bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2024‒05‒19
fifty-five papers selected by
Christian Frezza, Universität zu Köln
  1. mTORC1 regulates cell survival under glucose starvation through 4EBP1/2-mediated translational reprogramming of fatty acid metabolism.
  2. Unexpected roles for AMPK in the suppression of autophagy and the reactivation of MTORC1 signaling during prolonged amino acid deprivation.
  3. Mitochondrial F0F1-ATP synthase governs the induction of mitochondrial fission.
  4. HIF2α-dependent inhibition of mitochondrial clustering of glutaminase suppresses clear cell renal cell carcinoma.
  5. Mitochondrial heterogeneity and adaptations to cellular needs.
  6. Serine synthesis controls mitochondrial biogenesis in macrophages.
  7. Nuclear export is a limiting factor in eukaryotic mRNA metabolism.
  8. Arginine deprivation enriches lung cancer proteomes with cysteine by inducing arginine-to-cysteine substitutants.
  9. Why cells need iron: a compendium of iron utilisation.
  10. Autophagy counters inflammation-driven glycolytic impairment in aging hematopoietic stem cells.
  11. Genome-wide CRISPR screens in spheroid culture reveal that the tumor suppressor LKB1 inhibits growth via the PIKFYVE lipid kinase.
  12. AMPK as a mediator of tissue preservation: time for a shift in dogma?
  13. IRE1α determines ferroptosis sensitivity through regulation of glutathione synthesis.
  14. Unraveling ETC complex I function in ferroptosis reveals a potential ferroptosis-inducing therapeutic strategy for LKB1-deficient cancers.
  15. A metabolic atlas of mouse aging.
  16. Cysteine substitutants emerge in lung cancer proteomes during arginine restriction.
  17. NADPH composite index analysis quantifies the relationship between compartmentalized NADPH dynamics and growth rates in cancer cells.
  18. The aged tumor microenvironment limits T cell control of cancer.
  19. Mega study charts how genetic variants affect metabolism.
  20. The RIPK1 death domain restrains ZBP1- and TRIF-mediated cell death and inflammation.
  21. One-carbon unit supplementation fuels purine synthesis in tumor-infiltrating T cells and augments checkpoint blockade.
  22. Metabolic regulation of single synaptic vesicle exo- and endocytosis in hippocampal synapses.
  23. Analysis of somatic mutations in whole blood from 200,618 individuals identifies pervasive positive selection and novel drivers of clonal hematopoiesis.
  24. Ironing out the role of ferroptosis in immunity.
  25. Liver ACOX1 regulates levels of circulating lipids that promote metabolic health through adipose remodeling.
  26. ARID1A suppresses R-loop-mediated STING-type I interferon pathway activation of anti-tumor immunity.
  27. Arteriovenous metabolomics in pigs reveals CFTR regulation ofmetabolism inmultiple organs.
  28. Octyl itaconate enhances VSVΔ51 oncolytic virotherapy by multitarget inhibition of antiviral and inflammatory pathways.
  29. The emerging roles of glutamine amidotransferases in metabolism and immune defense.
  30. Glutamine promotes human CD8+ T cells and counteracts imiquimod-induced T cell hyporesponsiveness.
  31. L-2-hydroxyglutarate remodeling of the epigenome and epitranscriptome creates a metabolic vulnerability in kidney cancer models.
  32. Emerging Roles of Vitamin B12 in Aging and Inflammation.
  33. The killifish germline regulates longevity and somatic repair in a sex-specific manner.
  34. Identification of the extracellular membrane protein ENPP3 as a major cGAMP hydrolase and innate immune checkpoint.
  35. SIN-3 transcriptional coregulator maintains mitochondrial homeostasis and polyamine flux.
  36. A cell-free nutrient-supplemented perfusate allows four-day ex vivo metabolic preservation of human kidneys.
  37. N-MYC impairs innate immune signaling in high-grade serous ovarian carcinoma.
  38. Transcription stress at telomeres leads to cytosolic DNA release and paracrine senescence.
  39. Decoding the interplay between genetic and non-genetic drivers of metastasis.
  40. mTORC1/S6K1 signaling promotes sustained oncogenic translation through modulating CRL3IBTK-mediated ubiquitination of eIF4A1 in cancer cells.
  41. PGC-1α integrates insulin signaling with mitochondrial physiology and behavior in a Drosophila model of Fragile X Syndrome.
  42. Matrix stiffening promotes perinuclear clustering of mitochondria.
  43. Mitochondrial function and gastrointestinal diseases.
  44. Core facilities coming of age.
  45. Mammalian pexophagy at a glance.
  46. Non-hypermutator cancers access driver mutations through reversals in germline mutational bias.
  47. The integrated stress response promotes neural stem cell survival under conditions of mitochondrial dysfunction in neurodegeneration.
  48. Systematic dissection of tumor-normal single-cell ecosystems across a thousand tumors of 30 cancer types.
  49. Aging and cancer.
  50. Overcoming Nutrient Stress: Integrin αvβ3-Driven Metabolic Adaptation Supports Tumor Initiation.
  51. Spatial genomic, biochemical and cellular mechanisms underlying meningioma heterogeneity and evolution.
  52. Single-cell mtDNA dynamics in tumors is driven by coregulation of nuclear and mitochondrial genomes.
  53. Targeting OXCT1-mediated ketone metabolism reprograms macrophages to promote antitumor immunity via CD8+ T cells in hepatocellular carcinoma.
  54. DNA damage induces p53-independent apoptosis through ribosome stalling.
  55. Mechano-metabolism of adherent cells in 2D and 3D microenvironments.
  1. Nat Commun. 2024 May 14. 15(1): 4083
    mTORC1 regulates cell survival under glucose starvation through 4EBP1/2-mediated translational reprogramming of fatty acid metabolism.
    Tal Levy, Kai Voeltzke, Laura Hruby, Khawla Alasad, Zuelal Bas, Marteinn Snaebjörnsson, Ran Marciano, Katerina Scharov, Mélanie Planque, Kim Vriens, Stefan Christen, Cornelius M Funk, Christina Hassiepen, Alisa Kahler, Beate Heider, Daniel Picard, Jonathan K M Lim, Anja Stefanski, Katja Bendrin, Andres Vargas-Toscano, Ulf D Kahlert, Kai Stühler, Marc Remke, Moshe Elkabets, Thomas G P Grünewald, Andreas S Reichert, Sarah-Maria Fendt, Almut Schulze, Guido Reifenberger, Barak Rotblat, Gabriel Leprivier.
      Energetic stress compels cells to evolve adaptive mechanisms to adjust their metabolism. Inhibition of mTOR kinase complex 1 (mTORC1) is essential for cell survival during glucose starvation. How mTORC1 controls cell viability during glucose starvation is not well understood. Here we show that the mTORC1 effectors eukaryotic initiation factor 4E binding proteins 1/2 (4EBP1/2) confer protection to mammalian cells and budding yeast under glucose starvation. Mechanistically, 4EBP1/2 promote NADPH homeostasis by preventing NADPH-consuming fatty acid synthesis via translational repression of Acetyl-CoA Carboxylase 1 (ACC1), thereby mitigating oxidative stress. This has important relevance for cancer, as oncogene-transformed cells and glioma cells exploit the 4EBP1/2 regulation of ACC1 expression and redox balance to combat energetic stress, thereby supporting transformation and tumorigenicity in vitro and in vivo. Clinically, high EIF4EBP1 expression is associated with poor outcomes in several cancer types. Our data reveal that the mTORC1-4EBP1/2 axis provokes a metabolic switch essential for survival during glucose starvation which is exploited by transformed and tumor cells.
    DOI:  https://doi.org/10.1038/s41467-024-48386-y
  2. Autophagy. 2024 May 14.
    Unexpected roles for AMPK in the suppression of autophagy and the reactivation of MTORC1 signaling during prolonged amino acid deprivation.
    Dubek Kazyken, Sydney G Dame, Claudia Wang, Maxwell Wadley, Diane C Fingar.
      AMPK promotes catabolic and suppresses anabolic cell metabolism to promote cell survival during energetic stress, in part by inhibiting MTORC1, an anabolic kinase requiring sufficient levels of amino acids. We found that cells lacking AMPK displayed increased apoptotic cell death during nutrient stress caused by prolonged amino acid deprivation. We presumed that impaired macroautophagy/autophagy explained this phenotype, as a prevailing view posits that AMPK initiates autophagy (often a pro-survival response) through phosphorylation of ULK1. Unexpectedly, however, autophagy remained unimpaired in cells lacking AMPK, as monitored by several autophagic readouts in several cell lines. More surprisingly, the absence of AMPK increased ULK1 signaling and MAP1LC3B/LC3B lipidation during amino acid deprivation while AMPK-mediated phosphorylation of ULK1 S555 (a site proposed to initiate autophagy) decreased upon amino acid withdrawal or pharmacological MTORC1 inhibition. In addition, activation of AMPK with compound 991, glucose deprivation, or AICAR blunted autophagy induced by amino acid withdrawal. These results demonstrate that AMPK activation and glucose deprivation suppress autophagy. As AMPK controlled autophagy in an unexpected direction, we examined how AMPK controls MTORC1 signaling. Paradoxically, we observed impaired reactivation of MTORC1 in cells lacking AMPK upon prolonged amino acid deprivation. Together these results oppose established views that AMPK promotes autophagy and inhibits MTORC1 universally. Moreover, they reveal unexpected roles for AMPK in the suppression of autophagy and the support of MTORC1 signaling in the context of prolonged amino acid deprivation. These findings prompt a reevaluation of how AMPK and its control of autophagy and MTORC1 affect health and disease.
    Keywords:  ATG16L1; EIF4EBP1/4EBP1; LC3B; MTOR; RPS6KB1/S6K1; ULK1
    DOI:  https://doi.org/10.1080/15548627.2024.2355074
  3. iScience. 2024 May 17. 27(5): 109808
    Mitochondrial F0F1-ATP synthase governs the induction of mitochondrial fission.
    Charlène Lhuissier, Valérie Desquiret-Dumas, Anaïs Girona, Jennifer Alban, Justine Faure, Julien Cassereau, Philippe Codron, Guy Lenaers, Olivier R Baris, Naïg Gueguen, Arnaud Chevrollier.
      Mitochondrial dynamics is a process that balances fusion and fission events, the latter providing a mechanism for segregating dysfunctional mitochondria. Fission is controlled by the mitochondrial membrane potential (ΔΨm), optic atrophy 1 (OPA1) cleavage, and DRP1 recruitment. It is thought that this process is closely linked to the activity of the mitochondrial respiratory chain (MRC). However, we report here that MRC inhibition does not decrease ΔΨm nor increase fission, as evidenced by hyperconnected mitochondria. Conversely, blocking F0F1-ATP synthase activity induces fragmentation. We show that the F0F1-ATP synthase is sensing the inhibition of MRC activity by immediately promoting its reverse mode of action to hydrolyze matrix ATP and restoring ΔΨm, thus preventing fission. While this reverse mode is expected to be inhibited by the ATPase inhibitor ATPIF1, we show that this sensing is independent of this factor. We have unraveled an unexpected role of F0F1-ATP synthase in controlling the induction of fission by sensing and maintaining ΔΨm.
    Keywords:  Biochemistry; Cell biology; Functional aspects of cell biology
    DOI:  https://doi.org/10.1016/j.isci.2024.109808
  4. bioRxiv. 2024 May 05. pii: 2024.05.04.592520. [Epub ahead of print]
    HIF2α-dependent inhibition of mitochondrial clustering of glutaminase suppresses clear cell renal cell carcinoma.
