bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2023–10–15
fifty papers selected by
Christian Frezza, Universität zu Köln
  1. Apoptotic stress causes mtDNA release during senescence and drives the SASP.
  2. Structural rather than catalytic role for mitochondrial respiratory chain supercomplexes.
  3. Forward genetic screens identify mechanisms of resistance to small molecule lactate dehydrogenase inhibitors.
  4. Mitochondrial DNA breaks activate an integrated stress response to reestablish homeostasis.
  5. Reactive nitrogen species inhibit branched chain alpha-ketoacid dehydrogenase complex and impact muscle cell metabolism.
  6. COX17 acetylation via MOF-KANSL complex promotes mitochondrial integrity and function.
  7. Tetracyclines activate mitoribosome quality control and reduce ER stress to promote cell survival.
  8. The functional significance of mitochondrial respiratory chain supercomplexes.
  9. Succinate dehydrogenase is essential for epigenetic and metabolic homeostasis in hearts.
  10. The yin and yang of itaconate metabolism and its impact on the tumor microenvironment.
  11. Arginine reprograms metabolism in liver cancer via RBM39.
  12. MOF moves into mitochondria.
  13. Positive regulation of oxidative phosphorylation by nuclear myosin 1 protects cells from metabolic reprogramming and tumorigenesis in mice.
  14. Loss of succinyl-CoA synthetase in mouse forebrain results in hypersuccinylation with perturbed neuronal transcription and metabolism.
  15. CD8+ T cells in the cancer-immunity cycle.
  16. Systematic investigation of mitochondrial transfer between cancer cells and T cells at single-cell resolution.
  17. Cancer cell-intrinsic mechanisms driving acquired immune tolerance.
  18. Growing and dividing: how O-GlcNAcylation leads the way.
  19. Taking the STING out of CIN.
  20. Glutamine mimicry suppresses tumor progression through asparagine metabolism in pancreatic ductal adenocarcinoma.
  21. Stimulator of Interferon Genes (STING) Triggers Adipocyte Autophagy.
  22. Lysosomal cystine controls ferroptosis in cancer.
  23. Oncogenic context shapes the fitness landscape of tumor suppression.
  24. Tumor Immunogenicity Is Enhanced by Altering Mitochondrial Electron Flow.
  25. BOLA3 and NFU1 link mitoribosome iron-sulfur cluster assembly to multiple mitochondrial dysfunctions syndrome.
  26. Metabolic support by macrophages sustains colonic epithelial homeostasis.
  27. Anti-obesity drugs' side effects: what we know so far.
  28. Mitochondrial regulator PGC-1a in neuronal metabolism and brain aging.
  29. Hem25p is required for mitochondrial IPP transport in fungi.
  30. The landscape of cell-free mitochondrial DNA in liquid biopsy for cancer detection.
  31. The malate shuttle detoxifies ammonia in exhausted T cells by producing 2-ketoglutarate.
  32. CHCHD10 mutations induce tissue-specific mitochondrial DNA deletions with a distinct signature.
  33. Circadian disruption does not alter tumorigenesis in a mouse model of lymphoma.
  34. Lysosomes in senescence and aging.
  35. GDF15 is required for cold-induced thermogenesis and contributes to improved systemic metabolic health following loss of OPA1 in brown adipocytes.
  36. The History of Animal and Plant Sulfite Oxidase-A Personal View.
  37. Cancer as a Disease of Development Gone Awry.
  38. Transfer RNAs as dynamic and critical regulators of cancer progression.
  39. Arginine Expedites Erastin-Induced Ferroptosis through Fumarate.
  40. The metabolomic physics of complex diseases.
  41. Glial-derived mitochondrial signals affect neuronal proteostasis and aging.
  42. CD38 regulates ovarian function and fecundity via NAD+ metabolism.
  43. A Markov constraint to uniquely identify elementary flux mode weights in unimolecular metabolic networks.
  44. The structural mechanism of dimeric DONSON in replicative helicase activation.
  45. SUN1/2 controls macrophage polarization via modulating nuclear size and stiffness.
  46. The Pro-Oncogenic Protein IF1 Promotes Proliferation of Anoxic Cancer Cells during Re-Oxygenation.
  47. Higher-order structural organization of the mitochondrial proteome charted by in situ cross-linking mass spectrometry.
  48. Clonal Hematopoiesis, Inflammation, and Hematologic Malignancy.
  49. Subclonal Somatic Copy-Number Alterations Emerge and Dominate in Recurrent Osteosarcoma.
  50. Cytoplasmic division cycles without the nucleus and mitotic CDK/cyclin complexes.
  1. Nature. 2023 Oct 11.
    Apoptotic stress causes mtDNA release during senescence and drives the SASP.
    Stella Victorelli, Hanna Salmonowicz, James Chapman, Helene Martini, Maria Grazia Vizioli, Joel S Riley, Catherine Cloix, Ella Hall-Younger, Jair Machado Espindola-Netto, Diana Jurk, Anthony B Lagnado, Lilian Sales Gomez, Joshua N Farr, Dominik Saul, Rebecca Reed, George Kelly, Madeline Eppard, Laura C Greaves, Zhixun Dou, Nicholas Pirius, Karolina Szczepanowska, Rebecca A Porritt, Huijie Huang, Timothy Y Huang, Derek A Mann, Claudio Akio Masuda, Sundeep Khosla, Haiming Dai, Scott H Kaufmann, Emmanouil Zacharioudakis, Evripidis Gavathiotis, Nathan K LeBrasseur, Xue Lei, Alva G Sainz, Viktor I Korolchuk, Peter D Adams, Gerald S Shadel, Stephen W G Tait, João F Passos.
      Senescent cells drive age-related tissue dysfunction partially through the induction of a chronic senescence-associated secretory phenotype (SASP)1. Mitochondria are major regulators of the SASP; however, the underlying mechanisms have not been elucidated2. Mitochondria are often essential for apoptosis, a cell fate distinct from cellular senescence. During apoptosis, widespread mitochondrial outer membrane permeabilization (MOMP) commits a cell to die3. Here we find that MOMP occurring in a subset of mitochondria is a feature of cellular senescence. This process, called minority MOMP (miMOMP), requires BAX and BAK macropores enabling the release of mitochondrial DNA (mtDNA) into the cytosol. Cytosolic mtDNA in turn activates the cGAS-STING pathway, a major regulator of the SASP. We find that inhibition of MOMP in vivo decreases inflammatory markers and improves healthspan in aged mice. Our results reveal that apoptosis and senescence are regulated by similar mitochondria-dependent mechanisms and that sublethal mitochondrial apoptotic stress is a major driver of the SASP. We provide proof-of-concept that inhibition of miMOMP-induced inflammation may be a therapeutic route to improve healthspan.
    DOI:  https://doi.org/10.1038/s41586-023-06621-4
  2. Elife. 2023 Oct 12. pii: RP88084. [Epub ahead of print]12
    Structural rather than catalytic role for mitochondrial respiratory chain supercomplexes.
    Michele Brischigliaro, Alfredo Cabrera-Orefice, Susanne Arnold, Carlo Viscomi, Massimo Zeviani, Erika Fernández-Vizarra.
      Mammalian mitochondrial respiratory chain (MRC) complexes are able to associate into quaternary structures named supercomplexes (SCs), which normally coexist with non-bound individual complexes. The functional significance of SCs has not been fully clarified and the debate has been centered on whether or not they confer catalytic advantages compared with the non-bound individual complexes. Mitochondrial respiratory chain organization does not seem to be conserved in all organisms. In fact, and differently from mammalian species, mitochondria from Drosophila melanogaster tissues are characterized by low amounts of SCs, despite the high metabolic demands and MRC activity shown by these mitochondria. Here, we show that attenuating the biogenesis of individual respiratory chain complexes was accompanied by increased formation of stable SCs, which are missing in Drosophila melanogaster in physiological conditions. This phenomenon was not accompanied by an increase in mitochondrial respiratory activity. Therefore, we conclude that SC formation is necessary to stabilize the complexes in suboptimal biogenesis conditions, but not for the enhancement of respiratory chain catalysis.
    Keywords:  D. melanogaster; Drosophila; Mitochondria; OXPHOS; biochemistry; chemical biology; supercomplexes
    DOI:  https://doi.org/10.7554/eLife.88084
  3. bioRxiv. 2023 Sep 30. pii: 2023.09.30.560315. [Epub ahead of print]
    Forward genetic screens identify mechanisms of resistance to small molecule lactate dehydrogenase inhibitors.
    Anderson R Frank, Florentina Vandiver, David G McFadden.
      Altered metabolism is a hallmark of cancer; however, it has been difficult to specifically target metabolism in cancer for therapeutic benefit. Cancers with genetically defined defects in metabolic enzymes constitute a subset of cancers where targeting metabolism is potentially accessible. Hürthle cell carcinoma of the thyroid (HTC) tumors frequently harbor deleterious mitochondrial DNA (mtDNA) mutations in subunits of complex I of the mitochondrial electron transport chain (ETC). Previous work has shown that HTC models with deleterious mtDNA mutations exhibit mitochondrial ETC defects that expose lactate dehydrogenase (LDH) as a therapeutic vulnerability. Here, we performed forward genetic screens to identify mechanisms of resistance to small molecule LDH inhibitors. We identified two distinct mechanisms of resistance: upregulation of an LDH isoform and a compound-specific resistance mutation. Using these tools, we demonstrate that the anti-cancer activity of LDH inhibitors in cell line and xenograft models of complex I-mutant HTC is through on-target LDH inhibition.
    DOI:  https://doi.org/10.1101/2023.09.30.560315
  4. Mol Cell. 2023 Oct 08. pii: S1097-2765(23)00753-0. [Epub ahead of print]
    Mitochondrial DNA breaks activate an integrated stress response to reestablish homeostasis.
    Yi Fu, Olivia Sacco, Emily DeBitetto, Evgeny Kanshin, Beatrix Ueberheide, Agnel Sfeir.
