bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2024–12–22
fifty-one papers selected by
Christian Frezza, Universität zu Köln
  1. Subcellular NAD+ pools are interconnected and buffered by mitochondrial NAD.
  2. Why eating less slows ageing: this molecule is key.
  3. Mitochondrial metabolism and epigenetic crosstalk drive the SASP.
  4. Guardians of the cell: mitochondria as a rheostat for cellular NAD+ levels.
  5. SLMO transfers phosphatidylserine between the outer and inner mitochondrial membrane in Drosophila.
  6. Mapping mitochondrial aging.
  7. A bile acid could explain how calorie restriction slows ageing.
  8. Metformin targets mitochondrial complex I to lower blood glucose levels.
  9. Pan-cancer analysis of biallelic inactivation in tumor suppressor genes identifies KEAP1 zygosity as a predictive biomarker in lung cancer.
  10. A cholesterol metabolite against ferroptosis.
  11. Too old for healthy aging? Exploring age limits of longevity treatments.
  12. A family of NADPH/NADP+ biosensors reveals in vivo dynamics of central redox metabolism across eukaryotes.
  13. Role of Fatty Acids β-Oxidation in the Metabolic Interactions Between Organs.
  14. Imaging NRF2 activation in non-small cell lung cancer with positron emission tomography.
  15. Mitochondrial respiration atlas reveals differential changes in mitochondrial function across sex and age.
  16. USP39 regulates pyruvate handling in non-small cell lung cancer.
  17. Rejuvenating aged osteoprogenitors for bone repair.
  18. P-cadherin mechanoactivates tumor-mesothelium metabolic coupling to promote ovarian cancer metastasis.
  19. Engineered extrachromosomal oncogene amplifications promote tumorigenesis.
  20. Metabolic immunoengineering approaches to enhance CD8+ T cell-based cancer immunotherapy.
  21. Aged neurons don't register energy need.
  22. The cGAS-STING pathway activates transcription factor TFEB to stimulate lysosome biogenesis and pathogen clearance.
  23. Conversion of pyridoxal to pyridoxamine with NH3 and H2 on nickel generates a protometabolic nitrogen shuttle under serpentinizing conditions.
  24. Inter-organ communication is a critical machinery to regulate metabolism and aging.
  25. How does mitochondrial Ca2+ change during ischemia and reperfusion? Implications for activation of the permeability transition pore.
  26. Mitochondrial dysfunction has a central role in diabetic kidney disease.
  27. Epigenetic suppression of creatine kinase B in adipocytes links endoplasmic reticulum stress to obesity-associated inflammation.
  28. A proteome-wide yeast degron collection for the dynamic study of protein function.
  29. A blood test detects aged cells.
  30. Time-of-day control of mitochondria regulates NLRP3 inflammasome activation in macrophages.
  31. Exploring tryptophan metabolism in cardiometabolic diseases.
  32. A Compensated Clock: Temperature and Nutritional Compensation Mechanisms Across Circadian Systems.
  33. Endogenous interactomes of MFN1 and MFN2 provide novel insights into interorganelle communication and autophagy.
  34. The polarizing nature of fructose.
  35. Lysosomal/mitochondrial interaction promotes tumor growth in squamous cell carcinoma of the head and neck.
  36. Systems Biology of the Cancer Cell.
  37. Spatial transcriptomic clocks reveal cell proximity effects in brain ageing.
  38. Dysregulation of PI4P in the trans Golgi regions activates the mammalian Golgi stress response.
  39. Macropinocytosis controls metabolic stress-driven CAF subtype identity in pancreatic cancer.
  40. Exercise as Mitochondrial Medicine: How Does the Exercise Prescription Affect Mitochondrial Adaptations to Training?
  41. Increased mitochondrial mutation heteroplasmy induces aging phenotypes in pluripotent stem cells and their differentiated progeny.
  42. Pathogenic mitochondrial DNA variants are associated with response to anti-VEGF therapy in ovarian cancer PDX models.
  43. Functional heterogeneity of fibroblasts in primary tumors and metastases.
  44. Painting lysosomes to study organelle heterogeneity.
  45. Selenoprotein O Promotes Melanoma Metastasis and Regulates Mitochondrial Complex II Activity.
  46. Unveiling adipose populations linked to metabolic health in obesity.
  47. An antibiotic that mediates immune destruction of senescent cancer cells.
  48. Adjusting the clock for cancer immunotherapy.
  49. YTHDF2 promotes ATP synthesis and immune evasion in B cell malignancies.
  50. A whole food, plant-based diet reduces amino acid levels in patients with metastatic breast cancer.
  51. Intermittent fasting triggers interorgan communication to suppress hair follicle regeneration.
  1. Nat Metab. 2024 Dec;6(12): 2319-2337
    Subcellular NAD+ pools are interconnected and buffered by mitochondrial NAD.
    Lena E Høyland, Magali R VanLinden, Marc Niere, Øyvind Strømland, Suraj Sharma, Jörn Dietze, Ingvill Tolås, Eva Lucena, Ersilia Bifulco, Lars J Sverkeli, Camila Cimadamore-Werthein, Hanan Ashrafi, Kjellfrid F Haukanes, Barbara van der Hoeven, Christian Dölle, Cédric Davidsen, Ina K N Pettersen, Karl J Tronstad, Svein A Mjøs, Faisal Hayat, Mikhail V Makarov, Marie E Migaud, Ines Heiland, Mathias Ziegler.
      The coenzyme NAD+ is consumed by signalling enzymes, including poly-ADP-ribosyltransferases (PARPs) and sirtuins. Ageing is associated with a decrease in cellular NAD+ levels, but how cells cope with persistently decreased NAD+ concentrations is unclear. Here, we show that subcellular NAD+ pools are interconnected, with mitochondria acting as a rheostat to maintain NAD+ levels upon excessive consumption. To evoke chronic, compartment-specific overconsumption of NAD+, we engineered cell lines stably expressing PARP activity in mitochondria, the cytosol, endoplasmic reticulum or peroxisomes, resulting in a decline of cellular NAD+ concentrations by up to 50%. Isotope-tracer flux measurements and mathematical modelling show that the lowered NAD+ concentration kinetically restricts NAD+ consumption to maintain a balance with the NAD+ biosynthesis rate, which remains unchanged. Chronic NAD+ deficiency is well tolerated unless mitochondria are directly targeted. Mitochondria maintain NAD+ by import through SLC25A51 and reversibly cleave NAD+ to nicotinamide mononucleotide and ATP when NMNAT3 is present. Thus, these organelles can maintain an additional, virtual NAD+ pool. Our results are consistent with a well-tolerated ageing-related NAD+ decline as long as the vulnerable mitochondrial pool is not directly affected.
    DOI:  https://doi.org/10.1038/s42255-024-01174-w
  2. Nature. 2024 Dec 18.
    Why eating less slows ageing: this molecule is key.
    Heidi Ledford.
      
    Keywords:  Ageing; Metabolism
    DOI:  https://doi.org/10.1038/d41586-024-04220-5
  3. Res Sq. 2024 Dec 05. pii: rs.3.rs-5278203. [Epub ahead of print]
    Mitochondrial metabolism and epigenetic crosstalk drive the SASP.
    Joao Passos, Helene Martini, Jodie Birch, Francisco Marques, Stella Victorelli, Anthony Lagnado, Nicholas Pirius, Ana Franco, Gung Lee, Yeaeun Han, Jennifer Rowsey, Alexandre Gaspar-Maia, Aaron Havas, Rabi Murad, Xue Lei, Rebecca Porritt, Oliver Maddocks, Diana Jurk, Sundeep Khosla, Peter Adams.
      Senescent cells drive tissue dysfunction through the senescence-associated secretory phenotype (SASP). We uncovered a central role for mitochondria in the epigenetic regulation of the SASP, where mitochondrial-derived metabolites, specifically citrate and acetyl-CoA, fuel histone acetylation at SASP gene loci, promoting their expression. We identified the mitochondrial citrate carrier (SLC25A1) and ATP-citrate lyase (ACLY) as critical for this process. Inhibiting these pathways selectively suppresses SASP without affecting cell cycle arrest, highlighting their potential as therapeutic targets for age-related inflammation. Notably, SLC25A1 inhibition reduces systemic inflammation and extends healthspan in aged mice, establishing mitochondrial metabolism as pivotal to the epigenetic control of aging.
    DOI:  https://doi.org/10.21203/rs.3.rs-5278203/v1
  4. Nat Metab. 2024 Dec;6(12): 2215-2217
    Guardians of the cell: mitochondria as a rheostat for cellular NAD+ levels.
    Fiona M Fitzpatrick, Nora Kory.
      
    DOI:  https://doi.org/10.1038/s42255-024-01160-2
  5. PLoS Biol. 2024 Dec;22(12): e3002941
    SLMO transfers phosphatidylserine between the outer and inner mitochondrial membrane in Drosophila.
    Siwen Zhao, Xuguang Jiang, Ning Li, Tao Wang.
