bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2023–09–24
forty papers selected by
Christian Frezza, Universität zu Köln
  1. Manipulating mitochondrial electron flow enhances tumor immunogenicity.
  2. Reductive carboxylation epigenetically instructs T cell differentiation.
  3. Formate supplementation enhances anti-tumor CD8+ T cell fitness and efficacy of PD-1 blockade.
  4. Acetate acts as a metabolic immunomodulator by bolstering T-cell effector function and potentiating antitumor immunity in breast cancer.
  5. BAP1 promotes osteoclast function by metabolic reprogramming.
  6. Metabolic modulation of mitochondrial mass during CD4+ T cell activation.
  7. Brain-body communication in metabolic control.
  8. Mitochondrial protein and organelle quality control-Lessons from budding yeast.
  9. Metabolic control of antitumor immunity.
  10. Mitochondria-ER contact mediated by MFN2-SERCA2 interaction supports CD8+ T cell metabolic fitness and function in tumors.
  11. Spotlight on human studies.
  12. Pathogenic mitochondrial DNA mutations inhibit melanoma metastasis.
  13. Spatially aware deep learning reveals tumor heterogeneity patterns that encode distinct kidney cancer states.
  14. The post-translational regulation of transcription factor EB (TFEB) in health and disease.
  15. Regulation of nucleo-cytosolic 26S proteasome translocation by aromatic amino acids via mTOR is essential for cell survival under stress.
  16. Temporal landscape of mitochondrial proteostasis governed by the UPRmt.
  17. Neuronal mTORC1 inhibition promotes longevity without suppressing anabolic growth and reproduction in C. elegans.
  18. A Rare Case of Synchronous Fumarate Hydratase-Deficient Renal Cell Carcinoma and Clear Cell Renal Cell Carcinoma With Fumarate Hydratase and von Hippel-Lindau Gene Mutations: A Clinicopathologic and Molecular Study.
  19. Dietary fat and lipid metabolism in the tumor microenvironment.
  20. The dual role of citrate in cancer.
  21. Regulatory circuits of mitophagy restrict distinct modes of cell death during memory CD8+ T cell formation.
  22. Fatty acid oxidation mediated by malonyl-CoA decarboxylase represses renal cell carcinoma progression.
  23. Low glucose metabolite 3-phosphoglycerate switches PHGDH from serine synthesis to p53 activation to control cell fate.
  24. CPT1A-mediated fatty acid oxidation confers cancer cell resistance to immune-mediated cytolytic killing.
  25. PD-1 instructs a tumor-suppressive metabolic program that restricts glycolysis and restrains AP-1 activity in T cell lymphoma.
  26. Peroxisomal ROS control cytosolic Mycobacterium tuberculosis replication in human macrophages.
  27. Molecular basis for maternal inheritance of human mitochondrial DNA.
  28. A DNA nanodevice for mapping sodium at single-organelle resolution.
  29. The Lysosomal Calcium Channel TRPML1 Maintains Mitochondrial Fitness in NK Cells through Interorganelle Cross-Talk.
  30. Glutamine availability unleashes dendritic cells' anti-tumor power.
  31. Cholinergic neurons trigger epithelial Ca2+ currents to heal the gut.
  32. The β1-adrenergic receptor links sympathetic nerves to T cell exhaustion.
  33. PARylated PDHE1α generates acetyl-CoA for local chromatin acetylation and DNA damage repair.
  34. Pioneer factors - key regulators of chromatin and gene expression.
  35. Structural basis of the activation of TRPV5 channels by long-chain acyl-Coenzyme-A.
  36. RNA folding studies inside peptide-rich droplets reveal roles of modified nucleosides at the origin of life.
  37. Palbociclib releases the latent differentiation capacity of neuroblastoma cells.
  38. Coenzyme Q10 trapping in mitochondrial complex I underlies Leber's hereditary optic neuropathy.
  39. A physicochemical perspective on cellular ageing.
  40. The Constraints of Allotopic Expression.
  1. Science. 2023 Sep 22. 381(6664): 1316-1323
    Manipulating mitochondrial electron flow enhances tumor immunogenicity.
    Kailash Chandra Mangalhara, Siva Karthik Varanasi, Melissa A Johnson, Mannix J Burns, Gladys R Rojas, Pau B Esparza Moltó, Alva G Sainz, Nimesha Tadepalle, Keene L Abbott, Gaurav Mendiratta, Dan Chen, Yagmur Farsakoglu, Tenzin Kunchok, Filipe Araujo Hoffmann, Bianca Parisi, Mercedes Rincon, Matthew G Vander Heiden, Marcus Bosenberg, Diana C Hargreaves, Susan M Kaech, Gerald S Shadel.
      Although tumor growth requires the mitochondrial electron transport chain (ETC), the relative contribution of complex I (CI) and complex II (CII), the gatekeepers for initiating electron flow, remains unclear. In this work, we report that the loss of CII, but not that of CI, reduces melanoma tumor growth by increasing antigen presentation and T cell-mediated killing. This is driven by succinate-mediated transcriptional and epigenetic activation of major histocompatibility complex-antigen processing and presentation (MHC-APP) genes independent of interferon signaling. Furthermore, knockout of methylation-controlled J protein (MCJ), to promote electron entry preferentially through CI, provides proof of concept of ETC rewiring to achieve antitumor responses without side effects associated with an overall reduction in mitochondrial respiration in noncancer cells. Our results may hold therapeutic potential for tumors that have reduced MHC-APP expression, a common mechanism of cancer immunoevasion.
    DOI:  https://doi.org/10.1126/science.abq1053
  2. Nature. 2023 Sep 20.
    Reductive carboxylation epigenetically instructs T cell differentiation.
    Alison Jaccard, Tania Wyss, Noelia Maldonado-Pérez, Jan A Rath, Alessio Bevilacqua, Jhan-Jie Peng, Anouk Lepez, Christine Von Gunten, Fabien Franco, Kung-Chi Kao, Nicolas Camviel, Francisco Martín, Bart Ghesquière, Denis Migliorini, Caroline Arber, Pedro Romero, Ping-Chih Ho, Mathias Wenes.
      Protective immunity against pathogens or cancer is mediated by the activation and clonal expansion of antigen-specific naive T cells into effector T cells. To sustain their rapid proliferation and effector functions, naive T cells switch their quiescent metabolism to an anabolic metabolism through increased levels of aerobic glycolysis, but also through mitochondrial metabolism and oxidative phosphorylation, generating energy and signalling molecules1-3. However, how that metabolic rewiring drives and defines the differentiation of T cells remains unclear. Here we show that proliferating effector CD8+ T cells reductively carboxylate glutamine through the mitochondrial enzyme isocitrate dehydrogenase 2 (IDH2). Notably, deletion of the gene encoding IDH2 does not impair the proliferation of T cells nor their effector function, but promotes the differentiation of memory CD8+ T cells. Accordingly, inhibiting IDH2 during ex vivo manufacturing of chimeric antigen receptor (CAR) T cells induces features of memory T cells and enhances antitumour activity in melanoma, leukaemia and multiple myeloma. Mechanistically, inhibition of IDH2 activates compensating metabolic pathways that cause a disequilibrium in metabolites regulating histone-modifying enzymes, and this maintains chromatin accessibility at genes that are required for the differentiation of memory T cells. These findings show that reductive carboxylation in CD8+ T cells is dispensable for their effector response and proliferation, but that it mainly produces a pattern of metabolites that epigenetically locks CD8+ T cells into a terminal effector differentiation program. Blocking this metabolic route allows the increased formation of memory T cells, which could be exploited to optimize the therapeutic efficacy of CAR T cells.
    DOI:  https://doi.org/10.1038/s41586-023-06546-y
  3. Cancer Discov. 2023 Sep 20.
    Formate supplementation enhances anti-tumor CD8+ T cell fitness and efficacy of PD-1 blockade.
    Jared H Rowe, Ilaria Elia, Osmaan Shahid, Emily F Gaudiano, Natalia E Sifnugel, Sheila Johnson, Amy G Reynolds, Megan E Fung, Shakchhi Joshi, Martin W LaFleur, Joon Seok Park, Kristen E Pauken, Joshua D Rabinowitz, Gordon J Freeman, Marcia C Haigis, Arlene H Sharpe.