      Mitochondrial DNA double-strand breaks (mtDSBs) lead to the degradation of circular genomes and a reduction in copy number; yet, the cellular response in human cells remains elusive. Here, using mitochondrial-targeted restriction enzymes, we show that a subset of cells with mtDSBs exhibited defective mitochondrial protein import, reduced respiratory complexes, and loss of membrane potential. Electron microscopy confirmed the altered mitochondrial membrane and cristae ultrastructure. Intriguingly, mtDSBs triggered the integrated stress response (ISR) via the phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) by DELE1 and heme-regulated eIF2α kinase (HRI). When ISR was inhibited, the cells experienced intensified mitochondrial defects and slower mtDNA recovery post-breakage. Lastly, through proteomics, we identified ATAD3A-a membrane-bound protein interacting with nucleoids-as potentially pivotal in relaying signals from impaired genomes to the inner mitochondrial membrane. In summary, our study delineates the cascade connecting damaged mitochondrial genomes to the cytoplasm and highlights the significance of the ISR in maintaining mitochondrial homeostasis amid genome instability.
    Keywords:  ATAD3A; double-strand breaks; integrated stress response; mitochondrial DNA; protein import
    DOI:  https://doi.org/10.1016/j.molcel.2023.09.026
  5. J Biol Chem. 2023 Oct 10. pii: S0021-9258(23)02361-X. [Epub ahead of print] 105333
    Reactive nitrogen species inhibit branched chain alpha-ketoacid dehydrogenase complex and impact muscle cell metabolism.
    Nicholas L Arp, Gretchen L Seim, James A Votava, Jordyn Josephson, Jing Fan.
      Branched chain α-ketoacid dehydrogenase complex (BCKDC) is the rate-limiting enzyme in branched chain amino acid (BCAA) catabolism, a metabolic pathway with great importance for human health. BCKDC belongs to the mitochondrial α-ketoacid dehydrogenase complex family, which also includes pyruvate dehydrogenase complex (PDHC) and oxoglutarate dehydrogenase complex (OGDC). Here we revealed that BCKDC can be substantially inhibited by reactive nitrogen species (RNS) via a mechanism similar to what we recently discovered with PDHC and OGDC - RNS can cause inactivating covalent modifications of the lipoic arm on its E2 subunit. In addition, we showed that such reaction between RNS and the lipoic arm of the E2 subunit can further promote inhibition of the E3 subunits of α-ketoacid dehydrogenase complexes. We examined the impacts of this RNS-mediated BCKDC inhibition in muscle cells, an important site of BCAA metabolism, and demonstrated that the nitric oxide production induced by cytokine stimulation leads to a strong inhibition of BCKDC activity and BCAA oxidation in myotubes and myoblasts. More broadly, nitric oxide production reduced the level of functional lipoic arms across the multiple α-ketoacid dehydrogenases and led to intracellular accumulation of their substrates (α-ketoacids), decrease of their products (acyl-CoAs), and a lower cellular energy charge. In sum, this work revealed a new mechanism for BCKDC regulation, demonstrated that RNS can generally inhibit all α-ketoacid dehydrogenases, which has broad physiological implications across multiple cell types, and elucidated the mechanistic connection between RNS-driven inhibitory modifications on the E2 and E3 subunits of α-ketoacid dehydrogenases.
    Keywords:  branched chain amino acid; metabolic regulation; mitochondria metabolism; nitric oxide; α-ketoacid dehydrogenase
    DOI:  https://doi.org/10.1016/j.jbc.2023.105333
  6. Nat Metab. 2023 Oct 09.
    COX17 acetylation via MOF-KANSL complex promotes mitochondrial integrity and function.
    Sukanya Guhathakurta, Niyazi Umut Erdogdu, Juliane J Hoffmann, Iga Grzadzielewska, Alexander Schendzielorz, Janine Seyfferth, Christoph U Mårtensson, Mauro Corrado, Adam Karoutas, Bettina Warscheid, Nikolaus Pfanner, Thomas Becker, Asifa Akhtar.
      Reversible acetylation of mitochondrial proteins is a regulatory mechanism central to adaptive metabolic responses. Yet, how such functionally relevant protein acetylation is achieved remains unexplored. Here we reveal an unprecedented role of the MYST family lysine acetyltransferase MOF in energy metabolism via mitochondrial protein acetylation. Loss of MOF-KANSL complex members leads to mitochondrial defects including fragmentation, reduced cristae density and impaired mitochondrial electron transport chain complex IV integrity in primary mouse embryonic fibroblasts. We demonstrate COX17, a complex IV assembly factor, as a bona fide acetylation target of MOF. Loss of COX17 or expression of its non-acetylatable mutant phenocopies the mitochondrial defects observed upon MOF depletion. The acetylation-mimetic COX17 rescues these defects and maintains complex IV activity even in the absence of MOF, suggesting an activatory role of mitochondrial electron transport chain protein acetylation. Fibroblasts from patients with MOF syndrome who have intellectual disability also revealed respiratory defects that could be restored by alternative oxidase, acetylation-mimetic COX17 or mitochondrially targeted MOF. Overall, our findings highlight the critical role of MOF-KANSL complex in mitochondrial physiology and provide new insights into MOF syndrome.
    DOI:  https://doi.org/10.1038/s42255-023-00904-w
  7. EMBO Rep. 2023 Oct 11. e57228
    Tetracyclines activate mitoribosome quality control and reduce ER stress to promote cell survival.
    Conor T Ronayne, Thomas D Jackson, Christopher F Bennett, Elizabeth A Perry, Noa Kantorovic, Pere Puigserver.
      Mitochondrial diseases are a group of disorders defined by defects in oxidative phosphorylation caused by nuclear- or mitochondrial-encoded gene mutations. A main cellular phenotype of mitochondrial disease mutations is redox imbalances and inflammatory signaling underlying pathogenic signatures of these patients. One method to rescue this cell death vulnerability is the inhibition of mitochondrial translation using tetracyclines. However, the mechanisms whereby tetracyclines promote cell survival are unknown. Here, we show that tetracyclines inhibit the mitochondrial ribosome and promote survival through suppression of endoplasmic reticulum (ER) stress. Tetracyclines increase mitochondrial levels of the mitoribosome quality control factor MALSU1 (Mitochondrial Assembly of Ribosomal Large Subunit 1) and promote its recruitment to the mitoribosome large subunit, where MALSU1 is necessary for tetracycline-induced survival and suppression of ER stress. Glucose starvation induces ER stress to activate the unfolded protein response and IRE1α-mediated cell death that is inhibited by tetracyclines. These studies establish a new interorganelle communication whereby inhibition of the mitoribosome signals to the ER to promote survival, implicating basic mechanisms of cell survival and treatment of mitochondrial diseases.
    Keywords:  IRE1α; MALSU1; mitochondrial disease; mitoribosome; tetracyclines
    DOI:  https://doi.org/10.15252/embr.202357228
  8. EMBO Rep. 2023 Oct 12. e57092
    The functional significance of mitochondrial respiratory chain supercomplexes.
    Andreas Kohler, Antoni Barrientos, Flavia Fontanesi, Martin Ott.
      The mitochondrial respiratory chain (MRC) is a key energy transducer in eukaryotic cells. Four respiratory chain complexes cooperate in the transfer of electrons derived from various metabolic pathways to molecular oxygen, thereby establishing an electrochemical gradient over the inner mitochondrial membrane that powers ATP synthesis. This electron transport relies on mobile electron carries that functionally connect the complexes. While the individual complexes can operate independently, they are in situ organized into large assemblies termed respiratory supercomplexes. Recent structural and functional studies have provided some answers to the question of whether the supercomplex organization confers an advantage for cellular energy conversion. However, the jury is still out, regarding the universality of these claims. In this review, we discuss the current knowledge on the functional significance of MRC supercomplexes, highlight experimental limitations, and suggest potential new strategies to overcome these obstacles.
    Keywords:  Mitochondria; bioenergetics; electron transfer; respiratory chain; supercomplexes
    DOI:  https://doi.org/10.15252/embr.202357092
  9. Basic Res Cardiol. 2023 Oct 11. 118(1): 45
    Succinate dehydrogenase is essential for epigenetic and metabolic homeostasis in hearts.
    Wenwen Li, Li Quan, Kun Peng, Yanru Wang, Xianhua Wang, Quan Chen, Heping Cheng, Qi Ma.
      A hallmark of heart failure is a metabolic switch away from fatty acids β-oxidation (FAO) to glycolysis. Here, we show that succinate dehydrogenase (SDH) is required for maintenance of myocardial homeostasis of FAO/glycolysis. Mice with cardiomyocyte-restricted deletion of subunit b or c of SDH developed a dilated cardiomyopathy and heart failure. Hypertrophied hearts displayed a decrease in FAO, while glucose uptake and glycolysis were augmented, which was reversed by enforcing FAO fuels via a high-fat diet, which also improved heart failure of mutant mice. SDH-deficient hearts exhibited an increase in genome-wide DNA methylation associated with accumulation of succinate, a metabolite known to inhibit DNA demethylases, resulting in changes of myocardial transcriptomic landscape. Succinate induced DNA hypermethylation and depressed the expression of FAO genes in myocardium, leading to imbalanced FAO/glycolysis. Inhibition of succinate by α-ketoglutarate restored transcriptional profiles and metabolic disorders in SDH-deficient cardiomyocytes. Thus, our findings reveal the essential role for SDH in metabolic remodeling of failing hearts, and highlight the potential of therapeutic strategies to prevent cardiac dysfunction in the setting of SDH deficiency.
    Keywords:  DNA methylation; Heart failure; Myocardial metabolism; SDH; Succinate
    DOI:  https://doi.org/10.1007/s00395-023-01015-z
  10. Curr Opin Biotechnol. 2023 Oct 06. pii: S0958-1669(23)00106-4. [Epub ahead of print]84 102996
    The yin and yang of itaconate metabolism and its impact on the tumor microenvironment.
    Fangfang Chen, Birte Dowerg, Thekla Cordes.