    Boa Kim, Wencao Zhao, Nathan J Coffey, Caitlyn E Bowman, Michael Noji, Cholsoon Jang, M Celeste Simon, Zoltan Arany.
      Clear cell renal cell carcinomas (ccRCC) are largely driven by HIF2α and are avid consumers of glutamine. However, inhibitors of glutaminase1 (GLS1), the first step in glutaminolysis, have not shown benefit in phase III trials, and HIF2α inhibition, recently FDA-approved for treatment of ccRCC, shows great but incomplete benefits, underscoring the need to better understand the roles of glutamine and HIF2α in ccRCC. Here, we report that glutamine deprivation rapidly redistributes GLS1 into isolated clusters within mitochondria across diverse cell types, excluding ccRCC. GLS1 clustering is rapid (1-3 hours) and reversible, is specifically driven by the level of intracellular glutamate, and is mediated by mitochondrial fission. Clustered GLS1 has markedly enhanced glutaminase activity and promotes cell death under glutamine-deprived conditions. We further show that HIF2α prevents GLS1 clustering, independently of its transcriptional activity, thereby protecting ccRCC cells from cell death induced by glutamine deprivation. Reversing this protection, by genetic expression of GLS1 mutants that constitutively cluster, enhances ccRCC cell death in culture and suppresses ccRCC growth in vivo . These finding provide multiple insights into cellular glutamine handling, including a novel metabolic pathway by which HIF2α promotes ccRCC, and reveals a potential therapeutic avenue to synergize with HIF2α inhibition in the treatment of ccRCC.
    DOI:  https://doi.org/10.1101/2024.05.04.592520
  5. Nat Cell Biol. 2024 May;26(5): 674-686
    Mitochondrial heterogeneity and adaptations to cellular needs.
    Melia Granath-Panelo, Shingo Kajimura.
      Although it is well described that mitochondria are at the epicentre of the energy demands of a cell, it is becoming important to consider how each cell tailors its mitochondrial composition and functions to suit its particular needs beyond ATP production. Here we provide insight into mitochondrial heterogeneity throughout development as well as in tissues with specific energy demands and discuss how mitochondrial malleability contributes to cell fate determination and tissue remodelling.
    DOI:  https://doi.org/10.1038/s41556-024-01410-1
  6. Sci Adv. 2024 May 17. 10(20): eadn2867
    Serine synthesis controls mitochondrial biogenesis in macrophages.
    Chuanlong Wang, Muyang Zhao, Peng Bin, Yuyi Ye, Qingyi Chen, Zhiru Tang, Wenkai Ren.
      Mitochondrial dysfunction is the pivotal driving factor of multiple inflammatory diseases, and targeting mitochondrial biogenesis represents an efficacious approach to ameliorate such dysfunction in inflammatory diseases. Here, we demonstrated that phosphoglycerate dehydrogenase (PHGDH) deficiency promotes mitochondrial biogenesis in inflammatory macrophages. Mechanistically, PHGDH deficiency boosts mitochondrial reactive oxygen species (mtROS) by suppressing cytoplasmic glutathione synthesis. mtROS provokes hypoxia-inducible factor-1α signaling to direct nuclear specificity protein 1 and nuclear respiratory factor 1 transcription. Moreover, myeloid Phgdh deficiency reverses diet-induced obesity. Collectively, this study reveals that a mechanism involving de novo serine synthesis orchestrates mitochondrial biogenesis via mitochondrial-to-nuclear communication, and provides a potential therapeutic target for tackling inflammatory diseases and mitochondria-mediated diseases.
    DOI:  https://doi.org/10.1126/sciadv.adn2867
  7. PLoS Comput Biol. 2024 May 16. 20(5): e1012059
    Nuclear export is a limiting factor in eukaryotic mRNA metabolism.
    Jason M Müller, Katharina Moos, Till Baar, Kerstin C Maier, Kristina Zumer, Achim Tresch.
      The eukaryotic mRNA life cycle includes transcription, nuclear mRNA export and degradation. To quantify all these processes simultaneously, we perform thiol-linked alkylation after metabolic labeling of RNA with 4-thiouridine (4sU), followed by sequencing of RNA (SLAM-seq) in the nuclear and cytosolic compartments of human cancer cells. We develop a model that reliably quantifies mRNA-specific synthesis, nuclear export, and nuclear and cytosolic degradation rates on a genome-wide scale. We find that nuclear degradation of polyadenylated mRNA is negligible and nuclear mRNA export is slow, while cytosolic mRNA degradation is comparatively fast. Consequently, an mRNA molecule generally spends most of its life in the nucleus. We also observe large differences in the nuclear export rates of different 3'UTR transcript isoforms. Furthermore, we identify genes whose expression is abruptly induced upon metabolic labeling. These transcripts are exported substantially faster than average mRNAs, suggesting the existence of alternative export pathways. Our results highlight nuclear mRNA export as a limiting factor in mRNA metabolism and gene regulation.
    DOI:  https://doi.org/10.1371/journal.pcbi.1012059
  8. Mol Cell. 2024 May 16. pii: S1097-2765(24)00327-7. [Epub ahead of print]84(10): 1904-1916.e7
    Arginine deprivation enriches lung cancer proteomes with cysteine by inducing arginine-to-cysteine substitutants.
    Chao Yang, Abhijeet Pataskar, Xiaodong Feng, Jasmine Montenegro Navarro, Inés Paniagua, Jacqueline J L Jacobs, Esther A Zaal, Celia R Berkers, Onno B Bleijerveld, Reuven Agami.
      Many types of human cancers suppress the expression of argininosuccinate synthase 1 (ASS1), a rate-limiting enzyme for arginine production. Although dependency on exogenous arginine can be harnessed by arginine-deprivation therapies, the impact of ASS1 suppression on the quality of the tumor proteome is unknown. We therefore interrogated proteomes of cancer patients for arginine codon reassignments (substitutants) and surprisingly identified a strong enrichment for cysteine (R>C) in lung tumors specifically. Most R>C events did not coincide with genetically encoded R>C mutations but were likely products of tRNA misalignments. The expression of R>C substitutants was highly associated with oncogenic kelch-like epichlorohydrin (ECH)-associated protein 1 (KEAP1)-pathway mutations and suppressed by intact-KEAP1 in KEAP1-mutated cancer cells. Finally, functional interrogation indicated a key role for R>C substitutants in cell survival to cisplatin, suggesting that regulatory codon reassignments endow cancer cells with more resilience to stress. Thus, we present a mechanism for enriching lung cancer proteomes with cysteines that may affect therapeutic decisions.
    Keywords:  aberrant mRNA translation; amino acid shortage; arginine deprivation; chemotherapy; cysteine; ferroptosis; lung cancer; substitutants
    DOI:  https://doi.org/10.1016/j.molcel.2024.04.012
  9. Trends Endocrinol Metab. 2024 May 16. pii: S1043-2760(24)00109-7. [Epub ahead of print]
    Why cells need iron: a compendium of iron utilisation.
    Megan R Teh, Andrew E Armitage, Hal Drakesmith.
      Iron deficiency is globally prevalent, causing an array of developmental, haematological, immunological, neurological, and cardiometabolic impairments, and is associated with symptoms ranging from chronic fatigue to hair loss. Within cells, iron is utilised in a variety of ways by hundreds of different proteins. Here, we review links between molecular activities regulated by iron and the pathophysiological effects of iron deficiency. We identify specific enzyme groups, biochemical pathways, cellular functions, and cell lineages that are particularly iron dependent. We provide examples of how iron deprivation influences multiple key systems and tissues, including immunity, hormone synthesis, and cholesterol metabolism. We propose that greater mechanistic understanding of how cellular iron influences physiological processes may lead to new therapeutic opportunities across a range of diseases.
    Keywords:  bioenergetics; enzymes; iron; metabolism; mitochondria
    DOI:  https://doi.org/10.1016/j.tem.2024.04.015
  10. Cell Stem Cell. 2024 May 13. pii: S1934-5909(24)00174-7. [Epub ahead of print]
    Autophagy counters inflammation-driven glycolytic impairment in aging hematopoietic stem cells.
    Paul V Dellorusso, Melissa A Proven, Fernando J Calero-Nieto, Xiaonan Wang, Carl A Mitchell, Felix Hartmann, Meelad Amouzgar, Patricia Favaro, Andrew DeVilbiss, James W Swann, Theodore T Ho, Zhiyu Zhao, Sean C Bendall, Sean Morrison, Berthold Göttgens, Emmanuelle Passegué.
      Autophagy is central to the benefits of longevity signaling programs and to hematopoietic stem cell (HSC) response to nutrient stress. With age, a subset of HSCs increases autophagy flux and preserves regenerative capacity, but the signals triggering autophagy and maintaining the functionality of autophagy-activated old HSCs (oHSCs) remain unknown. Here, we demonstrate that autophagy is an adaptive cytoprotective response to chronic inflammation in the aging murine bone marrow (BM) niche. We find that inflammation impairs glucose uptake and suppresses glycolysis in oHSCs through Socs3-mediated inhibition of AKT/FoxO-dependent signaling, with inflammation-mediated autophagy engagement preserving functional quiescence by enabling metabolic adaptation to glycolytic impairment. Moreover, we show that transient autophagy induction via a short-term fasting/refeeding paradigm normalizes glycolytic flux and significantly boosts oHSC regenerative potential. Our results identify inflammation-driven glucose hypometabolism as a key driver of HSC dysfunction with age and establish autophagy as a targetable node to reset oHSC regenerative capacity.
    Keywords:  aging; autophagy; hematopoietic stem cells; inflammation; metabolism; regeneration
    DOI:  https://doi.org/10.1016/j.stem.2024.04.020
  11. Proc Natl Acad Sci U S A. 2024 May 21. 121(21): e2403685121
    Genome-wide CRISPR screens in spheroid culture reveal that the tumor suppressor LKB1 inhibits growth via the PIKFYVE lipid kinase.
    John R Ferrarone, Jerin Thomas, Arun M Unni, Yuxiang Zheng, Michal J Nagiec, Eric E Gardner, Oksana Mashadova, Kate Li, Nikos Koundouros, Antonino Montalbano, Meer Mustafa, Lewis C Cantley, John Blenis, Neville E Sanjana, Harold Varmus.
      The tumor suppressor LKB1 is a serine/threonine protein kinase that is frequently mutated in human lung adenocarcinoma (LUAD). LKB1 regulates a complex signaling network that is known to control cell polarity and metabolism; however, the pathways that mediate the tumor-suppressive activity of LKB1 are incompletely defined. To identify mechanisms of LKB1-mediated growth suppression, we developed a spheroid-based cell culture assay to study LKB1-dependent growth. We then performed genome-wide CRISPR screens in spheroidal culture and found that LKB1 suppresses growth, in part, by activating the PIKFYVE lipid kinase. Finally, we used chemical inhibitors and a pH-sensitive reporter to determine that LKB1 impairs growth by promoting the internalization of wild-type EGFR in a PIKFYVE-dependent manner.
    Keywords:  EGFR; LKB1; PIKFYVE; STK11
    DOI:  https://doi.org/10.1073/pnas.2403685121
  12. Nat Rev Endocrinol. 2024 May 17.
    AMPK as a mediator of tissue preservation: time for a shift in dogma?
    Henning Tim Langer, Maria Rohm, Marcus DaSilva Goncalves, Lykke Sylow.
