bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2024–12–08
forty-two papers selected by
Christian Frezza, Universität zu Köln
  1. Ageing limits stemness and tumorigenesis by reprogramming iron homeostasis.
  2. SiRCle (Signature Regulatory Clustering) model integration reveals mechanisms of phenotype regulation in renal cancer.
  3. OPA1 and disease-causing mutants perturb mitochondrial nucleoid distribution.
  4. Glutamine is critical for the maintenance of type 1 conventional dendritic cells in normal tissue and the tumor microenvironment.
  5. An acute microglial metabolic response controls metabolism and improves memory.
  6. The cells that help the immune system fight lung cancer.
  7. Coordination of cytochrome bc1 complex assembly at MICOS.
  8. The liver converts fructose into lipids to fuel tumours.
  9. Respiratory complex II acting as a homeostatic regulatory sensor.
  10. Epi-microRNA mediated metabolic reprogramming counteracts hypoxia to preserve affinity maturation.
  11. Species differences in glycerol-3-phosphate metabolism reveals trade-offs between metabolic adaptations and cell proliferation.
  12. RANK drives structured intestinal epithelial expansion during pregnancy.
  13. OCIAD1 and prohibitins regulate the stability of the TIM23 protein translocase.
  14. Differential activity of MAPK signalling defines fibroblast subtypes in pancreatic cancer.
  15. Therapeutic hypoxia for mitochondrial disease via enhancement of hemoglobin affinity and inhibition of HIF-2α.
  16. Unraveling bidirectional evolution of unstable mitochondrial DNA mutations in hepatocellular carcinoma at single-cell resolution.
  17. FAHD1 and mitochondrial metabolism: a decade of pioneering discoveries.
  18. Applying single-cell and single-nucleus genomics to studies of cellular heterogeneity and cell fate transitions in the nervous system.
  19. Women in Autophagy: an initiative to promote gender parity in science.
  20. Mitochondrial calcium uniporter complex controls T-cell-mediated immune responses.
  21. Ageing of stem cells reduces their capacity to form tumours.
  22. Rhythmic astrocytic GABA production synchronizes neuronal circadian timekeeping in the suprachiasmatic nucleus.
  23. Opportunities and challenges of single-cell and spatially resolved genomics methods for neuroscience discovery.
  24. Discovering geroprotectors through the explainable artificial intelligence-based platform AgeXtend.
  25. Dietary fructose enhances tumour growth indirectly via interorgan lipid transfer.
  26. Seipin governs phosphatidic acid homeostasis at the inner nuclear membrane.
  27. What is ageing? Even the field's researchers can't agree.
  28. β-hydroxybutyrate is a metabolic regulator of proteostasis in the aged and Alzheimer disease brain.
  29. Diverse NKT cells regulate early inflammation and neurological outcomes after cardiac arrest and resuscitation.
  30. Regulation of ROS signaling by TIGAR induces cancer-modulating responses in the tumor microenvironment.
  31. The oestrous cycle stage affects mammary tumour sensitivity to chemotherapy.
  32. Frequent transitions in self-assembly across the evolution of a central metabolic enzyme.
  33. Metabolic modelling links Warburg effect to collagen formation, angiogenesis and inflammation in the tumoral stroma.
  34. Metabolic imaging distinguishes ovarian cancer subtypes and detects their early and variable responses to treatment.
  35. TPM4 condensates glycolytic enzymes and facilitates actin reorganization under hyperosmotic stress.
  36. Amino Acid and Glucose Fermentation Maintain ATP Content in Mouse and Human Malignant Glioma Cells.
  37. Redox-dependent purine degradation triggers postnatal loss of cardiac regeneration potential.
  38. Alternative splicing of Clock transcript mediates the response of circadian clocks to temperature changes.
  39. p53 induces circFRMD4A to suppress cancer development through glycolytic reprogramming and cuproptosis.
  40. Mitochondrial respiratory supercomplexes gear up for heat generation in brown adipose tissue.
  41. Clinical research framework proposal for ketogenic metabolic therapy in glioblastoma.
  42. Measuring the rate of NADPH consumption by glutathione reductase in the cytosol and mitochondria.
  1. Nature. 2024 Dec 04.
    Ageing limits stemness and tumorigenesis by reprogramming iron homeostasis.
    Xueqian Zhuang, Qing Wang, Simon Joost, Alexander Ferrena, David T Humphreys, Zhuxuan Li, Melissa Blum, Klavdija Krause, Selena Ding, Yuna Landais, Yingqian Zhan, Yang Zhao, Ronan Chaligne, Joo-Hyeon Lee, Sebastian E Carrasco, Umeshkumar K Bhanot, Richard P Koche, Matthew J Bott, Pekka Katajisto, Yadira M Soto-Feliciano, Thomas Pisanic, Tiffany Thomas, Deyou Zheng, Emily S Wong, Tuomas Tammela.
      Ageing is associated with a decline in the number and fitness of adult stem cells1,2. Ageing-associated loss of stemness is posited to suppress tumorigenesis3,4, but this hypothesis has not been tested in vivo. Here we use physiologically aged autochthonous genetically engineered5,6 mouse models and primary cells5,6 to demonstrate that ageing suppresses lung cancer initiation and progression by degrading the stemness of the alveolar cell of origin. This phenotype is underpinned by the ageing-associated induction of the transcription factor NUPR1 and its downstream target lipocalin-2 in the cell of origin in mice and humans, which leads to functional iron insufficiency in the aged cells. Genetic inactivation of the NUPR1-lipocalin-2 axis or iron supplementation rescues stemness and promotes the tumorigenic potential of aged alveolar cells. Conversely, targeting the NUPR1-lipocalin-2 axis is detrimental to young alveolar cells through ferroptosis induction. Ageing-associated DNA hypomethylation at specific enhancer sites is associated with increased NUPR1 expression, which is recapitulated in young alveolar cells through DNA methylation inhibition. We uncover that ageing drives functional iron insufficiency that leads to loss of stemness and tumorigenesis but promotes resistance to ferroptosis. These findings have implications for the therapeutic modulation of cellular iron homeostasis in regenerative medicine and in cancer prevention. Furthermore, our findings are consistent with a model whereby most human cancers initiate at a young age, thereby highlighting the importance of directing cancer prevention efforts towards young individuals.
    DOI:  https://doi.org/10.1038/s41586-024-08285-0
  2. Genome Med. 2024 Dec 04. 16(1): 144
    SiRCle (Signature Regulatory Clustering) model integration reveals mechanisms of phenotype regulation in renal cancer.
    Ariane Mora, Christina Schmidt, Brad Balderson, Christian Frezza, Mikael Bodén.
       BACKGROUND: Clear cell renal cell carcinoma (ccRCC) tumours develop and progress via complex remodelling of the kidney epigenome, transcriptome, proteome and metabolome. Given the subsequent tumour and inter-patient heterogeneity, drug-based treatments report limited success, calling for multi-omics studies to extract regulatory relationships, and ultimately, to develop targeted therapies. Yet, methods for multi-omics integration to reveal mechanisms of phenotype regulation are lacking.
    METHODS: Here, we present SiRCle (Signature Regulatory Clustering), a method to integrate DNA methylation, RNA-seq and proteomics data at the gene level by following central dogma of biology, i.e. genetic information proceeds from DNA, to RNA, to protein. To identify regulatory clusters across the different omics layers, we group genes based on the layer where the gene's dysregulation first occurred. We combine the SiRCle clusters with a variational autoencoder (VAE) to reveal key features from omics' data for each SiRCle cluster and compare patient subpopulations in a ccRCC and a PanCan cohort.
    RESULTS: Applying SiRCle to a ccRCC cohort, we showed that glycolysis is upregulated by DNA hypomethylation, whilst mitochondrial enzymes and respiratory chain complexes are translationally suppressed. Additionally, we identify metabolic enzymes associated with survival along with the possible molecular driver behind the gene's perturbations. By using the VAE to integrate omics' data followed by statistical comparisons between tumour stages on the integrated space, we found a stage-dependent downregulation of proximal renal tubule genes, hinting at a loss of cellular identity in cancer cells. We also identified the regulatory layers responsible for their suppression. Lastly, we applied SiRCle to a PanCan cohort and found common signatures across ccRCC and PanCan in addition to the regulatory layer that defines tissue identity.
    CONCLUSIONS: Our results highlight SiRCle's ability to reveal mechanisms of phenotype regulation in cancer, both specifically in ccRCC and broadly in a PanCan context. SiRCle ranks genes according to biological features. https://github.com/ArianeMora/SiRCle_multiomics_integration .
    Keywords:  Clear cell renal cell carcinoma; Integration; Machine learning; Metabolism; Multi-omics; PanCan; Regulation; Variational autoencoder
    DOI:  https://doi.org/10.1186/s13073-024-01415-3
  3. Cell Death Dis. 2024 Nov 30. 15(11): 870
    OPA1 and disease-causing mutants perturb mitochondrial nucleoid distribution.
    J Macuada, I Molina-Riquelme, G Vidal, N Pérez-Bravo, C Vásquez-Trincado, G Aedo, D Lagos, P Yu-Wai-Man, R Horvath, T J Rudge, B Cartes-Saavedra, V Eisner.