      The tumor microenvironment (TME) consists of a network of metabolically interconnected tumor and immune cell types. Macrophages influence the metabolic composition within the TME, which directly impacts the metabolic state and drug response of tumors. The accumulation of oncometabolites, such as succinate, fumarate, and 2-hydroxyglutarate, represents metabolic vulnerabilities in cancer that can be targeted therapeutically. Immunometabolites are emerging as metabolic regulators of the TME impacting immune cell functions and cancer cell growth. Here, we discuss recent discoveries on the potential impact of itaconate on the TME. We highlight how itaconate influences metabolic pathways relevant to immune responses and cancer cell proliferation. We also consider the therapeutic implications of manipulating itaconate metabolism as an immunotherapeutic strategy to constrain tumor growth.
    DOI:  https://doi.org/10.1016/j.copbio.2023.102996
  11. Cell. 2023 Sep 26. pii: S0092-8674(23)01032-2. [Epub ahead of print]
    Arginine reprograms metabolism in liver cancer via RBM39.
    Dirk Mossmann, Christoph Müller, Sujin Park, Brendan Ryback, Marco Colombi, Nathalie Ritter, Diana Weißenberger, Eva Dazert, Mairene Coto-Llerena, Sandro Nuciforo, Lauriane Blukacz, Caner Ercan, Veronica Jimenez, Salvatore Piscuoglio, Fatima Bosch, Luigi M Terracciano, Uwe Sauer, Markus H Heim, Michael N Hall.
      Metabolic reprogramming is a hallmark of cancer. However, mechanisms underlying metabolic reprogramming and how altered metabolism in turn enhances tumorigenicity are poorly understood. Here, we report that arginine levels are elevated in murine and patient hepatocellular carcinoma (HCC), despite reduced expression of arginine synthesis genes. Tumor cells accumulate high levels of arginine due to increased uptake and reduced arginine-to-polyamine conversion. Importantly, the high levels of arginine promote tumor formation via further metabolic reprogramming, including changes in glucose, amino acid, nucleotide, and fatty acid metabolism. Mechanistically, arginine binds RNA-binding motif protein 39 (RBM39) to control expression of metabolic genes. RBM39-mediated upregulation of asparagine synthesis leads to enhanced arginine uptake, creating a positive feedback loop to sustain high arginine levels and oncogenic metabolism. Thus, arginine is a second messenger-like molecule that reprograms metabolism to promote tumor growth.
    Keywords:  AGMAT; ARG1; ASNS; RBM39; arginine; hepatocellular carcinoma; indisulam; metabolism
    DOI:  https://doi.org/10.1016/j.cell.2023.09.011
  12. Nat Metab. 2023 Oct 09.
    MOF moves into mitochondria.
    Natalie Niemi.
      
    DOI:  https://doi.org/10.1038/s42255-023-00892-x
  13. Nat Commun. 2023 Oct 10. 14(1): 6328
    Positive regulation of oxidative phosphorylation by nuclear myosin 1 protects cells from metabolic reprogramming and tumorigenesis in mice.
    Tomas Venit, Oscar Sapkota, Wael Said Abdrabou, Palanikumar Loganathan, Renu Pasricha, Syed Raza Mahmood, Nadine Hosny El Said, Shimaa Sherif, Sneha Thomas, Salah Abdelrazig, Shady Amin, Davide Bedognetti, Youssef Idaghdour, Mazin Magzoub, Piergiorgio Percipalle.
      Metabolic reprogramming is one of the hallmarks of tumorigenesis. Here, we show that nuclear myosin 1 (NM1) serves as a key regulator of cellular metabolism. NM1 directly affects mitochondrial oxidative phosphorylation (OXPHOS) by regulating mitochondrial transcription factors TFAM and PGC1α, and its deletion leads to underdeveloped mitochondria inner cristae and mitochondrial redistribution within the cell. These changes are associated with reduced OXPHOS gene expression, decreased mitochondrial DNA copy number, and deregulated mitochondrial dynamics, which lead to metabolic reprogramming of NM1 KO cells from OXPHOS to aerobic glycolysis.This, in turn, is associated with a metabolomic profile typical for cancer cells, namely increased amino acid-, fatty acid-, and sugar metabolism, and increased glucose uptake, lactate production, and intracellular acidity. NM1 KO cells form solid tumors in a mouse model, suggesting that the metabolic switch towards aerobic glycolysis provides a sufficient carcinogenic signal. We suggest that NM1 plays a role as a tumor suppressor and that NM1 depletion may contribute to the Warburg effect at the onset of tumorigenesis.
    DOI:  https://doi.org/10.1038/s41467-023-42093-w
  14. Cell Rep. 2023 Oct 10. pii: S2211-1247(23)01253-6. [Epub ahead of print]42(10): 113241
    Loss of succinyl-CoA synthetase in mouse forebrain results in hypersuccinylation with perturbed neuronal transcription and metabolism.
    Makayla S Lancaster, Byungwook Kim, Emma H Doud, Mason D Tate, Ahmad D Sharify, Hongyu Gao, Duojiao Chen, Ed Simpson, Patrick Gillespie, Xiaona Chu, Marcus J Miller, Yue Wang, Yunlong Liu, Amber L Mosley, Jungsu Kim, Brett H Graham.
      Lysine succinylation is a subtype of protein acylation associated with metabolic regulation of succinyl-CoA in the tricarboxylic acid cycle. Deficiency of succinyl-CoA synthetase (SCS), the tricarboxylic acid cycle enzyme catalyzing the interconversion of succinyl-CoA to succinate, results in mitochondrial encephalomyopathy in humans. This report presents a conditional forebrain-specific knockout (KO) mouse model of Sucla2, the gene encoding the ATP-specific beta isoform of SCS, resulting in postnatal deficiency of the entire SCS complex. Results demonstrate that accumulation of succinyl-CoA in the absence of SCS leads to hypersuccinylation within the murine cerebral cortex. Specifically, increased succinylation is associated with functionally significant reduced activity of respiratory chain complex I and widescale alterations in chromatin landscape and gene expression. Integrative analysis of the transcriptomic data also reveals perturbations in regulatory networks of neuronal transcription in the KO forebrain. Together, these findings provide evidence that protein succinylation plays a significant role in the pathogenesis of SCS deficiency.
    Keywords:  ATAC sequencing; CP: Metabolism; CP: Neuroscience; RNA sequencing; chromatin; electron transport chain; mass spectrometry; metabolism; neurons; post-translational modification; succinyl-CoA synthetase; succinylation
    DOI:  https://doi.org/10.1016/j.celrep.2023.113241
  15. Immunity. 2023 Oct 10. pii: S1074-7613(23)00410-7. [Epub ahead of print]56(10): 2231-2253
    CD8+ T cells in the cancer-immunity cycle.
    Josephine R Giles, Anna-Maria Globig, Susan M Kaech, E John Wherry.
      CD8+ T cells are end effectors of cancer immunity. Most forms of effective cancer immunotherapy involve CD8+ T cell effector function. Here, we review the current understanding of T cell function in cancer, focusing on key CD8+ T cell subtypes and states. We discuss factors that influence CD8+ T cell differentiation and function in cancer through a framework that incorporates the classic three-signal model and a fourth signal-metabolism-and also consider the impact of the tumor microenvironment from a T cell perspective. We argue for the notion of immunotherapies as "pro-drugs" that act to augment or modulate T cells, which ultimately serve as the drug in vivo, and for the importance of overall immune health in cancer treatment and prevention. The progress in understanding T cell function in cancer has and will continue to improve harnessing of the immune system across broader tumor types to benefit more patients.
    Keywords:  CD8 T cells; T cell exhaustion; cancer; immune checkpoint blockade; immunology; immunotherapy; metabolism
    DOI:  https://doi.org/10.1016/j.immuni.2023.09.005
  16. Cancer Cell. 2023 Oct 09. pii: S1535-6108(23)00319-7. [Epub ahead of print]41(10): 1788-1802.e10
    Systematic investigation of mitochondrial transfer between cancer cells and T cells at single-cell resolution.
    Hongyi Zhang, Xuexin Yu, Jianfeng Ye, Huiyu Li, Jing Hu, Yuhao Tan, Yan Fang, Esra Akbay, Fulong Yu, Chen Weng, Vijay G Sankaran, Robert M Bachoo, Elizabeth Maher, John Minna, Anli Zhang, Bo Li.
      Mitochondria (MT) participate in most metabolic activities of mammalian cells. A near-unidirectional mitochondrial transfer from T cells to cancer cells was recently observed to "metabolically empower" cancer cells while "depleting immune cells," providing new insights into tumor-T cell interaction and immune evasion. Here, we leverage single-cell RNA-seq technology and introduce MERCI, a statistical deconvolution method for tracing and quantifying mitochondrial trafficking between cancer and T cells. Through rigorous benchmarking and validation, MERCI accurately predicts the recipient cells and their relative mitochondrial compositions. Application of MERCI to human cancer samples identifies a reproducible MT transfer phenotype, with its signature genes involved in cytoskeleton remodeling, energy production, and TNF-α signaling pathways. Moreover, MT transfer is associated with increased cell cycle activity and poor clinical outcome across different cancer types. In summary, MERCI enables systematic investigation of an understudied aspect of tumor-T cell interactions that may lead to the development of therapeutic opportunities.
    Keywords:  Mitochondrial Transfer; Statistical Deconvolution; T cell dysfunction; Tumor-Immune Interaction; mtDNA sequencing.; single cell genomics
    DOI:  https://doi.org/10.1016/j.ccell.2023.09.003
  17. Immunity. 2023 Oct 10. pii: S1074-7613(23)00409-0. [Epub ahead of print]56(10): 2270-2295
    Cancer cell-intrinsic mechanisms driving acquired immune tolerance.
    Ehsan Ghorani, Charles Swanton, Sergio A Quezada.
      Immune evasion is a hallmark of cancer, enabling tumors to survive contact with the host immune system and evade the cycle of immune recognition and destruction. Here, we review the current understanding of the cancer cell-intrinsic factors driving immune evasion. We focus on T cells as key effectors of anti-cancer immunity and argue that cancer cells evade immune destruction by gaining control over pathways that usually serve to maintain physiological tolerance to self. Using this framework, we place recent mechanistic advances in the understanding of cancer immune evasion into broad categories of control over T cell localization, antigen recognition, and acquisition of optimal effector function. We discuss the redundancy in the pathways involved and identify knowledge gaps that must be overcome to better target immune evasion, including the need for better, routinely available tools that incorporate the growing understanding of evasion mechanisms to stratify patients for therapy and trials.