      Ground-breaking discoveries have established 5'-AMP-activated protein kinase (AMPK) as a central sensor of metabolic stress in cells and tissues. AMPK is activated through cellular starvation, exercise and drugs by either directly or indirectly affecting the intracellular AMP (or ADP) to ATP ratio. In turn, AMPK regulates multiple processes of cell metabolism, such as the maintenance of cellular ATP levels, via the regulation of fatty acid oxidation, glucose uptake, glycolysis, autophagy, mitochondrial biogenesis and degradation, and insulin sensitivity. Moreover, AMPK inhibits anabolic processes, such as lipogenesis and protein synthesis. These findings support the notion that AMPK is a crucial regulator of cell catabolism. However, studies have revealed that AMPK's role in cell homeostasis might not be as unidirectional as originally thought. This Review explores emerging evidence for AMPK as a promoter of cell survival and an enhancer of anabolic capacity in skeletal muscle and adipose tissue during catabolic crises. We discuss AMPK-activating interventions for tissue preservation during tissue wasting in cancer-associated cachexia and explore the clinical potential of AMPK activation in wasting conditions. Overall, we provide arguments that call for a shift in the current dogma of AMPK as a mere regulator of cell catabolism, concluding that AMPK has an unexpected role in tissue preservation.
    DOI:  https://doi.org/10.1038/s41574-024-00992-y
  13. Nat Commun. 2024 May 15. 15(1): 4114
    IRE1α determines ferroptosis sensitivity through regulation of glutathione synthesis.
    Dadi Jiang, Youming Guo, Tianyu Wang, Liang Wang, Yuelong Yan, Ling Xia, Rakesh Bam, Zhifen Yang, Hyemin Lee, Takao Iwawaki, Boyi Gan, Albert C Koong.
      Cellular sensitivity to ferroptosis is primarily regulated by mechanisms mediating lipid hydroperoxide detoxification. We show that inositol-requiring enzyme 1 (IRE1α), an endoplasmic reticulum (ER) resident protein critical for the unfolded protein response (UPR), also determines cellular sensitivity to ferroptosis. Cancer and normal cells depleted of IRE1α gain resistance to ferroptosis, while enhanced IRE1α expression promotes sensitivity to ferroptosis. Mechanistically, IRE1α's endoribonuclease activity cleaves and down-regulates the mRNA of key glutathione biosynthesis regulators glutamate-cysteine ligase catalytic subunit (GCLC) and solute carrier family 7 member 11 (SLC7A11). This activity of IRE1α is independent of its role in regulating the UPR and is evolutionarily conserved. Genetic deficiency and pharmacological inhibition of IRE1α have similar effects in inhibiting ferroptosis and reducing renal ischemia-reperfusion injury in mice. Our findings reveal a previously unidentified role of IRE1α to regulate ferroptosis and suggests inhibition of IRE1α as a promising therapeutic strategy to mitigate ferroptosis-associated pathological conditions.
    DOI:  https://doi.org/10.1038/s41467-024-48330-0
  14. Mol Cell. 2024 May 16. pii: S1097-2765(24)00324-1. [Epub ahead of print]84(10): 1964-1979.e6
    Unraveling ETC complex I function in ferroptosis reveals a potential ferroptosis-inducing therapeutic strategy for LKB1-deficient cancers.
    Chao Mao, Guang Lei, Amber Horbath, Min Wang, Zhengze Lu, Yuelong Yan, Xiaoguang Liu, Lavanya Kondiparthi, Xiong Chen, Jun Cheng, Qidong Li, Zhihao Xu, Li Zhuang, Bingliang Fang, Joseph R Marszalek, Masha V Poyurovsky, Kellen Olszewski, Boyi Gan.
      The role of the mitochondrial electron transport chain (ETC) in regulating ferroptosis is not fully elucidated. Here, we reveal that pharmacological inhibition of the ETC complex I reduces ubiquinol levels while decreasing ATP levels and activating AMP-activated protein kinase (AMPK), the two effects known for their roles in promoting and suppressing ferroptosis, respectively. Consequently, the impact of complex I inhibitors on ferroptosis induced by glutathione peroxidase 4 (GPX4) inhibition is limited. The pharmacological inhibition of complex I in LKB1-AMPK-inactivated cells, or genetic ablation of complex I (which does not trigger apparent AMPK activation), abrogates the AMPK-mediated ferroptosis-suppressive effect and sensitizes cancer cells to GPX4-inactivation-induced ferroptosis. Furthermore, complex I inhibition synergizes with radiotherapy (RT) to selectively suppress the growth of LKB1-deficient tumors by inducing ferroptosis in mouse models. Our data demonstrate a multifaceted role of complex I in regulating ferroptosis and propose a ferroptosis-inducing therapeutic strategy for LKB1-deficient cancers.
    Keywords:  AMPK; ETC complex I; LKB1; cancer therapy; ferroptosis; lipid peroxidation; mitochondria
    DOI:  https://doi.org/10.1016/j.molcel.2024.04.009
  15. bioRxiv. 2024 May 05. pii: 2024.05.04.592445. [Epub ahead of print]
    A metabolic atlas of mouse aging.
    Steven E Pilley, Dominik Awad, Djakim Latumalea, Edgar Esparza, Li Zhang, Xuanyi Shi, Maximilian Unfried, Shuo Wang, Racheal Mulondo, Sriraksha Bharadwaj Kashyap, Darius Moaddeli, Peter Sajjakulnukit, Damien Sutton, Harrison Wong, Aeowynn J Coakley, Gilberto Garcia, Ryo Higuchi-Sanabria, Sophia Liu, Bingfei Yu, William B Tu, Brian K Kennedy, Costas A Lyssiotis, Peter J Mullen.
      Humans are living longer, but this is accompanied by an increased incidence of age-related chronic diseases. Many of these diseases are influenced by age-associated metabolic dysregulation, but how metabolism changes in multiple organs during aging in males and females is not known. Answering this could reveal new mechanisms of aging and age-targeted therapeutics. In this study, we describe how metabolism changes in 12 organs in male and female mice at 5 different ages. Organs show distinct patterns of metabolic aging that are affected by sex differently. Hydroxyproline shows the most consistent change across the dataset, decreasing with age in 11 out of 12 organs investigated. We also developed a metabolic aging clock that predicts biological age and identified alpha-ketoglutarate, previously shown to extend lifespan in mice, as a key predictor of age. Our results reveal fundamental insights into the aging process and identify new therapeutic targets to maintain organ health.
    DOI:  https://doi.org/10.1101/2024.05.04.592445
  16. Mol Cell. 2024 May 16. pii: S1097-2765(24)00384-8. [Epub ahead of print]84(10): 1819-1821
    Cysteine substitutants emerge in lung cancer proteomes during arginine restriction.
    Dennis J Hsu, Sohail F Tavazoie.
      In this issue of Molecular Cell, Yang et al.1 find that arginine-to-cysteine substitutants are enriched in a subset of lung cancer proteomes, potentiated by arginine deprivation, and promote resistance to chemotherapy.
    DOI:  https://doi.org/10.1016/j.molcel.2024.04.019
  17. bioRxiv. 2024 Apr 29. pii: 2024.04.27.591477. [Epub ahead of print]
    NADPH composite index analysis quantifies the relationship between compartmentalized NADPH dynamics and growth rates in cancer cells.
    Sun Jin Moon, Anush Chiappino-Pepe, Wentao Dong, Joanne K Kelleher, Matthew Vander Heiden, Gregory Stephanopoulos, Hadley D Sikes.
      NADPH, a highly compartmentalized electron donor in mammalian cells, plays essential roles in cell metabolism. However, little is known about how cytosolic and mitochondrial NADPH dynamics relate to cancer cell growth rates in response to varying nutrient conditions. To address this issue, we present NADPH composite index analysis, which quantifies the relationship between compartmentalized NADPH dynamics and growth rates using genetically encoded NADPH sensors, automated image analysis pipeline, and correlation analysis. Through this analysis, we demonstrated that compartmentalized NADPH dynamics patterns were cancer cell-type dependent. Specifically, cytosolic and mitochondrial NADPH dynamics of MDA-MB-231 decreased in response to serine deprivation, while those of HCT-116 increased in response to serine or glutamine deprivation. Furthermore, by introducing a fractional contribution parameter, we correlated cytosolic and mitochondrial NADPH dynamics to growth rates. Using this parameter, we identified cancer cell lines whose growth rates were selectively inhibited by targeting cytosolic or mitochondrial NADPH metabolism. Mechanistically, we identified citrate transporter as a key mitochondrial transporter that maintains compartmentalized NADPH dynamics and growth rates. Altogether, our results present a significant advance in quantifying the relationship between compartmentalized NADPH dynamics and cancer cell growth rates, highlighting a potential of targeting compartmentalized NADPH metabolism for selective cancer cell growth inhibitions.
    DOI:  https://doi.org/10.1101/2024.04.27.591477
  18. Nat Immunol. 2024 May 14.
    The aged tumor microenvironment limits T cell control of cancer.
    Alex C Y Chen, Sneha Jaiswal, Daniela Martinez, Cansu Yerinde, Keely Ji, Velita Miranda, Megan E Fung, Sarah A Weiss, Maria Zschummel, Kazuhiro Taguchi, Christopher S Garris, Thorsten R Mempel, Nir Hacohen, Debattama R Sen.
      The etiology and effect of age-related immune dysfunction in cancer is not completely understood. Here we show that limited priming of CD8+ T cells in the aged tumor microenvironment (TME) outweighs cell-intrinsic defects in limiting tumor control. Increased tumor growth in aging is associated with reduced CD8+ T cell infiltration and function. Transfer of T cells from young mice does not restore tumor control in aged mice owing to rapid induction of T cell dysfunction. Cell-extrinsic signals in the aged TME drive a tumor-infiltrating age-associated dysfunctional (TTAD) cell state that is functionally, transcriptionally and epigenetically distinct from canonical T cell exhaustion. Altered natural killer cell-dendritic cell-CD8+ T cell cross-talk in aged tumors impairs T cell priming by conventional type 1 dendritic cells and promotes TTAD cell formation. Aged mice are thereby unable to benefit from therapeutic tumor vaccination. Critically, myeloid-targeted therapy to reinvigorate conventional type 1 dendritic cells can improve tumor control and restore CD8+ T cell immunity in aging.
    DOI:  https://doi.org/10.1038/s41590-024-01828-7
  19. Nature. 2024 May 14.
    Mega study charts how genetic variants affect metabolism.
      
    Keywords:  Genetics; Metabolism
    DOI:  https://doi.org/10.1038/d41586-024-00458-1
  20. Immunity. 2024 May 07. pii: S1074-7613(24)00221-8. [Epub ahead of print]
    The RIPK1 death domain restrains ZBP1- and TRIF-mediated cell death and inflammation.
    Takashi Imai, Juan Lin, Göksu Gökberk Kaya, Eunjin Ju, Vangelis Kondylis, Konstantinos Kelepouras, Gianmaria Liccardi, Chun Kim, Manolis Pasparakis.
      RIPK1 is a multi-functional kinase that regulates cell death and inflammation and has been implicated in the pathogenesis of inflammatory diseases. RIPK1 acts in a kinase-dependent and kinase-independent manner to promote or suppress apoptosis and necroptosis, but the underlying mechanisms remain poorly understood. Here, we show that a mutation (R588E) disrupting the RIPK1 death domain (DD) caused perinatal lethality induced by ZBP1-mediated necroptosis. Additionally, these mice developed postnatal inflammatory pathology, which was mediated by necroptosis-independent TNFR1, TRADD, and TRIF signaling, partially requiring RIPK3. Our biochemical mechanistic studies revealed that ZBP1- and TRIF-mediated activation of RIPK3 required RIPK1 kinase activity in wild-type cells but not in Ripk1R588E/R588E cells, suggesting that DD-dependent oligomerization of RIPK1 and its interaction with FADD determine the mechanisms of RIPK3 activation by ZBP1 and TRIF. Collectively, these findings revealed a critical physiological role of DD-dependent RIPK1 signaling that is important for the regulation of tissue homeostasis and inflammation.