      Optic atrophy protein 1 (OPA1) mediates inner mitochondrial membrane (IMM) fusion and cristae organization. Mutations in OPA1 cause autosomal dominant optic atrophy (ADOA), a leading cause of blindness. Cells from ADOA patients show impaired mitochondrial fusion, cristae structure, bioenergetic function, and mitochondrial DNA (mtDNA) integrity. The mtDNA encodes electron transport chain subunits and is packaged into nucleoids spread within the mitochondrial population. Nucleoids interact with the IMM, and their distribution is tightly linked to mitochondrial fusion and cristae shaping. Yet, little is known about the physio-pathological relevance of nucleoid distribution. We studied the effect of OPA1 and ADOA-associated mutants on nucleoid distribution using high-resolution confocal microscopy. We applied a novel model incorporating the mitochondrial context, separating nucleoid distribution into the array in the mitochondrial population and intramitochondrial longitudinal distribution. Opa1-null cells showed decreased mtDNA levels and nucleoid abundance. Also, loss of Opa1 led to an altered distribution of nucleoids in the mitochondrial population, loss of cristae periodicity, and altered nucleoids to cristae proximity partly rescued by OPA1 isoform 1. Overexpression of WT OPA1 or ADOA-causing mutants c.870+5 G > A or c.2713 C > T in WT cells, showed perturbed nucleoid array in the mitochondria population associated with cristae disorganization, which was partly reproduced in Skeletal muscle-derived fibroblasts from ADOA patients harboring the same mutants. Opa1-null and cells overexpressing ADOA mutants accumulated mitochondria without nucleoids. Interestingly, intramitochondrial nucleoid distribution was only altered in Opa1-null cells. Altogether, our results highlight the relevance of OPA1 in nucleoid distribution in the mitochondrial landscape and at a single-organelle level and shed light on new components of ADOA etiology.
    DOI:  https://doi.org/10.1038/s41419-024-07165-9
  4. Proc Natl Acad Sci U S A. 2024 Dec 10. 121(50): e2412157121
    Glutamine is critical for the maintenance of type 1 conventional dendritic cells in normal tissue and the tumor microenvironment.
    Graham P Lobel, Nanumi Han, William A Molina Arocho, Michal Silber, Jason Shoush, Michael C Noji, Tsun Ki Jerrick To, Li Zhai, Nicholas P Lesner, M Celeste Simon, Malay Haldar.
      Proliferating tumor cells take up glutamine for anabolic processes, engendering glutamine deficiency in the tumor microenvironment. How this might impact immune cells is not well understood. Using multiple mouse models of soft tissue sarcomas, glutamine antagonists, as well as genetic and pharmacological inhibition of glutamine utilization, we found that the number and frequency of conventional dendritic cells (cDCs) is dependent on microenvironmental glutamine levels. cDCs comprise two distinct subsets-cDC1s and cDC2s, with the former subset playing a critical role in antigen cross-presentation and tumor immunity. While both subsets show dependence on glutamine, cDC1s are particularly sensitive. Notably, glutamine antagonism did not reduce the frequency of DC precursors but decreased the proliferation and survival of cDC1s. Further studies suggest a role of the nutrient sensing mechanistic target of rapamycin (mTOR) signaling pathway in this process. Taken together, these findings uncover glutamine dependence of cDC1s that is coopted by tumors to escape immune responses.
    Keywords:  dendritic cells; glutamine; tumor microenvironment
    DOI:  https://doi.org/10.1073/pnas.2412157121
  5. Elife. 2024 Dec 03. pii: RP87120. [Epub ahead of print]12
    An acute microglial metabolic response controls metabolism and improves memory.
    Anne Drougard, Eric H Ma, Vanessa Wegert, Ryan Sheldon, Ilaria Panzeri, Naman Vatsa, Stefanos Apostle, Luca Fagnocchi, Judith Schaf, Klaus Gossens, Josephine Völker, Shengru Pang, Anna Bremser, Erez Dror, Francesca Giacona, Sagar Sagar, Michael X Henderson, Marco Prinz, Russell G Jones, John Andrew Pospisilik.
      Chronic high-fat feeding triggers metabolic dysfunction including obesity, insulin resistance, and diabetes. How high-fat intake first triggers these pathophysiological states remains unknown. Here, we identify an acute microglial metabolic response that rapidly translates intake of high-fat diet (HFD) to a surprisingly beneficial effect on metabolism and spatial/learning memory. High-fat intake rapidly increases palmitate levels in cerebrospinal fluid and triggers a wave of microglial metabolic activation characterized by mitochondrial membrane activation and fission as well as metabolic skewing toward aerobic glycolysis. These effects are detectable throughout the brain and can be detected within as little as 12 hr of HFD exposure. In vivo, microglial ablation and conditional DRP1 deletion show that the microglial metabolic response is necessary for the acute effects of HFD. 13C-tracing experiments reveal that in addition to processing via β-oxidation, microglia shunt a substantial fraction of palmitate toward anaplerosis and re-release of bioenergetic carbons into the extracellular milieu in the form of lactate, glutamate, succinate, and intriguingly, the neuroprotective metabolite itaconate. Together, these data identify microglia as a critical nutrient regulatory node in the brain, metabolizing away harmful fatty acids and liberating the same carbons as alternate bioenergetic and protective substrates for surrounding cells. The data identify a surprisingly beneficial effect of short-term HFD on learning and memory.
    Keywords:  cell biology; diabetes; inflammation; memory; metabolism; microglia; mitochondria; mouse; neuroscience
    DOI:  https://doi.org/10.7554/eLife.87120
  6. Nature. 2024 Dec;636(8041): 11
    The cells that help the immune system fight lung cancer.
      
    Keywords:  Cancer
    DOI:  https://doi.org/10.1038/d41586-024-03857-6
  7. EMBO Rep. 2024 Dec 02.
    Coordination of cytochrome bc1 complex assembly at MICOS.
    Ralf M Zerbes, Lilia Colina-Tenorio, Maria Bohnert, Karina von der Malsburg, Christian D Peikert, Carola S Mehnert, Inge Perschil, Rhena F U Klar, Rinse de Boer, Anita Kram, Ida van der Klei, Silke Oeljeklaus, Bettina Warscheid, Heike Rampelt, Martin van der Laan.
      The boundary and cristae domains of the mitochondrial inner membrane are connected by crista junctions. Most cristae membrane proteins are nuclear-encoded and inserted by the mitochondrial protein import machinery into the inner boundary membrane. Thus, they must overcome the diffusion barrier imposed by crista junctions to reach their final location. Here, we show that respiratory chain complexes and assembly intermediates are physically connected to the mitochondrial contact site and cristae organizing system (MICOS) that is essential for the formation and stability of crista junctions. We identify the inner membrane protein Mar26 (Fmp10) as a determinant in the biogenesis of the cytochrome bc1 complex (complex III). Mar26 couples a Rieske Fe/S protein-containing assembly intermediate to MICOS. Our data indicate that Mar26 maintains an assembly-competent Rip1 pool at crista junctions where complex III maturation likely occurs. MICOS facilitates efficient Rip1 assembly by recruiting complex III assembly intermediates to crista junctions. We propose that MICOS, via interaction with assembly factors such as Mar26, contributes to the spatial and temporal coordination of respiratory chain biogenesis.
    Keywords:   bc 1 Complex; Cristae; MICOS; Mitochondria; Respiratory Chain
    DOI:  https://doi.org/10.1038/s44319-024-00336-x
  8. Nature. 2024 Dec 04.
    The liver converts fructose into lipids to fuel tumours.
    Hyllana C D Medeiros, Sophia Y Lunt.
      
    Keywords:  Cancer; Metabolism
    DOI:  https://doi.org/10.1038/d41586-024-03653-2
  9. Phys Chem Chem Phys. 2024 Dec 02.
    Respiratory complex II acting as a homeostatic regulatory sensor.
    Muhammad A Hagras.
      The succinate-ubiquinone oxidoreductase (SQR) complex connects two of the cell's most vital energy-producing metabolic processes: the tricarboxylic acid cycle and the electron transport chain. Hence, the SQR complex is essential in cell metabolism, and its malfunction leads to the progression of multiple metabolic disorders and other diseases, such as cancer. In the current study, we calculated the electron tunneling (ET) pathways between the different redox systems in the SQR complex, including the SQR ligands and the distant heme b redox center, using the broken-symmetry semi-empirical ZINDO method. Interestingly, we discovered a water channel running from the mitochondrial matrix, filling the space between Fe3S4 and heme b redox centers. To investigate the physiological function of the water channel, we performed extensive molecular dynamics (MD) simulations of the membrane-embedded SQR complex in small and large water boxes, representing regular (MDA) and extended (MDB) volume states, respectively. We found that under regular volume conditions (MDA), the ET reaction is conducted through both the iron-sulfur cluster chain (i.e., pathway A) and through heme b (i.e., pathway B). Hence, the SQR complex encompasses an internal interferometer similar to the Mach-Zender interferometer, such that the tunneling electron experiences a self-interference effect through pathways A and B, enhancing the SQR complex's overall ET thermodynamics and favoring the forward ET direction of oxidizing succinate to fumarate and reducing ubiquinone to ubiquinol. On the other hand, we found that under extended volume conditions (MDB), the internal water channel of the SQR complex "senses" the expansion in the mitochondrial volume, pushing the heme b and Fe4S3 redox centers apart and hence lowering the SQR equilibrium constant to almost unity. Therefore, the SQR complex could be driven to work in the reverse direction, catalyzing the production of ubiquinone molecules essential for the physiological function of respiratory complexes I and III and restoring the inner-mitochondrial membrane potential, which leads to restoring the function of the H-K anti-porter, pumping K+ outward from the matrix and restoring the regular mitochondrial volume.
