bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2023–11–26
47 papers selected by
Christian Frezza, Universität zu Köln
  1. Inferring mitochondrial and cytosolic metabolism by coupling isotope tracing and deconvolution.
  2. Lysosomes as coordinators of cellular catabolism, metabolic signalling and organ physiology.
  3. A century of the Warburg effect.
  4. Determination of Metabolic Fluxes by Deep Learning of Isotope Labeling Patterns.
  5. Mitochondrial nucleoid condensates drive peripheral fission through high membrane curvature.
  6. Vitamin B5 Supports Oncogenic Metabolism in MYC-Driven Breast Cancer.
  7. Proline and dihydroorotate dehydrogenase promote a hyper-proliferative state and dampen ferroptosis in cancer cells by rewiring mitochondrial redox metabolism.
  8. Linking neuropsychiatric disease to neuronal metabolism.
  9. Sirtuin3 ensures the metabolic plasticity of neurotransmission during glucose deprivation.
  10. Mitochondrial phosphoproteomes are functionally specialized across tissues.
  11. A distinct Acyl-CoA binding protein (ACBP6) shapes tissue plasticity during nutrient adaptation in Drosophila.
  12. Mitochondrial fission drives neuronal metabolic burden to promote stress susceptibility in male mice.
  13. Glucose-6-phosphate dehydrogenase deficiency accelerates pancreatic acinar-to-ductal metaplasia.
  14. Toward Systems-Level Metabolic Analysis in Endocrine Disorders and Cancer.
  15. Cell-specific modulation of mitochondrial respiration and metabolism by the pro-apoptotic Bcl-2 family members Bax and Bak.
  16. Microautophagy regulated by STK38 and GABARAPs is essential to repair lysosomes and prevent aging.
  17. Cardiac macrophage metabolism in health and disease.
  18. The tRNA-GCN2-FBXO22-axis-mediated mTOR ubiquitination senses amino acid insufficiency.
  19. Learning from circadian rhythm to transform cancer prevention, prognosis, and survivorship care.
  20. Mitochondrial One-Carbon Metabolism is Required for TGF-β-Induced Glycine Synthesis and Collagen Protein Production.
  21. Adipose cDC1s contribute to obesity-associated inflammation through STING-dependent IL-12 production.
  22. A metabolic axis of immune intractability.
  23. Longitudinal dynamics of the tumor hypoxia response: From enzyme activity to biological phenotype.
  24. 2D and 3D multiplexed subcellular profiling of nuclear instability in human cancer.
  25. HILPS, a long noncoding RNA essential for global oxygen sensing in humans.
  26. What can we learn about acid-base transporters in cancer from studying somatic mutations in their genes?
  27. Nucleotide excision repair deficiency is a targetable therapeutic vulnerability in clear cell renal cell carcinoma.
  28. SETD2 deficiency accelerates sphingomyelin accumulation and promotes the development of renal cancer.
  29. Reactivation of the G1 enhancer landscape underlies core circuitry addiction to SWI/SNF.
  30. Hereditary succinate dehydrogenase-deficient renal cell carcinoma.
  31. Quick tips for interpreting cell death experiments.
  32. Age-associated transcriptional stress due to accelerated elongation and increased stalling of RNAPII.
  33. Intra-promoter switch of transcription initiation sites in proliferation signaling-dependent RNA metabolism.
  34. Anomalous peroxidase activity of cytochrome c is the primary pathogenic target in Barth syndrome.
  35. Epithelial IFNγ signalling and compartmentalized antigen presentation orchestrate gut immunity.
  36. Heme Biosynthesis is Crucial for Cell Survival and Mitochondrial OXPHOS after X Irradiation.
  37. Combined inhibition of MTAP and MAT2a mimics synthetic lethality in tumor models via PRMT5 inhibition.
  38. Trans-vaccenic acid reprograms CD8+ T cells and anti-tumour immunity.
  39. Adipo-glial signaling mediates metabolic adaptation in peripheral nerve regeneration.
  40. Metabolic reprogramming driven by EZH2 inhibition depends on cell-matrix interactions.
  41. The lifelong natural history of clonal hematopoiesis and its links to myeloid malignancy.
  42. Circadian clock factors regulate the first condensation reaction of fatty acid synthesis in Arabidopsis.
  43. Modeling Red Blood Cell Metabolism in the Omics Era.
  44. Extracellular Delivery of Functional Mitochondria Rescues the Dysfunction of CD4+ T Cells in Aging.
  45. LUBAC is required for RIG-I sensing of RNA viruses.
  46. Mitochondrial hyperfusion induces metabolic remodeling in lung endothelial cells by modifying the activities of electron transport chain complexes I and III.
