncover molecular mechanisms of regulated cell death subroutines and identifies drug targets for the treatment of diverse pathological states such as senescence, cancer, and fibrosis.
    Keywords:  CRISPR; Death-seq; cell death; death screen; genome-wide; positive selection; pulmonary fibrosis; senescence; senolytics; synthetic lethality
    DOI:  https://doi.org/10.1016/j.cmet.2023.08.008
  37. Free Radic Biol Med. 2023 Sep 13. pii: S0891-5849(23)00627-5. [Epub ahead of print]
    Nrf2 depletion in the context of loss-of-function Keap1 leads to mitolysosome accumulation.
    Sharadha Dayalan Naidu, Plamena R Angelova, Elena V Knatko, Chiara Leonardi, Miroslav Novak, Laureano de la Vega, Ian G Ganley, Andrey Y Abramov, Albena T Dinkova-Kostova.
      Transcription factor nuclear factor erythroid 2 p45-related factor 2 (Nrf2) is the principal determinant of the cellular redox homeostasis, contributing to mitochondrial function, integrity and bioenergetics. The main negative regulator of Nrf2 is Kelch-like ECH associated protein 1 (Keap1), a substrate adaptor for Cul3/Rbx1 ubiquitin ligase, which continuously targets Nrf2 for ubiquitination and proteasomal degradation. Loss-of-function mutations in Keap1 occur frequently in lung cancer, leading to constitutive Nrf2 activation. We used the human lung cancer cell line A549 and its CRISPR/Cas9-generated homozygous Nrf2-knockout (Nrf2-KO) counterpart to assess the role of Nrf2 on mitochondrial health. To confirm that the observed effects of Nrf2 deficiency are not due to clonal selection or long-term adaptation to the absence of Nrf2, we also depleted Nrf2 by siRNA (siNFE2L2), thus creating populations of Nrf2-knockdown (Nrf2-KD) A549 cells. Nrf2 deficiency decreased mitochondrial respiration, but increased the mitochondrial membrane potential, mass, DNA content, and the number of mitolysosomes. The proportion of ATG7 and ATG3 within their respective LC3B conjugates was increased in Nrf2-deficient cells with mutant Keap1, whereas the formation of new autophagosomes was not affected. Thus, in lung cancer cells with loss-of-function Keap1, Nrf2 facilitates mitolysosome degradation thereby ensuring timely clearance of damaged mitochondria.
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.09.009
  38. Trends Genet. 2023 Sep 14. pii: S0168-9525(23)00186-5. [Epub ahead of print]
    The evolution of aging and lifespan.
    Stacy Li, Juan Manuel Vazquez, Peter H Sudmant.
      Aging is a nearly inescapable trait among organisms yet lifespan varies tremendously across different species and spans several orders of magnitude in vertebrates alone. This vast phenotypic diversity is driven by distinct evolutionary trajectories and tradeoffs that are reflected in patterns of diversification and constraint in organismal genomes. Age-specific impacts of selection also shape allele frequencies in populations, thus impacting disease susceptibility and environment-specific mortality risk. Further, the mutational processes that spawn this genetic diversity in both germline and somatic cells are strongly influenced by age and life history. We discuss recent advances in our understanding of the evolution of aging and lifespan at organismal, population, and cellular scales, and highlight outstanding questions that remain unanswered.
    Keywords:  aging; diversity; evolution; genetics; lifespan; mutation
    DOI:  https://doi.org/10.1016/j.tig.2023.08.005
  39. PLoS Comput Biol. 2023 Sep;19(9): e1011374
    Mathematical reconstruction of the metabolic network in an in-vitro multiple myeloma model.
    Elias Vera-Siguenza, Cristina Escribano-Gonzalez, Irene Serrano-Gonzalo, Kattri-Liis Eskla, Fabian Spill, Daniel Tennant.
      It is increasingly apparent that cancer cells, in addition to remodelling their metabolism to survive and proliferate, adapt and manipulate the metabolism of other cells. This property may be a telling sign that pre-clinical tumour metabolism studies exclusively utilising in-vitro mono-culture models could prove to be limited for uncovering novel metabolic targets able to translate into clinical therapies. Although this is increasingly recognised, and work towards addressing the issue is becoming routinary much remains poorly understood. For instance, knowledge regarding the biochemical mechanisms through which cancer cells manipulate non-cancerous cell metabolism, and the subsequent impact on their survival and proliferation remains limited. Additionally, the variations in these processes across different cancer types and progression stages, and their implications for therapy, also remain largely unexplored. This study employs an interdisciplinary approach that leverages the predictive power of mathematical modelling to enrich experimental findings. We develop a functional multicellular in-silico model that facilitates the qualitative and quantitative analysis of the metabolic network spawned by an in-vitro co-culture model of bone marrow mesenchymal stem- and myeloma cell lines. To procure this model, we devised a bespoke human genome constraint-based reconstruction workflow that combines aspects from the legacy mCADRE & Metabotools algorithms, the novel redHuman algorithm, along with 13C-metabolic flux analysis. Our workflow transforms the latest human metabolic network matrix (Recon3D) into two cell-specific models coupled with a metabolic network spanning a shared growth medium. When cross-validating our in-silico model against the in-vitro model, we found that the in-silico model successfully reproduces vital metabolic behaviours of its in-vitro counterpart; results include cell growth predictions, respiration rates, as well as support for observations which suggest cross-shuttling of redox-active metabolites between cells.
    DOI:  https://doi.org/10.1371/journal.pcbi.1011374
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