      The tumor microenvironment (TME) restricts anti-tumor CD8+ T cell function and immunotherapy responses. Cancer cells compromise metabolic fitness of CD8+ T cells within the TME, but the mechanisms are largely unknown. Here we demonstrate one carbon (1C) metabolism is enhanced in T cells in an antigen-specific manner. Therapeutic supplementation of 1C metabolism using formate enhances CD8+ T cell fitness and anti-tumor efficacy of PD-1 blockade in B16-OVA tumors. Formate supplementation drives transcriptional alterations in CD8+ T cell metabolism and increases gene signatures for cellular proliferation and activation. Combined formate and anti-PD-1 therapy increases tumor-infiltrating CD8+ T cells, which are essential for the enhanced tumor control. Our data demonstrate formate provides metabolic support to CD8+ T cells reinvigorated by anti-PD-1 to overcome a metabolic vulnerability in 1C metabolism in the TME to further improve T cell function.
    DOI:  https://doi.org/10.1158/2159-8290.CD-22-1301
  4. Nat Cancer. 2023 Sep 18.
    Acetate acts as a metabolic immunomodulator by bolstering T-cell effector function and potentiating antitumor immunity in breast cancer.
    Katelyn D Miller, Seamus O'Connor, Katherine A Pniewski, Toshitha Kannan, Reyes Acosta, Gauri Mirji, Sara Papp, Michael Hulse, Dzmitry Mukha, Sabina I Hlavaty, Kelsey N Salcido, Fabrizio Bertolazzi, Yellamelli V V Srikanth, Steven Zhao, Kathryn E Wellen, Rahul S Shinde, Daniel T Claiborne, Andrew Kossenkov, Joseph M Salvino, Zachary T Schug.
      Acetate metabolism is an important metabolic pathway in many cancers and is controlled by acetyl-CoA synthetase 2 (ACSS2), an enzyme that catalyzes the conversion of acetate to acetyl-CoA. While the metabolic role of ACSS2 in cancer is well described, the consequences of blocking tumor acetate metabolism on the tumor microenvironment and antitumor immunity are unknown. We demonstrate that blocking ACSS2, switches cancer cells from acetate consumers to producers of acetate thereby freeing acetate for tumor-infiltrating lymphocytes to use as a fuel source. We show that acetate supplementation metabolically bolsters T-cell effector functions and proliferation. Targeting ACSS2 with CRISPR-Cas9 guides or a small-molecule inhibitor promotes an antitumor immune response and enhances the efficacy of chemotherapy in preclinical breast cancer models. We propose a paradigm for targeting acetate metabolism in cancer in which inhibition of ACSS2 dually acts to impair tumor cell metabolism and potentiate antitumor immunity.
    DOI:  https://doi.org/10.1038/s43018-023-00636-6
  5. Nat Commun. 2023 Sep 22. 14(1): 5923
    BAP1 promotes osteoclast function by metabolic reprogramming.
    Nidhi Rohatgi, Wei Zou, Yongjia Li, Kevin Cho, Patrick L Collins, Eric Tycksen, Gaurav Pandey, Carl J DeSelm, Gary J Patti, Anwesha Dey, Steven L Teitelbaum.
      Treatment of osteoporosis commonly diminishes osteoclast number which suppresses bone formation thus compromising fracture prevention. Bone formation is not suppressed, however, when bone degradation is reduced by retarding osteoclast functional resorptive capacity, rather than differentiation. We find deletion of deubiquitinase, BRCA1-associated protein 1 (Bap1), in myeloid cells (Bap1∆LysM), arrests osteoclast function but not formation. Bap1∆LysM osteoclasts fail to organize their cytoskeleton which is essential for bone degradation consequently increasing bone mass in both male and female mice. The deubiquitinase activity of BAP1 modifies osteoclast function by metabolic reprogramming. Bap1 deficient osteoclast upregulate the cystine transporter, Slc7a11, by enhanced H2Aub occupancy of its promoter. SLC7A11 controls cellular reactive oxygen species levels and redirects the mitochondrial metabolites away from the tricarboxylic acid cycle, both being necessary for osteoclast function. Thus, in osteoclasts BAP1 appears to regulate the epigenetic-metabolic axis and is a potential target to reduce bone degradation while maintaining osteogenesis in osteoporotic patients.
    DOI:  https://doi.org/10.1038/s41467-023-41629-4
  6. Cell Chem Biol. 2023 Aug 31. pii: S2451-9456(23)00280-5. [Epub ahead of print]
    Metabolic modulation of mitochondrial mass during CD4+ T cell activation.
    Kiran Kurmi, Dan Liang, Robert van de Ven, Peter Georgiev, Brandon Mark Gassaway, SeongJun Han, Giulia Notarangelo, Isaac S Harris, Cong-Hui Yao, Joon Seok Park, Song-Hua Hu, Jingyu Peng, Jefte M Drijvers, Sarah Boswell, Artem Sokolov, Stephanie K Dougan, Peter K Sorger, Steven P Gygi, Arlene H Sharpe, Marcia C Haigis.
      Mitochondrial biogenesis initiates within hours of T cell receptor (TCR) engagement and is critical for T cell activation, function, and survival; yet, how metabolic programs support mitochondrial biogenesis during TCR signaling is not fully understood. Here, we performed a multiplexed metabolic chemical screen in CD4+ T lymphocytes to identify modulators of metabolism that impact mitochondrial mass during early T cell activation. Treatment of T cells with pyrvinium pamoate early during their activation blocks an increase in mitochondrial mass and results in reduced proliferation, skewed CD4+ T cell differentiation, and reduced cytokine production. Furthermore, administration of pyrvinium pamoate at the time of induction of experimental autoimmune encephalomyelitis, an experimental model of multiple sclerosis in mice, prevented the onset of clinical disease. Thus, modulation of mitochondrial biogenesis may provide a therapeutic strategy for modulating T cell immune responses.
    Keywords:  CD4(+) T cells; T cell differentiation; high-throughput metabolic screen; mitochondrial biogenesis; pyruvate oxidation; pyrvinium pamoate
    DOI:  https://doi.org/10.1016/j.chembiol.2023.08.008
  7. Trends Endocrinol Metab. 2023 Sep 14. pii: S1043-2760(23)00167-4. [Epub ahead of print]
    Brain-body communication in metabolic control.
    Alessandro Furlan, Paul Petrus.
      A thorough understanding of the mechanisms controlling energy homeostasis is needed to prevent and treat metabolic morbidities. While the contribution of organs such as the liver, muscle, adipose tissue, and pancreas to the regulation of energy has received wide attention, less is known about the interplay with the nervous system. Here, we highlight the role of the nervous systems in regulating metabolism beyond the classic hypothalamic endocrine signaling models and discuss the contribution of circadian rhythms, higher brain regions, and sociodemographic variables in the energy equation. We infer that interdisciplinary approaches are key to conceptually advancing the current research frontier and devising innovative therapies to prevent and treat metabolic disease.
    Keywords:  circadian rhythms; interorgan communication; metabolic disease; metabolism; nervous system
    DOI:  https://doi.org/10.1016/j.tem.2023.08.014
  8. IUBMB Life. 2023 Sep 20.
    Mitochondrial protein and organelle quality control-Lessons from budding yeast.
    Emily Jie-Ning Yang, Pin-Chao Liao, Liza Pon.
      Mitochondria are essential for normal cellular function and have emerged as key aging determinants. Indeed, defects in mitochondrial function have been linked to cardiovascular, skeletal muscle and neurodegenerative diseases, premature aging, and age-linked diseases. Here, we describe mechanisms for mitochondrial protein and organelle quality control. These surveillance mechanisms mediate repair or degradation of damaged or mistargeted mitochondrial proteins, segregate mitochondria based on their functional state during asymmetric cell division, and modulate cellular fitness, the response to stress, and lifespan control in yeast and other eukaryotes.
    Keywords:  ageing; mitochondria; mitochondrial reactive oxygen species; oxidative stress; reactive oxygen species
    DOI:  https://doi.org/10.1002/iub.2783
  9. Science. 2023 Sep 22. 381(6664): 1287-1288
    Metabolic control of antitumor immunity.
    Andromachi Pouikli, Christian Frezza.
      Mitochondrial metabolite reduces melanoma growth by boosting antigen presentation.