    Keywords:  FADD; RIPK1; TNFR1; TRADD; TRIF; ZBP1; apoptosis; caspase-8; inflammation; necroptosis
    DOI:  https://doi.org/10.1016/j.immuni.2024.04.016
  21. Cell Chem Biol. 2024 May 16. pii: S2451-9456(24)00169-7. [Epub ahead of print]31(5): 932-943.e8
    One-carbon unit supplementation fuels purine synthesis in tumor-infiltrating T cells and augments checkpoint blockade.
    Xincheng Xu, Zihong Chen, Caroline R Bartman, Xi Xing, Kellen Olszewski, Joshua D Rabinowitz.
      Nucleotides perform important metabolic functions, carrying energy and feeding nucleic acid synthesis. Here, we use isotope tracing-mass spectrometry to quantitate contributions to purine nucleotides from salvage versus de novo synthesis. We further explore the impact of augmenting a key precursor for purine synthesis, one-carbon (1C) units. We show that tumors and tumor-infiltrating T cells (relative to splenic or lymph node T cells) synthesize purines de novo. Shortage of 1C units for T cell purine synthesis is accordingly a potential bottleneck for anti-tumor immunity. Supplementing 1C units by infusing formate drives formate assimilation into purines in tumor-infiltrating T cells. Orally administered methanol functions as a formate pro-drug, with deuteration enabling kinetic control of formate production. Safe doses of methanol raise formate levels and augment anti-PD-1 checkpoint blockade in MC38 tumors, tripling durable regressions. Thus, 1C deficiency can gate antitumor immunity and this metabolic checkpoint can be overcome with pharmacological 1C supplementation.
    DOI:  https://doi.org/10.1016/j.chembiol.2024.04.007
  22. Cell Rep. 2024 May 16. pii: S2211-1247(24)00546-1. [Epub ahead of print]43(5): 114218
    Metabolic regulation of single synaptic vesicle exo- and endocytosis in hippocampal synapses.
    Jongyun Myeong, Marion I Stunault, Vitaly A Klyachko, Ghazaleh Ashrafi.
      Glucose has long been considered a primary energy source for synaptic function. However, it remains unclear to what extent alternative fuels, such as lactate/pyruvate, contribute to powering synaptic transmission. By detecting individual release events in hippocampal synapses, we find that mitochondrial ATP production regulates basal vesicle release probability and release location within the active zone (AZ), evoked by single action potentials. Mitochondrial inhibition shifts vesicle release closer to the AZ center and alters the efficiency of vesicle retrieval by increasing the occurrence of ultrafast endocytosis. Furthermore, we uncover that terminals can use oxidative fuels to maintain the vesicle cycle during trains of activity. Mitochondria are sparsely distributed along hippocampal axons, and we find that terminals containing mitochondria display enhanced vesicle release and reuptake during high-frequency trains. Our findings suggest that mitochondria not only regulate several fundamental features of synaptic transmission but may also contribute to modulation of short-term synaptic plasticity.
    Keywords:  ATP; CP: Metabolism; CP: Neuroscience; glycolysis; hippocampal neuron; mitochondria; nerve terminal; synapse; synaptic transmission
    DOI:  https://doi.org/10.1016/j.celrep.2024.114218
  23. Nat Genet. 2024 May 14.
    Analysis of somatic mutations in whole blood from 200,618 individuals identifies pervasive positive selection and novel drivers of clonal hematopoiesis.
    Nicholas Bernstein, Michael Spencer Chapman, Kudzai Nyamondo, Zhenghao Chen, Nicholas Williams, Emily Mitchell, Peter J Campbell, Robert L Cohen, Jyoti Nangalia.
      Human aging is marked by the emergence of a tapestry of clonal expansions in dividing tissues, particularly evident in blood as clonal hematopoiesis (CH). CH, linked to cancer risk and aging-related phenotypes, often stems from somatic mutations in a set of established genes. However, the majority of clones lack known drivers. Here we infer gene-level positive selection in whole blood exomes from 200,618 individuals in UK Biobank. We identify 17 additional genes, ZBTB33, ZNF318, ZNF234, SPRED2, SH2B3, SRCAP, SIK3, SRSF1, CHEK2, CCDC115, CCL22, BAX, YLPM1, MYD88, MTA2, MAGEC3 and IGLL5, under positive selection at a population level, and validate this selection pattern in 10,837 whole genomes from single-cell-derived hematopoietic colonies. Clones with mutations in these genes grow in frequency and size with age, comparable to classical CH drivers. They correlate with heightened risk of infection, death and hematological malignancy, highlighting the significance of these additional genes in the aging process.
    DOI:  https://doi.org/10.1038/s41588-024-01755-1
  24. Immunity. 2024 May 14. pii: S1074-7613(24)00140-7. [Epub ahead of print]57(5): 941-956
    Ironing out the role of ferroptosis in immunity.
    Hannah N Bell, Brent R Stockwell, Weiping Zou.
      Ferroptosis is a type of regulated cell death that drives the pathophysiology of many diseases. Oxidative stress is detectable in many types of regulated cell death, but only ferroptosis involves lipid peroxidation and iron dependency. Ferroptosis originates and propagates from several organelles, including the mitochondria, endoplasmic reticulum, Golgi, and lysosomes. Recent data have revealed that immune cells can both induce and undergo ferroptosis. A mechanistic understanding of how ferroptosis regulates immunity is critical to understanding how ferroptosis controls immune responses and how this is dysregulated in disease. Translationally, more work is needed to produce ferroptosis-modulating immunotherapeutics. This review focuses on the role of ferroptosis in immune-related diseases, including infection, autoimmune diseases, and cancer. We discuss how ferroptosis is regulated in immunity, how this regulation contributes to disease pathogenesis, and how targeting ferroptosis may lead to novel therapies.
    Keywords:  ACSL4; FSP1; SLC7A11; T cell; apoptosis; cancer therapy; ferroptosis; glutathione; immune checkpoint blockade; interferon; pyroptosis; system xc(-)
    DOI:  https://doi.org/10.1016/j.immuni.2024.03.019
  25. Nat Commun. 2024 May 17. 15(1): 4214
    Liver ACOX1 regulates levels of circulating lipids that promote metabolic health through adipose remodeling.
    Dongliang Lu, Anyuan He, Min Tan, Marguerite Mrad, Amal El Daibani, Donghua Hu, Xuejing Liu, Brian Kleiboeker, Tao Che, Fong-Fu Hsu, Monika Bambouskova, Clay F Semenkovich, Irfan J Lodhi.
      The liver gene expression of the peroxisomal β-oxidation enzyme acyl-coenzyme A oxidase 1 (ACOX1), which catabolizes very long chain fatty acids (VLCFA), increases in the context of obesity, but how this pathway impacts systemic energy metabolism remains unknown. Here, we show that hepatic ACOX1-mediated β-oxidation regulates inter-organ communication involved in metabolic homeostasis. Liver-specific knockout of Acox1 (Acox1-LKO) protects mice from diet-induced obesity, adipose tissue inflammation, and systemic insulin resistance. Serum from Acox1-LKO mice promotes browning in cultured white adipocytes. Global serum lipidomics show increased circulating levels of several species of ω-3 VLCFAs (C24-C28) with previously uncharacterized physiological role that promote browning, mitochondrial biogenesis and Glut4 translocation through activation of the lipid sensor GPR120 in adipocytes. This work identifies hepatic peroxisomal β-oxidation as an important regulator of metabolic homeostasis and suggests that manipulation of ACOX1 or its substrates may treat obesity-associated metabolic disorders.
    DOI:  https://doi.org/10.1038/s41467-024-48471-2
  26. Cell. 2024 May 09. pii: S0092-8674(24)00451-3. [Epub ahead of print]
    ARID1A suppresses R-loop-mediated STING-type I interferon pathway activation of anti-tumor immunity.
    Matthew B Maxwell, Marianne S Hom-Tedla, Jawoon Yi, Shitian Li, Samuel A Rivera, Jingting Yu, Mannix J Burns, Helen M McRae, Braden T Stevenson, Katherine E Coakley, Josephine Ho, Kameneff Bojorquez Gastelum, Joshua C Bell, Alexander C Jones, Ramez N Eskander, Emily C Dykhuizen, Gerald S Shadel, Susan M Kaech, Diana C Hargreaves.
      Clinical trials have identified ARID1A mutations as enriched among patients who respond favorably to immune checkpoint blockade (ICB) in several solid tumor types independent of microsatellite instability. We show that ARID1A loss in murine models is sufficient to induce anti-tumor immune phenotypes observed in ARID1A mutant human cancers, including increased CD8+ T cell infiltration and cytolytic activity. ARID1A-deficient cancers upregulated an interferon (IFN) gene expression signature, the ARID1A-IFN signature, associated with increased R-loops and cytosolic single-stranded DNA (ssDNA). Overexpression of the R-loop resolving enzyme, RNASEH2B, or cytosolic DNase, TREX1, in ARID1A-deficient cells prevented cytosolic ssDNA accumulation and ARID1A-IFN gene upregulation. Further, the ARID1A-IFN signature and anti-tumor immunity were driven by STING-dependent type I IFN signaling, which was required for improved responsiveness of ARID1A mutant tumors to ICB treatment. These findings define a molecular mechanism underlying anti-tumor immunity in ARID1A mutant cancers.
    Keywords:  ARID1A; R-loops; STING; SWI/SNF complex; anti-tumor immunity; cancer immunotherapy; cytosolic DNA; type I IFN
    DOI:  https://doi.org/10.1016/j.cell.2024.04.025
  27. J Clin Invest. 2024 May 14. pii: e174500. [Epub ahead of print]
    Arteriovenous metabolomics in pigs reveals CFTR regulation ofmetabolism inmultiple organs.
    Hosung Bae, Bo Ram Kim, Sunhee Jung, Johnny Le, Dana M van der Heide, Wenjie Yu, Sang Hee Park, Brieanna M Hilkin, Nicholas D Gansemer, Linda S Powers, Taekyung Kang, David K Meyerholz, Victor L Schuster, Cholsoon Jang, Michael J Welsh.
      Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene cause cystic fibrosis (CF), a multiorgan disease that exhibits diverse metabolic defects. However, other than specific CFTR mutations, the factors that influence disease progression and severity remain poorly understood. Aberrant metabolite levels have been reported, but whether CFTR loss itself or secondary abnormalities (infection, inflammation, malnutrition, and various treatments) drive metabolic defects are uncertain. Here, we implemented comprehensive arteriovenous metabolomics in newborn CF pigs, and the results revealed CFTR as a bona fide regulator of metabolism. CFTR loss impaired metabolite exchange across organs, including disrupted lung uptake of fatty acids yet enhanced uptake of arachidonic acid, a precursor of pro-inflammatory cytokines. CFTR loss also impaired kidney reabsorption of amino acids and lactate and abolished renal glucose homeostasis. These and additional unexpected metabolic defects prior to disease manifestations reveal a fundamental role for CFTR in controlling multi-organ metabolism. Such discovery informs a basic understanding of CF, provides a foundation for future investigation, and has implications for developing therapies targeting only a single tissue.