    Keywords:  acquired tolerance; cancer immune evasion; cancer immunotherapy
    DOI:  https://doi.org/10.1016/j.immuni.2023.09.004
  18. J Biol Chem. 2023 Oct 09. pii: S0021-9258(23)02358-X. [Epub ahead of print] 105330
    Growing and dividing: how O-GlcNAcylation leads the way.
    Harmony Saunders, Wagner B Dias, Chad Slawson.
      Cell cycle errors can lead to mutations, chromosomal instability, or death; thus, the precise control of cell cycle progression is essential for viability. The nutrient-sensing post-translational modification, O-GlcNAc, regulates the cell cycle allowing one central control point directing progression of the cell cycle. O-GlcNAc is a single N-acetylglucosamine sugar modification to intracellular proteins that is dynamically added and removed by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), respectively. These enzymes act as a rheostat to fine-tune protein function in response to a plethora of stimuli from nutrients to hormones. O-GlcNAc modulates mitogenic growth signaling, senses nutrient flux through the hexosamine biosynthetic pathway, and coordinates with other nutrient-sensing enzymes to progress cells through Gap phase 1 (G1). At the G1/S transition, O-GlcNAc modulates checkpoint control, while in S Phase O-GlcNAcylation coordinates the replication fork. DNA replication errors activate O-GlcNAcylation to control the function of the tumor suppressor p53 at Gap Phase 2 (G2). Finally, in Mitosis (M phase), O-GlcNAc controls M phase progression and the organization of the mitotic spindle and midbody. Critical for M phase control is the interplay between OGT and OGA with mitotic kinases. Importantly, disruptions in OGT and OGA activity induce M phase defects and aneuploidy. These data point to an essential role for the O-GlcNAc rheostat in regulating cell division. In this review, we highlight O-GlcNAc nutrient sensing regulating G1; O-GlcNAc control of DNA replication and repair; and finally, O-GlcNAc organization of mitotic progression and spindle dynamics.
    Keywords:  Cyclin; Mini-chromosome complex; Nutrient sensing; O-GlcNAc; O-GlcNAc Transferase; O-GlcNAcase; Spindle; cell cycle; mTOR; p53
    DOI:  https://doi.org/10.1016/j.jbc.2023.105330
  19. Trends Cancer. 2023 Oct 06. pii: S2405-8033(23)00194-2. [Epub ahead of print]
    Taking the STING out of CIN.
    Anouk van den Brink, Floris Foijer.
      Chromosomal instability (CIN), a hallmark of cancer, promotes cell-intrinsic inflammatory signaling. Although inflammation is generally considered tumor-suppressive, this relationship is more complex in cancers with CIN. We discuss new findings by Li et al. that can explain how cancer cells with CIN tolerate, adopt, and rewire the CIN-induced inflammatory response to fuel tumorigenesis.
    Keywords:  STING; cancer; chromosomal instability; inflammation; metastasis
    DOI:  https://doi.org/10.1016/j.trecan.2023.09.010
  20. Nat Cancer. 2023 Oct 09.
    Glutamine mimicry suppresses tumor progression through asparagine metabolism in pancreatic ductal adenocarcinoma.
    Maria Victoria Recouvreux, Shea F Grenier, Yijuan Zhang, Edgar Esparza, Guillem Lambies, Cheska Marie Galapate, Swetha Maganti, Karen Duong-Polk, Deepika Bhullar, Razia Naeem, David A Scott, Andrew M Lowy, Hervé Tiriac, Cosimo Commisso.
      In pancreatic ductal adenocarcinoma (PDAC), glutamine is a critical nutrient that drives a wide array of metabolic and biosynthetic processes that support tumor growth. Here, we elucidate how 6-diazo-5-oxo-L-norleucine (DON), a glutamine antagonist that broadly inhibits glutamine metabolism, blocks PDAC tumor growth and metastasis. We find that DON significantly reduces asparagine production by inhibiting asparagine synthetase (ASNS), and that the effects of DON are rescued by asparagine. As a metabolic adaptation, PDAC cells upregulate ASNS expression in response to DON, and we show that ASNS levels are inversely correlated with DON efficacy. We also show that L-asparaginase (ASNase) synergizes with DON to affect the viability of PDAC cells, and that DON and ASNase combination therapy has a significant impact on metastasis. These results shed light on the mechanisms that drive the effects of glutamine mimicry and point to the utility of cotargeting adaptive responses to control PDAC progression.
    DOI:  https://doi.org/10.1038/s43018-023-00649-1
  21. Cells. 2023 Sep 24. pii: 2345. [Epub ahead of print]12(19):
    Stimulator of Interferon Genes (STING) Triggers Adipocyte Autophagy.
    Kornél Z Varga, Katalin Gyurina, Ádám Radványi, Tibor Pál, László Sasi-Szabó, Haidong Yu, Enikő Felszeghy, Tamás Szabó, Tamás Röszer.
      Innate immune signaling in adipocytes affects systemic metabolism. Cytosolic nucleic acid sensing has been recently shown to stimulate thermogenic adipocyte differentiation and protect from obesity; however, DNA efflux from adipocyte mitochondria is a potential proinflammatory signal that causes adipose tissue dysfunction and insulin resistance. Cytosolic DNA activates the stimulator of interferon response genes (STING), a key signal transducer which triggers type I interferon (IFN-I) expression; hence, STING activation is expected to induce IFN-I response and adipocyte dysfunction. However, we show herein that mouse adipocytes had a diminished IFN-I response to STING stimulation by 2'3'-cyclic-GMP-AMP (cGAMP). We also show that cGAMP triggered autophagy in murine and human adipocytes. In turn, STING inhibition reduced autophagosome number, compromised the mitochondrial network and caused inflammation and fat accumulation in adipocytes. STING hence stimulates a process that removes damaged mitochondria, thereby protecting adipocytes from an excessive IFN-I response to mitochondrial DNA efflux. In summary, STING appears to limit inflammation in adipocytes by promoting mitophagy under non-obesogenic conditions.
    Keywords:  STING; adipocyte; immunity; inflammation; interferons; mitochondria
    DOI:  https://doi.org/10.3390/cells12192345
  22. Nat Cell Biol. 2023 Oct;25(10): 1405
    Lysosomal cystine controls ferroptosis in cancer.
    Zhe Wang.
      
    DOI:  https://doi.org/10.1038/s41556-023-01252-3
  23. Nat Commun. 2023 Oct 12. 14(1): 6422
    Oncogenic context shapes the fitness landscape of tumor suppression.
    Lily M Blair, Joseph M Juan, Lafia Sebastian, Vy B Tran, Wensheng Nie, Gregory D Wall, Mehmet Gerceker, Ian K Lai, Edwin A Apilado, Gabriel Grenot, David Amar, Giorgia Foggetti, Mariana Do Carmo, Zeynep Ugur, Debbie Deng, Alex Chenchik, Maria Paz Zafra, Lukas E Dow, Katerina Politi, Jonathan J MacQuitty, Dmitri A Petrov, Monte M Winslow, Michael J Rosen, Ian P Winters.
      Tumors acquire alterations in oncogenes and tumor suppressor genes in an adaptive walk through the fitness landscape of tumorigenesis. However, the interactions between oncogenes and tumor suppressor genes that shape this landscape remain poorly resolved and cannot be revealed by human cancer genomics alone. Here, we use a multiplexed, autochthonous mouse platform to model and quantify the initiation and growth of more than one hundred genotypes of lung tumors across four oncogenic contexts: KRAS G12D, KRAS G12C, BRAF V600E, and EGFR L858R. We show that the fitness landscape is rugged-the effect of tumor suppressor inactivation often switches between beneficial and deleterious depending on the oncogenic context-and shows no evidence of diminishing-returns epistasis within variants of the same oncogene. These findings argue against a simple linear signaling relationship amongst these three oncogenes and imply a critical role for off-axis signaling in determining the fitness effects of inactivating tumor suppressors.
    DOI:  https://doi.org/10.1038/s41467-023-42156-y
  24. Cancer Discov. 2023 Oct 13. OF1
    Tumor Immunogenicity Is Enhanced by Altering Mitochondrial Electron Flow.
      Mitochondrial CII loss reduces tumor growth by increasing antigen presentation and T cell-mediated killing.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2023-160
  25. Nucleic Acids Res. 2023 Oct 12. pii: gkad842. [Epub ahead of print]
    BOLA3 and NFU1 link mitoribosome iron-sulfur cluster assembly to multiple mitochondrial dysfunctions syndrome.
    Hui Zhong, Alexandre Janer, Oleh Khalimonchuk, Hana Antonicka, Eric A Shoubridge, Antoni Barrientos.
      The human mitochondrial ribosome contains three [2Fe-2S] clusters whose assembly pathway, role, and implications for mitochondrial and metabolic diseases are unknown. Here, structure-function correlation studies show that the clusters play a structural role during mitoribosome assembly. To uncover the assembly pathway, we have examined the effect of silencing the expression of Fe-S cluster biosynthetic and delivery factors on mitoribosome stability. We find that the mitoribosome receives its [2Fe-2S] clusters from the GLRX5-BOLA3 node. Additionally, the assembly of the small subunit depends on the mitoribosome biogenesis factor METTL17, recently reported containing a [4Fe-4S] cluster, which we propose is inserted via the ISCA1-NFU1 node. Consistently, fibroblasts from subjects suffering from 'multiple mitochondrial dysfunction' syndrome due to mutations in BOLA3 or NFU1 display previously unrecognized attenuation of mitochondrial protein synthesis that contributes to their cellular and pathophysiological phenotypes. Finally, we report that, in addition to their structural role, one of the mitoribosomal [2Fe-2S] clusters and the [4Fe-4S] cluster in mitoribosome assembly factor METTL17 sense changes in the redox environment, thus providing a way to regulate organellar protein synthesis accordingly.