    DOI:  https://doi.org/10.1126/science.adk1785
  10. Sci Immunol. 2023 Sep 29. 8(87): eabq2424
    Mitochondria-ER contact mediated by MFN2-SERCA2 interaction supports CD8+ T cell metabolic fitness and function in tumors.
    Jie-Feng Yang, Xudong Xing, Li Luo, Xin-Wei Zhou, Jian-Xiong Feng, Kang-Bo Huang, Huashan Liu, Shanzhao Jin, Yi-Na Liu, Shi-Hui Zhang, Yi-Hui Pan, Bing Yu, Jin-Yu Yang, Yu-Lu Cao, Yun Cao, Cliff Y Yang, Yuan Wang, Yuxia Zhang, Jiang Li, Xiaojun Xia, Tiebang Kang, Rui-Hua Xu, Ping Lan, Jun-Hang Luo, Hui Han, Fan Bai, Song Gao.
      Metabolic fitness of T cells is essential for their vitality, which is largely dependent on the behavior of the mitochondria. The nature of mitochondrial behavior in tumor-infiltrating T cells remains poorly understood. In this study, we show that mitofusin-2 (MFN2) expression is positively correlated with the prognosis of multiple cancers. Genetic ablation of Mfn2 in CD8+ T cells dampens mitochondrial metabolism and function and promotes tumor progression. In tumor-infiltrating CD8+ T cells, MFN2 enhances mitochondria-endoplasmic reticulum (ER) contact by interacting with ER-embedded Ca2+-ATPase SERCA2, facilitating the mitochondrial Ca2+ influx required for efficient mitochondrial metabolism. MFN2 stimulates the ER Ca2+ retrieval activity of SERCA2, thereby preventing excessive mitochondrial Ca2+ accumulation and apoptosis. Elevating mitochondria-ER contact by increasing MFN2 in CD8+ T cells improves the efficacy of cancer immunotherapy. Thus, we reveal a tethering-and-buffering mechanism of organelle cross-talk that regulates the metabolic fitness of tumor-infiltrating CD8+ T cells and highlights the therapeutic potential of enhancing MFN2 expression to optimize T cell function.
    DOI:  https://doi.org/10.1126/sciimmunol.abq2424
  11. Nat Metab. 2023 Sep;5(9): 1441
    Spotlight on human studies.
      
    DOI:  https://doi.org/10.1038/s42255-023-00900-0
  12. bioRxiv. 2023 Sep 05. pii: 2023.09.01.555986. [Epub ahead of print]
    Pathogenic mitochondrial DNA mutations inhibit melanoma metastasis.
    Spencer D Shelton, Sara House, Vijayashree Ramesh, Zhenkang Chen, Tao Wei, Xun Wang, Claire B Llamas, Siva Sai Krishna Venigalla, Cameron J Menezes, Zhiyu Zhao, Jennifer G Gill, Ralph J DeBerardinis, Sean J Morrison, Alpaslan Tasdogan, Prashant Mishra.
      Mitochondrial DNA (mtDNA) mutations are frequently observed in cancer, but their contribution to tumor progression is controversial. To evaluate the impact of mtDNA variants on tumor growth and metastasis, we created human melanoma cytoplasmic hybrid (cybrid) cell lines transplanted with wildtype mtDNA or pathogenic mtDNA encoding variants that partially or completely inhibit oxidative phosphorylation. Homoplasmic pathogenic mtDNA cybrids reliably established tumors despite dysfunctional oxidative phosphorylation. However, pathogenic mtDNA variants disrupted spontaneous metastasis of subcutaneous tumors and decreased the abundance of circulating melanoma cells in the blood. Pathogenic mtDNA did not induce anoikis or inhibit organ colonization of melanoma cells following intravenous injections. Instead, migration and invasion were reduced, indicating that limited circulation entry functions as a metastatic bottleneck amidst mtDNA dysfunction. Furthermore, analysis of selective pressure exerted on the mitochondrial genomes of heteroplasmic cybrid lines revealed a suppression of pathogenic mtDNA allelic frequency during melanoma growth. Collectively, these findings demonstrate that functional mtDNA is favored during melanoma growth and enables metastatic entry into the blood.
    DOI:  https://doi.org/10.1101/2023.09.01.555986
  13. Cell Rep Med. 2023 09 19. pii: S2666-3791(23)00356-7. [Epub ahead of print]4(9): 101189
    Spatially aware deep learning reveals tumor heterogeneity patterns that encode distinct kidney cancer states.
    Jackson Nyman, Thomas Denize, Ziad Bakouny, Chris Labaki, Breanna M Titchen, Kevin Bi, Surya Narayanan Hari, Jacob Rosenthal, Nicita Mehta, Bowen Jiang, Bijaya Sharma, Kristen Felt, Renato Umeton, David A Braun, Scott Rodig, Toni K Choueiri, Sabina Signoretti, Eliezer M Van Allen.
      Clear cell renal cell carcinoma (ccRCC) is molecularly heterogeneous, immune infiltrated, and selectively sensitive to immune checkpoint inhibition (ICI). However, the joint tumor-immune states that mediate ICI response remain elusive. We develop spatially aware deep-learning models of tumor and immune features to learn representations of ccRCC tumors using diagnostic whole-slide images (WSIs) in untreated and treated contexts (n = 1,102 patients). We identify patterns of grade heterogeneity in WSIs not achievable through human pathologist analysis, and these graph-based "microheterogeneity" structures associate with PBRM1 loss of function and with patient outcomes. Joint analysis of tumor phenotypes and immune infiltration identifies a subpopulation of highly infiltrated, microheterogeneous tumors responsive to ICI. In paired multiplex immunofluorescence images of ccRCC, microheterogeneity associates with greater PD1 activation in CD8+ lymphocytes and increased tumor-immune interactions. Our work reveals spatially interacting tumor-immune structures underlying ccRCC biology that may also inform selective response to ICI.
    Keywords:  AI; artificial intelligence; computational histopathology; computer vision; deep learning; immunotherapy; kidney cancer; precision medicine; tumor heterogeneity
    DOI:  https://doi.org/10.1016/j.xcrm.2023.101189
  14. EMBO Rep. 2023 Sep 20. e57574
    The post-translational regulation of transcription factor EB (TFEB) in health and disease.
    Michael Takla, Swati Keshri, David C Rubinsztein.
      Transcription factor EB (TFEB) is a basic helix-loop-helix leucine zipper transcription factor that acts as a master regulator of lysosomal biogenesis, lysosomal exocytosis, and macro-autophagy. TFEB contributes to a wide range of physiological functions, including mitochondrial biogenesis and innate and adaptive immunity. As such, TFEB is an essential component of cellular adaptation to stressors, ranging from nutrient deprivation to pathogenic invasion. The activity of TFEB depends on its subcellular localisation, turnover, and DNA-binding capacity, all of which are regulated at the post-translational level. Pathological states are characterised by a specific set of stressors, which elicit post-translational modifications that promote gain or loss of TFEB function in the affected tissue. In turn, the resulting increase or decrease in survival of the tissue in which TFEB is more or less active, respectively, may either benefit or harm the organism as a whole. In this way, the post-translational modifications of TFEB account for its otherwise paradoxical protective and deleterious effects on organismal fitness in diseases ranging from neurodegeneration to cancer. In this review, we describe how the intracellular environment characteristic of different diseases alters the post-translational modification profile of TFEB, enabling cellular adaptation to a particular pathological state.
    Keywords:  TFEB; autophagy; lysosome; mitochondria; post-translational modification
    DOI:  https://doi.org/10.15252/embr.202357574
  15. Mol Cell. 2023 Sep 21. pii: S1097-2765(23)00652-4. [Epub ahead of print]83(18): 3333-3346.e5
    Regulation of nucleo-cytosolic 26S proteasome translocation by aromatic amino acids via mTOR is essential for cell survival under stress.
    Ido Livneh, Victoria Cohen-Kaplan, Bertrand Fabre, Ifat Abramovitch, Chen Lulu, Nishanth Belugali Nataraj, Ikrame Lazar, Tamar Ziv, Yosef Yarden, Yaniv Zohar, Eyal Gottlieb, Aaron Ciechanover.