      Phospholipids are critical building blocks of mitochondria, and proper mitochondrial function and architecture rely on phospholipids that are primarily transported from the endoplasmic reticulum (ER). Here, we show that mitochondrial form and function rely on synthesis of phosphatidylserine (PS) in the ER through phosphatidylserine synthase (PSS), trafficking of PS from ER to mitochondria (and within mitochondria), and the conversion of PS to phosphatidylethanolamine (PE) by phosphatidylserine decarboxylase (PISD) in the inner mitochondrial membrane (IMM). Using a forward genetic screen in Drosophila, we found that Slowmo (SLMO) specifically transfers PS from the outer mitochondrial membrane (OMM) to the IMM within the inner boundary membrane (IBM) domain. Thus, SLMO is required for shaping mitochondrial morphology, but its putative conserved binding partner, dTRIAP, is not. Importantly, SLMO's role in maintaining mitochondrial morphology is conserved in humans via the SLMO2 protein and is independent of mitochondrial dynamics. Our results highlight the importance of a conserved PSS-SLMO-PISD pathway in maintaining the structure and function of mitochondria.
    DOI:  https://doi.org/10.1371/journal.pbio.3002941
  6. Elife. 2024 Dec 20. pii: e105191. [Epub ahead of print]13
    Mapping mitochondrial aging.
    Alessandro Bitto.
      Measuring mitochondrial respiration in frozen tissue samples provides the first comprehensive atlas of how aging affects mitochondrial function in mice.
    Keywords:  aging; cellular respiration; computational biology; mitochondria; mouse; respiration atlas; sex; systems biology
    DOI:  https://doi.org/10.7554/eLife.105191
  7. Nature. 2024 Dec 18.
    A bile acid could explain how calorie restriction slows ageing.
    David A Sinclair.
      
    Keywords:  Ageing; Metabolism; Microbiome; Nutrition
    DOI:  https://doi.org/10.1038/d41586-024-04062-1
  8. Sci Adv. 2024 Dec 20. 10(51): eads5466
    Metformin targets mitochondrial complex I to lower blood glucose levels.
    Colleen R Reczek, Ram P Chakrabarty, Karis B D'Alessandro, Zachary L Sebo, Rogan A Grant, Peng Gao, G R Budinger, Navdeep S Chandel.
      Metformin is among the most prescribed antidiabetic drugs, but the primary molecular mechanism by which metformin lowers blood glucose levels is unknown. Previous studies have proposed numerous mechanisms by which acute metformin lowers blood glucose, including the inhibition of mitochondrial complex I of the electron transport chain (ETC). Here, we used transgenic mice that globally express the Saccharomyces cerevisiae internal alternative NADH dehydrogenase (NDI1) protein to determine whether the glucose-lowering effect of acute oral administration of metformin requires inhibition of mitochondrial complex I of the ETC in vivo. NDI1 is a yeast NADH dehydrogenase enzyme that complements the loss of mammalian mitochondrial complex I electron transport function and is insensitive to pharmacologic mitochondrial complex I inhibitors including metformin. We demonstrate that NDI1 expression attenuates metformin's ability to lower blood glucose levels under standard chow and high-fat diet conditions. Our results indicate that acute oral administration of metformin targets mitochondrial complex I to lower blood glucose.
    DOI:  https://doi.org/10.1126/sciadv.ads5466
  9. Cell. 2024 Dec 12. pii: S0092-8674(24)01327-8. [Epub ahead of print]
    Pan-cancer analysis of biallelic inactivation in tumor suppressor genes identifies KEAP1 zygosity as a predictive biomarker in lung cancer.
    Mark Zucker, Maria A Perry, Samuel I Gould, Arielle Elkrief, Anton Safonov, Rohit Thummalapalli, Miika Mehine, Debyani Chakravarty, A Rose Brannon, Marc Ladanyi, Pedram Razavi, Mark T A Donoghue, Yonina R Murciano-Goroff, Kristiana Grigoriadis, Nicholas McGranahan, Mariam Jamal-Hanjani, Charles Swanton, Yuan Chen, Ronglai Shen, Sarat Chandarlapaty, David B Solit, Nikolaus Schultz, Michael F Berger, Jason Chang, Adam J Schoenfeld, Francisco J Sánchez-Rivera, Ed Reznik, Chaitanya Bandlamudi.
      The canonical model of tumor suppressor gene (TSG)-mediated oncogenesis posits that loss of both alleles is necessary for inactivation. Here, through allele-specific analysis of sequencing data from 48,179 cancer patients, we define the prevalence, selective pressure for, and functional consequences of biallelic inactivation across TSGs. TSGs largely assort into distinct classes associated with either pan-cancer (Class 1) or lineage-specific (Class 2) patterns of selection for biallelic loss, although some TSGs are predominantly monoallelically inactivated (Class 3/4). We demonstrate that selection for biallelic inactivation can be utilized to identify driver genes in non-canonical contexts, including among variants of unknown significance (VUSs) of several TSGs such as KEAP1. Genomic, functional, and clinical data collectively indicate that KEAP1 VUSs phenocopy established KEAP1 oncogenic alleles and that zygosity, rather than variant classification, is predictive of therapeutic response. TSG zygosity is therefore a fundamental determinant of disease etiology and therapeutic sensitivity.
    Keywords:  KEAP1; Knudson's two-hit; biallelic inactivation; biallelic loss; cancer genomics; clinical sequencing; lung cancer; pancancer; predictive biomarkers; tumor suppressor genes
    DOI:  https://doi.org/10.1016/j.cell.2024.11.010
  10. Nat Cancer. 2024 Dec 17.
    A cholesterol metabolite against ferroptosis.
    Julieta Alfonso.
      
    DOI:  https://doi.org/10.1038/s43018-024-00849-3
  11. NPJ Metab Health Dis. 2024 ;2(1): 37
    Too old for healthy aging? Exploring age limits of longevity treatments.
    Prerana Shrikant Chaudhari, Maria A Ermolaeva.
      It is well documented that aging elicits metabolic failures, while poor metabolism contributes to accelerated aging. Metabolism in general, and energy metabolism in particular are also effective entry points for interventions that extend lifespan and improve organ function during aging. In this review, we discuss common metabolic remedies for healthy aging from the angle of their potential age-specificity. We demonstrate that some well-known metabolic treatments are mostly effective in young and middle-aged organisms, while others maintain high efficacy independently of age. The mechanistic basis of presence or lack of the age limitations is laid out and discussed.
    Keywords:  Energy metabolism; Metabolism; Mitochondria; Physiology
    DOI:  https://doi.org/10.1038/s44324-024-00040-3
  12. Nat Commun. 2024 Dec 19. 15(1): 10704
    A family of NADPH/NADP+ biosensors reveals in vivo dynamics of central redox metabolism across eukaryotes.
    Marie Scherschel, Jan-Ole Niemeier, Lianne J H C Jacobs, Markus D A Hoffmann, Anika Diederich, Christopher Bell, Pascal Höhne, Sonja Raetz, Johanna B Kroll, Janina Steinbeck, Sophie Lichtenauer, Jan Multhoff, Jannik Zimmermann, Tanmay Sadhanasatish, R Alexander Rothemann, Carsten Grashoff, Joris Messens, Emmanuel Ampofo, Matthias W Laschke, Jan Riemer, Leticia Prates Roma, Markus Schwarzländer, Bruce Morgan.
      The NADPH/NADP+ redox couple is central to metabolism and redox signalling. NADP redox state is differentially regulated by distinct enzymatic machineries at the subcellular compartment level. Nonetheless, a detailed understanding of subcellular NADP redox dynamics is limited by the availability of appropriate tools. Here, we introduce NAPstars, a family of genetically encoded, fluorescent protein-based NADP redox state biosensors. NAPstars offer real-time, specific measurements, across a broad-range of NADP redox states, with subcellular resolution. NAPstar measurements in yeast, plants, and mammalian cell models, reveal a conserved robustness of cytosolic NADP redox homoeostasis. NAPstars uncover cell cycle-linked NADP redox oscillations in yeast and illumination- and hypoxia-dependent NADP redox changes in plant leaves. By applying NAPstars in combination with selective impairment of the glutathione and thioredoxin antioxidative pathways under acute oxidative challenge, we find an unexpected and conserved role for the glutathione system as the primary mediator of antioxidative electron flux.
    DOI:  https://doi.org/10.1038/s41467-024-55302-x
  13. Int J Mol Sci. 2024 Nov 27. pii: 12740. [Epub ahead of print]25(23):
    Role of Fatty Acids β-Oxidation in the Metabolic Interactions Between Organs.
    Alexander V Panov, Vladimir I Mayorov, Sergey I Dikalov.
      In recent decades, several discoveries have been made that force us to reconsider old ideas about mitochondria and energy metabolism in the light of these discoveries. In this review, we discuss metabolic interaction between various organs, the metabolic significance of the primary substrates and their metabolic pathways, namely aerobic glycolysis, lactate shuttling, and fatty acids β-oxidation. We rely on the new ideas about the supramolecular structure of the mitochondrial respiratory chain (respirasome), the necessity of supporting substrates for fatty acids β-oxidation, and the reverse electron transfer via succinate dehydrogenase during β-oxidation. We conclude that ATP production during fatty acid β-oxidation has its upper limits and thus cannot support high energy demands alone. Meanwhile, β-oxidation creates conditions that significantly accelerate the cycle: glucose-aerobic glycolysis-lactate-gluconeogenesis-glucose. Therefore, glycolytic ATP production becomes an important energy source in high energy demand. In addition, lactate serves as a mitochondrial substrate after converting to pyruvate + H+ by the mitochondrial lactate dehydrogenase. All coupled metabolic pathways are irreversible, and the enzymes are organized into multienzyme structures.