    DOI:  https://doi.org/10.1093/nar/gkad842
  26. Cell Metab. 2023 Sep 29. pii: S1550-4131(23)00341-8. [Epub ahead of print]
    Metabolic support by macrophages sustains colonic epithelial homeostasis.
    Stephanie Deborah Fritsch, Nyamdelger Sukhbaatar, Karine Gonzales, Alishan Sahu, Loan Tran, Andrea Vogel, Mario Mazic, Jayne Louise Wilson, Stephan Forisch, Hannah Mayr, Raimund Oberle, Jakob Weiszmann, Martin Brenner, Roeland Vanhoutte, Melanie Hofmann, Sini Pirnes-Karhu, Christoph Magnes, Torben Kühnast, Wolfram Weckwerth, Christoph Bock, Kristaps Klavins, Markus Hengstschläger, Christine Moissl-Eichinger, Gernot Schabbauer, Gerda Egger, Eija Pirinen, Steven H L Verhelst, Thomas Weichhart.
      The intestinal epithelium has a high turnover rate and constantly renews itself through proliferation of intestinal crypt cells, which depends on insufficiently characterized signals from the microenvironment. Here, we showed that colonic macrophages were located directly adjacent to epithelial crypt cells in mice, where they metabolically supported epithelial cell proliferation in an mTORC1-dependent manner. Specifically, deletion of tuberous sclerosis complex 2 (Tsc2) in macrophages activated mTORC1 signaling that protected against colitis-induced intestinal damage and induced the synthesis of the polyamines spermidine and spermine. Epithelial cells ingested these polyamines and rewired their cellular metabolism to optimize proliferation and defense. Notably, spermine directly stimulated proliferation of colon epithelial cells and colon organoids. Genetic interference with polyamine production in macrophages altered global polyamine levels in the colon and modified epithelial cell proliferation. Our results suggest that macrophages act as "commensals" that provide metabolic support to promote efficient self-renewal of the colon epithelium.
    Keywords:  arginase-1; homeostasis; immunometabolism; intestine; mTOR; mTORC1; macrophages; polyamines; spermine
    DOI:  https://doi.org/10.1016/j.cmet.2023.09.010
  27. Nature. 2023 Oct 13.
    Anti-obesity drugs' side effects: what we know so far.
    Mariana Lenharo.
      
    Keywords:  Medical research; Metabolism; Obesity
    DOI:  https://doi.org/10.1038/d41586-023-03183-3
  28. bioRxiv. 2023 Sep 29. pii: 2023.09.29.559526. [Epub ahead of print]
    Mitochondrial regulator PGC-1a in neuronal metabolism and brain aging.
    Dylan C Souder, Eric R McGregor, Timothy W Rhoads, Josef P Clark, Tiaira J Porter, Kevin Eliceiri, Darcie L Moore, Luigi Puglielli, Rozalyn M Anderson.
      The brain is a high energy tissue, and the cell types of which it is comprised are distinct in function and in metabolic requirements. The transcriptional co-activator PGC-1a is a master regulator of mitochondrial function and is highly expressed in the brain; however, its cell-type specific role in regulating metabolism has not been well established. Here, we show that PGC-1a is responsive to aging and that expression of the neuron specific PGC-1a isoform allows for specialization in metabolic adaptation. Transcriptional profiles of the cortex from male mice show an impact of age on immune, inflammatory, and neuronal functional pathways and a highly integrated metabolic response that is associated with decreased expression of PGC-1a. Proteomic analysis confirms age-related changes in metabolism and further shows changes in ribosomal and RNA splicing pathways. We show that neurons express a specialized PGC-1a isoform that becomes active during differentiation from stem cells and is further induced during the maturation of isolated neurons. Neuronal but not astrocyte PGC-1a responds robustly to inhibition of the growth sensitive kinase GSK3b, where the brain specific promoter driven dominant isoform is repressed. The GSK3b inhibitor lithium broadly reprograms metabolism and growth signaling, including significantly lower expression of mitochondrial and ribosomal pathway genes and suppression of growth signaling, which are linked to changes in mitochondrial function and neuronal outgrowth. In vivo, lithium treatment significantly changes the expression of genes involved in cortical growth, endocrine, and circadian pathways. These data place the GSK3b/PGC-1a axis centrally in a growth and metabolism network that is directly relevant to brain aging.
    DOI:  https://doi.org/10.1101/2023.09.29.559526
  29. Nat Cell Biol. 2023 Oct 09.
    Hem25p is required for mitochondrial IPP transport in fungi.
    Jonathan Tai, Rachel M Guerra, Sean W Rogers, Zixiang Fang, Laura K Muehlbauer, Evgenia Shishkova, Katherine A Overmyer, Joshua J Coon, David J Pagliarini.
      Coenzyme Q (CoQ, ubiquinone) is an essential cellular cofactor composed of a redox-active quinone head group and a long hydrophobic polyisoprene tail. How mitochondria access cytosolic isoprenoids for CoQ biosynthesis is a longstanding mystery. Here, via a combination of genetic screening, metabolic tracing and targeted uptake assays, we reveal that Hem25p-a mitochondrial glycine transporter required for haem biosynthesis-doubles as an isopentenyl pyrophosphate (IPP) transporter in Saccharomyces cerevisiae. Mitochondria lacking Hem25p failed to efficiently incorporate IPP into early CoQ precursors, leading to loss of CoQ and turnover of CoQ biosynthetic proteins. Expression of Hem25p in Escherichia coli enabled robust IPP uptake and incorporation into the CoQ biosynthetic pathway. HEM25 orthologues from diverse fungi, but not from metazoans, were able to rescue hem25∆ CoQ deficiency. Collectively, our work reveals that Hem25p drives the bulk of mitochondrial isoprenoid transport for CoQ biosynthesis in fungi.
    DOI:  https://doi.org/10.1038/s41556-023-01250-5
  30. Genome Biol. 2023 Oct 12. 24(1): 229
    The landscape of cell-free mitochondrial DNA in liquid biopsy for cancer detection.
    Ymke van der Pol, Norbert Moldovan, Jip Ramaker, Sanne Bootsma, Kristiaan J Lenos, Louis Vermeulen, Shahneen Sandhu, Idris Bahce, D Michiel Pegtel, Stephen Q Wong, Sarah-Jane Dawson, Dineika Chandrananda, Florent Mouliere.
       BACKGROUND: Existing methods to detect tumor signal in liquid biopsy have focused on the analysis of nuclear cell-free DNA (cfDNA). However, non-nuclear cfDNA and in particular mitochondrial DNA (mtDNA) has been understudied. We hypothesize that an increase in mtDNA in plasma could reflect the presence of cancer, and that leveraging cell-free mtDNA could enhance cancer detection.
    RESULTS: We survey 203 healthy and 664 cancer plasma samples from three collection centers covering 12 cancer types with whole genome sequencing to catalogue the plasma mtDNA fraction. The mtDNA fraction is increased in individuals with cholangiocarcinoma, colorectal, liver, pancreatic, or prostate cancer, in comparison to that in healthy individuals. We detect almost no increase of mtDNA fraction in individuals with other cancer types. The mtDNA fraction in plasma correlates with the cfDNA tumor fraction as determined by somatic mutations and/or copy number aberrations. However, the mtDNA fraction is also elevated in a fraction of patients without an apparent increase in tumor-derived cfDNA. A predictive model integrating mtDNA and copy number analysis increases the area under the curve (AUC) from 0.73 when using copy number alterations alone to an AUC of 0.81.
    CONCLUSIONS: The mtDNA signal retrieved by whole genome sequencing has the potential to boost the detection of cancer when combined with other tumor-derived signals in liquid biopsies.
    Keywords:  Cancer; Cell-free DNA; Liquid biopsy; Mitochondrial DNA; Sequencing
    DOI:  https://doi.org/10.1186/s13059-023-03074-w
  31. Nat Immunol. 2023 Oct 09.
    The malate shuttle detoxifies ammonia in exhausted T cells by producing 2-ketoglutarate.
    Nina Weisshaar, Sicong Ma, Yanan Ming, Alaa Madi, Alessa Mieg, Marvin Hering, Ferdinand Zettl, Kerstin Mohr, Nora Ten Bosch, Diana Stichling, Michael Buettner, Gernot Poschet, Glynis Klinke, Michael Schulz, Nina Kunze-Rohrbach, Carolin Kerber, Isabel Madeleine Klein, Jingxia Wu, Xi Wang, Guoliang Cui.
      The malate shuttle is traditionally understood to maintain NAD+/NADH balance between the cytosol and mitochondria. Whether the malate shuttle has additional functions is unclear. Here we show that chronic viral infections induce CD8+ T cell expression of GOT1, a central enzyme in the malate shuttle. Got1 deficiency decreased the NAD+/NADH ratio and limited antiviral CD8+ T cell responses to chronic infection; however, increasing the NAD+/NADH ratio did not restore T cell responses. Got1 deficiency reduced the production of the ammonia scavenger 2-ketoglutarate (2-KG) from glutaminolysis and led to a toxic accumulation of ammonia in CD8+ T cells. Supplementation with 2-KG assimilated and detoxified ammonia in Got1-deficient T cells and restored antiviral responses. These data indicate that the major function of the malate shuttle in CD8+ T cells is not to maintain the NAD+/NADH balance but rather to detoxify ammonia and enable sustainable ammonia-neutral glutamine catabolism in CD8+ T cells during chronic infection.
    DOI:  https://doi.org/10.1038/s41590-023-01636-5
  32. Hum Mol Genet. 2023 Oct 10. pii: ddad161. [Epub ahead of print]
    CHCHD10 mutations induce tissue-specific mitochondrial DNA deletions with a distinct signature.
    Mario K Shammas, Yu Nie, Alexandra Gilsrud, Xiaoping Huang, Derek P Narendra, Patrick F Chinnery.