      The proteasome is responsible for removal of ubiquitinated proteins. Although several aspects of its regulation (e.g., assembly, composition, and post-translational modifications) have been unraveled, studying its adaptive compartmentalization in response to stress is just starting to emerge. We found that following amino acid starvation, the proteasome is translocated from its large nuclear pool to the cytoplasm-a response regulated by newly identified mTOR-agonistic amino acids-Tyr, Trp, and Phe (YWF). YWF relay their signal upstream of mTOR through Sestrin3 by disrupting its interaction with the GATOR2 complex. The triad activates mTOR toward its downstream substrates p62 and transcription factor EB (TFEB), affecting both proteasomal and autophagic activities. Proteasome translocation stimulates cytosolic proteolysis which replenishes amino acids, thus enabling cell survival. In contrast, nuclear sequestration of the proteasome following mTOR activation by YWF inhibits this proteolytic adaptive mechanism, leading to cell death, which establishes this newly identified pathway as a key stress-coping mechanism.
    Keywords:  UPS; aromatic amino acids; mTOR; proteasome dynamics; protein quality control; proteolysis; stress response
    DOI:  https://doi.org/10.1016/j.molcel.2023.08.016
  16. Sci Adv. 2023 Sep 22. 9(38): eadh8228
    Temporal landscape of mitochondrial proteostasis governed by the UPRmt.
    Louise Uoselis, Runa Lindblom, Wai Kit Lam, Catharina J Küng, Marvin Skulsuppaisarn, Grace Khuu, Thanh N Nguyen, Danielle L Rudler, Aleksandra Filipovska, Ralf B Schittenhelm, Michael Lazarou.
      Breakdown of mitochondrial proteostasis activates quality control pathways including the mitochondrial unfolded protein response (UPRmt) and PINK1/Parkin mitophagy. However, beyond the up-regulation of chaperones and proteases, we have a limited understanding of how the UPRmt remodels and restores damaged mitochondrial proteomes. Here, we have developed a functional proteomics framework, termed MitoPQ (Mitochondrial Proteostasis Quantification), to dissect the UPRmt's role in maintaining proteostasis during stress. We find essential roles for the UPRmt in both protecting and repairing proteostasis, with oxidative phosphorylation metabolism being a central target of the UPRmt. Transcriptome analyses together with MitoPQ reveal that UPRmt transcription factors drive independent signaling arms that act in concert to maintain proteostasis. Unidirectional interplay between the UPRmt and PINK1/Parkin mitophagy was found to promote oxidative phosphorylation recovery when the UPRmt failed. Collectively, this study defines the network of proteostasis mediated by the UPRmt and highlights the value of functional proteomics in decoding stressed proteomes.
    DOI:  https://doi.org/10.1126/sciadv.adh8228
  17. PLoS Genet. 2023 Sep 18. 19(9): e1010938
    Neuronal mTORC1 inhibition promotes longevity without suppressing anabolic growth and reproduction in C. elegans.
    Hannah J Smith, Anne Lanjuin, Arpit Sharma, Aditi Prabhakar, Ewelina Nowak, Peter G Stine, Rohan Sehgal, Klement Stojanovski, Benjamin D Towbin, William B Mair.
      mTORC1 (mechanistic target of rapamycin complex 1) is a metabolic sensor that promotes growth when nutrients are abundant. Ubiquitous inhibition of mTORC1 extends lifespan in multiple organisms but also disrupts several anabolic processes resulting in stunted growth, slowed development, reduced fertility, and disrupted metabolism. However, it is unclear if these pleotropic effects of mTORC1 inhibition can be uncoupled from longevity. Here, we utilize the auxin-inducible degradation (AID) system to restrict mTORC1 inhibition to C. elegans neurons. We find that neuron-specific degradation of RAGA-1, an upstream activator of mTORC1, or LET-363, the ortholog of mammalian mTOR, is sufficient to extend lifespan in C. elegans. Unlike raga-1 loss of function genetic mutations or somatic AID of RAGA-1, neuronal AID of RAGA-1 robustly extends lifespan without impairing body size, developmental rate, brood size, or neuronal function. Moreover, while degradation of RAGA-1 in all somatic tissues alters the expression of thousands of genes, demonstrating the widespread effects of mTORC1 inhibition, degradation of RAGA-1 in neurons only results in around 200 differentially expressed genes with a specific enrichment in metabolism and stress response. Notably, our work demonstrates that targeting mTORC1 specifically in the nervous system in C. elegans uncouples longevity from growth and reproductive impairments, and that many canonical effects of low mTORC1 activity are not required to promote healthy aging. These data challenge previously held ideas about the mechanisms of mTORC1 lifespan extension and underscore the potential of promoting longevity by neuron-specific mTORC1 modulation.
    DOI:  https://doi.org/10.1371/journal.pgen.1010938
  18. Int J Surg Pathol. 2023 Sep 16. 10668969231195072
    A Rare Case of Synchronous Fumarate Hydratase-Deficient Renal Cell Carcinoma and Clear Cell Renal Cell Carcinoma With Fumarate Hydratase and von Hippel-Lindau Gene Mutations: A Clinicopathologic and Molecular Study.
    Hui Wen, Linmao Zheng, Mengxin Zhang, Xiuyi Pan, Duohao Wang, Jinyu Qian, Xingming Zhang, Qiao Zhou, Ni Chen.
      Fumarate hydratase-deficient renal cell carcinoma (FH-deficient RCC) is a rare and aggressive tumor characterized by pathogenic alterations in the fumarate hydratase (FH) gene. Clear cell renal cell carcinoma (clear cell RCC) is a common renal cell carcinoma (RCC) associated with von Hippel-Lindau (VHL) gene variations. Here, we reported a case of bilateral RCCs. A 60-year-old man was admitted to hospital with a 3.6 cm × 3.3 cm mass in the right kidney and a 2.8 cm × 2.3 cm nodule in the left kidney. Pathologically, the right tumor showed a nested growth pattern of cells with clear cytoplasm and was FH positive and 2-succinylcysteine (2SC) negative. The left tumor demonstrated a high-grade papillary pattern and was FH negative and 2SC positive. Whole-exome sequencing and Sanger sequencing identified a germline FH c.563A > T mutation in both the tumors and an additional somatic VHL c.479_480insA mutation in the right tumor, confirming the diagnosis of clear cell RCC and FH-deficient RCC in the right and left kidneys, respectively. We reported a rare case of synchronous bilateral clear cell RCC (right) and FH-deficient RCC (left) likely driven by somatic VHL mutation and germline FH mutation, respectively.
    Keywords:  FH mutation; VHL mutation; clear cell renal cell carcinoma; fumarate hydratase-deficient renal cell carcinoma; synchronous bilateral renal cell carcinoma
    DOI:  https://doi.org/10.1177/10668969231195072
  19. Biochim Biophys Acta Rev Cancer. 2023 Sep 16. pii: S0304-419X(23)00133-6. [Epub ahead of print] 188984
    Dietary fat and lipid metabolism in the tumor microenvironment.
    Swagata Goswami, Qiming Zhang, Cigdem Elif Celik, Ethan M Reich, Ömer H Yilmaz.
      Metabolic reprogramming has been considered a core hallmark of cancer, in which excessive accumulation of lipids promote cancer initiation, progression and metastasis. Lipid metabolism is often considered as the digestion and absorption process of dietary fat, and the ways in which cancer cells utilize lipids are often influenced by the complex interactions within the tumor microenvironment. Among multiple cancer risk factors, obesity has a positive association with multiple cancer types, while diets like calorie restriction and fasting improve health and delay cancer. Impact of these diets on tumorigenesis or cancer prevention are generally studied on cancer cells, despite heterogeneity of the tumor microenvironment. Cancer cells regularly interact with these heterogeneous microenvironmental components, including immune and stromal cells, to promote cancer progression and metastasis, and there is an intricate metabolic crosstalk between these compartments. Here, we focus on discussing fat metabolism and response to dietary fat in the tumor microenvironment, focusing on both immune and stromal components and shedding light on therapeutic strategies surrounding lipid metabolic and signaling pathways.
    Keywords:  Fatty acid; High fat diet; Immunosuppression; Lipid metabolism; Obesity; Therapeutic intervention; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.bbcan.2023.188984
  20. Biochim Biophys Acta Rev Cancer. 2023 Sep 15. pii: S0304-419X(23)00136-1. [Epub ahead of print] 188987
    The dual role of citrate in cancer.