    Keywords:  aerobic glycolysis; beta-oxidation; fatty acids; gluconeogenesis; lactate; metabolism; mitochondria; respirasome
    DOI:  https://doi.org/10.3390/ijms252312740
  14. Nat Commun. 2024 Dec 17. 15(1): 10484
    Imaging NRF2 activation in non-small cell lung cancer with positron emission tomography.
    Hannah E Greenwood, Abigail R Barber, Richard S Edwards, Will E Tyrrell, Madeleine E George, Sofia N Dos Santos, Friedrich Baark, Muhammet Tanc, Eman Khalil, Aimee Falzone, Nathan P Ward, Janine M DeBlasi, Laura Torrente, Pritin N Soni, David R Pearce, George Firth, Lydia M Smith, Oskar Vilhelmsson Timmermand, Ariana Huebner, Charles Swanton, Robert E Hynds, Gina M DeNicola, Timothy H Witney.
      Mutations in the NRF2-KEAP1 pathway are common in non-small cell lung cancer (NSCLC) and confer broad-spectrum therapeutic resistance, leading to poor outcomes. Currently, there is no means to non-invasively identify NRF2 activation in living subjects. Here, we show that positron emission tomography imaging with the system xc- radiotracer, [18F]FSPG, provides a sensitive and specific marker of NRF2 activation in orthotopic, patient-derived, and genetically engineered mouse models of NSCLC. We found a NRF2-related gene expression signature in a large cohort of NSCLC patients, suggesting an opportunity to preselect patients prior to [18F]FSPG imaging. Furthermore, we reveal that system xc- is a metabolic vulnerability that can be therapeutically targeted with an antibody-drug conjugate for sustained tumour growth suppression. Overall, our results establish [18F]FSPG as a predictive marker of therapy resistance in NSCLC and provide the basis for the clinical evaluation of both imaging and therapeutic agents that target this important antioxidant pathway.
    DOI:  https://doi.org/10.1038/s41467-024-54852-4
  15. Elife. 2024 Dec 20. pii: RP96926. [Epub ahead of print]13
    Mitochondrial respiration atlas reveals differential changes in mitochondrial function across sex and age.
    Dylan C Sarver, Muzna Saqib, Fangluo Chen, G William Wong.
      Organ function declines with age, and large-scale transcriptomic analyses have highlighted differential aging trajectories across tissues. The mechanism underlying shared and organ-selective functional changes across the lifespan, however, still remains poorly understood. Given the central role of mitochondria in powering cellular processes needed to maintain tissue health, we therefore undertook a systematic assessment of respiratory activity across 33 different tissues in young (2.5 months) and old (20 months) mice of both sexes. Our high-resolution mitochondrial respiration atlas reveals: (1) within any group of mice, mitochondrial activity varies widely across tissues, with the highest values consistently seen in heart, brown fat, and kidney; (2) biological sex is a significant but minor contributor to mitochondrial respiration, and its contributions are tissue-specific, with major differences seen in the pancreas, stomach, and white adipose tissue; (3) age is a dominant factor affecting mitochondrial activity, especially across most brain regions, different fat depots, skeletal muscle groups, eyes, and different regions of the gastrointestinal tract; (4) age effects can be sex- and tissue-specific, with some of the largest effects seen in pancreas, heart, adipose tissue, and skeletal muscle; and (5) while aging alters the functional trajectories of mitochondria in a majority of tissues, some are remarkably resilient to age-induced changes. Altogether, our data provide the most comprehensive compendium of mitochondrial respiration and illuminate functional signatures of aging across diverse tissues and organ systems.
    Keywords:  aging; computational biology; mitochondria; mouse; respiration atlas; sex; systems biology
    DOI:  https://doi.org/10.7554/eLife.96926
  16. Cell Death Discov. 2024 Dec 18. 10(1): 502
    USP39 regulates pyruvate handling in non-small cell lung cancer.
    Tina Becirovic, Boxi Zhang, Helin Vakifahmetoglu-Norberg, Vitaliy O Kaminskyy, Elena Kochetkova, Erik Norberg.
      The ubiquitin-specific peptidase 39 (USP39) belongs to the USP family of cysteine proteases representing the largest group of human deubiquitinases (DUBs). While the oncogenic function of USP39 has been investigated in various cancer types, its roles in non-small cell lung cancer (NSCLC) remain largely unknown. Here, by applying a gene set enrichment analysis (GSEA) on lung adenocarcinoma tissues and metabolite set enrichment analysis (MSEA) on NSCLC cells depleted of USP39, we identified a previously unknown link between USP39 and the metabolism in NSCLC cells. Mechanistically, we uncovered a component of the pyruvate dehydrogenase (PDH) complex, pyruvate dehydrogenase E1 subunit alpha (PDHA), as a target of USP39. We further present that USP39 silencing caused an elevation in Lys63 ubiquitination on PDHA and a reduction in the PDH complex activity, the levels of TCA cycle intermediates, mitochondrial respiration, cell proliferation in vitro, and of tumor growth in vivo. Consistently, citrate supplementation restored mitochondrial respiration and cell growth in USP39-depleted cells. Our study elucidates and describes how USP39 regulates pyruvate metabolism through a deubiquitylation process that affects NSCLC tumor growth.
    DOI:  https://doi.org/10.1038/s41420-024-02264-0
  17. Elife. 2024 Dec 18. pii: RP104068. [Epub ahead of print]13
    Rejuvenating aged osteoprogenitors for bone repair.
    Joshua Reeves, Pierre Tournier, Pierre Becquart, Robert Carton, Yin Tang, Alessandra Vigilante, Dong Fang, Shukry J Habib.
      Aging is marked by a decline in tissue regeneration, posing significant challenges to an increasingly older population. Here, we investigate age-related impairments in calvarial bone healing and introduce a novel two-part rejuvenation strategy to restore youthful repair. We demonstrate that aging negatively impacts the calvarial bone structure and its osteogenic tissues, diminishing osteoprogenitor number and function and severely impairing bone formation. Notably, increasing osteogenic cell numbers locally fails to rescue repair in aged mice, identifying the presence of intrinsic cellular deficits. Our strategy combines Wnt-mediated osteoprogenitor expansion with intermittent fasting, which leads to a striking restoration of youthful levels of bone healing. We find that intermittent fasting improves osteoprogenitor function, benefits that can be recapitulated by modulating NAD+-dependent pathways or the gut microbiota, underscoring the multifaceted nature of this intervention. Mechanistically, we identify mitochondrial dysfunction as a key component in age-related decline in osteoprogenitor function and show that both cyclical nutrient deprivation and Nicotinamide mononucleotide rejuvenate mitochondrial health, enhancing osteogenesis. These findings offer a promising therapeutic avenue for restoring youthful bone repair in aged individuals, with potential implications for rejuvenating other tissues.
    Keywords:  Wnt; aging; bone; intermittent fasting; mouse; osteoprogenitors; regenerative medicine; rejuvenation; stem cells
    DOI:  https://doi.org/10.7554/eLife.104068
  18. Cell Rep. 2024 Dec 18. pii: S2211-1247(24)01447-5. [Epub ahead of print]44(1): 115096
    P-cadherin mechanoactivates tumor-mesothelium metabolic coupling to promote ovarian cancer metastasis.
    Jing Ma, Sally Kit Yan To, Katie Sze Wai Fung, Kun Wang, Jiangwen Zhang, Alfonso Hing Wan Ngan, Susan Yung, Tak Mao Chan, Carmen Chak Lui Wong, Philip Pun Ching Ip, Ling Peng, Hong-Yan Guo, Chi Bun Chan, Alice Sze Tsai Wong.
      Cancer adhesion to the mesothelium is critical for peritoneal metastasis, but how metastatic cells adapt to the biomechanical microenvironment remains unclear. Our study demonstrates that highly metastatic (HM), but not non-metastatic, ovarian cancer cells selectively activate the peritoneal mesothelium. HM cells exert a stronger adhesive force on mesothelial cells via P-cadherin, an adhesion molecule abundant in late-stage tumors. Mechanical activation of P-cadherin enhances lipogenic gene expression and lipid content in HM cells through SREBP1. P-cadherin also induces glycolysis in the interacting mesothelium without affecting lipogenic activity, with the resulting lactate serving as a substrate for lipogenesis in HM cells. Nanodelivery of small interfering RNA (siRNA) targeting P-cadherin or MCT1/4 transporters significantly suppresses metastasis in mice. Moreover, increased fatty acid synthase levels in metastatic patient samples correlate with high P-cadherin expression, supporting enhanced de novo lipogenesis in the metastatic niche. This study reveals P-cadherin-mediated mechano-metabolic coupling as a promising target to restrain metastasis.
    Keywords:  CP: Cancer; CP: Metabolism; P-cadherin; adhesion; glycolysis; lipogenesis; mechanotransduction; metabolic reprogramming; ovarian cancer; peritoneal metastasis; tumor mesothelium
    DOI:  https://doi.org/10.1016/j.celrep.2024.115096
  19. Nature. 2024 Dec 18.
    Engineered extrachromosomal oncogene amplifications promote tumorigenesis.