    DOI:  https://doi.org/10.1039/d4cp03552f
  10. Nat Commun. 2024 Dec 03. 15(1): 10516
    Epi-microRNA mediated metabolic reprogramming counteracts hypoxia to preserve affinity maturation.
    Rinako Nakagawa, Miriam Llorian, Sunita Varsani-Brown, Probir Chakravarty, Jeannie M Camarillo, David Barry, Roger George, Neil P Blackledge, Graham Duddy, Neil L Kelleher, Robert J Klose, Martin Turner, Dinis P Calado.
      To increase antibody affinity against pathogens, positively selected GC-B cells initiate cell division in the light zone (LZ) of germinal centers (GCs). Among these, higher-affinity clones migrate to the dark zone (DZ) and vigorously proliferate by utilizing energy provided by oxidative phosphorylation (OXPHOS). However, it remains unknown how positively selected GC-B cells adapt their metabolism for cell division in the glycolysis-dominant, cell cycle arrest-inducing, hypoxic LZ microenvironment. Here, we show that microRNA (miR)-155 mediates metabolic reprogramming during positive selection to protect high-affinity clones. Mechanistically, miR-155 regulates H3K36me2 levels in hypoxic conditions by directly repressing the histone lysine demethylase, Kdm2a, whose expression increases in response to hypoxia. The miR-155-Kdm2a interaction is crucial for enhancing OXPHOS through optimizing the expression of vital nuclear mitochondrial genes under hypoxia, thereby preventing excessive production of reactive oxygen species and subsequent apoptosis. Thus, miR-155-mediated epigenetic regulation promotes mitochondrial fitness in high-affinity GC-B cells, ensuring their expansion and consequently affinity maturation.
    DOI:  https://doi.org/10.1038/s41467-024-54937-0
  11. Biochim Biophys Acta Bioenerg. 2024 Dec 02. pii: S0005-2728(24)00500-0. [Epub ahead of print] 149530
    Species differences in glycerol-3-phosphate metabolism reveals trade-offs between metabolic adaptations and cell proliferation.
    Kateryna Gaertner, Mügen Terzioglu, Craig Michell, Riikka Tapanainen, Jaakko Pohjoismäki, Eric Dufour, Sina Saari.
      The temperate climate-adapted brown hare (Lepus europaeus) and the cold-adapted mountain hare (Lepus timidus) are closely related and interfertile species. However, their skin fibroblasts display distinct gene expression profiles related to fundamental cellular processes. This indicates important metabolic divergence between the two species. Through targeted metabolomics and metabolite tracing, we identified species-specific variations in glycerol 3-phosphate (G3P) metabolism. G3P is a key metabolite of the G3P shuttle, which transfers reducing equivalents from cytosolic NADH to the mitochondrial electron transport chain (ETC), consequently regulating glycolysis, lipid metabolism, and mitochondrial bioenergetics. Alterations in G3P metabolism have been implicated in multiple human pathologies including cancer and diabetes. We observed that mountain hare mitochondria exhibit elevated G3P shuttle activity, alongside increased membrane potential and decreased mitochondrial temperature. Silencing mitochondrial G3P dehydrogenase (GPD2), which couples the conversion of G3P to the ETC, uncovered its species-specific role in controlling mitochondrial membrane potential and highlighted its involvement in skin fibroblast thermogenesis. Unexpectedly, GPD2 silencing enhanced wound healing and cell proliferation rates in a species-specific manner. Our study underscores the pivotal role of the G3P shuttle in mediating physiological, bioenergetic, and metabolic divergence between these hare species.
    Keywords:  Glycerol-3-phosphate; Hares; Metabolism; Mitochondria; Mitochondrial membrane potential; Thermogenesis; Wound healing
    DOI:  https://doi.org/10.1016/j.bbabio.2024.149530
  12. Nature. 2024 Dec 04.
    RANK drives structured intestinal epithelial expansion during pregnancy.
    Masahiro Onji, Verena Sigl, Thomas Lendl, Maria Novatchkova, Asier Ullate-Agote, Amanda Andersson-Rolf, Ivona Kozieradzki, Rubina Koglgruber, Tsung-Pin Pai, Dominic Lichtscheidl, Komal Nayak, Matthias Zilbauer, Natalia A Carranza García, Laura Katharina Sievers, Maren Falk-Paulsen, Shane J F Cronin, Astrid Hagelkruys, Shinichiro Sawa, Lisa C Osborne, Philip Rosenstiel, Manolis Pasparakis, Jürgen Ruland, Hiroshi Takayanagi, Hans Clevers, Bon-Kyoung Koo, Josef M Penninger.
      During reproduction, multiple species such as insects and all mammals undergo extensive physiological and morphological adaptions to ensure health and survival of the mother and optimal development of the offspring. Here we report that the intestinal epithelium undergoes expansion during pregnancy and lactation in mammals. This enlargement of the intestinal surface area results in a novel geometry of expanded villi. Receptor activator of nuclear factor-κΒ (RANK, encoded by TNFRSF11A) and its ligand RANKL were identified as a molecular pathway involved in this villous expansion of the small intestine in vivo in mice and in intestinal mouse and human organoids. Mechanistically, RANK-RANKL protects gut epithelial cells from cell death and controls the intestinal stem cell niche through BMP receptor signalling, resulting in the elongation of villi and a prominent increase in the intestinal surface. As a transgenerational consequence, babies born to female mice that lack Rank in the intestinal epithelium show reduced weight and develop glucose intolerance after metabolic stress. Whereas gut epithelial remodelling in pregnancy/lactation is reversible, constitutive expression of an active form of RANK is sufficient to drive intestinal expansion followed by loss of villi and stem cells, and prevents the formation of Apcmin-driven small intestinal stem cell tumours. These data identify RANK-RANKL as a pathway that drives intestinal epithelial expansion in pregnancy/lactation, one of the most elusive and fundamental tissue remodelling events in mammalian life history and evolution.
    DOI:  https://doi.org/10.1038/s41586-024-08284-1
  13. Cell Rep. 2024 Dec 03. pii: S2211-1247(24)01389-5. [Epub ahead of print]43(12): 115038
    OCIAD1 and prohibitins regulate the stability of the TIM23 protein translocase.
    Praveenraj Elancheliyan, Klaudia K Maruszczak, Remigiusz Adam Serwa, Till Stephan, Ahmet Sadik Gulgec, Mayra A Borrero-Landazabal, Sonia Ngati, Aleksandra Gosk, Stefan Jakobs, Michal Wasilewski, Agnieszka Chacinska.
      Mitochondrial proteins are transported and sorted to the matrix or inner mitochondrial membrane by the presequence translocase TIM23. In yeast, this essential and highly conserved machinery is composed of the core subunits Tim23 and Tim17. The architecture, assembly, and regulation of the human TIM23 complex are poorly characterized. The human genome encodes two paralogs, TIMM17A and TIMM17B. Here, we describe an unexpected role of the ovarian cancer immunoreactive antigen domain-containing protein 1 (OCIAD1) and the prohibitin complex in the biogenesis of human TIM23. Prohibitins were required to stabilize both the TIMM17A- and TIMM17B-containing variants of the translocase. Interestingly, OCIAD1 assembled with the prohibitin complex to protect the TIMM17A variant from degradation by the YME1L protease. The expression of OCIAD1 was in turn regulated by the status of the TIM23 complex. We postulate that OCIAD1 together with prohibitins constitute a regulatory axis that differentially regulates variants of human TIM23.
    Keywords:  CP: Cell biology; OCIAD1; TIM23 translocase; biogenesis; mitochondria; prohibitin
    DOI:  https://doi.org/10.1016/j.celrep.2024.115038
  14. Nat Commun. 2024 Dec 03. 15(1): 10534
    Differential activity of MAPK signalling defines fibroblast subtypes in pancreatic cancer.
    Lisa Veghini, Davide Pasini, Rui Fang, Pietro Delfino, Dea Filippini, Christian Neander, Caterina Vicentini, Elena Fiorini, Francesca Lupo, Sabrina L D'Agosto, Carmine Carbone, Antonio Agostini, Geny Piro, Diego Rosa, Michele Bevere, Peter Markus, Diana Behrens, Claudio Luchini, Rita T Lawlor, Aldo Scarpa, Giulia Biffi, Phyllis F Cheung, Jens T Siveke, Vincenzo Corbo.
      Fibroblast heterogeneity is increasingly recognised across cancer conditions. Given their important contribution to disease progression, mapping fibroblasts' heterogeneity is critical to devise effective anti-cancer therapies. Cancer-associated fibroblasts (CAFs) represent the most abundant cell population in pancreatic ductal adenocarcinoma (PDAC). Whether CAF phenotypes are differently specified by PDAC cell lineages remains to be elucidated. Here, we reveal an important role for the MAPK signalling pathway in defining PDAC CAF phenotypes. We show that epithelial MAPK activity promotes the myofibroblastic differentiation of CAFs by sustaining the expression and secretion of TGF-β1. We integrate single-cell profiling of post-perturbation transcriptional responses from mouse models with cellular and spatial profiles of human tissues to define a MAPKhigh CAF (mapCAF) phenotype. We show that this phenotype associates with basal-like tumour cells and reduced frequency of CD8+ T cells. In addition to elevated MAPK activity, this mapCAF phenotype is characterized by TGF-β signalling, hypoxia responsive signatures, and immunoregulatory gene programs. Furthermore, the mapCAF signature is enriched in myofibroblastic CAFs from various cancer conditions and correlates with reduced response to immune checkpoint inhibition in melanoma. Altogether, our data expand our knowledge on CAF phenotype heterogeneity and reveal a potential strategy for targeting myofibroblastic CAFs in vivo.