    Philippe Icard, Luca Simula, Grit Zahn, Marco Alifano, Maria E Mycielska.
      Citrate is a key metabolite of the Krebs cycle that can also be exported in the cytosol, where it performs several functions. In normal cells, citrate sustains protein acetylation, lipid synthesis, gluconeogenesis, insulin secretion, bone tissues formation, spermatozoid mobility, and immune response. Dysregulation of citrate metabolism is implicated in several pathologies, including cancer. Here we discuss how cancer cells use citrate to sustain their proliferation, survival, and metastatic progression. Also, we propose two paradoxically opposite strategies to reduce tumour growth by targeting citrate metabolism in preclinical models. In the first strategy, we propose to administer in the tumor microenvironment a high amount of citrate, which can then act as a glycolysis inhibitor and apoptosis inducer, whereas the other strategy targets citrate transporters to starve cancer cells from citrate. These strategies, effective in several preclinical in vitro and in vivo cancer models, could be exploited in clinics, particularly to increase sensibility to current anti-cancer agents.
    Keywords:  Cancer; Citrate; Drug resistance; Warburg effect; pmCiC
    DOI:  https://doi.org/10.1016/j.bbcan.2023.188987
  21. Sci Immunol. 2023 Sep 29. 8(87): eadf7579
    Regulatory circuits of mitophagy restrict distinct modes of cell death during memory CD8+ T cell formation.
    Fabien Franco, Alessio Bevilacqua, Ruey-Mei Wu, Kung-Chi Kao, Chun-Pu Lin, Lorène Rousseau, Fu-Ti Peng, Yu-Ming Chuang, Jhan-Jie Peng, Jaeoh Park, Yingxi Xu, Antonino Cassotta, Yi-Ru Yu, Daniel E Speiser, Federica Sallusto, Ping-Chih Ho.
      Mitophagy, a central process guarding mitochondrial quality, is commonly impaired in human diseases such as Parkinson's disease, but its impact in adaptive immunity remains unclear. The differentiation and survival of memory CD8+ T cells rely on oxidative metabolism, a process that requires robust mitochondrial quality control. Here, we found that Parkinson's disease patients have a reduced frequency of CD8+ memory T cells compared with healthy donors and failed to form memory T cells upon vaccination against COVID-19, highlighting the importance of mitochondrial quality control for memory CD8+ T cell formation. We further uncovered that regulators of mitophagy, including Parkin and NIX, were up-regulated in response to interleukin-15 (IL-15) for supporting memory T cell formation. Mechanistically, Parkin suppressed VDAC1-dependent apoptosis in memory T cells. In contrast, NIX expression in T cells counteracted ferroptosis by preventing metabolic dysfunction resulting from impaired mitophagy. Together, our results indicate that the mitophagy machinery orchestrates survival and metabolic dynamics required for memory T cell formation, as well as highlight a deficit in T cell-mediated antiviral responses in Parkinson's disease patients.
    DOI:  https://doi.org/10.1126/sciimmunol.adf7579
  22. Cancer Res. 2023 Sep 20.
    Fatty acid oxidation mediated by malonyl-CoA decarboxylase represses renal cell carcinoma progression.
    Lijie Zhou, Yongbo Luo, Yuenan Liu, Youmiao Zeng, Junwei Tong, Mengting Li, Yaxin Hou, Kaixuan Du, Yabin Qi, Wenbang Pan, Yuanhao Liu, Rongli Wang, Fengyan Tian, Chaohui Gu, Ke Chen.
      Fatty acid metabolism reprogramming is a prominent feature of clear cell renal cell carcinoma (ccRCC). Increased lipid storage supports ccRCC progression, highlighting the importance of understanding the molecular mechanisms driving altered fatty acid synthesis in tumors. Here, we identified that malonyl-CoA decarboxylase (MLYCD), a key regulator of fatty acid anabolism, was downregulated in ccRCC, and low expression correlated with poor prognosis in patients. Restoring MLYCD expression in ccRCC cells decreased the content of malonyl CoA, which blocked de novo fatty acid synthesis and promoted fatty acid translocation into mitochondria for oxidation. Inhibition of lipid droplet accumulation induced by MLYCD-mediated fatty acid oxidation disrupted endoplasmic reticulum and mitochondrial homeostasis, increased reactive oxygen species levels, and induced ferroptosis. Moreover, overexpressing MLYCD reduced tumor growth and reversed resistance to sunitinib in vitro and in vivo. Mechanistically, HIF2α inhibited MLYCD translation by upregulating expression of eIF4G3 microexons. Together, this study demonstrates that fatty acid catabolism mediated by MLYCD disrupts lipid homeostasis to repress ccRCC progression. Activating MLYCD-mediated fatty acid metabolism could be a promising therapeutic strategy for treating ccRCC.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-23-0969
  23. Cell Res. 2023 Sep 19.
    Low glucose metabolite 3-phosphoglycerate switches PHGDH from serine synthesis to p53 activation to control cell fate.
    Yu-Qing Wu, Chen-Song Zhang, Jinye Xiong, Dong-Qi Cai, Chen-Zhe Wang, Yu Wang, Yan-Hui Liu, Yu Wang, Yiming Li, Jian Wu, Jianfeng Wu, Bin Lan, Xuefeng Wang, Siwei Chen, Xianglei Cao, Xiaoyan Wei, Hui-Hui Hu, Huiling Guo, Yaxin Yu, Abdul Ghafoor, Changchuan Xie, Yaying Wu, Zheni Xu, Cixiong Zhang, Mingxia Zhu, Xi Huang, Xiufeng Sun, Shu-Yong Lin, Hai-Long Piao, Jianyin Zhou, Sheng-Cai Lin.
      Glycolytic intermediary metabolites such as fructose-1,6-bisphosphate can serve as signals, controlling metabolic states beyond energy metabolism. However, whether glycolytic metabolites also play a role in controlling cell fate remains unexplored. Here, we find that low levels of glycolytic metabolite 3-phosphoglycerate (3-PGA) can switch phosphoglycerate dehydrogenase (PHGDH) from cataplerosis serine synthesis to pro-apoptotic activation of p53. PHGDH is a p53-binding protein, and when unoccupied by 3-PGA interacts with the scaffold protein AXIN in complex with the kinase HIPK2, both of which are also p53-binding proteins. This leads to the formation of a multivalent p53-binding complex that allows HIPK2 to specifically phosphorylate p53-Ser46 and thereby promote apoptosis. Furthermore, we show that PHGDH mutants (R135W and V261M) that are constitutively bound to 3-PGA abolish p53 activation even under low glucose conditions, while the mutants (T57A and T78A) unable to bind 3-PGA cause constitutive p53 activation and apoptosis in hepatocellular carcinoma (HCC) cells, even in the presence of high glucose. In vivo, PHGDH-T57A induces apoptosis and inhibits the growth of diethylnitrosamine-induced mouse HCC, whereas PHGDH-R135W prevents apoptosis and promotes HCC growth, and knockout of Trp53 abolishes these effects above. Importantly, caloric restriction that lowers whole-body glucose levels can impede HCC growth dependent on PHGDH. Together, these results unveil a mechanism by which glucose availability autonomously controls p53 activity, providing a new paradigm of cell fate control by metabolic substrate availability.
    DOI:  https://doi.org/10.1038/s41422-023-00874-4
  24. Proc Natl Acad Sci U S A. 2023 Sep 26. 120(39): e2302878120
    CPT1A-mediated fatty acid oxidation confers cancer cell resistance to immune-mediated cytolytic killing.
    Zheng Liu, Wenjie Liu, Wei Wang, Yibao Ma, Yufeng Wang, David L Drum, Jinyang Cai, Hallie Blevins, Eun Lee, Syed Shah, Paul B Fisher, Xinhui Wang, Xianjun Fang, Chunqing Guo, Xiang-Yang Wang.