    Davide Pradella, Minsi Zhang, Rui Gao, Melissa A Yao, Katarzyna M Gluchowska, Ylenia Cendon-Florez, Tanmay Mishra, Gaspare La Rocca, Moritz Weigl, Ziqi Jiao, Hieu H M Nguyen, Marta Lisi, Mateusz M Ozimek, Chiara Mastroleo, Kevin Chen, Felix Grimm, Jens Luebeck, Shu Zhang, Andrea Alice Zolli, Eric G Sun, Bhargavi Dameracharla, Zhengqiao Zhao, Yuri Pritykin, Carlie Sigel, Howard Y Chang, Paul S Mischel, Vineet Bafna, Cristina R Antonescu, Andrea Ventura.
      Focal gene amplifications are among the most common cancer-associated mutations1 but have proven challenging to engineer in primary cells and model organisms. Here we describe a general strategy to engineer large (more than 1 Mbp) focal amplifications mediated by extrachromosomal DNAs (ecDNAs)2 in a spatiotemporally controlled manner in cells and in mice. By coupling ecDNA formation with expression of selectable markers, we track the dynamics of ecDNA-containing cells under physiological conditions and in the presence of specific selective pressures. We also apply this approach to generate mice harbouring Cre-inducible Myc- and Mdm2-containing ecDNAs analogous to those occurring in human cancers. We show that the engineered ecDNAs spontaneously accumulate in primary cells derived from these animals, promoting their proliferation, immortalization and transformation. Finally, we demonstrate the ability of Mdm2-containing ecDNAs to promote tumour formation in an autochthonous mouse model of hepatocellular carcinoma. These findings offer insights into the role of ecDNA-mediated gene amplifications in tumorigenesis. We anticipate that this approach will be valuable for investigating further unresolved aspects of ecDNA biology and for developing new preclinical immunocompetent mouse models of human cancers harbouring specific focal gene amplifications.
    DOI:  https://doi.org/10.1038/s41586-024-08318-8
  20. Cell Syst. 2024 Dec 18. pii: S2405-4712(24)00346-6. [Epub ahead of print]15(12): 1225-1244
    Metabolic immunoengineering approaches to enhance CD8+ T cell-based cancer immunotherapy.
    Bing Feng, Rongrong Li, Weilin Li, Li Tang.
      Many cancer immunotherapies rely on robust CD8+ T cells capable of eliminating cancer cells and establishing long-term tumor control. Recent insights into immunometabolism highlight the importance of nutrients and metabolites in T cell activation and differentiation. Within the tumor microenvironment (TME), CD8+ tumor-infiltrating lymphocytes (TILs) undergo metabolic adaptations to survive but compromise their effector function and differentiation. Targeting metabolism holds promise for enhancing CD8+ T cell-mediated antitumor immunity. Here, we overview the metabolic features of CD8+ TILs and their impact on T cell effector function and differentiation. We also highlight immunoengineering strategies by leveraging the Yin-Yang of metabolic modulation for improving cancer immunotherapy.
    Keywords:  CD8(+) T cell; cancer immunotherapy; metabolic immunoengineering
    DOI:  https://doi.org/10.1016/j.cels.2024.11.010
  21. Science. 2024 Dec 20. 386(6728): 1349-1350
    Aged neurons don't register energy need.
    Deniz Bingul, Scott F Owen.
      Neuronal activity and mitochondrial gene expression become decoupled in aged mice.
    DOI:  https://doi.org/10.1126/science.adu4935
  22. Immunity. 2024 Dec 12. pii: S1074-7613(24)00532-6. [Epub ahead of print]
    The cGAS-STING pathway activates transcription factor TFEB to stimulate lysosome biogenesis and pathogen clearance.
    Yinfeng Xu, Qian Wang, Jun Wang, Chuying Qian, Yusha Wang, Sheng Lu, Lijiang Song, Zhengfu He, Wei Liu, Wei Wan.
      Induction of autophagy is an ancient function of the cyclic GMP-AMP (cGAMP) synthase (cGAS)-stimulator of interferon genes (STING) pathway through which autophagic cargoes are delivered to lysosomes for degradation. However, whether lysosome function is also modulated by the cGAS-STING pathway remains unknown. Here, we discovered that the cGAS-STING pathway upregulated lysosomal activity by stimulating lysosome biogenesis independently of the downstream protein kinase TANK-binding kinase 1 (TBK1). STING activation enhanced lysosome biogenesis through inducing the nuclear translocation of transcription factor EB (TFEB) as well as its paralogs transcription factor E3 (TFE3) and microphthalmia-associated transcription factor (MITF). STING-induced lipidation of GABA type A receptor-associated protein (GABARAP), an autophagy-related protein, on STING vesicles was responsible for TFEB activation. Membrane-bound GABARAP sequestered the GTPase-activating protein folliculin (FLCN) and FLCN-interacting protein (FNIP) complex to block its function toward the Rag GTPases Ras-related GTP-binding C and D (RagC and RagD), abolishing mechanistic target of rapamycin (mTOR) complex 1 (mTORC1)-dependent phosphorylation and inactivation of TFEB. Functionally, STING-induced lysosome biogenesis within cells facilitated the clearance of cytoplasmic DNA and invading pathogens. Thus, our findings reveal that induction of lysosome biogenesis is another important function of the cGAS-STING pathway.
    Keywords:  STING; TFEB; cGAS; innate immunity; lysosome
    DOI:  https://doi.org/10.1016/j.immuni.2024.11.017
  23. FEBS J. 2024 Dec 19.
    Conversion of pyridoxal to pyridoxamine with NH3 and H2 on nickel generates a protometabolic nitrogen shuttle under serpentinizing conditions.
    Manon Laura Schlikker, Max Brabender, Loraine Schwander, Carolina Garcia Garcia, Maximillian Burmeister, Sabine Metzger, Joseph Moran, William F Martin.
      Serpentinizing hydrothermal vents are likely sites for the origin of metabolism because they produce H2 as a source of electrons for CO2 reduction while depositing zero-valent iron, cobalt, and nickel as catalysts for organic reactions. Recent work has shown that solid-state nickel can catalyze the H2-dependent reduction of CO2 to various organic acids and their reductive amination with H2 and NH3 to biological amino acids under the conditions of H2-producing hydrothermal vents and that amino acid synthesis from NH3, H2, and 2-oxoacids is facile in the presence of Ni0. Such reactions suggest a metallic origin of metabolism during early biochemical evolution because single metals replace the function of over 130 enzymatic reactions at the core of metabolism in microbes that use the acetyl-CoA pathway of CO2 fixation. Yet solid-state catalysts tether primordial amino synthesis to a mineral surface. Many studies have shown that pyridoxal catalyzes transamination reactions without enzymes. Here we show that pyridoxamine, the NH2-transferring intermediate in pyridoxal-dependent transamination reactions, is generated from pyridoxal by reaction with NH3 (as little as 5 mm) and H2 (5 bar) on Ni0 as catalyst at pH 11 and 80 °C within hours. These conditions correspond to those in hydrothermal vents undergoing active serpentinization. The results indicate that at the origin of metabolism, pyridoxamine provided a soluble, organic amino donor for aqueous amino acid synthesis, mediating an evolutionary transition from NH3-dependent amino acid synthesis on inorganic surfaces to pyridoxamine-dependent organic reactions in the aqueous phase.
    Keywords:  hydrogen; hydrothermal vents; native metals; origin of life; serpentinization
    DOI:  https://doi.org/10.1111/febs.17357
  24. Trends Endocrinol Metab. 2024 Dec 17. pii: S1043-2760(24)00320-5. [Epub ahead of print]
    Inter-organ communication is a critical machinery to regulate metabolism and aging.
    Kyohei Tokizane, Shin-Ichiro Imai.
      Inter-organ communication (IOC) is a complex mechanism involved in maintaining metabolic homeostasis and healthy aging. Dysregulation of distinct forms of IOC is linked to metabolic derangements and age-related pathologies, implicating these processes as a potential target for therapeutic intervention to promote healthy aging. In this review, we delve into IOC mediated by hormonal signaling, circulating factors, organelle signaling, and neuronal networks and examine their roles in regulating metabolism and aging. Given the role of the hypothalamus as a high-order control center for aging and longevity, we particularly emphasize the importance of its communication with peripheral organs and pave the way for a better understanding of this critical machinery in metabolism and aging.
    Keywords:  aging; hypothalamus; inter-organ communication; metabolism
    DOI:  https://doi.org/10.1016/j.tem.2024.11.013
  25. J Gen Physiol. 2025 Jan 06. pii: e202313520. [Epub ahead of print]157(1):
    How does mitochondrial Ca2+ change during ischemia and reperfusion? Implications for activation of the permeability transition pore.
    Elizabeth Murphy, David A Eisner.
      Cardiac ischemia followed by reperfusion results in cardiac cell death, which has been attributed to an increase of mitochondrial Ca2+ concentration, resulting in activation of the mitochondrial permeability transition pore (PTP). Evaluating this hypothesis requires understanding of the mechanisms responsible for control of mitochondrial Ca2+ in physiological conditions and how they are altered during both ischemia and reperfusion. Ca2+ influx is thought to occur through the mitochondrial Ca2+ uniporter (MCU). However, with deletion of the MCU, an increase in mitochondrial Ca2+ still occurs, suggesting an alternative Ca2+ influx mechanism during ischemia. There is less certainty about the mechanisms responsible for Ca2+ efflux, with contributions from both Ca2+/H+ exchange and a Na+-dependent Ca2+ efflux pathway. The molecular details of both mechanisms are not fully resolved. We discuss this and the contributions of both pathways to the accumulation of mitochondrial Ca2+ during ischemia and reperfusion. We further discuss the role of mitochondrial Ca2+ in activation of the PTP.