    DOI:  https://doi.org/10.1038/s41467-024-54975-8
  15. J Clin Invest. 2024 Dec 02. pii: e185569. [Epub ahead of print]134(23):
    Therapeutic hypoxia for mitochondrial disease via enhancement of hemoglobin affinity and inhibition of HIF-2α.
    Hong Wang, Maria Miranda, Eizo Marutani, Paul Lichtenegger, Gregory R Wojtkiewicz, Fumito Ichinose, Vamsi K Mootha.
      
    Keywords:  Genetics; Hypoxia
    DOI:  https://doi.org/10.1172/JCI185569
  16. Hepatology. 2024 Oct 11.
    Unraveling bidirectional evolution of unstable mitochondrial DNA mutations in hepatocellular carcinoma at single-cell resolution.
    Kaixiang Zhou, Zhenni Wang, Wenjie Guo, Fanfan Xie, Qing Yuan, Shanshan Guo, Huanqin Zhang, Yang Liu, Xiwen Gu, Wenjie Song, Xu Guo, Jinliang Xing.
       BACKGROUND AND AIMS: Somatic mutations in mitochondrial DNA (mtDNA) are abundant in HCC and directly affect metabolic homeostasis and tumor progression. The mixed population of mutant and wild-type mtDNA alleles within a cell, termed heteroplasmy, can vary from cell-to-cell and orchestrate tumorigenesis. However, the systematic evolutionary dynamics of somatic mtDNA mutations in HCC tissues remain to be delineated at single-cell resolution.
    APPROACH AND RESULTS: We established the single-cell capture-based mtDNA sequencing approach for accurately detecting somatic mtDNA mutations at single-cell resolution. Based on single-cell capture-based mtDNA sequencing, the single-cell somatic mtDNA mutational landscape, intratumor heterogeneity (ITH), and spatiotemporal clonal evolution were systematically investigated in 1641 single cells from 11 patients with HCC and 528 single cells from 2 patient-derived xenografts mouse models. Our data revealed the presence of 2 distinct categories of mtDNA mutation at single-cell resolution, including stable mutations exhibiting similar heteroplasmy levels and unstable mutations exhibiting remarkable cell-to-cell variability of heteroplasmy levels. Furthermore, the proportion of unstable mtDNA mutations was positively associated with the ITH of patients with HCC, with high ITH reflecting the proliferative and aggressive clinicopathological features of HCC cells. In addition, reconstruction of the evolutionary history classified HCC evolution patterns as linear or branched. Notably, spatiotemporal lineage tracing in patient-derived xenograft mouse models and multifocal lesions revealed bidirectional evolution of unstable mtDNA mutations during HCC progression.
    CONCLUSIONS: Our study unravels the landscape of single-cell somatic mtDNA mutations in HCC tissues and reveals the bidirectional evolution of unstable mtDNA mutations, with potential implications for HCC stratification and therapeutic intervention.
    DOI:  https://doi.org/10.1097/HEP.0000000000001113
  17. FEBS J. 2024 Dec 06.
    FAHD1 and mitochondrial metabolism: a decade of pioneering discoveries.
    Elia Cappuccio, Max Holzknecht, Michèle Petit, Anne Heberle, Yana Rytchenko, Athanasios Seretis, Ciro L Pierri, Hubert Gstach, Pidder Jansen-Dürr, Alexander K H Weiss.
      This review consolidates a decade of research on fumarylacetoacetate hydrolase domain containing protein 1 (FAHD1), a mitochondrial oxaloacetate tautomerase and decarboxylase with profound implications in cellular metabolism. Despite its critical role as a regulator in mitochondrial metabolism, FAHD1 has remained an often-overlooked enzyme in broader discussions of mitochondrial function. After more than 12 years of research, it is increasingly clear that FAHD1's contributions to cellular metabolism, oxidative stress regulation, and disease processes such as cancer and aging warrant recognition in both textbooks and comprehensive reviews. The review delves into the broader implications of FAHD1 in mitochondrial function, emphasizing its roles in mitigating reactive oxygen species (ROS) levels and regulating complex II activity, particularly in cancer cells. This enzyme's significance is further highlighted in the context of aging, where FAHD1's activity has been shown to influence cellular senescence, mitochondrial quality control, and the aging process. Moreover, FAHD1's involvement in glutamine metabolism and its impact on cancer cell proliferation, particularly in aggressive breast cancer subtypes, underscores its potential as a therapeutic target. In addition to providing a comprehensive account of FAHD1's biochemical properties and structural insights, the review integrates emerging hypotheses regarding its role in metabolic reprogramming, immune regulation, and mitochondrial dynamics. By establishing a detailed understanding of FAHD1's physiological roles and therapeutic potential, this work advocates for FAHD1's recognition in foundational texts and resources, marking a pivotal step in its integration into mainstream metabolic research and clinical applications in treating metabolic disorders, cancer, and age-related diseases.
    Keywords:  FAHD1; ODx; ROS; TCA cycle; aging and cellular senescence; cancer metabolism; glutamine metabolism; mitochondrial dysfunction; mitochondrial metabolism
    DOI:  https://doi.org/10.1111/febs.17345
  18. Nat Neurosci. 2024 Dec;27(12): 2278-2291
    Applying single-cell and single-nucleus genomics to studies of cellular heterogeneity and cell fate transitions in the nervous system.
    Igor Adameyko, Trygve Bakken, Aparna Bhaduri, Chintan Chhatbar, Mariella G Filbin, David Gate, Hannah Hochgerner, Chang Nam Kim, Jordan Krull, Gioele La Manno, Qingyun Li, Sten Linnarsson, Qin Ma, Christian Mayer, Vilas Menon, Patricia Nano, Marco Prinz, Steve Quake, Christopher A Walsh, Jin Yang, Omer Ali Bayraktar, Ozgun Gokce, Naomi Habib, Genevieve Konopka, Shane A Liddelow, Tomasz J Nowakowski.
      Single-cell and single-nucleus genomic approaches can provide unbiased and multimodal insights. Here, we discuss what constitutes a molecular cell atlas and how to leverage single-cell omics data to generate hypotheses and gain insights into cell transitions in development and disease of the nervous system. We share points of reflection on what to consider during study design and implementation as well as limitations and pitfalls.
    DOI:  https://doi.org/10.1038/s41593-024-01827-9
  19. Nat Cell Biol. 2024 Dec 02.
    Women in Autophagy: an initiative to promote gender parity in science.
    Mericka McCabe, Patricia Boya, Ruey-Hwa Chen, Charleen T Chu, Maria Isabel Colombo, Laura Delgui, Eeva-Liisa Eskelinen, Maho Hamasaki, Malene Hansen, Congcong He, Marja Jäättelä, Adi Kimchi, Claudine Kraft, Mondira Kundu, Alicia Melendez, Sophie Pattingre, Tassula Proikas-Cezanne, Salwa Sebti, Anna Katharina Simon, Anne Simonsen, Sharon A Tooze, Maria Ines Vaccaro, Xiaochen Wang, Eileen White, Yan Zhao, Ana Maria Cuervo.
      
    DOI:  https://doi.org/10.1038/s41556-024-01566-w
  20. EMBO Rep. 2024 Dec 02.
    Mitochondrial calcium uniporter complex controls T-cell-mediated immune responses.
    Magdalena Shumanska, Dmitri Lodygin, Christine S Gibhardt, Christian Ickes, Ioana Stejerean-Todoran, Lena C M Krause, Kira Pahl, Lianne J H C Jacobs, Andrea Paluschkiwitz, Shuya Liu, Angela Boshnakovska, Niels Voigt, Tobias J Legler, Martin Haubrock, Miso Mitkovski, Gereon Poschmann, Peter Rehling, Sven Dennerlein, Jan Riemer, Alexander Flügel, Ivan Bogeski.
      T-cell receptor (TCR)-induced Ca2+ signals are essential for T-cell activation and function. In this context, mitochondria play an important role and take up Ca2+ to support elevated bioenergetic demands. However, the functional relevance of the mitochondrial-Ca2+-uniporter (MCU) complex in T-cells was not fully understood. Here, we demonstrate that TCR activation causes rapid mitochondrial Ca2+ (mCa2+) uptake in primary naive and effector human CD4+ T-cells. Compared to naive T-cells, effector T-cells display elevated mCa2+ and increased bioenergetic and metabolic output. Transcriptome and proteome analyses reveal molecular determinants involved in the TCR-induced functional reprogramming and identify signalling pathways and cellular functions regulated by MCU. Knockdown of MCUa (MCUaKD), diminishes mCa2+ uptake, mitochondrial respiration and ATP production, as well as T-cell migration and cytokine secretion. Moreover, MCUaKD in rat CD4+ T-cells suppresses autoimmune responses in an experimental autoimmune encephalomyelitis (EAE) multiple sclerosis model. In summary, we demonstrate that mCa2+ uptake through MCU is essential for proper T-cell function and has a crucial role in autoimmunity. T-cell specific MCU inhibition is thus a potential tool for targeting autoimmune disorders.