      Although tumor-intrinsic fatty acid β-oxidation (FAO) is implicated in multiple aspects of tumorigenesis and progression, the impact of this metabolic pathway on cancer cell susceptibility to immunotherapy remains unknown. Here, we report that cytotoxicity of killer T cells induces activation of FAO and upregulation of carnitine palmitoyltransferase 1A (CPT1A), the rate-limiting enzyme of FAO in cancer cells. The repression of CPT1A activity or expression renders cancer cells more susceptible to destruction by cytotoxic T lymphocytes. Our mechanistic studies reveal that FAO deficiency abrogates the prosurvival signaling in cancer cells under immune cytolytic stress. Furthermore, we identify T cell-derived IFN-γ as a major factor responsible for induction of CPT1A and FAO in an AMPK-dependent manner, indicating a dynamic interplay between immune effector cells and tumor targets. While cancer growth in the absence of CPT1A remains largely unaffected, established tumors upon FAO inhibition become significantly more responsive to cellular immunotherapies including chimeric antigen receptor-engineered human T cells. Together, these findings uncover a mode of cancer resistance and immune editing that can facilitate immune escape and limit the benefits of immunotherapies.
    Keywords:  cancer metabolism; carnitine palmitoyltransferase 1A; cellular immunotherapy; fatty acid oxidation; therapeutic resistance
    DOI:  https://doi.org/10.1073/pnas.2302878120
  25. Nat Cancer. 2023 Sep 18.
    PD-1 instructs a tumor-suppressive metabolic program that restricts glycolysis and restrains AP-1 activity in T cell lymphoma.
    Tim Wartewig, Jay Daniels, Miriam Schulz, Erik Hameister, Abhinav Joshi, Joonhee Park, Emma Morrish, Anuroop V Venkatasubramani, Filippo M Cernilogar, Frits H A van Heijster, Christian Hundshammer, Heike Schneider, Filippos Konstantinidis, Judith V Gabler, Christine Klement, Henry Kurniawan, Calvin Law, Yujin Lee, Sara Choi, Joan Guitart, Ignasi Forne, Jérôme Giustinani, Markus Müschen, Salvia Jain, David M Weinstock, Roland Rad, Nicolas Ortonne, Franz Schilling, Gunnar Schotta, Axel Imhof, Dirk Brenner, Jaehyuk Choi, Jürgen Ruland.
      The PDCD1-encoded immune checkpoint receptor PD-1 is a key tumor suppressor in T cells that is recurrently inactivated in T cell non-Hodgkin lymphomas (T-NHLs). The highest frequencies of PDCD1 deletions are detected in advanced disease, predicting inferior prognosis. However, the tumor-suppressive mechanisms of PD-1 signaling remain unknown. Here, using tractable mouse models for T-NHL and primary patient samples, we demonstrate that PD-1 signaling suppresses T cell malignancy by restricting glycolytic energy and acetyl coenzyme A (CoA) production. In addition, PD-1 inactivation enforces ATP citrate lyase (ACLY) activity, which generates extramitochondrial acetyl-CoA for histone acetylation to enable hyperactivity of activating protein 1 (AP-1) transcription factors. Conversely, pharmacological ACLY inhibition impedes aberrant AP-1 signaling in PD-1-deficient T-NHLs and is toxic to these cancers. Our data uncover genotype-specific vulnerabilities in PDCD1-mutated T-NHL and identify PD-1 as regulator of AP-1 activity.
    DOI:  https://doi.org/10.1038/s43018-023-00635-7
  26. J Cell Biol. 2023 Dec 04. pii: e202303066. [Epub ahead of print]222(12):
    Peroxisomal ROS control cytosolic Mycobacterium tuberculosis replication in human macrophages.
    Enrica Pellegrino, Beren Aylan, Claudio Bussi, Antony Fearns, Elliott M Bernard, Natalia Athanasiadi, Pierre Santucci, Laure Botella, Maximiliano G Gutierrez.
      Peroxisomes are organelles involved in many metabolic processes including lipid metabolism, reactive oxygen species (ROS) turnover, and antimicrobial immune responses. However, the cellular mechanisms by which peroxisomes contribute to bacterial elimination in macrophages remain elusive. Here, we investigated peroxisome function in iPSC-derived human macrophages (iPSDM) during infection with Mycobacterium tuberculosis (Mtb). We discovered that Mtb-triggered peroxisome biogenesis requires the ESX-1 type 7 secretion system, critical for cytosolic access. iPSDM lacking peroxisomes were permissive to Mtb wild-type (WT) replication but were able to restrict an Mtb mutant missing functional ESX-1, suggesting a role for peroxisomes in the control of cytosolic but not phagosomal Mtb. Using genetically encoded localization-dependent ROS probes, we found peroxisomes increased ROS levels during Mtb WT infection. Thus, human macrophages respond to the infection by increasing peroxisomes that generate ROS primarily to restrict cytosolic Mtb. Our data uncover a peroxisome-controlled, ROS-mediated mechanism that contributes to the restriction of cytosolic bacteria.
    DOI:  https://doi.org/10.1083/jcb.202303066
  27. Nat Genet. 2023 Sep 18.
    Molecular basis for maternal inheritance of human mitochondrial DNA.
    William Lee, Angelica Zamudio-Ochoa, Gina Buchel, Petar Podlesniy, Nuria Marti Gutierrez, Margalida Puigròs, Anna Calderon, Hsin-Yao Tang, Li Li, Aleksei Mikhalchenko, Amy Koski, Ramon Trullas, Shoukhrat Mitalipov, Dmitry Temiakov.
      Uniparental inheritance of mitochondrial DNA (mtDNA) is an evolutionary trait found in nearly all eukaryotes. In many species, including humans, the sperm mitochondria are introduced to the oocyte during fertilization1,2. The mechanisms hypothesized to prevent paternal mtDNA transmission include ubiquitination of the sperm mitochondria and mitophagy3,4. However, the causative mechanisms of paternal mtDNA elimination have not been defined5,6. We found that mitochondria in human spermatozoa are devoid of intact mtDNA and lack mitochondrial transcription factor A (TFAM)-the major nucleoid protein required to protect, maintain and transcribe mtDNA. During spermatogenesis, sperm cells express an isoform of TFAM, which retains the mitochondrial presequence, ordinarily removed upon mitochondrial import. Phosphorylation of this presequence prevents mitochondrial import and directs TFAM to the spermatozoon nucleus. TFAM relocalization from the mitochondria of spermatogonia to the spermatozoa nucleus directly correlates with the elimination of mtDNA, thereby explaining maternal inheritance in this species.
    DOI:  https://doi.org/10.1038/s41588-023-01505-9
  28. Nat Biotechnol. 2023 Sep 21.
    A DNA nanodevice for mapping sodium at single-organelle resolution.
    Junyi Zou, Koushambi Mitra, Palapuravan Anees, Daphne Oettinger, Joseph R Ramirez, Aneesh Tazhe Veetil, Priyanka Dutta Gupta, Rajini Rao, Jayson J Smith, Paschalis Kratsios, Yamuna Krishnan.
      Cellular sodium ion (Na+) homeostasis is integral to organism physiology. Our current understanding of Na+ homeostasis is largely limited to Na+ transport at the plasma membrane. Organelles may also contribute to Na+ homeostasis; however, the direction of Na+ flow across organelle membranes is unknown because organellar Na+ cannot be imaged. Here we report a pH-independent, organelle-targetable, ratiometric probe that reports lumenal Na+. It is a DNA nanodevice containing a Na+-sensitive fluorophore, a reference dye and an organelle-targeting domain. By measuring Na+ at single endosome resolution in mammalian cells and Caenorhabditis elegans, we discovered that lumenal Na+ levels in each stage of the endolysosomal pathway exceed cytosolic levels and decrease as endosomes mature. Further, we find that lysosomal Na+ levels in nematodes are modulated by the Na+/H+ exchanger NHX-5 in response to salt stress. The ability to image subcellular Na+ will unveil mechanisms of Na+ homeostasis at an increased level of cellular detail.
    DOI:  https://doi.org/10.1038/s41587-023-01950-1
  29. J Immunol. 2023 Sep 22. pii: ji2300406. [Epub ahead of print]
    The Lysosomal Calcium Channel TRPML1 Maintains Mitochondrial Fitness in NK Cells through Interorganelle Cross-Talk.
    Dennis Clement, Edina K Szabo, Silje Zandstra Krokeide, Merete Thune Wiiger, Marianna Vincenti, Daniel Palacios, Young-Tae Chang, Christian Grimm, Sandip Patel, Harald Stenmark, Andreas Brech, Rakesh Kumar Majhi, Karl-Johan Malmberg.