    DOI:  https://doi.org/10.1085/jgp.202313520
  26. Nat Rev Nephrol. 2024 Dec 16.
    Mitochondrial dysfunction has a central role in diabetic kidney disease.
    Shen Li, Katalin Susztak.
      
    DOI:  https://doi.org/10.1038/s41581-024-00919-w
  27. Mol Metab. 2024 Dec 13. pii: S2212-8778(24)00213-8. [Epub ahead of print] 102082
    Epigenetic suppression of creatine kinase B in adipocytes links endoplasmic reticulum stress to obesity-associated inflammation.
    Gianluca Renzi, Ivan Vlassakev, Mattias Hansen, Romane Higos, Simon Lecoutre, Merve Elmastas, Ondrej Hodek, Thomas Moritz, Lynn M Alaeddine, Scott Frendo-Cumbo, Ingrid Dahlman, Alastair Kerr, Salwan Maqdasy, Niklas Mejhert, Mikael Rydén.
      In white adipose tissue, disturbed creatine metabolism through reduced creatine kinase B (CKB) transcription contributes to obesity-related inflammation. However, the mechanisms regulating CKB expression in human white adipocytes remain unclear. By screening conditions perturbed in obesity, we identified endoplasmic reticulum (ER) stress as a key suppressor of CKB transcription across multiple cell types. Through follow-up studies, we found that ER stress through the IRE1-XBP1s pathway, promotes CKB promoter methylation via the methyltransferase DNMT3A. This epigenetic change represses CKB transcription, shifting metabolism towards glycolysis and increasing the production of the pro-inflammatory chemokine CCL2. We validated our findings in vivo, demonstrating that individuals living with obesity show an inverse relationship between CKB expression and promoter methylation in white adipocytes, along with elevated CCL2 secretion. Overall, our study uncovers a regulatory axis where ER stress drives inflammation in obesity by reducing CKB abundance, and consequently altering the bioenergetic state of the cell.
    Keywords:  Chromatin remodeling; Creatine pathway; Glycolysis; Immunometabolism; Tunicamycin
    DOI:  https://doi.org/10.1016/j.molmet.2024.102082
  28. J Cell Biol. 2025 Feb 03. pii: e202409050. [Epub ahead of print]224(2):
    A proteome-wide yeast degron collection for the dynamic study of protein function.
    Rosario Valenti, Yotam David, Dunya Edilbi, Benjamin Dubreuil, Angela Boshnakovska, Yeynit Asraf, Tomer-Meir Salame, Ehud Sass, Peter Rehling, Maya Schuldiner.
      Genome-wide collections of yeast strains, known as libraries, revolutionized the way systematic studies are carried out. Specifically, libraries that involve a cellular perturbation, such as the deletion collection, have facilitated key biological discoveries. However, short-term rewiring and long-term accumulation of suppressor mutations often obscure the functional consequences of such perturbations. We present the AID library which supplies "on demand" protein depletion to overcome these limitations. Here, each protein is tagged with a green fluorescent protein (GFP) and an auxin-inducible degron (AID), enabling rapid protein depletion that can be quantified systematically using the GFP element. We characterized the degradation response of all strains and demonstrated its utility by revisiting seminal yeast screens for genes involved in cell cycle progression as well as mitochondrial distribution and morphology. In addition to recapitulating known phenotypes, we also uncovered proteins with previously unrecognized roles in these central processes. Hence, our tool expands our knowledge of cellular biology and physiology by enabling access to phenotypes that are central to cellular physiology and therefore rapidly equilibrated.
    DOI:  https://doi.org/10.1083/jcb.202409050
  29. Nature. 2024 Dec 19.
    A blood test detects aged cells.
      
    Keywords:  Ageing
    DOI:  https://doi.org/10.1038/d41586-024-04172-w
  30. FASEB J. 2024 Dec 13. 38(24): e70235
    Time-of-day control of mitochondria regulates NLRP3 inflammasome activation in macrophages.
    James R O'Siorain, Shannon L Cox, Cloé Payet, Frances K Nally, Yan He, Tabea T Drewinksi, Oran D Kennedy, Jennifer K Dowling, Mark Mellett, James O Early, Annie M Curtis.
      Macrophages are innate immune cells that orchestrate the process of inflammation, which varies across time of day. This ensures appropriate biological timing of the immune response with the external environment. The NLRP3 inflammasome mediates IL-1-family cytokine release via pyroptosis. Mitochondria play a multifaceted role regulating NLRP3 inflammasome activity. Mitochondria exhibit distinct metabolic changes across time of day, which are influenced by clock genes. However, whether the macrophage clock regulates the NLRP3 inflammasome via mitochondrial control remains unclear. We find heightened mitochondrial membrane potential (Δψm) and enhanced NLRP3 inflammasome activation from peritoneal exudate cells (PECs) isolated at circadian time (CT) 12 compared to CT 0. In vitro time-of-day synchronization of bone-marrow derived macrophages (BMDMs) induced time-dependent differences in NLRP3 inflammasome activation. Myeloid-specific Bmal1-deletion enhanced NLRP3 inflammasome activity in PECs at CT0 and in unsynchronized BMDMs compared to controls. Pharmacologically disrupting Δψm in synchronized cells reduced NLRP3 inflammasome activation to comparable levels, and the same occurred with Bmal1-deletion. These results further demonstrate circadian clock timing of the NLRP3 inflammasome, which is dependent on mitochondrial function and driven through the circadian gene Bmal1.
    Keywords:  NLRP3 inflammasome; circadian rhythms; macrophages; mitochondria; pyroptosis
    DOI:  https://doi.org/10.1096/fj.202400508RR
  31. Trends Endocrinol Metab. 2024 Dec 17. pii: S1043-2760(24)00317-5. [Epub ahead of print]
    Exploring tryptophan metabolism in cardiometabolic diseases.
    Nirmala Mouttoulingam, Soraya Taleb.
      Tryptophan (Trp) metabolism is linked to health and disease, with indoleamine 2,3-dioxygenase 1 (IDO) being a key enzyme in its breakdown outside the liver. This process produces metabolites that influence metabolic and inflammatory responses. A distinctive feature of the gut is its involvement in three major Trp catabolic pathways: the IDO-driven kynurenine pathway, bacteria-produced indoles, and serotonin. Dysregulation of these pathways is associated with gastrointestinal and chronic inflammatory diseases. Understanding these mechanisms could reveal how gut function affects overall systemic health and disease susceptibility. Here, we review current insights into Trp metabolism, its impact on host physiology and cardiometabolic diseases, and its role in the gut-periphery connection, highlighting its relevance for therapeutic innovation.
    Keywords:  atherosclerosis; gut; indoleamine 2,3-dioxygenase 1; metabolic diseases; tryptophan
    DOI:  https://doi.org/10.1016/j.tem.2024.11.009
  32. Bioessays. 2024 Dec 18. e202400211
    A Compensated Clock: Temperature and Nutritional Compensation Mechanisms Across Circadian Systems.
    Elizabeth-Lauren Stevenson, Adrienne K Mehalow, Jennifer J Loros, Christina M Kelliher, Jay C Dunlap.
      Circadian rhythms are ∼24-h biological oscillations that enable organisms to anticipate daily environmental cycles, so that they may designate appropriate day/night functions that align with these changes. The molecular clock in animals and fungi consists of a transcription-translation feedback loop, the plant clock is comprised of multiple interlocking feedback-loops, and the cyanobacterial clock is driven by a phosphorylation cycle involving three main proteins. Despite the divergent core clock mechanisms across these systems, all circadian clocks are able to buffer period length against changes in the ambient growth environment, such as temperature and nutrients. This defining capability, termed compensation, is critical to proper timekeeping, yet the underlying mechanism(s) remain elusive. Here we examine the known players in, and the current models for, compensation across five circadian systems. While compensation models across these systems are not yet unified, common themes exist across them, including regulation via temperature-dependent changes in post-translational modifications.
    Keywords:  Arabidopsis; Drosophila; Neurospora; circadian rhythms; cyanobacteria; nutritional compensation; temperature compensation
    DOI:  https://doi.org/10.1002/bies.202400211
  33. Autophagy. 2024 Dec 15.
    Endogenous interactomes of MFN1 and MFN2 provide novel insights into interorganelle communication and autophagy.
    Isabel Gordaliza-Alaguero, Paula Sànchez-Fernàndez-de-Landa, Dragana Radivojevikj, Laura Villarreal, Gianluca Arauz-Garofalo, Marina Gay, Marta Martinez-Vicente, Jorge Seco, Pau Martin-Malpartida, Marta Vilaseca, María J Macías, Manuel Palacin, Saška Ivanova, Antonio Zorzano.