  47. Is clonal hematopoiesis 'mostly harmless'?
  1. Nat Commun. 2023 11 18. 14(1): 7525
    Inferring mitochondrial and cytosolic metabolism by coupling isotope tracing and deconvolution.
    Alon Stern, Mariam Fokra, Boris Sarvin, Ahmad Abed Alrahem, Won Dong Lee, Elina Aizenshtein, Nikita Sarvin, Tomer Shlomi.
      The inability to inspect metabolic activities within distinct subcellular compartments has been a major barrier to our understanding of eukaryotic cell metabolism. Previous work addressed this challenge by analyzing metabolism in isolated organelles, which grossly bias metabolic activity. Here, we describe a method for inferring physiological metabolic fluxes and metabolite concentrations in mitochondria and cytosol based on isotope tracing experiments performed with intact cells. This is made possible by computational deconvolution of metabolite isotopic labeling patterns and concentrations into cytosolic and mitochondrial counterparts, coupled with metabolic and thermodynamic modelling. Our approach lowers the uncertainty regarding compartmentalized fluxes and concentrations by one and three orders of magnitude compared to existing modelling approaches, respectively. We derive a quantitative view of mitochondrial and cytosolic metabolic activities in central carbon metabolism across cultured cell lines without performing cell fractionation, finding major variability in compartmentalized malate-aspartate shuttle fluxes. We expect our approach for inferring metabolism at a subcellular resolution to be instrumental for a variety of studies of metabolic dysfunction in human disease and for bioengineering.
    DOI:  https://doi.org/10.1038/s41467-023-42824-z
  2. Nat Rev Mol Cell Biol. 2023 Nov 24.
    Lysosomes as coordinators of cellular catabolism, metabolic signalling and organ physiology.
    Carmine Settembre, Rushika M Perera.
      Every cell must satisfy basic requirements for nutrient sensing, utilization and recycling through macromolecular breakdown to coordinate programmes for growth, repair and stress adaptation. The lysosome orchestrates these key functions through the synchronised interplay between hydrolytic enzymes, nutrient transporters and signalling factors, which together enable metabolic coordination with other organelles and regulation of specific gene expression programmes. In this Review, we discuss recent findings on lysosome-dependent signalling pathways, focusing on how the lysosome senses nutrient availability through its physical and functional association with mechanistic target of rapamycin complex 1 (mTORC1) and how, in response, the microphthalmia/transcription factor E (MiT/TFE) transcription factors exert feedback regulation on lysosome biogenesis. We also highlight the emerging interactions of lysosomes with other organelles, which contribute to cellular homeostasis. Lastly, we discuss how lysosome dysfunction contributes to diverse disease pathologies and how inherited mutations that compromise lysosomal hydrolysis, transport or signalling components lead to multi-organ disorders with severe metabolic and neurological impact. A deeper comprehension of lysosomal composition and function, at both the cellular and organismal level, may uncover fundamental insights into human physiology and disease.
    DOI:  https://doi.org/10.1038/s41580-023-00676-x
  3. Nat Metab. 2023 Nov;5(11): 1840-1843
    A century of the Warburg effect.
    Craig B Thompson, Karen H Vousden, Randall S Johnson, Willem H Koppenol, Helmut Sies, Zhimin Lu, Lydia W S Finley, Christian Frezza, Jiyeon Kim, Zeping Hu, Caroline R Bartman.
      
    DOI:  https://doi.org/10.1038/s42255-023-00927-3
  4. bioRxiv. 2023 Nov 08. pii: 2023.11.06.565907. [Epub ahead of print]
    Determination of Metabolic Fluxes by Deep Learning of Isotope Labeling Patterns.
    Richard C Law, Samantha O'Keeffe, Glenn Nurwono, Rachel Ki, Aliya Lakhani, Pin-Kuang Lai, Junyoung O Park.