      Mutations affecting the mitochondrial intermembrane space protein CHCHD10 cause human disease, but it is not known why different amino acid substitutions cause markedly different clinical phenotypes, including amyotrophic lateral sclerosis-frontotemporal dementia, spinal muscular atrophy Jokela-type, isolated autosomal dominant mitochondrial myopathy and cardiomyopathy. CHCHD10 mutations have been associated with deletions of mitochondrial DNA (mtDNA deletions), raising the possibility that these explain the clinical variability. Here, we sequenced mtDNA obtained from hearts, skeletal muscle, livers and spinal cords of WT and Chchd10 G58R or S59L knockin mice to characterize the mtDNA deletion signatures of the two mutant lines. We found that the deletion levels were higher in G58R and S59L mice than in WT mice in some tissues depending on the Chchd10 genotype, and the deletion burden increased with age. Furthermore, we observed that the spinal cord was less prone to the development of mtDNA deletions than the other tissues examined. Finally, in addition to accelerating the rate of naturally occurring deletions, Chchd10 mutations also led to the accumulation of a novel set of deletions characterized by shorter direct repeats flanking the deletion breakpoints. Our results indicate that Chchd10 mutations in mice induce tissue-specific deletions which may also contribute to the clinical phenotype associated with these mutations in humans.
    Keywords:  miochondrial DNA; mitochondria; mtDNA deletions; neurodegeneration
    DOI:  https://doi.org/10.1093/hmg/ddad161
  33. F1000Res. 2023 ;12 49
    Circadian disruption does not alter tumorigenesis in a mouse model of lymphoma.
    Rebecca M Mello, Marie Pariollaud, Katja A Lamia.
      Background: Disruption of natural light cycles, as experienced by shift workers, is linked to enhanced cancer incidence. Several mouse models of cancer develop more severe disease when exposed to irregular light/dark cycles, supporting the connection between circadian disruption and increased cancer risk. Cryptochrome 2 (CRY2), a repressive component of the molecular circadian clock, facilitates turnover of the oncoprotein c-MYC, one mechanism that may link the molecular clock to tumorigenesis. In Eμ-MYC mice, which express transgenic c-MYC in B cells and develop aggressive lymphomas and leukemia, global Cry2 deletion reduces survival and enhances tumor formation. Lighting conditions that mimic the disruption experienced by shift workers dampen Cry2 transcripts in peripheral tissues of C57BL/6J mice. Although it is milder than homozygous deletion of Cry2, we hypothesized that reduced Cry2 rhythmicity could alter MYC protein accumulation and contribute to enhanced cancer risk caused by circadian disruption. We tested this hypothesis in MYC-driven lymphoma. Methods: We housed Eμ-MYC mice in light-tight boxes set to either control (continuous cycles of 12-hours of light followed by 12-hours of dark, LD12:12) or chronic jetlag (eight-hour light phase advances every two to three days, CJL) lighting conditions and assessed the impact of disrupted light cycles on survival and tumor formation in Eμ-MYC mice. Results: Environmental disruption of circadian rhythms did not alter tumor location, tumor growth, or survival in Eμ-MYC mice. Conclusions: Dampened rhythms of Cry2 following disruption of circadian light exposures is milder than deletion of Cry2. The lack of phenotype caused by altered circadian gene expression in contrast to enhanced tumorigenesis caused by homozygous deletion of Cry2 suggests that CRY2 dosage impacts this model. Importantly, these findings indicate that increased cancer risk associated with circadian disruption arises from one or more mechanisms that are not recapitulated here, and may be different in distinct tumor types.
    Keywords:  CRY2; c-MYC; chronic jetlag; circadian disruption; circadian rhythm; lymphoma
    DOI:  https://doi.org/10.12688/f1000research.125272.2
  34. EMBO Rep. 2023 Oct 09. e57265
    Lysosomes in senescence and aging.
    Jay Xiaojun Tan, Toren Finkel.
      Dysfunction of lysosomes, the primary hydrolytic organelles in animal cells, is frequently associated with aging and age-related diseases. At the cellular level, lysosomal dysfunction is strongly linked to cellular senescence or the induction of cell death pathways. However, the precise mechanisms by which lysosomal dysfunction participates in these various cellular or organismal phenotypes have remained elusive. The ability of lysosomes to degrade diverse macromolecules including damaged proteins and organelles puts lysosomes at the center of multiple cellular stress responses. Lysosomal activity is tightly regulated by many coordinated cellular processes including pathways that function inside and outside of the organelle. Here, we collectively classify these coordinated pathways as the lysosomal processing and adaptation system (LYPAS). We review evidence that the LYPAS is upregulated by diverse cellular stresses, its adaptability regulates senescence and cell death decisions, and it can form the basis for therapeutic manipulation for a wide range of age-related diseases and potentially for aging itself.
    Keywords:  LYPAS; age-related disease; autophagy; lysosomal quality control; senescence
    DOI:  https://doi.org/10.15252/embr.202357265
  35. Elife. 2023 Oct 11. pii: e86452. [Epub ahead of print]12
    GDF15 is required for cold-induced thermogenesis and contributes to improved systemic metabolic health following loss of OPA1 in brown adipocytes.
    Jayashree Jena, Luis Miguel García-Peña, Eric T Weatherford, Alex Marti, Sarah H Bjorkman, Kevin Kato, Jivan Koneru, Jason H Chen, Randy J Seeley, E Dale Abel, Renata O Pereira.
      We previously reported that mice lacking the protein optic atrophy 1 (OPA1 BKO) in brown adipose tissue (BAT) display induction of the activating transcription factor 4 (ATF4), which promotes fibroblast growth factor 21 (FGF21) secretion as a batokine. FGF21 increases metabolic rates under baseline conditions but is dispensable for the resistance to diet-induced obesity (DIO) reported in OPA1 BKO mice (Pereira et al., 2021). To determine alternative mediators of this phenotype, we performed transcriptome analysis, which revealed increased levels of growth differentiation factor 15 (GDF15), along with increased protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) levels in BAT. To investigate whether ATF4 induction was mediated by PERK and evaluate the contribution of GDF15 to the resistance to DIO, we selectively deleted PERK or GDF15 in OPA1 BKO mice. Mice with reduced OPA1 and PERK levels in BAT had preserved ISR activation. Importantly, simultaneous deletion of OPA1 and GDF15 partially reversed the resistance to DIO and abrogated the improvements in glucose tolerance. Furthermore, GDF15 was required to improve cold-induced thermogenesis in OPA1 BKO mice. Taken together, our data indicate that PERK is dispensable to induce the ISR, but GDF15 contributes to the resistance to DIO, and is required for glucose homeostasis and thermoregulation in OPA1 BKO mice by increasing energy expenditure.
    Keywords:  GDF15; PERK; biochemistry; brown adipose tissue; chemical biology; integrated stress response; mitochondrial stress; mouse
    DOI:  https://doi.org/10.7554/eLife.86452
  36. Molecules. 2023 Oct 09. pii: 6998. [Epub ahead of print]28(19):
    The History of Animal and Plant Sulfite Oxidase-A Personal View.
    Ralf R Mendel, Günter Schwarz.
      Sulfite oxidase is one of five molybdenum-containing enzymes known in eukaryotes where it catalyzes the oxidation of sulfite to sulfate. This review covers the history of sulfite oxidase research starting out with the early years of its discovery as a hepatic mitochondrial enzyme in vertebrates, leading to basic biochemical and structural properties that have inspired research for decades. A personal view on sulfite oxidase in plants, that sulfates are assimilated for their de novo synthesis of cysteine, is presented by Ralf Mendel with numerous unexpected findings and unique properties of this single-cofactor sulfite oxidase localized to peroxisomes. Guenter Schwarz connects his research to sulfite oxidase via its deficiency in humans, demonstrating its unique role amongst all molybdenum enzymes in humans. In essence, in both the plant and animal kingdoms, sulfite oxidase represents an important player in redox regulation, signaling and metabolism, thereby connecting sulfur and nitrogen metabolism in multiple ways.
    Keywords:  molybdenum; molybdenum cofactor; molybdenum cofactor deficiency; sulfite oxidase; sulfite oxidase deficiency; sulfur
    DOI:  https://doi.org/10.3390/molecules28196998
  37. Annu Rev Pathol. 2023 Oct 13.
    Cancer as a Disease of Development Gone Awry.
    Ben Z Stanger, Geoffrey M Wahl.
      In the 160 years since Rudolf Virchow first postulated that neoplasia arises by the same law that regulated the embryonic development, scientists have come to recognize the striking overlap between the molecular and cellular programs used by cancers and embryos. Advances in cancer biology and molecular techniques have further highlighted the similarities between carcinogenesis and embryogenesis, where cellular growth, differentiation, motility, and intercellular cross talk are mediated by common drivers and regulatory networks. This review highlights the many connections linking cancer biology and developmental biology to provide a deeper understanding of how a tissue's developmental history may both enable and constrain cancer cell evolution. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease, Volume 19 is January 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
    DOI:  https://doi.org/10.1146/annurev-pathmechdis-031621-025610
  38. Nat Rev Cancer. 2023 Oct 09.
    Transfer RNAs as dynamic and critical regulators of cancer progression.
    Alexandra M Pinzaru, Sohail F Tavazoie.
      Transfer RNAs (tRNAs) have been historically viewed as non-dynamic adaptors that decode the genetic code into proteins. Recent work has uncovered dynamic regulatory roles for these fascinating molecules. Advances in tRNA detection methods have revealed that specific tRNAs can become modulated upon DNA copy number and chromatin alterations and can also be perturbed by oncogenic signalling and transcriptional regulators in cancer cells or the tumour microenvironment. Such alterations in the levels of specific tRNAs have been shown to causally impact cancer progression, including metastasis. Moreover, sequencing methods have identified tRNA-derived small RNAs that influence various aspects of cancer progression, such as cell proliferation and invasion, and could serve as diagnostic and prognostic biomarkers or putative therapeutic targets in various cancers. Finally, there is accumulating evidence, including from genetic models, that specific tRNA synthetases - the enzymes responsible for charging tRNAs with amino acids - can either promote or suppress tumour formation. In this Review, we provide an overview of how deregulation of tRNAs influences cancer formation and progression.
    DOI:  https://doi.org/10.1038/s41568-023-00611-4
  39. Int J Mol Sci. 2023 Sep 27. pii: 14595. [Epub ahead of print]24(19):
    Arginine Expedites Erastin-Induced Ferroptosis through Fumarate.