    Keywords:  Autoimmunity; Calcium; MCU; Mitochondria; T-cell
    DOI:  https://doi.org/10.1038/s44319-024-00313-4
  21. Nature. 2024 Dec 04.
    Ageing of stem cells reduces their capacity to form tumours.
    Tatiana Cañeque, Raphaël Rodriguez.
      
    Keywords:  Ageing; Cancer; Stem cells
    DOI:  https://doi.org/10.1038/d41586-024-03721-7
  22. EMBO J. 2024 Dec 02.
    Rhythmic astrocytic GABA production synchronizes neuronal circadian timekeeping in the suprachiasmatic nucleus.
    Natalie Ness, Sandra Díaz-Clavero, Marieke M B Hoekstra, Marco Brancaccio.
      Astrocytes of the suprachiasmatic nucleus (SCN) can regulate sleep-wake cycles in mammals. However, the nature of the information provided by astrocytes to control circadian patterns of behavior is unclear. Neuronal circadian activity across the SCN is organized into spatiotemporal waves that govern seasonal adaptations and timely engagement of behavioral outputs. Here, we show that astrocytes across the mouse SCN exhibit instead a highly uniform, pulse-like nighttime activity. We find that rhythmic astrocytic GABA production via polyamine degradation provides an inhibitory nighttime tone required for SCN circuit synchrony, thereby acting as an internal astrocyte zeitgeber (or "astrozeit"). We further identify synaptic GABA and astrocytic GABA as two key players underpinning coherent spatiotemporal circadian patterns of SCN neuronal activity. In describing a new mechanism by which astrocytes contribute to circadian timekeeping, our work provides a general blueprint for understanding how astrocytes encode temporal information underlying complex behaviors in mammals.
    Keywords:  Astrocyte; Circadian Clock; GABA; MAO-B; SCN
    DOI:  https://doi.org/10.1038/s44318-024-00324-w
  23. Nat Neurosci. 2024 Dec;27(12): 2292-2309
    Opportunities and challenges of single-cell and spatially resolved genomics methods for neuroscience discovery.
    Boyan Bonev, Castelo-Branco Gonçalo, Fei Chen, Simone Codeluppi, M Ryan Corces, Jean Fan, Myriam Heiman, Kenneth Harris, Fumitaka Inoue, Manolis Kellis, Ariel Levine, Mo Lotfollahi, Chongyuan Luo, Kristen R Maynard, Mor Nitzan, Vijay Ramani, Rahul Satijia, Lucas Schirmer, Yin Shen, Na Sun, Gilad S Green, Fabian Theis, Xiao Wang, Joshua D Welch, Ozgun Gokce, Genevieve Konopka, Shane Liddelow, Evan Macosko, Omer Bayraktar, Naomi Habib, Tomasz J Nowakowski.
      Over the past decade, single-cell genomics technologies have allowed scalable profiling of cell-type-specific features, which has substantially increased our ability to study cellular diversity and transcriptional programs in heterogeneous tissues. Yet our understanding of mechanisms of gene regulation or the rules that govern interactions between cell types is still limited. The advent of new computational pipelines and technologies, such as single-cell epigenomics and spatially resolved transcriptomics, has created opportunities to explore two new axes of biological variation: cell-intrinsic regulation of cell states and expression programs and interactions between cells. Here, we summarize the most promising and robust technologies in these areas, discuss their strengths and limitations and discuss key computational approaches for analysis of these complex datasets. We highlight how data sharing and integration, documentation, visualization and benchmarking of results contribute to transparency, reproducibility, collaboration and democratization in neuroscience, and discuss needs and opportunities for future technology development and analysis.
    DOI:  https://doi.org/10.1038/s41593-024-01806-0
  24. Nat Aging. 2024 Dec 03.
    Discovering geroprotectors through the explainable artificial intelligence-based platform AgeXtend.
    Sakshi Arora, Aayushi Mittal, Subhadeep Duari, Sonam Chauhan, Nilesh Kumar Dixit, Sanjay Kumar Mohanty, Arushi Sharma, Saveena Solanki, Anmol Kumar Sharma, Vishakha Gautam, Pushpendra Singh Gahlot, Shiva Satija, Jeet Nanshi, Nikita Kapoor, Lavanya Cb, Debarka Sengupta, Parul Mehrotra, Tarini Shankar Ghosh, Gaurav Ahuja.
      Aging involves metabolic changes that lead to reduced cellular fitness, yet the role of many metabolites in aging is unclear. Understanding the mechanisms of known geroprotective molecules reveals insights into metabolic networks regulating aging and aids in identifying additional geroprotectors. Here we present AgeXtend, an artificial intelligence (AI)-based multimodal geroprotector prediction platform that leverages bioactivity data of known geroprotectors. AgeXtend encompasses modules that predict geroprotective potential, assess toxicity and identify target proteins and potential mechanisms. We found that AgeXtend accurately identified the pro-longevity effects of known geroprotectors excluded from training data, such as metformin and taurine. Using AgeXtend, we screened ~1.1 billion compounds and identified numerous potential geroprotectors, which we validated using yeast and Caenorhabditis elegans lifespan assays, as well as exploring microbiome-derived metabolites. Finally, we evaluated endogenous metabolites predicted as senomodulators using senescence assays in human fibroblasts, highlighting AgeXtend's potential to reveal unidentified geroprotectors and provide insights into aging mechanisms.
    DOI:  https://doi.org/10.1038/s43587-024-00763-4
  25. Nature. 2024 Dec 04.
    Dietary fructose enhances tumour growth indirectly via interorgan lipid transfer.
    Ronald Fowle-Grider, Joe L Rowles, Isabel Shen, Yahui Wang, Michaela Schwaiger-Haber, Alden J Dunham, Kay Jayachandran, Matthew Inkman, Michael Zahner, Fuad J Naser, Madelyn M Jackstadt, Jonathan L Spalding, Sarah Chiang, Kyle S McCommis, Roland E Dolle, Eva T Kramer, Sarah M Zimmerman, George P Souroullas, Brian N Finck, Leah P Shriver, Charles K Kaufman, Julie K Schwarz, Jin Zhang, Gary J Patti.
      Fructose consumption has increased considerably over the past five decades, largely due to the widespread use of high-fructose corn syrup as a sweetener1. It has been proposed that fructose promotes the growth of some tumours directly by serving as a fuel2,3. Here we show that fructose supplementation enhances tumour growth in animal models of melanoma, breast cancer and cervical cancer without causing weight gain or insulin resistance. The cancer cells themselves were unable to use fructose readily as a nutrient because they did not express ketohexokinase-C (KHK-C). Primary hepatocytes did express KHK-C, resulting in fructolysis and the excretion of a variety of lipid species, including lysophosphatidylcholines (LPCs). In co-culture experiments, hepatocyte-derived LPCs were consumed by cancer cells and used to generate phosphatidylcholines, the major phospholipid of cell membranes. In vivo, supplementation with high-fructose corn syrup increased several LPC species by more than sevenfold in the serum. Administration of LPCs to mice was sufficient to increase tumour growth. Pharmacological inhibition of ketohexokinase had no direct effect on cancer cells, but it decreased circulating LPC levels and prevented fructose-mediated tumour growth in vivo. These findings reveal that fructose supplementation increases circulating nutrients such as LPCs, which can enhance tumour growth through a cell non-autonomous mechanism.
    DOI:  https://doi.org/10.1038/s41586-024-08258-3
  26. Nat Commun. 2024 Dec 02. 15(1): 10486
    Seipin governs phosphatidic acid homeostasis at the inner nuclear membrane.
    Anete Romanauska, Edvinas Stankunas, Maya Schuldiner, Alwin Köhler.
      The nuclear envelope is a specialized subdomain of the endoplasmic reticulum and comprises the inner and outer nuclear membranes. Despite the crucial role of the inner nuclear membrane in genome regulation, its lipid metabolism remains poorly understood. Phosphatidic acid (PA) is essential for membrane growth as well as lipid storage. Using a genome-wide lipid biosensor screen in S. cerevisiae, we identify regulators of inner nuclear membrane PA homeostasis, including yeast Seipin, a known mediator of nuclear lipid droplet biogenesis. Here, we show that Seipin preserves nuclear envelope integrity by preventing its deformation and ectopic membrane formation. Mutations of specific regions of Seipin, some linked to human lipodystrophy, disrupt PA distribution at the inner nuclear membrane and nuclear lipid droplet formation. Investigating the Seipin co-factor Ldb16 reveals that a triacylglycerol binding site is crucial for lipid droplet formation, whereas PA regulation can be functionally separated. Our study highlights the potential of lipid biosensor screens for examining inner nuclear membrane lipid metabolism.
    DOI:  https://doi.org/10.1038/s41467-024-54811-z
  27. Nature. 2024 Dec 03.
    What is ageing? Even the field's researchers can't agree.
    Smriti Mallapaty.