    Keywords:  Amino acid metabolism; Ion channels; Metabolism; Monogenic diseases
    DOI:  https://doi.org/10.1172/JCI174500
  28. Nat Commun. 2024 May 15. 15(1): 4096
    Octyl itaconate enhances VSVΔ51 oncolytic virotherapy by multitarget inhibition of antiviral and inflammatory pathways.
    Naziia Kurmasheva, Aida Said, Boaz Wong, Priscilla Kinderman, Xiaoying Han, Anna H F Rahimic, Alena Kress, Madalina E Carter-Timofte, Emilia Holm, Demi van der Horst, Christoph F Kollmann, Zhenlong Liu, Chen Wang, Huy-Dung Hoang, Elina Kovalenko, Maria Chrysopoulou, Krishna Sundar Twayana, Rasmus N Ottosen, Esben B Svenningsen, Fabio Begnini, Anders E Kiib, Florian E H Kromm, Hauke J Weiss, Daniele Di Carlo, Michela Muscolini, Maureen Higgins, Mirte van der Heijden, Angelina Bardoul, Tong Tong, Attila Ozsvar, Wen-Hsien Hou, Vivien R Schack, Christian K Holm, Yunan Zheng, Melanie Ruzek, Joanna Kalucka, Laureano de la Vega, Walid A M Elgaher, Anders R Korshoej, Rongtuan Lin, John Hiscott, Thomas B Poulsen, Luke A O'Neill, Dominic G Roy, Markus M Rinschen, Nadine van Montfoort, Jean-Simon Diallo, Henner F Farin, Tommy Alain, David Olagnier.
      The presence of heterogeneity in responses to oncolytic virotherapy poses a barrier to clinical effectiveness, as resistance to this treatment can occur through the inhibition of viral spread within the tumor, potentially leading to treatment failures. Here we show that 4-octyl itaconate (4-OI), a chemical derivative of the Krebs cycle-derived metabolite itaconate, enhances oncolytic virotherapy with VSVΔ51 in various models including human and murine resistant cancer cell lines, three-dimensional (3D) patient-derived colon tumoroids and organotypic brain tumor slices. Furthermore, 4-OI in combination with VSVΔ51 improves therapeutic outcomes in a resistant murine colon tumor model. Mechanistically, we find that 4-OI suppresses antiviral immunity in cancer cells through the modification of cysteine residues in MAVS and IKKβ independently of the NRF2/KEAP1 axis. We propose that the combination of a metabolite-derived drug with an oncolytic virus agent can greatly improve anticancer therapeutic outcomes by direct interference with the type I IFN and NF-κB-mediated antiviral responses.
    DOI:  https://doi.org/10.1038/s41467-024-48422-x
  29. Nucleosides Nucleotides Nucleic Acids. 2024 May 14. 1-15
    The emerging roles of glutamine amidotransferases in metabolism and immune defense.
    Taolin Xie, Chao Qin, Ali Can Savas, Wayne Wei Yeh, Pinghui Feng.
      Glutamine amidotransferases (GATs) catalyze the synthesis of nucleotides, amino acids, glycoproteins and an enzyme cofactor, thus serving as key metabolic enzymes for cell proliferation. Carbamoyl-phosphate synthetase, Aspartate transcarbamoylase, and Dihydroorotase (CAD) is a multifunctional enzyme of the GAT family and catalyzes the first three steps of the de novo pyrimidine synthesis. Following our findings that cellular GATs are involved in immune evasion during herpesvirus infection, we discovered that CAD reprograms cellular metabolism to fuel aerobic glycolysis and nucleotide synthesis via deamidating RelA. Deamidated RelA activates the expression of key glycolytic enzymes, rather than that of the inflammatory NF-κB-responsive genes. As such, cancer cells prime RelA for deamidation via up-regulating CAD activity or accumulating RelA mutations. Interestingly, the recently emerged SARS-CoV-2 also activates CAD to couple evasion of inflammatory response to activated nucleotide synthesis. A small molecule inhibitor of CAD depletes nucleotide supply and boosts antiviral inflammatory response, thus greatly reducing SARS-CoV-2 replication. Additionally, we also found that CTP synthase 1 (CTPS1) deamidates interferon (IFN) regulatory factor 3 (IRF3) to mute IFN induction. Our previous studies have implicated phosphoribosyl formylglycinamidine synthase (PFAS) and phosphoribosyl pyrophosphate amidotransferase (PPAT) in deamidating retinoic acid-inducible gene I (RIG-I) and evading dsRNA-induced innate immune defense in herpesvirus infection. Overall, these studies have uncovered an unconventional enzymatic activity of cellular GATs in metabolism and immune defense, offering a molecular link intimately coupling these fundamental biological processes.
    Keywords:  Glutamine amidotransferase; innate immunity; nucleotide synthesis; protein deamidation; tumor metabolism; viral infection
    DOI:  https://doi.org/10.1080/15257770.2024.2351135
  30. iScience. 2024 May 17. 27(5): 109767
    Glutamine promotes human CD8+ T cells and counteracts imiquimod-induced T cell hyporesponsiveness.
    Luisa Bopp, Maria Lopéz Martinez, Clara Schumacher, Robert Seitz, Manuel Huerta Arana, Henning Klapproth, Dominika Lukas, Ju Hee Oh, Daniela Neumayer, Jan W Lackmann, Stefan Mueller, Esther von Stebut, Bent Brachvogel, Susanne Brodesser, Ramon I Klein Geltink, Mario Fabri.
      T cells protect tissues from cancer. Although investigations in mice showed that amino acids (AA) critically regulate T cell immunity, this remains poorly understood in humans. Here, we describe the AA composition of interstitial fluids in keratinocyte-derived skin cancers (KDSCs) and study the effect of AA on T cells using models of primary human cells and tissues. Gln contributed to ∼15% of interstitial AAs and promoted interferon gamma (IFN-γ), but not granzyme B (GzB) expression, in CD8+ T cells. Furthermore, the Toll-like receptor 7 agonist imiquimod (IMQ), a common treatment for KDSCs, down-regulated the metabolic gatekeepers c-MYC and mTORC1, as well as the AA transporter ASCT2 and intracellular Gln, Asn, Ala, and Asp in T cells. Reduced proliferation and IFN-γ expression, yet increased GzB, paralleled IMQ effects on AA. Finally, Gln was sufficient to promote IFN-γ-production in IMQ-treated T cells. Our findings indicate that Gln metabolism can be harnessed for treating KDSCs.
    Keywords:  Dermatology; Immunology
    DOI:  https://doi.org/10.1016/j.isci.2024.109767
  31. J Clin Invest. 2024 May 14. pii: e171294. [Epub ahead of print]
    L-2-hydroxyglutarate remodeling of the epigenome and epitranscriptome creates a metabolic vulnerability in kidney cancer models.
    Anirban Kundu, Garrett J Brinkley, Hyeyoung Nam, Suman Karki, Richard Kirkman, Madhuparna Pandit, EunHee Shim, Hayley Widden, Juan Liu, Yasaman Heidarian, Nader H Mahmoudzadeh, Alexander J Fitt, Devin Absher, Han-Fei Ding, David K Crossman, William J Placzek, Jason W Locasale, Dinesh Rakheja, Jonathan E McConathy, Rekha Ramachandran, Sejong Bae, Jason M Tennessen, Sunil Sudarshan.
      Tumor cells are known to undergo considerable metabolic reprogramming to meet their unique demands and drive tumor growth. At the same time, this reprogramming may come at a cost with resultant metabolic vulnerabilities. The small molecule L-2-hdroxyglutarate (L-2HG) is elevated in the most common histology of renal cancer. Similar to other oncometabolites, L-2HG has the potential to profoundly impact gene expression. Here, we demonstrate that L-2HG remodels amino acid metabolism in renal cancer cells through the combined effects on histone methylation and RNA N6-methyladenosine (m6A). The combined effects of L-2HG result in a metabolic liability that renders tumors cells reliant on exogenous serine to support proliferation, redox homeostasis, and tumor growth. In concert with these data, high L-2HG kidney cancers demonstrates reduced expression of multiple serine biosynthetic enzymes. Collectively, our data indicate that high L-2HG renal tumors could be specifically targeted by strategies that limit serine availability to tumors.
    Keywords:  Metabolism; Oncology; Urology
    DOI:  https://doi.org/10.1172/JCI171294
  32. Int J Mol Sci. 2024 May 06. pii: 5044. [Epub ahead of print]25(9):
    Emerging Roles of Vitamin B12 in Aging and Inflammation.
    Sergey Yu Simonenko, Daria A Bogdanova, Nikita A Kuldyushev.
      Vitamin B12 (cobalamin) is an essential nutrient for humans and animals. Metabolically active forms of B12-methylcobalamin and 5-deoxyadenosylcobalamin are cofactors for the enzymes methionine synthase and mitochondrial methylmalonyl-CoA mutase. Malfunction of these enzymes due to a scarcity of vitamin B12 leads to disturbance of one-carbon metabolism and impaired mitochondrial function. A significant fraction of the population (up to 20%) is deficient in vitamin B12, with a higher rate of deficiency among elderly people. B12 deficiency is associated with numerous hallmarks of aging at the cellular and organismal levels. Cellular senescence is characterized by high levels of DNA damage by metabolic abnormalities, increased mitochondrial dysfunction, and disturbance of epigenetic regulation. B12 deficiency could be responsible for or play a crucial part in these disorders. In this review, we focus on a comprehensive analysis of molecular mechanisms through which vitamin B12 influences aging. We review new data about how deficiency in vitamin B12 may accelerate cellular aging. Despite indications that vitamin B12 has an important role in health and healthy aging, knowledge of the influence of vitamin B12 on aging is still limited and requires further research.
    Keywords:  aging; cobalamin; inflammation; protein modifications; senescence; vitamin B12
    DOI:  https://doi.org/10.3390/ijms25095044
  33. Nat Aging. 2024 May 15.
    The killifish germline regulates longevity and somatic repair in a sex-specific manner.
    Eitan Moses, Tehila Atlan, Xue Sun, Roman Franěk, Atif Siddiqui, Georgi K Marinov, Sagiv Shifman, David M Zucker, Adi Oron-Gottesman, William J Greenleaf, Ehud Cohen, Oren Ram, Itamar Harel.
      Classical evolutionary theories propose tradeoffs among reproduction, damage repair and lifespan. However, the specific role of the germline in shaping vertebrate aging remains largely unknown. In this study, we used the turquoise killifish (Nothobranchius furzeri) to genetically arrest germline development at discrete stages and examine how different modes of infertility impact life history. We first constructed a comprehensive single-cell gonadal atlas, providing cell-type-specific markers for downstream phenotypic analysis. We show here that germline depletion-but not arresting germline differentiation-enhances damage repair in female killifish. Conversely, germline-depleted males instead showed an extension in lifespan and rejuvenated metabolic functions. Through further transcriptomic analysis, we highlight enrichment of pro-longevity pathways and genes in germline-depleted male killifish and demonstrate functional conservation of how these factors may regulate longevity in germline-depleted Caenorhabditis elegans. Our results, therefore, demonstrate that different germline manipulation paradigms can yield pronounced sexually dimorphic phenotypes, implying alternative responses to classical evolutionary tradeoffs.
    DOI:  https://doi.org/10.1038/s43587-024-00632-0
  34. Cell Rep. 2024 May 10. pii: S2211-1247(24)00537-0. [Epub ahead of print] 114209
    Identification of the extracellular membrane protein ENPP3 as a major cGAMP hydrolase and innate immune checkpoint.
    Rachel Mardjuki, Songnan Wang, Jacqueline Carozza, Bahar Zirak, Vishvak Subramanyam, Gita Abhiraman, Xuchao Lyu, Hani Goodarzi, Lingyin Li.