      Cytotoxic lymphocytes eliminate cancer cells through the release of lytic granules, a specialized form of secretory lysosomes. This compartment is part of the pleomorphic endolysosomal system and is distinguished by its highly dynamic Ca2+ signaling machinery. Several transient receptor potential (TRP) calcium channels play essential roles in endolysosomal Ca2+ signaling and ensure the proper function of these organelles. In this study, we examined the role of TRPML1 (TRP cation channel, mucolipin subfamily, member 1) in regulating the homeostasis of secretory lysosomes and their cross-talk with mitochondria in human NK cells. We found that genetic deletion of TRPML1, which localizes to lysosomes in NK cells, led to mitochondrial fragmentation with evidence of collapsed mitochondrial cristae. Consequently, TRPML1-/- NK92 (NK92ML1-/-) displayed loss of mitochondrial membrane potential, increased reactive oxygen species stress, reduced ATP production, and compromised respiratory capacity. Using sensitive organelle-specific probes, we observed that mitochondria in NK92ML1-/- cells exhibited evidence of Ca2+ overload. Moreover, pharmacological activation of the TRPML1 channel in primary NK cells resulted in upregulation of LC3-II, whereas genetic deletion impeded autophagic flux and increased accumulation of dysfunctional mitochondria. Thus, TRPML1 impacts autophagy and clearance of damaged mitochondria. Taken together, these results suggest that an intimate interorganelle communication in NK cells is orchestrated by the lysosomal Ca2+ channel TRPML1.
    DOI:  https://doi.org/10.4049/jimmunol.2300406
  30. Cell Chem Biol. 2023 Sep 21. pii: S2451-9456(23)00284-2. [Epub ahead of print]30(9): 1012-1014
    Glutamine availability unleashes dendritic cells' anti-tumor power.
    Mauro Corrado, Christian Frezza.
      Metabolic competition within the tumor microenvironment (TME) shapes the efficacy of anticancer immunity. In the August 3rd issue of Nature, Guo et al.1 show that glutamine is an intercellular metabolic checkpoint between cancer and immune cells. Targeting glutamine metabolism in the TME is a promising strategy to improve anti-cancer therapy.
    DOI:  https://doi.org/10.1016/j.chembiol.2023.08.012
  31. Nature. 2023 Sep 18.
    Cholinergic neurons trigger epithelial Ca2+ currents to heal the gut.
    Afroditi Petsakou, Yifang Liu, Ying Liu, Aram Comjean, Yanhui Hu, Norbert Perrimon.
      A fundamental and unresolved question in regenerative biology is how tissues return to homeostasis after injury. Answering this question is essential for understanding the etiology of chronic disorders such as inflammatory bowel diseases and cancer1. We used the Drosophila midgut2 to investigate this and discovered that during regeneration a subpopulation of cholinergic3 neurons triggers Ca2+ currents among intestinal epithelial cells, the enterocytes, to promote return to homeostasis. We found that down-regulation of the conserved cholinergic enzyme Acetylcholinesterase4 in the gut epithelium enables acetylcholine from specific TNF/Egr5-sensing cholinergic neurons to activate nicotinic receptors in innervated enterocytes. This activation triggers high Ca2+ that spreads in the epithelium through Inx2/Inx7 gap junctions6, promoting enterocyte maturation followed by reduction of proliferation and inflammation. Disrupting this process causes chronic injury consisting of ion imbalance, Yki/Yap activation7, cell death and increase of inflammatory cytokines reminiscent of inflammatory bowel diseases8. Altogether, the conserved cholinergic pathway facilitates epithelial Ca2+ currents that heal the intestinal epithelium. Our findings demonstrate nerve- and bioelectric9-dependent intestinal regeneration and advance our current understanding of how a tissue returns to homeostasis after injury.
    DOI:  https://doi.org/10.1038/s41586-023-06627-y
  32. Nature. 2023 Sep 20.
    The β1-adrenergic receptor links sympathetic nerves to T cell exhaustion.
    Anna-Maria Globig, Steven Zhao, Jessica Roginsky, Vivien I Maltez, Juan Guiza, Natalia Avina-Ochoa, Maximilian Heeg, Filipe Araujo Hoffmann, Omkar Chaudhary, Jiawei Wang, Gokhan Senturk, Dan Chen, Carolyn O'Connor, Samuel Pfaff, Ronald N Germain, Kurt A Schalper, Brinda Emu, Susan M Kaech.
      CD8+ T cells are essential components of the immune response against viral infections and tumours, and are capable of eliminating infected and cancerous cells. However, when the antigen cannot be cleared, T cells enter a state known as exhaustion1. Although it is clear that chronic antigen contributes to CD8+ T cell exhaustion, less is known about how stress responses in tissues regulate T cell function. Here we show a new link between the stress-associated catecholamines and the progression of T cell exhaustion through the β1-adrenergic receptor ADRB1. We identify that exhausted CD8+ T cells increase ADRB1 expression and that exposure of ADRB1+ T cells to catecholamines suppresses their cytokine production and proliferation. Exhausted CD8+ T cells cluster around sympathetic nerves in an ADRB1-dependent manner. Ablation of β1-adrenergic signalling limits the progression of T cells towards the exhausted state in chronic infection and improves effector functions when combined with immune checkpoint blockade (ICB) in melanoma. In a pancreatic cancer model resistant to ICB, β-blockers and ICB synergize to boost CD8+ T cell responses and induce the development of tissue-resident memory-like T cells. Malignant disease is associated with increased catecholamine levels in patients2,3, and our results establish a connection between the sympathetic stress response, tissue innervation and T cell exhaustion. Here, we uncover a new mechanism by which blocking β-adrenergic signalling in CD8+ T cells rejuvenates anti-tumour functions.
    DOI:  https://doi.org/10.1038/s41586-023-06568-6
  33. Nat Struct Mol Biol. 2023 Sep 21.
    PARylated PDHE1α generates acetyl-CoA for local chromatin acetylation and DNA damage repair.
    Jun Zhang, Feng Chen, Yuan Tian, Wenchao Xu, Qian Zhu, Zhenhai Li, Lingyu Qiu, Xiaopeng Lu, Bin Peng, Xiangyu Liu, Haiyun Gan, Baohua Liu, Xingzhi Xu, Wei-Guo Zhu.
      Chromatin relaxation is a prerequisite for the DNA repair machinery to access double-strand breaks (DSBs). Local histones around the DSBs then undergo prompt changes in acetylation status, but how the large demands of acetyl-CoA are met is unclear. Here, we report that pyruvate dehydrogenase 1α (PDHE1α) catalyzes pyruvate metabolism to rapidly provide acetyl-CoA in response to DNA damage. We show that PDHE1α is quickly recruited to chromatin in a polyADP-ribosylation-dependent manner, which drives acetyl-CoA generation to support local chromatin acetylation around DSBs. This process increases the formation of relaxed chromatin to facilitate repair-factor loading, genome stability and cancer cell resistance to DNA-damaging treatments in vitro and in vivo. Indeed, we demonstrate that blocking polyADP-ribosylation-based PDHE1α chromatin recruitment attenuates chromatin relaxation and DSB repair efficiency, resulting in genome instability and restored radiosensitivity. These findings support a mechanism in which chromatin-associated PDHE1α locally generates acetyl-CoA to remodel the chromatin environment adjacent to DSBs and promote their repair.
    DOI:  https://doi.org/10.1038/s41594-023-01107-3
  34. Nat Rev Genet. 2023 Sep 22.
    Pioneer factors - key regulators of chromatin and gene expression.
    Martha L Bulyk, Jacques Drouin, Melissa M Harrison, Jussi Taipale, Kenneth S Zaret.
      
    DOI:  https://doi.org/10.1038/s41576-023-00648-z
  35. Nat Commun. 2023 Sep 21. 14(1): 5883
    Structural basis of the activation of TRPV5 channels by long-chain acyl-Coenzyme-A.
    Bo-Hyun Lee, José J De Jesús Pérez, Vera Moiseenkova-Bell, Tibor Rohacs.