      MFN1 (mitofusin 1) and MFN2 are key players in mitochondrial fusion, endoplasmic reticulum (ER)-mitochondria juxtaposition, and macroautophagy/autophagy. However, the mechanisms by which these proteins participate in these processes are poorly understood. Here, we studied the interactomes of these two proteins by using CRISPR-Cas9 technology to insert an HA-tag at the C terminus of MFN1 and MFN2, and thus generating HeLa cell lines that endogenously expressed MFN1-HA or MFN2-HA. HA-affinity isolation followed by mass spectrometry identified potential interactors of MFN1 and MFN2. A substantial proportion of interactors were common for MFN1 and MFN2 and were regulated by nutrient deprivation. We validated novel ER and endosomal partners of MFN1 and/or MFN2 with a potential role in interorganelle communication. We characterized RAB5C (RAB5C, member RAS oncogene family) as an endosomal modulator of mitochondrial homeostasis, and SLC27A2 (solute carrier family 27 (fatty acid transporter), member 2) as a novel partner of MFN2 relevant in autophagy. We conclude that MFN proteins participate in nutrient-modulated pathways involved in organelle communication and autophagy.
    Keywords:  Autophagosomes; endosomes; mitochondria; mitochondria-endoplasmic reticulum contact sites; mitochondrial dynamics; nutrient deprivation
    DOI:  https://doi.org/10.1080/15548627.2024.2440843
  34. Sci Signal. 2024 Dec 10. 17(866): eadv0957
    The polarizing nature of fructose.
    Wei Wong.
      Dietary fructose skews tumor-associated macrophages toward a pro-cancer phenotype in colorectal tumors.
    DOI:  https://doi.org/10.1126/scisignal.adv0957
  35. Mol Cancer Res. 2024 Dec 19.
    Lysosomal/mitochondrial interaction promotes tumor growth in squamous cell carcinoma of the head and neck.
    Avani Gopalkrishnan, Nathaniel Wang, Silvia Cruz-Rangel, Abdul Yassin-Kassab, Sruti Shiva, Chareeni Kurukulasuriya, Satdarshan P Monga, Ralph J DeBerardinis, Heath D Skinner, Kirill Kiselyov, Umamaheswar Duvvuri.
      Communication between intracellular organelles including lysosomes and mitochondria has recently been shown to regulate cellular proliferation and fitness. The way lysosomes and mitochondria communicate with each other (lysosomal/mitochondrial interaction, LMI) is, emerging as a major determinant of tumor proliferation and growth. About 30% of squamous carcinomas (including squamous cell carcinoma of the head and neck, SCCHN) overexpress TMEM16A, a calcium-activated chloride channel, which promotes cellular growth and negatively correlates with patient survival. We have recently shown that TMEM16A drives lysosomal biogenesis, but its impact on mitochondrial function has not been explored. Here, we show that in the context of high TMEM16A SCCHN, (1) patients display increased mitochondrial content, specifically complex I; (2) In vitro and in vivo models uniquely depend on mitochondrial complex I activity for growth and survival; (3) NRF2 signaling is a critical linchpin that drives mitochondrial function, and (4) mitochondrial complex I and lysosomal function are codependent for proliferation. Taken together, our data demonstrate that coordinated lysosomal and mitochondrial activity and biogenesis via LMI drive tumor proliferation and facilitates a functional interaction between lysosomal and mitochondrial networks. Therefore, inhibition of LMI instauration may serve as a therapeutic strategy for patients with SCCHN. Implications: Intervention of lysosome-mitochondria interaction may serve as a therapeutic approach for patients with high TMEM16A expressing SCCHN.
    DOI:  https://doi.org/10.1158/1541-7786.MCR-24-0337
  36. Annu Rev Biomed Eng. 2024 Dec 17.
    Systems Biology of the Cancer Cell.
    Kevin A Janes, Matthew J Lazzara.
      Questions in cancer have engaged systems biologists for decades. During that time, the quantity of molecular data has exploded, but the need for abstractions, formal models, and simplifying insights has remained the same. This review brings together classic breakthroughs and recent findings in the field of cancer systems biology, focusing on cancer-cell pathways for tumorigenesis and therapeutic response. Cancer cells mutate and transduce information from their environment to alter gene expression, metabolism, and phenotypic states. Understanding the molecular architectures that make each of these steps possible is a long-term goal of cancer systems biology pursued by iterating between quantitative models and experiments. We argue that such iteration is the best path to deploying targeted therapies intelligently so that each patient receives the maximum benefit for their cancer.
    DOI:  https://doi.org/10.1146/annurev-bioeng-103122-030552
  37. Nature. 2024 Dec 18.
    Spatial transcriptomic clocks reveal cell proximity effects in brain ageing.
    Eric D Sun, Olivia Y Zhou, Max Hauptschein, Nimrod Rappoport, Lucy Xu, Paloma Navarro Negredo, Ling Liu, Thomas A Rando, James Zou, Anne Brunet.
      Old age is associated with a decline in cognitive function and an increase in neurodegenerative disease risk1. Brain ageing is complex and is accompanied by many cellular changes2. Furthermore, the influence that aged cells have on neighbouring cells and how this contributes to tissue decline is unknown. More generally, the tools to systematically address this question in ageing tissues have not yet been developed. Here we generate a spatially resolved single-cell transcriptomics brain atlas of 4.2 million cells from 20 distinct ages across the adult lifespan and across two rejuvenating interventions-exercise and partial reprogramming. We build spatial ageing clocks, machine learning models trained on this spatial transcriptomics atlas, to identify spatial and cell-type-specific transcriptomic fingerprints of ageing, rejuvenation and disease, including for rare cell types. Using spatial ageing clocks and deep learning, we find that T cells, which increasingly infiltrate the brain with age, have a marked pro-ageing proximity effect on neighbouring cells. Surprisingly, neural stem cells have a strong pro-rejuvenating proximity effect on neighbouring cells. We also identify potential mediators of the pro-ageing effect of T cells and the pro-rejuvenating effect of neural stem cells on their neighbours. These results suggest that rare cell types can have a potent influence on their neighbours and could be targeted to counter tissue ageing. Spatial ageing clocks represent a useful tool for studying cell-cell interactions in spatial contexts and should allow scalable assessment of the efficacy of interventions for ageing and disease.
    DOI:  https://doi.org/10.1038/s41586-024-08334-8
  38. J Biol Chem. 2024 Dec 13. pii: S0021-9258(24)02577-8. [Epub ahead of print] 108075
    Dysregulation of PI4P in the trans Golgi regions activates the mammalian Golgi stress response.
    Kanae Sasaki, Marika Toide, Takuya Adachi, Fumi Morishita, Yuto Watanabe, Hajime Tajima Sakurai, Sadao Wakabayashi, Satoshi Kusumi, Toshiyuki Yamaji, Kaori Sakurai, Daisuke Koga, Kentaro Hanada, Masafumi Yohda, Hiderou Yoshida.
      The Golgi stress response is an important cytoprotective system that enhances Golgi function in response to cellular demand, while cells damaged by prolonged Golgi stress undergo cell death. OSW-1, a natural compound with anticancer activity, potently inhibits OSBP that transports cholesterol and phosphatidylinositol-4-phosphate (PI4P) at contact sites between the endoplasmic reticulum and the Golgi apparatus. Previously, we reported that OSW-1 induces the Golgi stress response, resulting in Golgi stress-induced transcription and cell death. However, the underlying molecular mechanism has been unknown. To reveal the mechanism of a novel pathway of the Golgi stress response regulating transcriptional induction and cell death (the PI4P pathway), we performed a genome-wide knockout screen and found that transcriptional induction as well as cell death induced by OSW-1 was repressed by the loss of regulators of PI4P synthesis, such as PITPNB and PI4KB. Our data indicate that OSW-1 induces Golgi stress-dependent transcriptional induction and cell death through dysregulation of the PI4P metabolism in the Golgi.
    Keywords:  Golgi stress response; OSW-1; cancer; phosphatidylinositol-4-phosphate; the Genome-wide CRISPR-Cas9 knockout screening
    DOI:  https://doi.org/10.1016/j.jbc.2024.108075
  39. bioRxiv. 2024 Dec 05. pii: 2024.11.29.625709. [Epub ahead of print]
    Macropinocytosis controls metabolic stress-driven CAF subtype identity in pancreatic cancer.
    Yijuan Zhang, Li Ling, Swetha Maganti, Jennifer L Hope, Cheska Marie Galapate, Florent Carrette, Karen Duong-Polk, Anindya Bagchi, David A Scott, Andrew M Lowy, Linda M Bradley, Cosimo Commisso.
      Pancreatic ductal adenocarcinoma (PDAC) tumors are deficient in glutamine, an amino acid that tumor cells and CAFs use to sustain their fitness. In PDAC, both cell types stimulate macropinocytosis as an adaptive response to glutamine depletion. CAFs play a critical role in sculpting the tumor microenvironment, yet how adaptations to metabolic stress impact the stromal architecture remains elusive. In this study, we find that macropinocytosis functions to control CAF subtype identity when glutamine is limiting. Our data demonstrate that metabolic stress leads to an intrinsic inflammatory CAF (iCAF) program driven by MEK/ERK signaling. Utilizing in vivo models, we find that blocking macropinocytosis alters CAF subtypes and reorganizes the tumor stroma. Importantly, these changes in stromal architecture can be exploited to sensitize PDAC to immunotherapy and chemotherapy. Our findings demonstrate that metabolic stress plays a role in shaping the tumor microenvironment, and that this attribute can be harnessed for therapeutic impact.