      2'3'-Cyclic guanosine monophosphate (GMP)-AMP (cGAMP) is a second messenger synthesized upon detection of cytosolic double-stranded DNA (dsDNA) and passed between cells to facilitate downstream immune signaling. Ectonucleotide pyrophosphatase phosphodiesterase I (ENPP1), an extracellular enzyme, was the only metazoan hydrolase known to regulate cGAMP levels to dampen anti-cancer immunity. Here, we uncover ENPP3 as the second and likely the only other metazoan cGAMP hydrolase under homeostatic conditions. ENPP3 has a tissue expression pattern distinct from ENPP1's and accounts for all cGAMP hydrolysis activity in ENPP1-deficient mice. Importantly, we also show that, as with ENPP1, selectively abolishing ENPP3's cGAMP hydrolysis activity results in diminished cancer growth and metastasis of certain tumor types in a stimulator of interferon genes (STING)-dependent manner. Both ENPP1 and ENPP3 are extracellular enzymes, suggesting the dominant role that extracellular cGAMP must play as a mediator of cell-cell innate immune communication. Our work demonstrates that ENPP1 and ENPP3 non-redundantly dampen extracellular cGAMP-STING signaling, pointing to ENPP3 as a target for cancer immunotherapy.
    Keywords:  CP: Immunology; ENPP1; ENPP3; PD-1; STING; breast cancer; cGAMP; clinical trial; hydrolase; immune checkpoint; melanoma
    DOI:  https://doi.org/10.1016/j.celrep.2024.114209
  35. iScience. 2024 May 17. 27(5): 109789
    SIN-3 transcriptional coregulator maintains mitochondrial homeostasis and polyamine flux.
    Giovannetti Marina, Rodríguez-Palero María-Jesús, Fabrizio Paola, Nicolle Ophélie, Bedet Cécile, Michaux Grégoire, Witting Michael, Artal-Sanz Marta, Palladino Francesca.
      Mitochondrial function relies on the coordinated transcription of mitochondrial and nuclear genomes to assemble respiratory chain complexes. Across species, the SIN3 coregulator influences mitochondrial functions, but how its loss impacts mitochondrial homeostasis and metabolism in the context of a whole organism is unknown. Exploring this link is important because SIN3 haploinsufficiency causes intellectual disability/autism syndromes and SIN3 plays a role in tumor biology. Here we show that loss of C. elegans SIN-3 results in transcriptional deregulation of mitochondrial- and nuclear-encoded mitochondrial genes, potentially leading to mito-nuclear imbalance. Consistent with impaired mitochondrial function, sin-3 mutants show extensive mitochondrial fragmentation by transmission electron microscopy (TEM) and in vivo imaging, and altered oxygen consumption. Metabolomic analysis of sin-3 mutant animals revealed a mitochondria stress signature and deregulation of methionine flux, resulting in decreased S-adenosyl methionine (SAM) and increased polyamine levels. Our results identify SIN3 as a key regulator of mitochondrial dynamics and metabolic flux, with important implications for human pathologies.
    Keywords:  Cell biology; Omics; Systems biology
    DOI:  https://doi.org/10.1016/j.isci.2024.109789
  36. Nat Commun. 2024 May 13. 15(1): 3818
    A cell-free nutrient-supplemented perfusate allows four-day ex vivo metabolic preservation of human kidneys.
    Marlon J A de Haan, Marleen E Jacobs, Franca M R Witjas, Annemarie M A de Graaf, Elena Sánchez-López, Sarantos Kostidis, Martin Giera, Francisco Calderon Novoa, Tunpang Chu, Markus Selzner, Mehdi Maanaoui, Dorottya K de Vries, Jesper Kers, Ian P J Alwayn, Cees van Kooten, Bram Heijs, Gangqi Wang, Marten A Engelse, Ton J Rabelink.
      The growing disparity between the demand for transplants and the available donor supply, coupled with an aging donor population and increasing prevalence of chronic diseases, highlights the urgent need for the development of platforms enabling reconditioning, repair, and regeneration of deceased donor organs. This necessitates the ability to preserve metabolically active kidneys ex vivo for days. However, current kidney normothermic machine perfusion (NMP) approaches allow metabolic preservation only for hours. Here we show that human kidneys discarded for transplantation can be preserved in a metabolically active state up to 4 days when perfused with a cell-free perfusate supplemented with TCA cycle intermediates at subnormothermia (25 °C). Using spatially resolved isotope tracing we demonstrate preserved metabolic fluxes in the kidney microenvironment up to Day 4 of perfusion. Beyond Day 4, significant changes were observed in renal cell populations through spatial lipidomics, and increases in injury markers such as LDH, NGAL and oxidized lipids. Finally, we demonstrate that perfused kidneys maintain functional parameters up to Day 4. Collectively, these findings provide evidence that this approach enables metabolic and functional preservation of human kidneys over multiple days, establishing a solid foundation for future clinical investigations.
    DOI:  https://doi.org/10.1038/s41467-024-47106-w
  37. Sci Adv. 2024 May 17. 10(20): eadj5428
    N-MYC impairs innate immune signaling in high-grade serous ovarian carcinoma.
    Alex Miranda, Swetansu Pattnaik, Phineas T Hamilton, Monica Alvaro Fuss, Shreena Kalaria, Céline M Laumont, Julian Smazynski, Monica Mesa, Allyson Banville, Xinpei Jiang, Russell Jenkins, Israel Cañadas, Brad H Nelson.
      High-grade serous ovarian cancer (HGSC) is a challenging disease, especially for patients with immunologically "cold" tumors devoid of tumor-infiltrating lymphocytes (TILs). We found that HGSC exhibits among the highest levels of MYCN expression and transcriptional signature across human cancers, which is strongly linked to diminished features of antitumor immunity. N-MYC repressed basal and induced IFN type I signaling in HGSC cell lines, leading to decreased chemokine expression and T cell chemoattraction. N-MYC inhibited the induction of IFN type I by suppressing tumor cell-intrinsic STING signaling via reduced STING oligomerization, and by blunting RIG-I-like receptor signaling through inhibition of MAVS aggregation and localization in the mitochondria. Single-cell RNA sequencing of human clinical HGSC samples revealed a strong negative association between cancer cell-intrinsic MYCN transcriptional program and type I IFN signaling. Thus, N-MYC inhibits tumor cell-intrinsic innate immune signaling in HGSC, making it a compelling target for immunotherapy of cold tumors.
    DOI:  https://doi.org/10.1126/sciadv.adj5428
  38. Nat Commun. 2024 May 14. 15(1): 4061
    Transcription stress at telomeres leads to cytosolic DNA release and paracrine senescence.
    Athanasios Siametis, Kalliopi Stratigi, Despoina Giamaki, Georgia Chatzinikolaou, Alexia Akalestou-Clocher, Evi Goulielmaki, Brian Luke, Björn Schumacher, George A Garinis.
      Transcription stress has been linked to DNA damage -driven aging, yet the underlying mechanism remains unclear. Here, we demonstrate that Tcea1-/- cells, which harbor a TFIIS defect in transcription elongation, exhibit RNAPII stalling at oxidative DNA damage sites, impaired transcription, accumulation of R-loops, telomere uncapping, chromatin bridges, and genome instability, ultimately resulting in cellular senescence. We found that R-loops at telomeres causally contribute to the release of telomeric DNA fragments in the cytoplasm of Tcea1-/- cells and primary cells derived from naturally aged animals triggering a viral-like immune response. TFIIS-defective cells release extracellular vesicles laden with telomeric DNA fragments that target neighboring cells, which consequently undergo cellular senescence. Thus, transcription stress elicits paracrine signals leading to cellular senescence, promoting aging.
    DOI:  https://doi.org/10.1038/s41467-024-48443-6
  39. Nature. 2024 May;629(8012): 543-554
    Decoding the interplay between genetic and non-genetic drivers of metastasis.
    Panagiotis Karras, James R M Black, Nicholas McGranahan, Jean-Christophe Marine.
      Metastasis is a multistep process by which cancer cells break away from their original location and spread to distant organs, and is responsible for the vast majority of cancer-related deaths. Preventing early metastatic dissemination would revolutionize the ability to fight cancer. Unfortunately, the relatively poor understanding of the molecular underpinnings of metastasis has hampered the development of effective anti-metastatic drugs. Although it is now accepted that disseminating tumour cells need to acquire multiple competencies to face the many obstacles they encounter before reaching their metastatic site(s), whether these competencies are acquired through an accumulation of metastasis-specific genetic alterations and/or non-genetic events is often debated. Here we review a growing body of literature highlighting the importance of both genetic and non-genetic reprogramming events during the metastatic cascade, and discuss how genetic and non-genetic processes act in concert to confer metastatic competencies. We also describe how recent technological advances, and in particular the advent of single-cell multi-omics and barcoding approaches, will help to better elucidate the cross-talk between genetic and non-genetic mechanisms of metastasis and ultimately inform innovative paths for the early detection and interception of this lethal process.
    DOI:  https://doi.org/10.1038/s41586-024-07302-6
  40. Elife. 2024 May 13. pii: RP92236. [Epub ahead of print]12
    mTORC1/S6K1 signaling promotes sustained oncogenic translation through modulating CRL3IBTK-mediated ubiquitination of eIF4A1 in cancer cells.
    Dongyue Jiao, Huiru Sun, Xiaying Zhao, Yingji Chen, Zeheng Lv, Qing Shi, Yao Li, Chenji Wang, Kun Gao.
      Enhanced protein synthesis is a crucial molecular mechanism that allows cancer cells to survive, proliferate, metastasize, and develop resistance to anti-cancer treatments, and often arises as a consequence of increased signaling flux channeled to mRNA-bearing eukaryotic initiation factor 4F (eIF4F). However, the post-translational regulation of eIF4A1, an ATP-dependent RNA helicase and subunit of the eIF4F complex, is still poorly understood. Here, we demonstrate that IBTK, a substrate-binding adaptor of the Cullin 3-RING ubiquitin ligase (CRL3) complex, interacts with eIF4A1. The non-degradative ubiquitination of eIF4A1 catalyzed by the CRL3IBTK complex promotes cap-dependent translational initiation, nascent protein synthesis, oncogene expression, and cervical tumor cell growth both in vivo and in vitro. Moreover, we show that mTORC1 and S6K1, two key regulators of protein synthesis, directly phosphorylate IBTK to augment eIF4A1 ubiquitination and sustained oncogenic translation. This link between the CRL3IBTK complex and the mTORC1/S6K1 signaling pathway, which is frequently dysregulated in cancer, represents a promising target for anti-cancer therapies.
    Keywords:  cancer biology; cell biology; human; mTORC1/S6K1 signaling; phosphorylation; translation; tumorigenesis; ubiquitination
    DOI:  https://doi.org/10.7554/eLife.92236
  41. NPJ Metab Health Dis. 2024 ;pii: 2. [Epub ahead of print]2
    PGC-1α integrates insulin signaling with mitochondrial physiology and behavior in a Drosophila model of Fragile X Syndrome.
    Eliana D Weisz, Adam R Fenton, Thomas A Jongens.