      Fluxomics offers a direct readout of metabolic state but relies on indirect measurement. Stable isotope tracers imprint flux-dependent isotope labeling patterns on metabolites we measure; however, the relationship between labeling patterns and fluxes remains elusive. Here we innovate a two-stage machine learning framework termed ML-Flux that streamlines metabolic flux quantitation from isotope tracing. We train machine learning models by simulating atom transitions across five universal metabolic models starting from 26 13 C-glucose, 2 H-glucose, and 13 C-glutamine tracers within feasible flux space. ML-Flux employs deep-learning-based imputation to take variable measurements of labeling patterns as input and successive neural networks to convert the ensuing comprehensive labeling information into metabolic fluxes. Using ML-Flux with multi-isotope tracing, we obtain fluxes through central carbon metabolism that are comparable to those from a least-squares method but orders-of-magnitude faster. ML-Flux is deployed as a webtool to expand the accessibility of metabolic flux quantitation and afford actionable information on metabolism.
    DOI:  https://doi.org/10.1101/2023.11.06.565907
  5. Cell Rep. 2023 Nov 23. pii: S2211-1247(23)01484-5. [Epub ahead of print]42(12): 113472
    Mitochondrial nucleoid condensates drive peripheral fission through high membrane curvature.
    Qixin Chen, Liu-Yi Liu, Zhiqi Tian, Zhou Fang, Kang-Nan Wang, Xintian Shao, Chengying Zhang, Weiwei Zou, Fiona Rowan, Kangqiang Qiu, Baohua Ji, Jun-Lin Guan, Dechang Li, Zong-Wan Mao, Jiajie Diao.
      Mitochondria are dynamic organelles that undergo fusion and fission events, in which the mitochondrial membrane and DNA (mtDNA) play critical roles. The spatiotemporal organization of mtDNA reflects and impacts mitochondrial dynamics. Herein, to study the detailed dynamics of mitochondrial membrane and mtDNA, we rationally develop a dual-color fluorescent probe, mtGLP, that could be used for simultaneously monitoring mitochondrial membrane and mtDNA dynamics via separate color outputs. By combining mtGLP with structured illumination microscopy to monitor mitochondrial dynamics, we discover the formation of nucleoid condensates in damaged mitochondria. We further reveal that nucleoid condensates promoted the peripheral fission of damaged mitochondria via asymmetric segregation. Through simulations, we find that the peripheral fission events occurred when the nucleoid condensates interacted with the highly curved membrane regions at the two ends of the mitochondria. Overall, we show that mitochondrial nucleoid condensates utilize peripheral fission to maintain mitochondrial homeostasis.
    Keywords:  CP: Cell biology; chemical biology
    DOI:  https://doi.org/10.1016/j.celrep.2023.113472
  6. Cancer Discov. 2023 Nov 22. OF1
    Vitamin B5 Supports Oncogenic Metabolism in MYC-Driven Breast Cancer.
      Pantothetic acid is required for metabolic activity that supports MYC-driven breast tumor growth.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2023-185
  7. Biochim Biophys Acta Mol Cell Res. 2023 Nov 21. pii: S0167-4889(23)00212-4. [Epub ahead of print] 119639
    Proline and dihydroorotate dehydrogenase promote a hyper-proliferative state and dampen ferroptosis in cancer cells by rewiring mitochondrial redox metabolism.
    Ryan J Mailloux.
      Redox realignment is integral to the initiation, progression, and metastasis of cancer. This requires considerable metabolic rewiring to induce aberrant shifts in redox homeostasis that favor high hydrogen peroxide (H2O2) generation for the induction of a hyper-proliferative state. The ability of tumor cells to thrive under the oxidative burden imposed by this high H2O2 is achieved by increasing antioxidant defenses. This shift in the redox stress signaling threshold (RST) also dampens ferroptosis, an iron (Fe)-dependent form of cell death activated by oxidative distress and lipid peroxidation reactions. Mitochondria are central to the malignant transformation of normal cells to cancerous ones since these organelles supply building blocks for anabolism, govern ferroptosis, and serve as the major source of cell H2O2. This review summarizes advances in understanding the rewiring of redox reactions in mitochondria to promote carcinogenesis, focusing on how cancer cells hijack the electron transport chain (ETC) to promote proliferation and evasion of ferroptosis. I then apply emerging concepts in redox homeodynamics to discuss how the rewiring of the Krebs cycle and ETC promotes shifts in the RST to favor high rates of H2O2 generation for cell signaling. This discussion then focuses on proline dehydrogenase (PRODH) and dihydroorotate dehydrogenase (DHODH), two enzymes over expressed in cancers, and how their link to one another through the coenzyme Q10 (CoQ) pool generates a redox connection that forms a H2O2 signaling platform and pyrimidine synthesome that favors a hyper-proliferative state and disables ferroptosis.