    Xinxin Guo, Yubo Guo, Jiahuan Li, Qian Liu, Hao Wu.
      Ferroptosis is a newly characterized form of programmed cell death. The fundamental biochemical feature of ferroptosis is the lethal accumulation of iron-catalyzed lipid peroxidation. It has gradually been recognized that ferroptosis is implicated in the pathogenesis of a variety of human diseases. Increasing evidence has shed light on ferroptosis regulation by amino acid metabolism. Herein, we report that arginine deprivation potently inhibits erastin-induced ferroptosis, but not RSL3-induced ferroptosis, in several types of mammalian cells. Arginine presence reduces the intracellular glutathione (GSH) level by sustaining the biosynthesis of fumarate, which functions as a reactive α,β-unsaturated electrophilic metabolite and covalently binds to GSH to generate succinicGSH. siRNA-mediated knockdown of argininosuccinate lyase, the critical urea cycle enzyme directly catalyzing the biosynthesis of fumarate, significantly decreases cellular fumarate and thus relieves erastin-induced ferroptosis in the presence of arginine. Furthermore, fumarate is decreased during erastin exposure, suggesting that a protective mechanism exists to decelerate GSH depletion in response to pro-ferroptotic insult. Collectively, this study reveals the ferroptosis regulation by the arginine metabolism and expands the biochemical functionalities of arginine.
    Keywords:  arginine; argininosuccinate lyase; ferroptosis; fumarate; urea cycle
    DOI:  https://doi.org/10.3390/ijms241914595
  40. Proc Natl Acad Sci U S A. 2023 Oct 17. 120(42): e2308496120
    The metabolomic physics of complex diseases.
    Shuang Wu, Xiang Liu, Ang Dong, Claudia Gragnoli, Christopher Griffin, Jie Wu, Shing-Tung Yau, Rongling Wu.
      Human diseases involve metabolic alterations. Metabolomic profiles have served as a vital biomarker for the early identification of high-risk individuals and disease prevention. However, current approaches can only characterize individual key metabolites, without taking into account the reality that complex diseases are multifactorial, dynamic, heterogeneous, and interdependent. Here, we leverage a statistical physics model to combine all metabolites into bidirectional, signed, and weighted interaction networks and trace how the flow of information from one metabolite to the next causes changes in health state. Viewing a disease outcome as the consequence of complex interactions among its interconnected components (metabolites), we integrate concepts from ecosystem theory and evolutionary game theory to model how the health state-dependent alteration of a metabolite is shaped by its intrinsic properties and through extrinsic influences from its conspecifics. We code intrinsic contributions as nodes and extrinsic contributions as edges into quantitative networks and implement GLMY homology theory to analyze and interpret the topological change of health state from symbiosis to dysbiosis and vice versa. The application of this model to real data allows us to identify several hub metabolites and their interaction webs, which play a part in the formation of inflammatory bowel diseases. The findings by our model could provide important information on drug design to treat these diseases and beyond.
    Keywords:  allometric scaling law; evolutionary game theory; idopNetwork; metabolic interaction; quasi-dynamic ordinary differential equations
    DOI:  https://doi.org/10.1073/pnas.2308496120
  41. Sci Adv. 2023 Oct 13. 9(41): eadi1411
    Glial-derived mitochondrial signals affect neuronal proteostasis and aging.
    Raz Bar-Ziv, Naibedya Dutta, Adam Hruby, Edward Sukarto, Maxim Averbukh, Athena Alcala, Hope R Henderson, Jenni Durieux, Sarah U Tronnes, Qazi Ahmad, Theodore Bolas, Joel Perez, Julian G Dishart, Matthew Vega, Gilberto Garcia, Ryo Higuchi-Sanabria, Andrew Dillin.
      The nervous system plays a critical role in maintaining whole-organism homeostasis; neurons experiencing mitochondrial stress can coordinate the induction of protective cellular pathways, such as the mitochondrial unfolded protein response (UPRMT), between tissues. However, these studies largely ignored nonneuronal cells of the nervous system. Here, we found that UPRMT activation in four astrocyte-like glial cells in the nematode, Caenorhabditis elegans, can promote protein homeostasis by alleviating protein aggregation in neurons. Unexpectedly, we find that glial cells use small clear vesicles (SCVs) to signal to neurons, which then relay the signal to the periphery using dense-core vesicles (DCVs). This work underlines the importance of glia in establishing and regulating protein homeostasis within the nervous system, which can then affect neuron-mediated effects in organismal homeostasis and longevity.
    DOI:  https://doi.org/10.1126/sciadv.adi1411
  42. iScience. 2023 Oct 20. 26(10): 107949
    CD38 regulates ovarian function and fecundity via NAD+ metabolism.
    Rosalba Perrone, Prasanna Vadhana Ashok Kumaar, Lauren Haky, Cosmo Hahn, Rebeccah Riley, Julia Balough, Giuliana Zaza, Bikem Soygur, Kaitlyn Hung, Leandro Prado, Herbert G Kasler, Ritesh Tiwari, Hiroyuki Matsui, Genesis Vega Hormazabal, Indra Heckenbach, Morten Scheibye-Knudsen, Francesca E Duncan, Eric Verdin.
      Mammalian female reproductive lifespan is typically significantly shorter than life expectancy and is associated with a decrease in ovarian NAD+ levels. However, the mechanisms underlying this loss of ovarian NAD+ are unclear. Here, we show that CD38, an NAD+ consuming enzyme, is expressed in the ovarian extrafollicular space, primarily in immune cells, and its levels increase with reproductive age. Reproductively young mice lacking CD38 exhibit larger primordial follicle pools, elevated ovarian NAD+ levels, and increased fecundity relative to wild type controls. This larger ovarian reserve results from a prolonged window of follicle formation during early development. However, the beneficial effect of CD38 loss on reproductive function is not maintained at advanced age. Our results demonstrate a novel role of CD38 in regulating ovarian NAD+ metabolism and establishing the ovarian reserve, a critical process that dictates a female's reproductive lifespan.
    Keywords:  Biochemistry; Biological sciences; Physiology
    DOI:  https://doi.org/10.1016/j.isci.2023.107949
  43. J Theor Biol. 2023 Oct 05. pii: S0022-5193(23)00229-1. [Epub ahead of print]575 111632
    A Markov constraint to uniquely identify elementary flux mode weights in unimolecular metabolic networks.
    Justin G Chitpin, Theodore J Perkins.
      Elementary flux modes (EFMs) are minimal, steady state pathways characterizing a flux network. Fundamentally, all steady state fluxes in a network are decomposable into a linear combination of EFMs. While there is typically no unique set of EFM weights that reconstructs these fluxes, several optimization-based methods have been proposed to constrain the solution space by enforcing some notion of parsimony. However, it has long been recognized that optimization-based approaches may fail to uniquely identify EFM weights and return different feasible solutions across objective functions and solvers. Here we show that, for flux networks only involving single molecule transformations, these problems can be avoided by imposing a Markovian constraint on EFM weights. Our Markovian constraint guarantees a unique solution to the flux decomposition problem, and that solution is arguably more biophysically plausible than other solutions. We describe an algorithm for computing Markovian EFM weights via steady state analysis of a certain discrete-time Markov chain, based on the flux network, which we call the cycle-history Markov chain. We demonstrate our method with a differential analysis of EFM activity in a lipid metabolic network comparing healthy and Alzheimer's disease patients. Our method is the first to uniquely decompose steady state fluxes into EFM weights for any unimolecular metabolic network.
    Keywords:  Elementary flux mode; Flow decomposition; Flux network; Markov chain
    DOI:  https://doi.org/10.1016/j.jtbi.2023.111632
  44. Mol Cell. 2023 Oct 10. pii: S1097-2765(23)00761-X. [Epub ahead of print]
    The structural mechanism of dimeric DONSON in replicative helicase activation.
    Milos A Cvetkovic, Paolo Passaretti, Agata Butryn, Alicja Reynolds-Winczura, Georgia Kingsley, Aggeliki Skagia, Cyntia Fernandez-Cuesta, Divyasree Poovathumkadavil, Roger George, Anoop S Chauhan, Satpal S Jhujh, Grant S Stewart, Agnieszka Gambus, Alessandro Costa.
      The MCM motor of the replicative helicase is loaded onto origin DNA as an inactive double hexamer before replication initiation. Recruitment of activators GINS and Cdc45 upon S-phase transition promotes the assembly of two active CMG helicases. Although work with yeast established the mechanism for origin activation, how CMG is formed in higher eukaryotes is poorly understood. Metazoan Downstream neighbor of Son (DONSON) has recently been shown to deliver GINS to MCM during CMG assembly. What impact this has on the MCM double hexamer is unknown. Here, we used cryoelectron microscopy (cryo-EM) on proteins isolated from replicating Xenopus egg extracts to identify a double CMG complex bridged by a DONSON dimer. We find that tethering elements mediating complex formation are essential for replication. DONSON reconfigures the MCM motors in the double CMG, and primordial dwarfism patients' mutations disrupting DONSON dimerization affect GINS and MCM engagement in human cells and DNA synthesis in Xenopus egg extracts.
    Keywords:  DNA replication initiation; DONSON; Xenopus egg extract; cryo-EM; primordial dwarfism; replicative helicase
    DOI:  https://doi.org/10.1016/j.molcel.2023.09.029
  45. Nat Commun. 2023 Oct 12. 14(1): 6416
    SUN1/2 controls macrophage polarization via modulating nuclear size and stiffness.
    Shi Jiao, Chuanchuan Li, Fenghua Guo, Jinjin Zhang, Hui Zhang, Zhifa Cao, Wenjia Wang, Wenbo Bu, Mobin Lin, Junhong Lü, Zhaocai Zhou.