      Fragile X Syndrome (FXS) is the most prevalent monogenetic form of intellectual disability and autism. Recently, dysregulation of insulin signaling (IS) and aberrations in mitochondrial function have emerged as robust, evolutionarily conserved components of FXS pathophysiology. However, the mechanisms by which altered IS and mitochondrial dysfunction impact behavior in the context of FXS remain elusive. Here, we show that normalization of IS improves mitochondrial volume and function in flies that lack expression of dfmr1, the Drosophila homolog of the causal gene of FXS in humans. Further, we demonstrate that dysregulation of IS underlies diminished expression of the mitochondrial master regulator PGC-1α/Spargel in dfmr1 mutant flies. These results are behaviorally relevant, as we show that pan-neuronal augmentation of PGC-1α/Spargel improves circadian behavior in dfmr1 mutants. Notably, we also show that modulation of PGC-1α/Spargel expression in wild-type flies phenocopies the dfmr1 mutant circadian defect. Taken together, the results presented herein provide a mechanistic link between mitochondrial function and circadian behavior both in FXS pathogenesis as well as more broadly at the interface between metabolism and behavioral output.
    DOI:  https://doi.org/10.1038/s44324-024-00004-7
  42. Mol Biol Cell. 2024 May 17. mbcE23040139
    Matrix stiffening promotes perinuclear clustering of mitochondria.
    Piyush Daga, Basil Thurakkal, Simran Rawal, Tamal Das.
      Mechanical cues from the tissue microenvironment, such as the stiffness of the extracellular matrix, modulate cellular forms and functions. As numerous studies have shown, this modulation depends on the stiffness-dependent remodeling of cytoskeletal elements. In contrast, very little is known about how the intracellular organelles such as mitochondria respond to matrix stiffness and whether their form, function, and localization change accordingly. Here, we performed an extensive quantitative characterization of mitochondrial morphology, subcellular localization, dynamics, and membrane tension on soft and stiff matrices. This characterization revealed that while matrix stiffness affected all these aspects, matrix stiffening most distinctively led to an increased perinuclear clustering of mitochondria. Subsequently, we could identify the matrix stiffness-sensitive perinuclear localization of filamin as the key factor dictating this perinuclear clustering. The perinuclear and peripheral mitochondrial populations differed in their motility on soft matrix but surprisingly they did not show any difference on stiff matrix. Finally, perinuclear mitochondrial clustering appeared to be crucial for the nuclear localization of RUNX2 and hence for priming human mesenchymal stem cells towards osteogenesis on a stiff matrix. Taken together, we elucidate a dependence of mitochondrial localization on matrix stiffness, which possibly enables a cell to adapt to its microenvironment. [Media: see text] [Media: see text] [Media: see text] [Media: see text].
    DOI:  https://doi.org/10.1091/mbc.E23-04-0139
  43. Nat Rev Gastroenterol Hepatol. 2024 May 13.
    Mitochondrial function and gastrointestinal diseases.
    Parsa S Haque, Neeraj Kapur, Terrence A Barrett, Arianne L Theiss.
      Mitochondria are dynamic organelles that function in cellular energy metabolism, intracellular and extracellular signalling, cellular fate and stress responses. Mitochondria of the intestinal epithelium, the cellular interface between self and enteric microbiota, have emerged as crucial in intestinal health. Mitochondrial dysfunction occurs in gastrointestinal diseases, including inflammatory bowel diseases and colorectal cancer. In this Review, we provide an overview of the current understanding of intestinal epithelial cell mitochondrial metabolism, function and signalling to affect tissue homeostasis, including gut microbiota composition. We also discuss mitochondrial-targeted therapeutics for inflammatory bowel diseases and colorectal cancer and the evolving concept of mitochondrial impairment as a consequence versus initiator of the disease.
    DOI:  https://doi.org/10.1038/s41575-024-00931-2
  44. J Microsc. 2024 May 13.
    Core facilities coming of age.
    Sebastian Munck, Kurt I Anderson.
      
    DOI:  https://doi.org/10.1111/jmi.13319
  45. J Cell Sci. 2024 May 01. pii: jcs259775. [Epub ahead of print]137(9):
    Mammalian pexophagy at a glance.
    Justyna Bajdzienko, Anja Bremm.
      Peroxisomes are highly plastic organelles that are involved in several metabolic processes, including fatty acid oxidation, ether lipid synthesis and redox homeostasis. Their abundance and activity are dynamically regulated in response to nutrient availability and cellular stress. Damaged or superfluous peroxisomes are removed mainly by pexophagy, the selective autophagy of peroxisomes induced by ubiquitylation of peroxisomal membrane proteins or ubiquitin-independent processes. Dysregulated pexophagy impairs peroxisome homeostasis and has been linked to the development of various human diseases. Despite many recent insights into mammalian pexophagy, our understanding of this process is still limited compared to our understanding of pexophagy in yeast. In this Cell Science at a Glance article and the accompanying poster, we summarize current knowledge on the control of mammalian pexophagy and highlight which aspects require further attention. We also discuss the role of ubiquitylation in pexophagy and describe the ubiquitin machinery involved in regulating signals for the recruitment of phagophores to peroxisomes.
    Keywords:  Peroxisome; Pexophagy; Selective autophagy; Ubiquitylation
    DOI:  https://doi.org/10.1242/jcs.259775
  46. bioRxiv. 2024 May 03. pii: 2024.04.30.591900. [Epub ahead of print]
    Non-hypermutator cancers access driver mutations through reversals in germline mutational bias.
    Marwa Z Tuffaha, David Castellano, Claudia Serrano Colome, Ryan N Gutenkunst, Lindi M Wahl.
      Cancer is an evolutionary disease driven by mutations in asexually-reproducing somatic cells. In asexual microbes, bias reversals in the mutation spectrum can speed adaptation by increasing access to previously undersampled beneficial mutations. By analyzing tumors from 20 tissues, along with normal tissue and the germline, we demonstrate this effect in cancer. Non-hypermutated tumors reverse the germline mutation bias and have consistent spectra across tissues. These spectra changes carry the signature of hypoxia, and they facilitate positive selection in cancer genes. Hypermutated and non-hypermutated tumors thus acquire driver mutations differently: hypermutated tumors by higher mutation rates and non-hypermutated tumors by changing the mutation spectrum to reverse the germline mutation bias.
    DOI:  https://doi.org/10.1101/2024.04.30.591900
  47. Aging Cell. 2024 May 16. e14165
    The integrated stress response promotes neural stem cell survival under conditions of mitochondrial dysfunction in neurodegeneration.
    Mohamed Ariff Iqbal, Maria Bilen, Yubing Liu, Vanessa Jabre, Bensun C Fong, Imane Chakroun, Smitha Paul, Jingwei Chen, Steven Wade, Michel Kanaan, Mary-Ellen Harper, Mireille Khacho, Ruth S Slack.
      Impaired mitochondrial function is a hallmark of aging and a major contributor to neurodegenerative diseases. We have shown that disrupted mitochondrial dynamics typically found in aging alters the fate of neural stem cells (NSCs) leading to impairments in learning and memory. At present, little is known regarding the mechanisms by which neural stem and progenitor cells survive and adapt to mitochondrial dysfunction. Using Opa1-inducible knockout as a model of aging and neurodegeneration, we identify a decline in neurogenesis due to impaired stem cell activation and progenitor proliferation, which can be rescued by the mitigation of oxidative stress through hypoxia. Through sc-RNA-seq, we identify the ATF4 pathway as a critical mechanism underlying cellular adaptation to metabolic stress. ATF4 knockdown in Opa1-deficient NSCs accelerates cell death, while the increased expression of ATF4 enhances proliferation and survival. Using a Slc7a11 mutant, an ATF4 target, we show that ATF4-mediated glutathione production plays a critical role in maintaining NSC survival and function under stress conditions. Together, we show that the activation of the integrated stress response (ISR) pathway enables NSCs to adapt to metabolic stress due to mitochondrial dysfunction and metabolic stress and may serve as a therapeutic target to enhance NSC survival and function in aging and neurodegeneration.
    Keywords:  Hypoxia; Opa1; adult neurogenesis; intergrated stress response; metabolic adaptation; mitochondrial dynamics; neurodegeneration
    DOI:  https://doi.org/10.1111/acel.14165
  48. Nat Commun. 2024 May 14. 15(1): 4067
    Systematic dissection of tumor-normal single-cell ecosystems across a thousand tumors of 30 cancer types.
    Junho Kang, Jun Hyeong Lee, Hongui Cha, Jinhyeon An, Joonha Kwon, Seongwoo Lee, Seongryong Kim, Mert Yakup Baykan, So Yeon Kim, Dohyeon An, Ah-Young Kwon, Hee Jung An, Se-Hoon Lee, Jung Kyoon Choi, Jong-Eun Park.
      The complexity of the tumor microenvironment poses significant challenges in cancer therapy. Here, to comprehensively investigate the tumor-normal ecosystems, we perform an integrative analysis of 4.9 million single-cell transcriptomes from 1070 tumor and 493 normal samples in combination with pan-cancer 137 spatial transcriptomics, 8887 TCGA, and 1261 checkpoint inhibitor-treated bulk tumors. We define a myriad of cell states constituting the tumor-normal ecosystems and also identify hallmark gene signatures across different cell types and organs. Our atlas characterizes distinctions between inflammatory fibroblasts marked by AKR1C1 or WNT5A in terms of cellular interactions and spatial co-localization patterns. Co-occurrence analysis reveals interferon-enriched community states including tertiary lymphoid structure (TLS) components, which exhibit differential rewiring between tumor, adjacent normal, and healthy normal tissues. The favorable response of interferon-enriched community states to immunotherapy is validated using immunotherapy-treated cancers (n = 1261) including our lung cancer cohort (n = 497). Deconvolution of spatial transcriptomes discriminates TLS-enriched from non-enriched cell types among immunotherapy-favorable components. Our systematic dissection of tumor-normal ecosystems provides a deeper understanding of inter- and intra-tumoral heterogeneity.
    DOI:  https://doi.org/10.1038/s41467-024-48310-4
  49. Mol Cancer. 2024 May 18. 23(1): 106
    Aging and cancer.
    Léa Montégut, Carlos López-Otín, Guido Kroemer.
      Aging and cancer exhibit apparent links that we will examine in this review. The null hypothesis that aging and cancer coincide because both are driven by time, irrespective of the precise causes, can be confronted with the idea that aging and cancer share common mechanistic grounds that are referred to as 'hallmarks'. Indeed, several hallmarks of aging also contribute to carcinogenesis and tumor progression, but some of the molecular and cellular characteristics of aging may also reduce the probability of developing lethal cancer, perhaps explaining why very old age (> 90 years) is accompanied by a reduced incidence of neoplastic diseases. We will also discuss the possibility that the aging process itself causes cancer, meaning that the time-dependent degradation of cellular and supracellular functions that accompanies aging produces cancer as a byproduct or 'age-associated disease'. Conversely, cancer and its treatment may erode health and drive the aging process, as this has dramatically been documented for cancer survivors diagnosed during childhood, adolescence, and young adulthood. We conclude that aging and cancer are connected by common superior causes including endogenous and lifestyle factors, as well as by a bidirectional crosstalk, that together render old age not only a risk factor of cancer but also an important parameter that must be considered for therapeutic decisions.
    Keywords:  Age; Chemotherapy; Immunotherapy; Lifestyle; Modifiable risk factors
    DOI:  https://doi.org/10.1186/s12943-024-02020-z
  50. Cancer Res. 2024 May 15. 84(10): 1543-1545
    Overcoming Nutrient Stress: Integrin αvβ3-Driven Metabolic Adaptation Supports Tumor Initiation.
    Elena Rainero.