    Keywords:  Dihydroorotate dehydrogenase;; Ferroptosis; Hydrogen peroxide; Proline dehydrogense; Redox stress signaling threshold
    DOI:  https://doi.org/10.1016/j.bbamcr.2023.119639
  8. Nat Metab. 2023 Nov 20.
    Linking neuropsychiatric disease to neuronal metabolism.
    Mathias V Schmidt.
      
    DOI:  https://doi.org/10.1038/s42255-023-00929-1
  9. J Cell Biol. 2024 Jan 01. pii: e202305048. [Epub ahead of print]223(1):
    Sirtuin3 ensures the metabolic plasticity of neurotransmission during glucose deprivation.
    Anupama Tiwari, Arsalan Hashemiaghdam, Marissa A Laramie, Dario Maschi, Tristaan Haddad, Marion I Stunault, Carmen Bergom, Ali Javaheri, Vitaly Klyachko, Ghazaleh Ashrafi.
      Neurotransmission is an energetically expensive process that underlies cognition. During intense electrical activity or dietary restrictions, the glucose level in the brain plummets, forcing neurons to utilize alternative fuels. However, the molecular mechanisms of neuronal metabolic plasticity remain poorly understood. Here, we demonstrate that glucose-deprived neurons activate the CREB and PGC1α transcriptional program, which induces expression of the mitochondrial deacetylase Sirtuin 3 (Sirt3) both in vitro and in vivo. We show that Sirt3 localizes to axonal mitochondria and stimulates mitochondrial oxidative capacity in hippocampal nerve terminals. Sirt3 plays an essential role in sustaining synaptic transmission in the absence of glucose by providing metabolic support for the retrieval of synaptic vesicles after release. These results demonstrate that the transcriptional induction of Sirt3 facilitates the metabolic plasticity of synaptic transmission.
    DOI:  https://doi.org/10.1083/jcb.202305048
  10. Life Sci Alliance. 2024 Feb;pii: e202302147. [Epub ahead of print]7(2):
    Mitochondrial phosphoproteomes are functionally specialized across tissues.
    Fynn M Hansen, Laura S Kremer, Ozge Karayel, Isabell Bludau, Nils-Göran Larsson, Inge Kühl, Matthias Mann.
      Mitochondria are essential organelles whose dysfunction causes human pathologies that often manifest in a tissue-specific manner. Accordingly, mitochondrial fitness depends on versatile proteomes specialized to meet diverse tissue-specific requirements. Increasing evidence suggests that phosphorylation may play an important role in regulating tissue-specific mitochondrial functions and pathophysiology. Building on recent advances in mass spectrometry (MS)-based proteomics, we here quantitatively profile mitochondrial tissue proteomes along with their matching phosphoproteomes. We isolated mitochondria from mouse heart, skeletal muscle, brown adipose tissue, kidney, liver, brain, and spleen by differential centrifugation followed by separation on Percoll gradients and performed high-resolution MS analysis of the proteomes and phosphoproteomes. This in-depth map substantially quantifies known and predicted mitochondrial proteins and provides a resource of core and tissue-specific mitochondrial proteins (mitophos.de). Predicting kinase substrate associations for different mitochondrial compartments indicates tissue-specific regulation at the phosphoproteome level. Illustrating the functional value of our resource, we reproduce mitochondrial phosphorylation events on dynamin-related protein 1 responsible for its mitochondrial recruitment and fission initiation and describe phosphorylation clusters on MIGA2 linked to mitochondrial fusion.
    DOI:  https://doi.org/10.26508/lsa.202302147
  11. Nat Commun. 2023 Nov 21. 14(1): 7599
    A distinct Acyl-CoA binding protein (ACBP6) shapes tissue plasticity during nutrient adaptation in Drosophila.
    Xiaotong Li, Jason Karpac.