      
    Keywords:  Ageing; Diseases
    DOI:  https://doi.org/10.1038/d41586-024-03936-8
  28. Cell Chem Biol. 2024 Nov 25. pii: S2451-9456(24)00459-8. [Epub ahead of print]
    β-hydroxybutyrate is a metabolic regulator of proteostasis in the aged and Alzheimer disease brain.
    Sidharth S Madhavan, Stephanie Roa Diaz, Sawyer Peralta, Mitsunori Nomura, Christina D King, Kaya E Ceyhan, Anwen Lin, Dipa Bhaumik, Anna C Foulger, Samah Shah, Thanh Blade, Wyatt Gray, Manish Chamoli, Brenda Eap, Oishika Panda, Diego Diaz, Thelma Y Garcia, Brianna J Stubbs, Scott M Ulrich, Gordon J Lithgow, Birgit Schilling, Eric Verdin, Asish R Chaudhuri, John C Newman.
      Loss of proteostasis is a hallmark of aging and Alzheimer disease (AD). We identify β-hydroxybutyrate (βHB), a ketone body, as a regulator of protein solubility. βHB primarily provides ATP substrate during periods of reduced glucose availability, and regulates other cellular processes through protein interactions. We demonstrate βHB-induced protein insolubility is not dependent on covalent protein modification, pH, or solute load, and is observable in mouse brain in vivo after delivery of a ketone ester. This mechanism is selective for pathological proteins such as amyloid-β, and exogenous βHB ameliorates pathology in nematode models of amyloid-β aggregation toxicity. We generate libraries of the βHB-induced protein insolublome using mass spectrometry proteomics, and identify common protein domains and upstream regulators. We show enrichment of neurodegeneration-related proteins among βHB targets and the clearance of these targets from mouse brain. These data indicate a metabolically regulated mechanism of proteostasis relevant to aging and AD.
    Keywords:  Alzheimer disease; aging; ketone body; neurodegenerative disease; proteostasis
    DOI:  https://doi.org/10.1016/j.chembiol.2024.11.001
  29. Sci Transl Med. 2024 Dec 04. 16(776): eadq5796
    Diverse NKT cells regulate early inflammation and neurological outcomes after cardiac arrest and resuscitation.
    Immunology of Cardiac Arrest Network (I-CAN)
      Neurological injury drives most deaths and morbidity among patients hospitalized for out-of-hospital cardiac arrest (OHCA). Despite its clinical importance, there are no effective pharmacological therapies targeting post-cardiac arrest (CA) neurological injury. Here, we analyzed circulating immune cells from a large cohort of patients with OHCA, finding that lymphopenia independently associated with poor neurological outcomes. Single-cell RNA sequencing of immune cells showed that T cells with features of both innate T cells and natural killer (NK) cells were increased in patients with favorable neurological outcomes. We more specifically identified an early increase in circulating diverse NKT (dNKT) cells in a separate cohort of patients with OHCA who had good neurological outcomes. These cells harbored a diverse T cell receptor repertoire but were consistently specific for sulfatide antigen. In mice, we found that sulfatide-specific dNKT cells trafficked to the brain after CA and resuscitation. In the brains of mice lacking NKT cells (Cd1d-/-), we observed increased inflammatory chemokine and cytokine expression and accumulation of macrophages when compared with wild-type mice. Cd1d-/- mice also had increased neuronal injury, neurological dysfunction, and worse mortality after CA. To therapeutically enhance dNKT cell activity, we treated mice with sulfatide lipid after CA, showing that it improved neurological function. Together, these data show that sulfatide-specific dNKT cells are associated with good neurological outcomes after clinical OHCA and are neuroprotective in mice after CA. Strategies to enhance the number or function of dNKT cells may thus represent a treatment approach for CA.
    DOI:  https://doi.org/10.1126/scitranslmed.adq5796
  30. Proc Natl Acad Sci U S A. 2024 Dec 10. 121(50): e2416076121
    Regulation of ROS signaling by TIGAR induces cancer-modulating responses in the tumor microenvironment.
    Eric C Cheung, Douglas Strathdee, David Stevenson, Jack Coomes, Karen Blyth, Karen H Vousden.
      The consequences of reactive oxygen species (ROS) in cancer cells are complex and have been shown to both promote and retard tumorigenesis in different models. In mouse models of pancreatic ductal adenocarcinoma (PDAC), loss of the antioxidant defense gene Tigar results in both a reduction in the development of early pancreatic intraepithelial neoplasia and an increase in invasive and metastatic capacity, accompanied by decreased survival of mice lacking pancreatic TIGAR. We previously demonstrated that increased ROS following loss of TIGAR promotes various cancer cell-intrinsic changes that contribute to metastatic capacity, including epithelial to mesenchymal transition, enhanced migration and invasion, and an increase in ERK signaling. In this study, we show that pancreatic overexpression of TIGAR decreases metastatic capacity and migratory phenotypes in an aggressive model of PDAC, consistent with the concept that dynamic modulation of TIGAR in PDAC contributes to the development and progression of these tumors. Using TIGAR deficient and overexpressing mouse models, we find that the impact of modulation of TIGAR and ROS in PDAC cells also has a profound effect on the normal stromal cells surrounding the tumor. Loss of TIGAR promotes the production of cytokines by cancer cells that induce changes in the surrounding fibroblasts to adopt a tumor-supportive phenotype. Furthermore, these cytokines also attract macrophages that support PDAC dissemination and metastasis. Taken together our work shows that TIGAR-modulated ROS in PDAC can control cell intrinsic and extrinsic changes to impact tumor aggression.
    Keywords:  oxidative stress; pancreatic cancer; tumor microenvironment
    DOI:  https://doi.org/10.1073/pnas.2416076121
  31. Nature. 2024 Dec 04.
    The oestrous cycle stage affects mammary tumour sensitivity to chemotherapy.
    Laura Bornes, Lennart J van Winden, Veerle C M Geurts, Beaunelle de Bruijn, Leyla Azarang, Mirthe Lanfermeijer, Marika Caruso, Natalie Proost, Manon Boeije, Jeroen O Lohuis, Guillaume Belthier, Eulàlia Noguera Delgado, Nadia de Gruil, Judith R Kroep, Marieke van de Ven, Renee Menezes, Jelle Wesseling, Marleen Kok, Sabine Linn, Annegien Broeks, Huub H van Rossum, Colinda L G J Scheele, Jacco van Rheenen.
      The response of breast cancer to neoadjuvant chemotherapy (NAC) varies substantially, even when tumours belong to the same molecular or histological subtype1. Here we identify the oestrous cycle as an important contributor to this heterogeneity. In three mouse models of breast cancer, we show reduced responses to NAC when treatment is initiated during the dioestrus stage, when compared with initiation during the oestrus stage. Similar findings were observed in retrospective premenopausal cohorts of human patients. Mechanistically, the dioestrus stage exhibits systemic and localized changes, including (1) an increased number of cells undergoing epithelial-to-mesenchymal transition linked to chemoresistance2-4 and (2) decreased tumour vessel diameter, suggesting potential constraints to drug sensitivity and delivery. In addition, an elevated presence of macrophages, previously associated with chemoresistance induction5, characterizes the dioestrus phase. Whereas NAC disrupts the oestrous cycle, this elevated macrophage prevalence persists and depletion of macrophages mitigates the reduced therapy response observed when initiating treatment during dioestrus. Our data collectively demonstrate the oestrous cycle as a crucial infradian rhythm determining chemosensitivity, warranting future clinical studies to exploit optimal treatment initiation timing for enhanced chemotherapy outcomes.
    DOI:  https://doi.org/10.1038/s41586-024-08276-1
  32. Nat Commun. 2024 Dec 03. 15(1): 10515
    Frequent transitions in self-assembly across the evolution of a central metabolic enzyme.
    Franziska L Sendker, Tabea Schlotthauer, Christopher-Nils Mais, Yat Kei Lo, Mathias Girbig, Stefan Bohn, Thomas Heimerl, Daniel Schindler, Arielle Weinstein, Brian P H Metzger, Joseph W Thornton, Arvind Pillai, Gert Bange, Jan M Schuller, Georg K A Hochberg.
      Many enzymes assemble into homomeric protein complexes comprising multiple copies of one protein. Because structural form is usually assumed to follow function in biochemistry, these assemblies are thought to evolve because they provide some functional advantage. In many cases, however, no specific advantage is known and, in some cases, quaternary structure varies among orthologs. This has led to the proposition that self-assembly may instead vary neutrally within protein families. The extent of such variation has been difficult to ascertain because quaternary structure has until recently been difficult to measure on large scales. Here, we employ mass photometry, phylogenetics, and structural biology to interrogate the evolution of homo-oligomeric assembly across the entire phylogeny of prokaryotic citrate synthases - an enzyme with a highly conserved function. We discover a menagerie of different assembly types that come and go over the course of evolution, including cases of parallel evolution and reversions from complex to simple assemblies. Functional experiments in vitro and in vivo indicate that evolutionary transitions between different assemblies do not strongly influence enzyme catalysis. Our work suggests that enzymes can wander relatively freely through a large space of possible assembly states and demonstrates the power of characterizing structure-function relationships across entire phylogenies.
    DOI:  https://doi.org/10.1038/s41467-024-54408-6
  33. PLoS One. 2024 ;19(12): e0313962
    Metabolic modelling links Warburg effect to collagen formation, angiogenesis and inflammation in the tumoral stroma.