      Nutrient stress accompanies several stages of tumor progression, including metastasis formation. Metabolic reprogramming is a hallmark of cancer, and it has been associated with stress tolerance and anchorage-independent cell survival. Adaptive responses are required to support cancer cell survival under these conditions. In this issue of Cancer Research, Nam and colleagues showed that the extracellular matrix (ECM) receptor integrin β3 was upregulated in lung cancer cells in response to nutrient starvation, resulting in increased cell survival that was independent from ECM binding. Delving into the molecular mechanisms responsible for this, the authors found that integrin β3 promoted glutamine metabolism and oxidative phosphorylation (OXPHOS) by activating a Src/AMPK/PGC1α signaling pathway. Importantly, in vivo experiments confirmed that OXPHOS inhibition suppressed tumor initiation in an orthotopic model of lung cancer, while β3 knockout completely abrogated tumor initiation. These observations indicate that targeting signaling pathways downstream of αvβ3 could represent a promising therapeutic avenue to prevent lung cancer progression and metastasis. See related article by Nam et al., p. 1630.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-0453
  51. Nat Genet. 2024 May 17.
    Spatial genomic, biochemical and cellular mechanisms underlying meningioma heterogeneity and evolution.
    Calixto-Hope G Lucas, Kanish Mirchia, Kyounghee Seo, Hinda Najem, William C Chen, Naomi Zakimi, Kyla Foster, Charlotte D Eaton, Martha A Cady, Abrar Choudhury, S John Liu, Joanna J Phillips, Stephen T Magill, Craig M Horbinski, David A Solomon, Arie Perry, Harish N Vasudevan, Amy B Heimberger, David R Raleigh.
      Intratumor heterogeneity underlies cancer evolution and treatment resistance, but targetable mechanisms driving intratumor heterogeneity are poorly understood. Meningiomas are the most common primary intracranial tumors and are resistant to all medical therapies, and high-grade meningiomas have significant intratumor heterogeneity. Here we use spatial approaches to identify genomic, biochemical and cellular mechanisms linking intratumor heterogeneity to the molecular, temporal and spatial evolution of high-grade meningiomas. We show that divergent intratumor gene and protein expression programs distinguish high-grade meningiomas that are otherwise grouped together by current classification systems. Analyses of matched pairs of primary and recurrent meningiomas reveal spatial expansion of subclonal copy number variants associated with treatment resistance. Multiplexed sequential immunofluorescence and deconvolution of meningioma spatial transcriptomes using cell types from single-cell RNA sequencing show decreased immune infiltration, decreased MAPK signaling, increased PI3K-AKT signaling and increased cell proliferation, which are associated with meningioma recurrence. To translate these findings to preclinical models, we use CRISPR interference and lineage tracing approaches to identify combination therapies that target intratumor heterogeneity in meningioma cell co-cultures.
    DOI:  https://doi.org/10.1038/s41588-024-01747-1
  52. Nat Genet. 2024 May;56(5): 889-899
    Single-cell mtDNA dynamics in tumors is driven by coregulation of nuclear and mitochondrial genomes.
    Minsoo Kim, Alexander N Gorelick, Ignacio Vàzquez-García, Marc J Williams, Sohrab Salehi, Hongyu Shi, Adam C Weiner, Nick Ceglia, Tyler Funnell, Tricia Park, Sonia Boscenco, Ciara H O'Flanagan, Hui Jiang, Diljot Grewal, Cerise Tang, Nicole Rusk, Payam A Gammage, Andrew McPherson, Sam Aparicio, Sohrab P Shah, Ed Reznik.
      The extent of cell-to-cell variation in tumor mitochondrial DNA (mtDNA) copy number and genotype, and the phenotypic and evolutionary consequences of such variation, are poorly characterized. Here we use amplification-free single-cell whole-genome sequencing (Direct Library Prep (DLP+)) to simultaneously assay mtDNA copy number and nuclear DNA (nuDNA) in 72,275 single cells derived from immortalized cell lines, patient-derived xenografts and primary human tumors. Cells typically contained thousands of mtDNA copies, but variation in mtDNA copy number was extensive and strongly associated with cell size. Pervasive whole-genome doubling events in nuDNA associated with stoichiometrically balanced adaptations in mtDNA copy number, implying that mtDNA-to-nuDNA ratio, rather than mtDNA copy number itself, mediated downstream phenotypes. Finally, multimodal analysis of DLP+ and single-cell RNA sequencing identified both somatic loss-of-function and germline noncoding variants in mtDNA linked to heteroplasmy-dependent changes in mtDNA copy number and mitochondrial transcription, revealing phenotypic adaptations to disrupted nuclear/mitochondrial balance.
    DOI:  https://doi.org/10.1038/s41588-024-01724-8
  53. J Hepatol. 2024 May 15. pii: S0168-8278(24)00342-8. [Epub ahead of print]
    Targeting OXCT1-mediated ketone metabolism reprograms macrophages to promote antitumor immunity via CD8+ T cells in hepatocellular carcinoma.
    Chu-Xu Zhu, Kai Yan, Liang Chen, Rong-Rong Huang, Zhen-Hua Bian, Hao-Ran Wei, Xue-Mei Gu, Yang-Yang Zhao, Meng-Chu Liu, Cai-Xia Suo, Zhi-Kun Li, Zhi-Yi Yang, Min-Qiang Lu, Xue-Feng Hua, Liang Li, Zhi-Bin Zhao, Lin-Chong Sun, Hua-Feng Zhang, Ping Gao, Zhe-Xiong Lian.
      BACKGROUND & AIMS: The liver is the main organ of ketogenesis, while ketones are mainly metabolized in peripheral tissues via the critical enzyme OXCT1. We previously found that ketolysis is reactivated in hepatocellular carcinoma (HCC) cells through OXCT1 expression to promote tumor progression; however, whether OXCT1 regulates antitumor immunity remains unclear.METHODS: To investigate the expression pattern of OXCT1 in hepatocellular carcinoma in vivo, we conducted multiplex immunohistochemistry (mIHC) experiments on human HCC specimens. To explore the role of OXCT1 in mouse hepatocellular carcinoma tumor-associated macrophages (TAMs), we generated LysMcreOXCT1f/f (OXCT1 conditional knockout in macrophages) mice.
    RESULTS: Here, we found that inhibiting OXCT1 expression in tumor-associated macrophages reduced CD8+ T-cell exhaustion through the succinate-H3K4me3-Arg1 axis. Initially, we found that OXCT1 was highly expressed in liver macrophages under steady state and that OXCT expression was further increased in TAMs. OXCT1 deficiency in macrophages suppressed tumor growth by reprogramming TAMs toward an antitumor phenotype, reducing CD8+ T-cell exhaustion and increasing CD8+ T-cell cytotoxicity. Mechanistically, high OXCT1 expression induced the accumulation of succinate, a byproduct of ketolysis, in TAMs, which promoted Arg1 transcription by increasing the H3K4 trimethylation (H3K4me3) level in the Arg1 promoter. In addition, Pimozide, an inhibitor of OXCT1, suppressed Arg1 expression as well as TAM polarization toward the protumor phenotype, leading to decreasing CD8+ T-cell exhaustion and deceleration of tumor growth. Finally, high expression of OXCT1 in macrophages was positively associated with poor survival in HCC patients.
    CONCLUSIONS: In conclusion, our results demonstrate that OXCT1 epigenetically suppresses antitumor immunity, suggesting that suppressing OXCT1 activity in TAMs is an effective approach for treating liver cancer.
    IMPACT AND IMPLICATIONS: The intricate metabolism of liver macrophages plays a critical role in shaping HCC progression and immune modulation. Targeting macrophage metabolism to counteract immune suppression presents a promising avenue for HCC. Here, we found that ketogenesis gene OXCT1 was highly expressed in tumor-associated macrophages and promoted tumor growth by reprogramming TAMs toward a protumor phenotype. And the strategic pharmacological intervention or genetic downregulation of OXCT1 in TAMs enhances the antitumor immunity and decelerated tumor growth. Our results suggest that suppressing OXCT1 activity in TAMs is an effective approach for treating liver cancer.
    Keywords:  CD8(+) T cell; Hepatocellular carcinoma; Macrophage reprogramming; OXCT1; Pimozide
    DOI:  https://doi.org/10.1016/j.jhep.2024.05.007
  54. Science. 2024 May 17. 384(6697): 785-792
    DNA damage induces p53-independent apoptosis through ribosome stalling.
    Nicolaas J Boon, Rafaela A Oliveira, Pierré-René Körner, Adva Kochavi, Sander Mertens, Yuval Malka, Rhianne Voogd, Suzanne E M van der Horst, Maarten A Huismans, Lidwien P Smabers, Jonne M Draper, Lodewyk F A Wessels, Peter Haahr, Jeanine M L Roodhart, Ton N M Schumacher, Hugo J Snippert, Reuven Agami, Thijn R Brummelkamp.
      In response to excessive DNA damage, human cells can activate p53 to induce apoptosis. Cells lacking p53 can still undergo apoptosis upon DNA damage, yet the responsible pathways are unknown. We observed that p53-independent apoptosis in response to DNA damage coincided with translation inhibition, which was characterized by ribosome stalling on rare leucine-encoding UUA codons and globally curtailed translation initiation. A genetic screen identified the transfer RNAse SLFN11 and the kinase GCN2 as factors required for UUA stalling and global translation inhibition, respectively. Stalled ribosomes activated a ribotoxic stress signal conveyed by the ribosome sensor ZAKα to the apoptosis machinery. These results provide an explanation for the frequent inactivation of SLFN11 in chemotherapy-unresponsive tumors and highlight ribosome stalling as a signaling event affecting cell fate in response to DNA damage.
    DOI:  https://doi.org/10.1126/science.adh7950
  55. bioRxiv. 2024 May 03. pii: 2024.04.30.591879. [Epub ahead of print]
    Mechano-metabolism of adherent cells in 2D and 3D microenvironments.
    Anuja Jaganathan, Joshua Toth, Xingyu Chen, Laurent Pieuchot, Yihui Shen, Cynthia Reinhart-King, Vivek B Shenoy.
      Cells regulate their shape and metabolic activity in response to the mechano-chemical properties of their microenvironment. To elucidate the impact of matrix stiffness and ligand density on a cell's bioenergetics, we developed a non-equilibrium, active chemo-mechanical model that accounts for mechanical energy of the cell and matrix, chemical energy from ATP hydrolysis, interfacial energy, and mechano-sensitive regulation of stress fiber assembly through signaling. By integrating the kinetics and energetics of these processes we introduce the concept of the metabolic potential of the cell that, when minimized, gives experimentally testable predictions of the cell contractility, shape, and the ATP consumption. Specifically, we show that MDA-MB-231 breast cancer cells in 3D collagen gels follow a spherical to spindle to spherical change in morphology with increasing matrix stiffness consistent with experimental observations. This biphasic transition in cell shape emerges from a competition between increased contractility accompanied by ATP hydrolysis enabled by mechano-sensitive signaling, which lowers the volumetric contribution to the metabolic potential of elongated cells and the interfacial energy which is lower for spherical shapes. On 2D hydrogels, our model predicts a hemispherical to spindle to disc shape transition with increasing gel stiffness. In both cases, we show that increasing matrix stiffness monotonically increases the cell's contractility as well as ATP consumption. Our model also predicts how the increased energy demand in stiffer microenvironments is met by AMPK activation, which is confirmed through experimental measurement of activated AMPK levels as a function of matrix stiffness carried out here in both 2D and 3D micro-environments. Further, model predictions of increased AMPK activation on stiffer micro-environments are found to correlate strongly with experimentally measured upregulation of mitochondrial potential, glucose uptake and ATP levels. The insights from our model can be used to understand mechanosensitive regulation of metabolism in physiological events such as metastasis and tumor progression during which cells experience dynamic changes in their microenvironment and metabolic state.
    DOI:  https://doi.org/10.1101/2024.04.30.591879
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