      Long-chain acyl-coenzyme A (LC-CoA) is a crucial metabolic intermediate that plays important cellular regulatory roles, including activation and inhibition of ion channels. The structural basis of ion channel regulation by LC-CoA is not known. Transient receptor potential vanilloid 5 and 6 (TRPV5 and TRPV6) are epithelial calcium-selective ion channels. Here, we demonstrate that LC-CoA activates TRPV5 and TRPV6 in inside-out patches, and both exogenously supplied and endogenously produced LC-CoA can substitute for the natural ligand phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) in maintaining channel activity in intact cells. Utilizing cryo-electron microscopy, we determined the structure of LC-CoA-bound TRPV5, revealing an open configuration with LC-CoA occupying the same binding site as PI(4,5)P2 in previous studies. This is consistent with our finding that PI(4,5)P2 could not further activate the channels in the presence of LC-CoA. Our data provide molecular insights into ion channel regulation by a metabolic signaling molecule.
    DOI:  https://doi.org/10.1038/s41467-023-41577-z
  36. Sci Adv. 2023 Sep 22. 9(38): eadh5152
    RNA folding studies inside peptide-rich droplets reveal roles of modified nucleosides at the origin of life.
    McCauley O Meyer, Ryota Yamagami, Saehyun Choi, Christine D Keating, Philip C Bevilacqua.
      Compartmentalization of RNA in biopolymer-rich membraneless organelles is now understood to be pervasive and critical for the function of extant biology and has been proposed as a prebiotically plausible way to accumulate RNA. However, compartment-RNA interactions that drive encapsulation have the potential to influence RNA structure and function in compartment- and RNA sequence-dependent ways. Here, we detail next-generation sequencing (NGS) experiments performed in membraneless compartments called complex coacervates to characterize the fold of many different transfer RNAs (tRNAs) simultaneously under the potentially denaturing conditions of these compartments. Notably, we find that natural modifications favor the native fold of tRNAs in these compartments. This suggests that covalent RNA modifications could have played a critical role in metabolic processes at the origin of life.
    DOI:  https://doi.org/10.1126/sciadv.adh5152
  37. Dev Cell. 2023 Sep 09. pii: S1534-5807(23)00443-4. [Epub ahead of print]
    Palbociclib releases the latent differentiation capacity of neuroblastoma cells.
    Kirsty M Ferguson, Sarah L Gillen, Lewis Chaytor, Evon Poon, Daniel Marcos, Roshna Lawrence Gomez, Laura M Woods, Lidiya Mykhaylechko, Louis Elfari, Barbara Martins da Costa, Yann Jamin, Jason S Carroll, Louis Chesler, Fahad R Ali, Anna Philpott.
      Neuroblastoma is the most common extracranial solid tumor in infants, arising from developmentally stalled neural crest-derived cells. Driving tumor differentiation is a promising therapeutic approach for this devastating disease. Here, we show that the CDK4/6 inhibitor palbociclib not only inhibits proliferation but induces extensive neuronal differentiation of adrenergic neuroblastoma cells. Palbociclib-mediated differentiation is manifested by extensive phenotypic and transcriptional changes accompanied by the establishment of an epigenetic program driving expression of mature neuronal features. In vivo palbociclib significantly inhibits tumor growth in mouse neuroblastoma models. Furthermore, dual treatment with retinoic acid resets the oncogenic adrenergic core regulatory circuit of neuroblastoma cells, further suppresses proliferation, and can enhance differentiation, altering gene expression in ways that significantly correlate with improved patient survival. We therefore identify palbociclib as a therapeutic approach to dramatically enhance neuroblastoma differentiation efficacy that could be used in combination with retinoic acid to improve patient outcomes.
    Keywords:  CDK4; CDK6; cell cycle; differentiation; neuroblastoma; palbociclib; retinoic acid
    DOI:  https://doi.org/10.1016/j.devcel.2023.08.028
  38. Proc Natl Acad Sci U S A. 2023 Sep 26. 120(39): e2304884120
    Coenzyme Q10 trapping in mitochondrial complex I underlies Leber's hereditary optic neuropathy.
    Jack T Fuller, Steven Barnes, Lorenzo A Sadun, Pujan Ajmera, Anastassia N Alexandrova, Alfredo A Sadun.
      How does a single amino acid mutation occurring in the blinding disease, Leber's hereditary optic neuropathy (LHON), impair electron shuttling in mitochondria? We investigated changes induced by the m.3460 G>A mutation in mitochondrial protein ND1 using the tools of Molecular Dynamics and Free Energy Perturbation simulations, with the goal of determining the mechanism by which this mutation affects mitochondrial function. A recent analysis suggested that the mutation's replacement of alanine A52 with a threonine perturbs the stability of a region where binding of the electron shuttling protein, Coenzyme Q10, occurs. We found two functionally opposing changes involving the role of Coenzyme Q10. The first showed that quantum electron transfer from the terminal Fe/S complex, N2, to the Coenzyme Q10 headgroup, docked in its binding pocket, is enhanced. However, this positive adjustment is overshadowed by our finding that the mobility of Coenzyme Q10 in its oxidized and reduced states, entering and exiting its binding pocket, is disrupted by the mutation in a manner that leads to conditions promoting the generation of reactive oxygen species. An increase in reactive oxygen species caused by the LHON mutation has been proposed to be responsible for this optic neuropathy.
    Keywords:  Coenzyme Q10; blinding genetic disease; mitochondria; molecular dynamics simulation; quantum electron tunneling
    DOI:  https://doi.org/10.1073/pnas.2304884120
  39. Trends Biochem Sci. 2023 Sep 14. pii: S0968-0004(23)00210-4. [Epub ahead of print]
    A physicochemical perspective on cellular ageing.
    Sara N Mouton, Arnold J Boersma, Liesbeth M Veenhoff.
      Cellular ageing described at the molecular level is a multifactorial process that leads to a spectrum of ageing trajectories. There has been recent discussion about whether a decline in physicochemical homeostasis causes aberrant phase transitions, which are a driver of ageing. Indeed, the function of all biological macromolecules, regardless of their participation in biomolecular condensates, depends on parameters such as pH, crowding, and redox state. We expand on the physicochemical homeostasis hypothesis and summarise recent evidence that the intracellular milieu influences molecular processes involved in ageing.
    Keywords:  cell volume; macromolecular crowding; organellar crowding; pH; redox homeostasis; yeast
    DOI:  https://doi.org/10.1016/j.tibs.2023.08.007
  40. Mitochondrion. 2023 Sep 20. pii: S1567-7249(23)00083-1. [Epub ahead of print]
    The Constraints of Allotopic Expression.
    Felipe Nieto-Panqueva, Diana Rubalcava-Gracia, Patrice P Hamel, Diego González-Halphen.
      Allotopic expression is the functional transfer of an organellar gene to the nucleus, followed by synthesis of the gene product in the cytosol and import into the appropriate organellar sub compartment. Here, we focus on mitochondrial genes encoding OXPHOS subunits that were naturally transferred to the nucleus, and critically review experimental evidence that claim their allotopic expression. We emphasize aspects that may have been overlooked before, i.e., when modifying a mitochondrial gene for allotopic expression ━besides adapting the codon usage and including sequences encoding mitochondrial targeting signals━ three additional constraints should be considered: i) the average apparent free energy of membrane insertion (μΔGapp) of the transmembrane stretches (TMS) in proteins earmarked for the inner mitochondrial membrane, ii) the final, functional topology attained by each membrane-bound OXPHOS subunit; and iii) the defined mechanism by which the protein translocator TIM23 sorts cytosol-synthesized precursors. The mechanistic constraints imposed by TIM23 dictate the operation of two pathways through which alpha-helices in TMS are sorted, that eventually determine the final topology of membrane proteins. We used the biological hydrophobicity scale to assign an average apparent free energy of membrane insertion (μΔGapp) and a "traffic light" color code to all TMS of OXPHOS membrane proteins, thereby predicting which are more likely to be internalized into mitochondria if allotopically produced. We propose that the design of proteins for allotopic expression must make allowance for μΔGapp maximization of highly hydrophobic TMS in polypeptides whose corresponding genes have not been transferred to the nucleus in some organisms.
    Keywords:  TIM23; allotopic expression; apparent free energy of membrane insertion; membrane embedded proteins; mitochondrial complexes; oxidative phosphorylation; protein import; transmembrane stretches
    DOI:  https://doi.org/10.1016/j.mito.2023.09.004
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