    Maxime Mahout, Laurent Schwartz, Romain Attal, Ashraf Bakkar, Sabine Peres.
      Cancer cells are known to express the Warburg effect-increased glycolysis and formation of lactic acid even in the presence of oxygen-as well as high glutamine uptake. In tumors, cancer cells are surrounded by collagen, immune cells, and neoangiogenesis. Whether collagen formation, neoangiogenesis, and inflammation in cancer are associated with the Warburg effect needs to be established. Metabolic modelling has proven to be a tool of choice to understand biological reality better and make in silico predictions. Elementary Flux Modes (EFMs) are essential for conducting an unbiased decomposition of a metabolic model into its minimal functional units. EFMs can be investigated using our tool, aspefm, an innovative approach based on logic programming where biological constraints can be incorporated. These constraints allow networks to be characterized regardless of their size. Using a metabolic model of the human cell containing collagen, neoangiogenesis, and inflammation markers, we derived a subset of EFMs of biological relevance to the Warburg effect. Within this model, EFMs analysis provided more adequate results than parsimonious flux balance analysis and flux sampling. Upon further inspection, the EFM with the best linear regression fit to cancer cell lines exometabolomics data was selected. The minimal pathway, presenting the Warburg effect, collagen synthesis, angiogenesis, and release of inflammation markers, showed that collagen production was possible directly de novo from glutamine uptake and without extracellular import of glycine and proline, collagen's main constituents.
    DOI:  https://doi.org/10.1371/journal.pone.0313962
  34. Oncogene. 2024 Dec 06.
    Metabolic imaging distinguishes ovarian cancer subtypes and detects their early and variable responses to treatment.
    Ming Li Chia, Flaviu Bulat, Adam Gaunt, Susana Ros, Alan J Wright, Ashley Sawle, Luca Porcu, Maria Vias, James D Brenton, Kevin M Brindle.
      High grade serous ovarian cancer displays two metabolic subtypes; a high OXPHOS subtype that shows increased expression of genes encoding electron transport chain components, increased oxygen consumption, and increased chemosensitivity, and a low OXPHOS subtype that exhibits glycolytic metabolism and is more drug resistant. We show here in patient-derived organoids and in the xenografts obtained by their subcutaneous implantation that the low OXPHOS subtype shows higher lactate dehydrogenase activity and monocarboxylate transporter 4 expression than the high OXPHOS subtype and increased lactate labeling in 13C magnetic resonance spectroscopy (MRS) measurements of hyperpolarized [1-13C]pyruvate metabolism. There was no difference between the subtypes in PET measurements of 2-deoxy-2-[fluorine-18]fluoro-D-glucose ([18F]FDG) uptake. Both metabolic imaging techniques could detect the early response to Carboplatin treatment in drug-sensitive high OXPHOS xenografts and no response in drug-resistant in low OXPHOS xenografts. 13C magnetic resonance spectroscopic imaging of hyperpolarized [1-13C]pyruvate metabolism has the potential to be used clinically to distinguish low OXPHOS and high OXPHOS tumor deposits in HGSOC patients and to detect their differential responses to treatment.
    DOI:  https://doi.org/10.1038/s41388-024-03231-w
  35. Cell Discov. 2024 Dec 03. 10(1): 120
    TPM4 condensates glycolytic enzymes and facilitates actin reorganization under hyperosmotic stress.
    Wenzhong Yang, Yuan Wang, Geyao Liu, Yan Wang, Congying Wu.
      Actin homeostasis is fundamental for cell structure and consumes a large portion of cellular ATP. It has been documented in the literature that certain glycolytic enzymes can interact with actin, indicating an intricate interplay between the cytoskeleton and cellular metabolism. Here we report that hyperosmotic stress triggers actin severing and subsequent phase separation of the actin-binding protein tropomyosin 4 (TPM4). TPM4 condensates recruit glycolytic enzymes such as HK2, PFKM, and PKM2, while wetting actin filaments. Notably, the condensates of TPM4 and glycolytic enzymes are enriched of NADH and ATP, suggestive of their functional importance in cell metabolism. At cellular level, actin filament assembly is enhanced upon hyperosmotic stress and TPM4 condensation, while depletion of TPM4 impairs osmolarity-induced actin reorganization. At tissue level, colocalized condensates of TPM4 and glycolytic enzymes are observed in renal tissues subjected to hyperosmotic stress. Together, our findings suggest that stress-induced actin perturbation may act on TPM4 to organize glycolytic hubs that tether energy production to cytoskeletal reorganization.
    DOI:  https://doi.org/10.1038/s41421-024-00744-2
  36. ASN Neuro. 2024 ;16(1): 2422268
    Amino Acid and Glucose Fermentation Maintain ATP Content in Mouse and Human Malignant Glioma Cells.
    Derek C Lee, Linh Ta, Purna Mukherjee, Tomas Duraj, Marek Domin, Bennett Greenwood, Srada Karmacharya, Niven R Narain, Michael Kiebish, Christos Chinopoulos, Thomas N Seyfried.
      Energy is necessary for tumor cell viability and growth. Aerobic glucose-driven lactic acid fermentation is a common metabolic phenotype seen in most cancers including malignant gliomas. This metabolic phenotype is linked to abnormalities in mitochondrial structure and function. A luciferin-luciferase bioluminescence ATP assay was used to measure the influence of amino acids, glucose, and oxygen on ATP content and viability in mouse (VM-M3 and CT-2A) and human (U-87MG) glioma cells that differed in cell biology, genetic background, and species origin. Oxygen consumption was measured using the Resipher system. Extracellular lactate and succinate were measured as end products of the glycolysis and glutaminolysis pathways, respectively. The results showed that: (1) glutamine was a source of ATP content irrespective of oxygen. No other amino acid could replace glutamine in sustaining ATP content and viability; (2) ATP content persisted in the absence of glucose and under hypoxia, ruling out substantial contribution through either glycolysis or oxidative phosphorylation (OxPhos) under these conditions; (3) Mitochondrial complex IV inhibition showed that oxygen consumption was not an accurate measure for ATP production through OxPhos. The glutaminase inhibitor, 6-diazo-5-oxo-L-norleucine (DON), reduced ATP content and succinate export in cells grown in glutamine. The data suggests that mitochondrial substrate level phosphorylation in the glutamine-driven glutaminolysis pathway contributes to ATP content in these glioma cells. A new model is presented highlighting the synergistic interaction between the high-throughput glycolysis and glutaminolysis pathways that drive malignant glioma growth and maintain ATP content through the aerobic fermentation of both glucose and glutamine.
    Keywords:  Fermentation; glioblastoma; glutaminolysis; mitochondrial substrate level phosphorylation; succinate
    DOI:  https://doi.org/10.1080/17590914.2024.2422268
  37. Redox Biol. 2024 Nov 25. pii: S2213-2317(24)00420-8. [Epub ahead of print]79 103442
    Redox-dependent purine degradation triggers postnatal loss of cardiac regeneration potential.
    Yuichi Saito, Yuki Sugiura, Akane Sakaguchi, Tai Sada, Chihiro Nishiyama, Rae Maeda, Mari Kaneko, Hiroshi Kiyonari, Wataru Kimura.
      Postnatal cardiomyocyte cell cycle withdrawal is a critical step wherein the mammalian heart loses regenerative potential after birth. Here, we conducted interspecies multi-omic comparisons between the mouse heart and that of the opossum, which have different postnatal time-windows for cardiomyocyte cell cycle withdrawal. Xanthine metabolism was activated in both postnatal hearts in parallel with cardiomyocyte cell cycle arrest. The pentose phosphate pathway (PPP) which produces NADPH was found to decrease simultaneously. Postnatal myocardial tissues became oxidized accordingly, and administration of antioxidants to neonatal mice altered the PPP and suppressed the postnatal activation of cardiac xanthine metabolism. These results suggest a redox-driven postnatal switch from purine synthesis to degradation in the heart. Importantly, inhibition of xanthine metabolism in the postnatal heart extended postnatal duration of cardiomyocyte proliferation and maintained postnatal heart regeneration potential in mice. These findings highlight a novel role of xanthine metabolism as a redox-dependent metabolic regulator of cardiac regeneration potential.
    Keywords:  Cell cycle arrest; Heart regeneration; Interspecies comparison; Pentose phosphate pathway; Xanthine metabolism
    DOI:  https://doi.org/10.1016/j.redox.2024.103442
  38. Proc Natl Acad Sci U S A. 2024 Dec 10. 121(50): e2410680121
    Alternative splicing of Clock transcript mediates the response of circadian clocks to temperature changes.
    Yao D Cai, Xianhui Liu, Gary K Chow, Sergio Hidalgo, Kiya C Jackson, Cameron D Vasquez, Zita Y Gao, Vu H Lam, Christine A Tabuloc, Haiyan Zheng, Caifeng Zhao, Joanna C Chiu.