    Keywords:  CAF heterogeneity; Metabolic stress; drug delivery; macropinocytosis; pancreatic cancer; stromal architecture; tumor microenvironment
    DOI:  https://doi.org/10.1101/2024.11.29.625709
  40. Annu Rev Physiol. 2024 Dec 10.
    Exercise as Mitochondrial Medicine: How Does the Exercise Prescription Affect Mitochondrial Adaptations to Training?
    David J Bishop, Matthew J-C Lee, Martin Picard.
      Mitochondria are multifaceted organelles with several life-sustaining functions beyond energy transformation, including cell signaling, calcium homeostasis, hormone synthesis, programmed cell death (apoptosis), and others. A defining aspect of these dynamic organelles is their remarkable plasticity, which allows them to sense, respond, and adapt to various stressors. In particular, it is well-established that the stress of exercise provides a powerful stimulus that can trigger transient or enduring changes to mitochondrial molecular features, activities, integrated functions, behaviors, and cell-dependent mitochondrial phenotypes. Evidence documenting the many beneficial mitochondrial adaptations to exercise has led to the notion of exercise as a mitochondrial medicine. However, as with other medicines, it is important to understand the optimal prescription (i.e., type, dose, frequency, duration). In this review, we build on a systematic biological framework that distinguishes between domains of mitochondrial biology to critically evaluate how different exercise prescription variables influence mitochondrial adaptations to training.
    DOI:  https://doi.org/10.1146/annurev-physiol-022724-104836
  41. Aging Cell. 2024 Dec 16. e14402
    Increased mitochondrial mutation heteroplasmy induces aging phenotypes in pluripotent stem cells and their differentiated progeny.
    Amy R Vandiver, Alejandro Torres, Amberly Sanden, Thang L Nguyen, Jasmine Gasilla, Mary T Doan, Vahan Martirosian, Austin Hoang, Jonathan Wanagat, Michael A Teitell.
      The mitochondrial genome (mtDNA) is an important source of inherited extranuclear variation. Clonal increases in mtDNA mutation heteroplasmy have been implicated in aging and disease, although the impact of this shift on cell function is challenging to assess. Reprogramming to pluripotency affects mtDNA mutation heteroplasmy. We reprogrammed three human fibroblast lines with known heteroplasmy for deleterious mtDNA point or deletion mutations. Quantification of mutation heteroplasmy in the resulting 76 induced pluripotent stem cell (iPSC) clones yielded a bimodal distribution, creating three sets of clones with high levels or absent mutation heteroplasmy with matched nuclear genomes. iPSC clones with elevated deletion mutation heteroplasmy show altered growth dynamics, which persist in iPSC-derived progenitor cells. We identify transcriptomic and metabolic shifts consistent with increased investment in neutral lipid synthesis as well as increased epigenetic age in high mtDNA deletion mutation iPSC, consistent with changes occurring in cellular aging. Together, these data demonstrate that high mtDNA mutation heteroplasmy induces changes occurring in cellular aging.
    Keywords:  aging; iPSC; mitochondria; mtDNA mutation
    DOI:  https://doi.org/10.1111/acel.14402
  42. J Exp Clin Cancer Res. 2024 Dec 19. 43(1): 325
    Pathogenic mitochondrial DNA variants are associated with response to anti-VEGF therapy in ovarian cancer PDX models.
    Daniele Boso, Ilaria Piga, Chiara Trento, Sonia Minuzzo, Eleonora Angi, Luisa Iommarini, Elisabetta Lazzarini, Leonardo Caporali, Claudio Fiorini, Luigi D'Angelo, Monica De Luise, Ivana Kurelac, Matteo Fassan, Anna Maria Porcelli, Filippo Navaglia, Ilaria Billato, Giovanni Esposito, Giuseppe Gasparre, Chiara Romualdi, Stefano Indraccolo.
       BACKGROUND: Mitochondrial DNA (mtDNA) pathogenic variants have been reported in several solid tumors including ovarian cancer (OC), the most lethal gynecologic malignancy, and raised interest as they potentially induce mitochondrial dysfunction and rewiring of cellular metabolism. Despite advances in recent years, functional characterization of mtDNA variants in cancer and their possible modulation of drug response remain largely uncharted.
    METHODS: Here, we characterized mtDNA variants in OC patient derived xenografts (PDX) and investigated their impact on cancer cells at multiple levels.
    RESULTS: Genetic analysis revealed that mtDNA variants predicted as pathogenic, mainly involving complex I and IV genes, were present in all but one PDX (n = 20) at different levels of heteroplasmy, including 7 PDXs with homoplasmic variants. Functional analyses demonstrated that pathogenic mtDNA variants impacted on respiratory complexes activity and subunits abundance as well as on mitochondrial morphology. Moreover, PDX cells bearing homoplasmic mtDNA variants behaved as glucose-addicted and could barely survive glucose starvation in vitro. RNA-seq analysis indicated that mtDNA mutated (heteroplasmy > 50%) PDXs were endowed with upregulated glycolysis and other pathways connected with cancer metabolism. These findings led us to investigate whether pathogenic mtDNA variants correlated with response to anti-VEGF therapy, since the latter was shown to reduce glucose availability in tumors. Strikingly, PDXs bearing homoplasmic pathogenic mtDNA variants associated with improved survival upon anti-VEGF treatment in mice, compared with mtDNA wild type or low heteroplasmy PDXs.
    CONCLUSIONS: These results hint at mtDNA variants as potential biomarkers of response to antiangiogenic drugs.
    Keywords:  Antiangiogenic therapy; Mitochondrial DNA mutations; Ovarian cancer; Patient-derived xenografts; Predictive biomarkers
    DOI:  https://doi.org/10.1186/s13046-024-03239-w
  43. Trends Cancer. 2024 Dec 13. pii: S2405-8033(24)00260-7. [Epub ahead of print]
    Functional heterogeneity of fibroblasts in primary tumors and metastases.
    Priscilla S W Cheng, Marta Zaccaria, Giulia Biffi.
      Cancer-associated fibroblasts (CAFs) are abundant components of the tumor microenvironment (TME) of most solid malignancies and have emerged as key regulators of cancer progression and therapy response. Although recent technological advances have uncovered substantial CAF molecular heterogeneity at the single-cell level, defining functional roles for most described CAF populations remains challenging. With the aim of bridging CAF molecular and functional heterogeneity, this review focuses on recently identified functional interactions of CAF subtypes with malignant cells, immune cells, and other stromal cells in primary tumors and metastases. Dissecting the heterogeneous functional crosstalk of specific CAF populations with other components is starting to uncover candidate combinatorial strategies for therapeutically targeting the TME and cancer progression.
    Keywords:  cancer-associated fibroblasts; fibroblast heterogeneity; metastases; primary tumors; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.trecan.2024.11.005
  44. J Cell Biol. 2025 Jan 06. pii: e202412011. [Epub ahead of print]224(1):
    Painting lysosomes to study organelle heterogeneity.
    Di Chen, Maximiliano G Gutierrez.
      Like other organelles, the heterogeneity of lysosomes within a single cell has been challenging to capture and study in detail. In this issue, Chen and Gutierrez discuss new work that tackles this question using DNA-PAINT imaging, from Lakadamyali and colleagues (https://doi.org/10.1083/jcb.202403116).
    DOI:  https://doi.org/10.1083/jcb.202412011
  45. Cancer Res. 2024 Dec 19.
    Selenoprotein O Promotes Melanoma Metastasis and Regulates Mitochondrial Complex II Activity.
    Luiza Martins Nascentes Melo, Marie Sabatier, Vijayashree Ramesh, Krystina J Szylo, Cameron S Fraser, Alexandra Pon, Evann C Mitchell, Kelly A Servage, Gabriele Allies, Isa V Westedt, Feyza Cansiz, Jonathan Krystkiewicz, Andrea Kutritz, Dirk Schadendorf, Sean J Morrison, Jessalyn M Ubellacker, Anju Sreelatha, Alpaslan Tasdogan.
      Evolutionarily conserved selenoprotein O (SELENOO) catalyzes a post-translational protein modification known as AMPylation that is essential for the oxidative stress response in bacteria and yeast. Given that oxidative stress experienced in the blood limits survival of metastasizing melanoma cells, SELENOO might be able to impact metastatic potential. However, further work is needed to elucidate the substrates and functional relevance of the mammalian homologue of SELENOO. Here, we revealed that SELENOO promotes cancer metastasis and identified substrates of SELENOO in mammalian mitochondria. In patients with melanoma, high SELENOO expression was correlated with metastasis and poor overall survival. In a murine model of spontaneous melanoma metastasis, SELENOO deficiency significantly reduced metastasis to distant visceral organs, which could be rescued by treatment with the antioxidant N-acetylcysteine. Mechanistically, SELENOO AMPylated multiple mitochondrial substrates, including succinate dehydrogenase subunit A, one of the four key subunits of mitochondrial complex II. Consistently, SELENOO-deficient cells featured increased mitochondrial complex II activity. Together, these findings demonstrate that SELENOO deficiency limits melanoma metastasis by modulating mitochondrial function and oxidative stress.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-23-2194
  46. Cell Metab. 2024 Dec 11. pii: S1550-4131(24)00452-2. [Epub ahead of print]
    Unveiling adipose populations linked to metabolic health in obesity.