      Alteration of the size and stiffness of the nucleus triggered by environmental cues are thought to be important for eukaryotic cell fate and function. However, it remains unclear how context-dependent nuclear remodeling occurs and reprograms gene expression. Here we identify the nuclear envelope proteins SUN1/2 as mechano-regulators of the nucleus during M1 polarization of the macrophage. Specifically, we show that LPS treatment decreases the protein levels of SUN1/2 in a CK2-βTrCP-dependent manner to shrink and soften the nucleus, therefore altering the chromatin accessibility for M1-associated gene expression. Notably, the transmembrane helix of SUN1/2 is solely required and sufficient for the nuclear mechano-remodeling. Consistently, SUN1/2 depletion in macrophages facilitates their phagocytosis, tissue infiltration, and proinflammatory cytokine production, thereby boosting the antitumor immunity in mice. Thus, our study demonstrates that, in response to inflammatory cues, SUN1/2 proteins act as mechano-regulators to remodel the nucleus and chromatin for M1 polarization of the macrophage.
    DOI:  https://doi.org/10.1038/s41467-023-42187-5
  46. Int J Mol Sci. 2023 Sep 27. pii: 14624. [Epub ahead of print]24(19):
    The Pro-Oncogenic Protein IF1 Promotes Proliferation of Anoxic Cancer Cells during Re-Oxygenation.
    Riccardo Righetti, Silvia Grillini, Valentina Del Dotto, Anna Costanzini, Francesca Liuzzi, Claudia Zanna, Gianluca Sgarbi, Giancarlo Solaini, Alessandra Baracca.
      Cancer cells overexpress IF1, the endogenous protein that inhibits the hydrolytic activity of ATP synthase when mitochondrial membrane potential (ΔμH+) falls, as in ischemia. Other roles have been ascribed to IF1, but the associated molecular mechanisms are still under debate. We investigated the ability of IF1 to promote survival and proliferation in osteosarcoma and colon carcinoma cells exposed to conditions mimicking ischemia and reperfusion, as occurs in vivo, particularly in solid tumors. IF1-silenced and parental cells were exposed to the FCCP uncoupler to collapse ΔμH+ and the bioenergetics of cell models were validated. All the uncoupled cells preserved mitochondrial mass, but the implemented mechanisms differed in IF1-expressing and IF1-silenced cells. Indeed, the membrane potential collapse and the energy charge preservation allowed an increase in both mitophagy and mitochondrial biogenesis in IF1-expressing cells only. Interestingly, the presence of IF1 also conferred a proliferative advantage to cells highly dependent on oxidative phosphorylation when the uncoupler was washed out, mimicking cell re-oxygenation. Overall, our results indicate that IF1, by allowing energy preservation and promoting mitochondrial renewal, can favor proliferation of anoxic cells and tumor growth. Therefore, hindering the action of IF1 may be promising for the therapy of tumors that rely on oxidative phosphorylation for energy production.
    Keywords:  143B osteosarcoma cells; ATP synthase; HCT116 colon carcinoma cells; anoxia; autophagy; biogenesis; metabolism; mitochondria; mitophagy; oxidative phosphorylation
    DOI:  https://doi.org/10.3390/ijms241914624
  47. Mol Cell Proteomics. 2023 Oct 05. pii: S1535-9476(23)00168-8. [Epub ahead of print] 100657
    Higher-order structural organization of the mitochondrial proteome charted by in situ cross-linking mass spectrometry.
    Johannes F Hevler, Albert J R Heck.
      Mitochondria are densely packed with proteins, of which most are involved physically or more transiently in protein-protein interactions (PPIs). Mitochondria host among others all enzymes of the Krebs cycle and the oxidative phosphorylation (OXPHOS) pathway and are foremost associated with cellular bioenergetics (1, 2). However, mitochondria are also important contributors to apoptotic cell death (3) and contain their own genome (4) indicating that they play additionally an eminent role in processes beyond bioenergetics (5). Despite intense efforts in identifying and characterizing mitochondrial protein complexes by structural biology and proteomics techniques, many PPIs have remained elusive. Several of these (membrane embedded) PPIs are less stable in-vitro hampering their characterization by most contemporary methods in structural biology. Particularly in these cases, cross-linking mass spectrometry (XL-MS) has proven valuable for the in-depth characterization of mitochondrial protein complexes in situ. Here, we highlight experimental strategies for the analysis of proteome-wide protein-protein interactions in mitochondria using XL-MS. We showcase the ability of in situ XL-MS as a tool to map sub-organelle interactions and topologies, and aid in refining structural models of protein complexes. We describe some of the most recent technological advances in XL-MS that may benefit the in situ characterization of PPIs even further, especially when combined with electron microscopy and structural modelling.
    Keywords:  In situ cross-linking mass spectrometry; cross-linking reagents; membrane complexes; mitochondria; protein localization; protein-protein interactions
    DOI:  https://doi.org/10.1016/j.mcpro.2023.100657
  48. Annu Rev Pathol. 2023 Oct 13.
    Clonal Hematopoiesis, Inflammation, and Hematologic Malignancy.
    Rashmi Kanagal-Shamanna, David B Beck, Katherine R Calvo.
      Somatic or acquired mutations are postzygotic genetic variations that can occur within any tissue. These mutations accumulate during aging and have classically been linked to malignant processes. Tremendous advancements over the past years have led to a deeper understanding of the role of somatic mutations in benign and malignant age-related diseases. Here, we review the somatic mutations that accumulate in the blood and their connection to disease states, with a particular focus on inflammatory diseases and myelodysplastic syndrome. We include a definition of clonal hematopoiesis (CH) and an overview of the origins and implications of these mutations. In addition, we emphasize somatic disorders with overlapping inflammation and hematologic disease beyond CH, including paroxysmal nocturnal hemoglobinuria and aplastic anemia, focusing on VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. Finally, we provide a practical view of the implications of somatic mutations in clinical hematology, pathology, and beyond. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease, Volume 19 is January 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
    DOI:  https://doi.org/10.1146/annurev-pathmechdis-051222-122724
  49. Cancer Res. 2023 Oct 09. OF1-OF17
    Subclonal Somatic Copy-Number Alterations Emerge and Dominate in Recurrent Osteosarcoma.
    Michael D Kinnaman, Simone Zaccaria, Alvin Makohon-Moore, Brian Arnold, Max F Levine, Gunes Gundem, Juan E Arango Ossa, Dominik Glodzik, M Irene Rodríguez-Sánchez, Nancy Bouvier, Shanita Li, Emily Stockfisch, Marisa Dunigan, Cassidy Cobbs, Umesh K Bhanot, Daoqi You, Katelyn Mullen, Jerry P Melchor, Michael V Ortiz, Tara J O'Donohue, Emily K Slotkin, Leonard H Wexler, Filemon S Dela Cruz, Meera R Hameed, Julia L Glade Bender, William D Tap, Paul A Meyers, Elli Papaemmanuil, Andrew L Kung, Christine A Iacobuzio-Donahue.
      Multiple large-scale genomic profiling efforts have been undertaken in osteosarcoma to define the genomic drivers of tumorigenesis, therapeutic response, and disease recurrence. The spatial and temporal intratumor heterogeneity could also play a role in promoting tumor growth and treatment resistance. We conducted longitudinal whole-genome sequencing of 37 tumor samples from 8 patients with relapsed or refractory osteosarcoma. Each patient had at least one sample from a primary site and a metastatic or relapse site. Subclonal copy-number alterations were identified in all patients except one. In 5 patients, subclones from the primary tumor emerged and dominated at subsequent relapses. MYC gain/amplification was enriched in the treatment-resistant clones in 6 of 7 patients with multiple clones. Amplifications in other potential driver genes, such as CCNE1, RAD21, VEGFA, and IGF1R, were also observed in the resistant copy-number clones. A chromosomal duplication timing analysis revealed that complex genomic rearrangements typically occurred prior to diagnosis, supporting a macroevolutionary model of evolution, where a large number of genomic aberrations are acquired over a short period of time followed by clonal selection, as opposed to ongoing evolution. A mutational signature analysis of recurrent tumors revealed that homologous repair deficiency (HRD)-related SBS3 increases at each time point in patients with recurrent disease, suggesting that HRD continues to be an active mutagenic process after diagnosis. Overall, by examining the clonal relationships between temporally and spatially separated samples from patients with relapsed/refractory osteosarcoma, this study sheds light on the intratumor heterogeneity and potential drivers of treatment resistance in this disease.
    SIGNIFICANCE: The chemoresistant population in recurrent osteosarcoma is subclonal at diagnosis, emerges at the time of primary resection due to selective pressure from neoadjuvant chemotherapy, and is characterized by unique oncogenic amplifications.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-23-0385
  50. Cell. 2023 Oct 12. pii: S0092-8674(23)01031-0. [Epub ahead of print]186(21): 4694-4709.e16
    Cytoplasmic division cycles without the nucleus and mitotic CDK/cyclin complexes.
    Anand Bakshi, Fabio Echegaray Iturra, Andrew Alamban, Miquel Rosas-Salvans, Sophie Dumont, Mustafa G Aydogan.
      Cytoplasmic divisions are thought to rely on nuclear divisions and mitotic signals. We demonstrate in Drosophila embryos that cytoplasm can divide repeatedly without nuclei and mitotic CDK/cyclin complexes. Cdk1 normally slows an otherwise faster cytoplasmic division cycle, coupling it with nuclear divisions, and when uncoupled, cytoplasm starts dividing before mitosis. In developing embryos where CDK/cyclin activity can license mitotic microtubule (MT) organizers like the spindle, cytoplasmic divisions can occur without the centrosome, a principal organizer of interphase MTs. However, centrosomes become essential in the absence of CDK/cyclin activity, implying that the cytoplasm can employ either the centrosome-based interphase or CDK/cyclin-dependent mitotic MTs to facilitate its divisions. Finally, we present evidence that autonomous cytoplasmic divisions occur during unperturbed fly embryogenesis and that they may help extrude mitotically stalled nuclei during blastoderm formation. We postulate that cytoplasmic divisions occur in cycles governed by a yet-to-be-uncovered clock mechanism autonomous from CDK/cyclin complexes.
    Keywords:  Cdk; Drosophila embryo; autonomous clocks; cell cycle; centrosome; cyclin; cytokinesis; epithelial homeostasis; microtubules; mitosis
    DOI:  https://doi.org/10.1016/j.cell.2023.09.010
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