      Circadian clocks respond to temperature changes over the calendar year, allowing organisms to adjust their daily biological rhythms to optimize health and fitness. In Drosophila, seasonal adaptations are regulated by temperature-sensitive alternative splicing (AS) of period (per) and timeless (tim) genes that encode key transcriptional repressors of clock gene expression. Although Clock (Clk) gene encodes the critical activator of circadian gene expression, AS of its transcripts and its potential role in temperature regulation of clock function have not been explored. Here, we observed that Clk transcripts undergo temperature-sensitive AS. Specifically, cold temperature leads to the production of an alternative Clk transcript, hereinafter termed Clk-cold, which encodes a CLK isoform with an in-frame deletion of four amino acids proximal to the DNA binding domain. Notably, serine 13 (S13), which we found to be a CK1α-dependent phosphorylation site, is deleted in CLK-cold protein. We demonstrated that upon phosphorylation at CLK(S13), CLK-DNA interaction is reduced, thus decreasing transcriptional activity of CLK. This is in agreement with our findings that CLK occupancy at clock genes and transcriptional output are elevated at cold temperature likely due to higher amounts of CLK-cold isoforms that lack S13 residue. Finally, we showed that PER promotes CK1α-dependent phosphorylation of CLK(S13), supporting kinase-scaffolding role of repressor proteins as a conserved feature in the regulation of eukaryotic circadian clocks. This study provides insights into the complex collaboration between AS and phospho-regulation in shaping temperature responses of the circadian clock.
    Keywords:  alternative splicing; circadian rhythm; phosphorylation; post-translational modification; temperature
    DOI:  https://doi.org/10.1073/pnas.2410680121
  39. Mol Cell. 2024 Nov 27. pii: S1097-2765(24)00918-3. [Epub ahead of print]
    p53 induces circFRMD4A to suppress cancer development through glycolytic reprogramming and cuproptosis.
    Quan Liao, Jun Deng, Jing Tong, Yu Gan, Weiwei Hong, Hanzhi Dong, Mingming Cao, Chen Xiong, Yajie Chen, Bangxiang Xie, Fu-Ying Yang, Aikede Alifu, Guang-Biao Zhou, Shenglin Huang, Jianping Xiong, Qian Hao, Xiang Zhou.
      Cuproptosis is a type of copper-induced cell death that mainly impacts cells relying on mitochondrial metabolism. Although p53 regulates glycolytic metabolism, its role in cuproptosis remains unclear. Here, we report that the circular RNA, circFRMD4A, is crucial for p53-mediated metabolic reprogramming and cuproptosis. CircFRMD4A originates from the transcript of FRMD4A, which is transcriptionally activated by p53, and the formation of circFRMD4A is facilitated by the RNA-binding protein EWSR1. CircFRMD4A functions as a tumor suppressor and enhances the sensitivity of cancer cells to elesclomol-induced cuproptosis. Mechanistic analysis reveals that circFRMD4A interacts with and inactivates the pyruvate kinase PKM2, leading to a decrease in lactate production and a redirection of glycolytic flux toward the tricarboxylic acid cycle. Finally, p53 agonists and elesclomol coordinately suppress the growth of cancer in a xenograft mouse model. Altogether, our study uncovers that p53 promotes glycolytic reprogramming and cuproptosis via circFRMD4A and suggests a potential combination strategy against cancers with wild-type p53.
    Keywords:  EWSR1; FRMD4A; PKM2; TCA cycle; cancer therapy; circular RNA; cuproptosis; glycolysis; p53; tumor metabolism
    DOI:  https://doi.org/10.1016/j.molcel.2024.11.013
  40. Cell Metab. 2024 Dec 03. pii: S1550-4131(24)00418-2. [Epub ahead of print]36(12): 2491-2492
    Mitochondrial respiratory supercomplexes gear up for heat generation in brown adipose tissue.
    Andreas Carlström, Martin Ott.
      Mitochondrial energy conversion supplies cellular energy but can also provide heat in brown adipose tissue (BAT). In a recent study, Shin and Latorre-Muro et al.1 show that respiratory supercomplexes in BAT are remodeled during cold to provide a tighter coupling, revealing a novel, physiologically important role for these supramolecular assemblies.
    DOI:  https://doi.org/10.1016/j.cmet.2024.10.022
  41. BMC Med. 2024 12 05. 22(1): 578
    Clinical research framework proposal for ketogenic metabolic therapy in glioblastoma.
    Tomás Duraj, Miriam Kalamian, Giulio Zuccoli, Joseph C Maroon, Dominic P D'Agostino, Adrienne C Scheck, Angela Poff, Sebastian F Winter, Jethro Hu, Rainer J Klement, Alicia Hickson, Derek C Lee, Isabella Cooper, Barbara Kofler, Kenneth A Schwartz, Matthew C L Phillips, Colin E Champ, Beth Zupec-Kania, Jocelyn Tan-Shalaby, Fabiano M Serfaty, Egiroh Omene, Gabriel Arismendi-Morillo, Michael Kiebish, Richard Cheng, Ahmed M El-Sakka, Axel Pflueger, Edward H Mathews, Donese Worden, Hanping Shi, Raffaele Ivan Cincione, Jean Pierre Spinosa, Abdul Kadir Slocum, Mehmet Salih Iyikesici, Atsuo Yanagisawa, Geoffrey J Pilkington, Anthony Chaffee, Wafaa Abdel-Hadi, Amr K Elsamman, Pavel Klein, Keisuke Hagihara, Zsófia Clemens, George W Yu, Athanasios E Evangeliou, Janak K Nathan, Kris Smith, David Fortin, Jorg Dietrich, Purna Mukherjee, Thomas N Seyfried.
      Glioblastoma (GBM) is the most aggressive primary brain tumor in adults, with a universally lethal prognosis despite maximal standard therapies. Here, we present a consensus treatment protocol based on the metabolic requirements of GBM cells for the two major fermentable fuels: glucose and glutamine. Glucose is a source of carbon and ATP synthesis for tumor growth through glycolysis, while glutamine provides nitrogen, carbon, and ATP synthesis through glutaminolysis. As no tumor can grow without anabolic substrates or energy, the simultaneous targeting of glycolysis and glutaminolysis is expected to reduce the proliferation of most if not all GBM cells. Ketogenic metabolic therapy (KMT) leverages diet-drug combinations that inhibit glycolysis, glutaminolysis, and growth signaling while shifting energy metabolism to therapeutic ketosis. The glucose-ketone index (GKI) is a standardized biomarker for assessing biological compliance, ideally via real-time monitoring. KMT aims to increase substrate competition and normalize the tumor microenvironment through GKI-adjusted ketogenic diets, calorie restriction, and fasting, while also targeting glycolytic and glutaminolytic flux using specific metabolic inhibitors. Non-fermentable fuels, such as ketone bodies, fatty acids, or lactate, are comparatively less efficient in supporting the long-term bioenergetic and biosynthetic demands of cancer cell proliferation. The proposed strategy may be implemented as a synergistic metabolic priming baseline in GBM as well as other tumors driven by glycolysis and glutaminolysis, regardless of their residual mitochondrial function. Suggested best practices are provided to guide future KMT research in metabolic oncology, offering a shared, evidence-driven framework for observational and interventional studies.
    Keywords:  Cancer; Glioblastoma; Glutaminolysis; Metabolism; Precision medicine; Research design; Warburg Effect
    DOI:  https://doi.org/10.1186/s12916-024-03775-4
  42. PLoS One. 2024 ;19(12): e0309886
    Measuring the rate of NADPH consumption by glutathione reductase in the cytosol and mitochondria.
    Kenneth K Y Ting, Eric Floro, Riley Dow, Jenny Jongstra-Bilen, Myron I Cybulsky, Jonathan V Rocheleau.
       BACKGROUND: NADPH is an essential co-factor supporting the function of enzymes that participate in both inflammatory and anti-inflammatory pathways in myeloid cells, particularly macrophages. Although individual NADPH-dependent pathways are well characterized, how these opposing pathways are co-regulated to orchestrate an optimized inflammatory response is not well understood. To investigate this, techniques to track the consumption of NADPH need to be applied. Deuterium tracing of NADPH remains the gold standard in the field, yet this setup of mass-spectrometry is technically challenging and not readily available to most research groups. Furthermore, NADPH pools are compartmentalized in various organelles with no known membrane transporters, suggesting that NADPH-dependent pathways are regulated in an organelle-specific manner. Conventional methods such as commercial kits are limited to quantifying NADPH in whole cells and not at the resolution of specific organelles. These limitations reflect the need for a novel assay that can readily measure the consumption rate of NADPH in different organelles.
    METHODS: We devised an assay that measures the consumption rate of NADPH by glutathione-disulfide reductase (GSR) in the mitochondria and the cytosol of RAW264.7 macrophage cell lines. RAW264.7 cells were transfected with Apollo-NADP+ sensors targeted to the mitochondria or the cytosol, followed by the treatment of 2-deoxyglucose and diamide. Intravital imaging over time then determined GSR-dependent NADPH consumption in an organelle-specific manner.
    DISCUSSION: In lipopolysaccharide (LPS)-stimulated RAW264.7 cells, cytosolic and mitochondrial NADPH was consumed by GSR in a time-dependent manner. This finding was cross validated with a commercially available NADPH kit that detects NADPH in whole cells. Loading of RAW264.7 cells with oxidized low-density lipoprotein followed by LPS stimulation elevated GSR expression, and this correlated with a more rapid drop in cytosolic and mitochondrial NADPH in our assay. The current limitation of our assay is applicability to transfectable cell lines, and higher expression of plasmid-encoded sensors relative to endogenous glucose-6-phosphate dehydrogenase.
    DOI:  https://doi.org/10.1371/journal.pone.0309886
This page is being maintained by Thomas Krichel. It was last updated on 2024‒12‒08 at 6:17.