    Isabel Reinisch, Adhideb Ghosh, Falko Noé, Wenfei Sun, Hua Dong, Peter Leary, Arne Dietrich, Anne Hoffmann, Matthias Blüher, Christian Wolfrum.
      Precision medicine is still not considered as a standard of care in obesity treatment, despite a large heterogeneity in the metabolic phenotype of individuals with obesity. One of the strongest factors influencing the variability in metabolic disease risk is adipose tissue (AT) dysfunction; however, there is little understanding of the link between distinct cell populations, cell-type-specific transcriptional programs, and disease severity. Here, we generated a comprehensive cellular map of subcutaneous and visceral AT of individuals with metabolically healthy and unhealthy obesity. By combining single-nucleus RNA-sequencing data with bulk transcriptomics and clinical parameters, we identified that mesothelial cells, adipocytes, and adipocyte-progenitor cells exhibit the strongest correlation with metabolic disease. Furthermore, we uncovered cell-specific transcriptional programs, such as the transitioning of mesothelial cells to a mesenchymal phenotype, that are involved in uncoupling obesity from metabolic disease. Together, these findings provide valuable insights by revealing biological drivers of clinical endpoints.
    Keywords:  adipocytes; adipose tissue; insulin resistance; insulin sensitivity; mesothelial cells; metabolically healthy obesity; obesity; precision medicine; snRNA-seq; visceral adipose tissue
    DOI:  https://doi.org/10.1016/j.cmet.2024.11.006
  47. Proc Natl Acad Sci U S A. 2024 Dec 24. 121(52): e2417724121
    An antibiotic that mediates immune destruction of senescent cancer cells.
    Gabriele Casagrande Raffi, Jian Chen, Xuezhao Feng, Zhen Chen, Cor Lieftink, Shuang Deng, Jinzhe Mo, Chuting Zeng, Marit Steur, Jing Wang, Onno B Bleijerveld, Liesbeth Hoekman, Nicole van der Wel, Feng Wang, Roderick Beijersbergen, Jian Zheng, Rene Bernards, Liqin Wang.
      Drugs that eliminate senescent cells, senolytics, can be powerful when combined with prosenescence cancer therapies. Using a CRISPR/Cas9-based genetic screen, we identify here SLC25A23 as a vulnerability of senescent cancer cells. Suppressing SLC25A23 disrupts cellular calcium homeostasis, impairs oxidative phosphorylation, and interferes with redox signaling, leading to death of senescent cells. These effects can be replicated by salinomycin, a cation ionophore antibiotic. Salinomycin prompts a pyroptosis-apoptosis-necroptosis (PAN)optosis-like cell death in senescent cells, including apoptosis and two forms of immunogenic cell death: necroptosis and pyroptosis. Notably, we observed that salinomycin treatment or SLC25A23 suppression elevates reactive oxygen species, upregulating death receptor 5 via Jun N-terminal protein kinase (JNK) pathway activation. We show that a combination of a death receptor 5 (DR5) agonistic antibody and salinomycin is a robust senolytic cocktail. We provide evidence that this drug combination provokes a potent natural killer (NK) and CD8+ T cell-mediated immune destruction of senescent cancer cells, mediated by the pyroptotic cytokine interleukin 18 (IL18).
    Keywords:  pyroptosis; senescence; senolytics
    DOI:  https://doi.org/10.1073/pnas.2417724121
  48. Nat Cancer. 2024 Dec 17.
    Adjusting the clock for cancer immunotherapy.
    Julieta Alfonso.
      
    DOI:  https://doi.org/10.1038/s43018-024-00834-w
  49. Cell. 2024 Dec 12. pii: S0092-8674(24)01324-2. [Epub ahead of print]
    YTHDF2 promotes ATP synthesis and immune evasion in B cell malignancies.
    Zhenhua Chen, Chengwu Zeng, Lu Yang, Yuan Che, Meiling Chen, Lillian Sau, Bintao Wang, Keren Zhou, Yu Chen, Ying Qing, Chao Shen, Tingjian Zhang, Mark Wunderlich, Dong Wu, Wei Li, Kitty Wang, Keith Leung, Miao Sun, Tingting Tang, Xin He, Lianjun Zhang, Srividya Swaminathan, James C Mulloy, Markus Müschen, Huilin Huang, Hengyou Weng, Gang Xiao, Xiaolan Deng, Jianjun Chen.
      Long-term durable remission in patients with B cell malignancies following chimeric antigen receptor (CAR)-T cell immunotherapy remains unsatisfactory, often due to antigen escape. Malignant B cell transformation and oncogenic growth relies on efficient ATP synthesis, although the underlying mechanisms remain unclear. Here, we report that YTHDF2 facilitates energy supply and antigen escape in B cell malignancies, and its overexpression alone is sufficient to cause B cell transformation and tumorigenesis. Mechanistically, YTHDF2 functions as a dual reader where it stabilizes mRNAs as a 5-methylcytosine (m5C) reader via recruiting PABPC1, thereby enhancing their expression and ATP synthesis. Concomitantly, YTHDF2 also promotes immune evasion by destabilizing other mRNAs as an N6-methyladenosine (m6A) reader. Small-molecule-mediated targeting of YTHDF2 suppresses aggressive B cell malignancies and sensitizes them to CAR-T cell therapy.
    Keywords:  ATP production; B cell malignancies; CAR-T; CD19; MHC-II; YTHDF2; m(5)C; m(6)A; metabolism
    DOI:  https://doi.org/10.1016/j.cell.2024.11.007
  50. Cancer Metab. 2024 Dec 19. 12(1): 38
    A whole food, plant-based diet reduces amino acid levels in patients with metastatic breast cancer.
    TashJaé Q Scales, Bradley Smith, Lisa M Blanchard, Nellie Wixom, Emily T Tuttle, Brian J Altman, Luke J Peppone, Joshua Munger, Thomas M Campbell, Erin K Campbell, Isaac S Harris.
       BACKGROUND: Amino acids are critical to tumor survival. Tumors can acquire amino acids from the surrounding microenvironment, including the serum. Limiting dietary amino acids is suggested to influence their serum levels. Further, a plant-based diet is reported to contain fewer amino acids than an animal-based diet. The extent to which a plant-based diet lowers the serum levels of amino acids in patients with cancer is unclear.
    METHODS: Patients with metastatic breast cancer (n = 17) were enrolled in a clinical trial with an ad libitum whole food, plant-based diet for 8 weeks without calorie or portion restriction. Dietary changes by participants were monitored using a three-day food record. Serum was collected from participants at baseline and 8 weeks. Food records and serum were analyzed for metabolic changes.
    RESULTS: We found that a whole food, plant-based diet resulted in a lower intake of calories, fat, and amino acids and higher levels of fiber. Additionally, body weight, serum insulin, and IGF were reduced in participants. The diet contained lower levels of essential and non-essential amino acids, except for arginine (glutamine and asparagine were not measured). Importantly, the lowered dietary intake of amino acids translated to reduced serum levels of amino acids in participants (5/9 essential amino acids; 4/11 non-essential amino acids).
    CONCLUSIONS: These findings provide a tractable approach to limiting amino acid levels in persons with cancer. This data lays a foundation for studying the relationship between amino acids in patients and tumor progression. Further, a whole-food, plant-based diet has the potential to synergize with cancer therapies that exploit metabolic vulnerabilities.
    TRIAL REGISTRATION: The clinical trial was registered with ClinicalTrials.gov identifier NCT03045289 on 2017-02-07.
    Keywords:  Amino acids; Calories; Cancer; Carbohydrate; Diet; Fat; Fiber; Plant-based; Protein; Whole food
    DOI:  https://doi.org/10.1186/s40170-024-00368-w
  51. Cell. 2024 Nov 26. pii: S0092-8674(24)01311-4. [Epub ahead of print]
    Intermittent fasting triggers interorgan communication to suppress hair follicle regeneration.
    Han Chen, Chao Liu, Shiyao Cui, Yingqian Xia, Ke Zhang, Hanxiao Cheng, Jingyu Peng, Xiaoling Yu, Luyang Li, Hualin Yu, Jufang Zhang, Ju-Sheng Zheng, Bing Zhang.
      Intermittent fasting has gained global popularity for its potential health benefits, although its impact on somatic stem cells and tissue biology remains elusive. Here, we report that commonly used intermittent fasting regimens inhibit hair follicle regeneration by selectively inducing apoptosis in activated hair follicle stem cells (HFSCs). This effect is independent of calorie reduction, circadian rhythm alterations, or the mTORC1 cellular nutrient-sensing mechanism. Instead, fasting activates crosstalk between adrenal glands and dermal adipocytes in the skin, triggering the rapid release of free fatty acids into the niche, which in turn disrupts the normal metabolism of HFSCs and elevates their cellular reactive oxygen species levels, causing oxidative damage and apoptosis. A randomized clinical trial (NCT05800730) indicates that intermittent fasting inhibits human hair growth. Our study uncovers an inhibitory effect of intermittent fasting on tissue regeneration and identifies interorgan communication that eliminates activated HFSCs and halts tissue regeneration during periods of unstable nutrient supply.
    Keywords:  hair follicle regeneration; hair follicle stem cells; hair growth; intermittent fasting; somatic stem cells
    DOI:  https://doi.org/10.1016/j.cell.2024.11.004
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