      Nutrient availability is a major selective force in the evolution of metazoa, and thus plasticity in tissue function and morphology is shaped by adaptive responses to nutrient changes. Utilizing Drosophila, we reveal that distinct calibration of acyl-CoA metabolism, mediated by Acbp6 (Acyl-CoA binding-protein 6), is critical for nutrient-dependent tissue plasticity. Drosophila Acbp6, which arose by evolutionary duplication and binds acyl-CoA to tune acetyl-CoA metabolism, is required for intestinal resizing after nutrient deprivation through activating intestinal stem cell proliferation from quiescence. Disruption of acyl-CoA metabolism by Acbp6 attenuation drives aberrant 'switching' of metabolic networks in intestinal enterocytes during nutrient adaptation, impairing acetyl-CoA metabolism and acetylation amid intestinal resizing. We also identified STAT92e, whose function is influenced by acetyl-CoA levels, as a key regulator of acyl-CoA and nutrient-dependent changes in stem cell activation. These findings define a regulatory mechanism, shaped by acyl-CoA metabolism, that adjusts proliferative homeostasis to coordinately regulate tissue plasticity during nutrient adaptation.
    DOI:  https://doi.org/10.1038/s41467-023-43362-4
  12. Nat Metab. 2023 Nov 20.
    Mitochondrial fission drives neuronal metabolic burden to promote stress susceptibility in male mice.
    Wan-Ting Dong, Li-Hong Long, Qiao Deng, Duo Liu, Jia-Lin Wang, Fang Wang, Jian-Guo Chen.
      Neurons are particularly susceptible to energy fluctuations in response to stress. Mitochondrial fission is highly regulated to generate ATP via oxidative phosphorylation; however, the role of a regulator of mitochondrial fission in neuronal energy metabolism and synaptic efficacy under chronic stress remains elusive. Here, we show that chronic stress promotes mitochondrial fission in the medial prefrontal cortex via activating dynamin-related protein 1 (Drp1), resulting in mitochondrial dysfunction in male mice. Both pharmacological inhibition and genetic reduction of Drp1 ameliorates the deficit of excitatory synaptic transmission and stress-related depressive-like behavior. In addition, enhancing Drp1 fission promotes stress susceptibility, which is alleviated by coenzyme Q10, which potentiates mitochondrial ATP production. Together, our findings unmask the role of Drp1-dependent mitochondrial fission in the deficits of neuronal metabolic burden and depressive-like behavior and provides medication basis for metabolism-related emotional disorders.
    DOI:  https://doi.org/10.1038/s42255-023-00924-6
  13. bioRxiv. 2023 Nov 08. pii: 2023.11.06.565895. [Epub ahead of print]
    Glucose-6-phosphate dehydrogenase deficiency accelerates pancreatic acinar-to-ductal metaplasia.
    Megan D Radyk, Barbara S Nelson, Christopher J Halbrook, Alexander Wood, Brooke Lavoie, Lucie Salvatore, Gabriel Corfas, Justin A Colacino, Yatrik M Shah, Howard C Crawford, Costas A Lyssiotis.
      Activating mutations in KRAS extensively reprogram cellular metabolism to support the continuous growth, proliferation, and survival of pancreatic tumors. Targeting these metabolic dependencies are promising approaches for the treatment of established tumors. However, metabolic reprogramming is required early during tumorigenesis to provide transformed cells selective advantage towards malignancy. Acinar cells can give rise to pancreatic tumors through acinar-to-ductal metaplasia (ADM). Dysregulation of pathways that maintain acinar homeostasis accelerate tumorigenesis. During ADM, acinar cells transdifferentiate to duct-like cells, a process driven by oncogenic KRAS . The metabolic reprogramming that is required for the transdifferentiation in ADM is unclear. We performed transcriptomic analysis on mouse acinar cells undergoing ADM and found metabolic programs are globally enhanced, consistent with the transition of a specialized cell to a less differentiated phenotype with proliferative potential. Indeed, we and others have demonstrated how inhibiting metabolic pathways necessary for ADM can prevent transdifferentiation and tumorigenesis. Here, we also find NRF2-target genes are differentially expressed during ADM. Among these, we focused on the increase in the gene coding for NADPH-producing enzyme, Glucose-6-phosphate dehydrogenase (G6PD). Using established mouse models of Kras G12D -driven pancreatic tumorigenesis and G6PD-deficiency, we find that mutant G6pd accelerates ADM and pancreatic intraepithelial neoplasia. Acceleration of cancer initiation with G6PD-deficiency is dependent on its NADPH-generating function in reactive oxygen species (ROS) management, as opposed to other outputs of the pentose phosphate pathway. Together, this work provides new insights into the function of metabolic pathways during early tumorigenesis.
    DOI:  https://doi.org/10.1101/2023.11.06.565895
  14. Endocrinol Metab (Seoul). 2023 Nov 21.
    Toward Systems-Level Metabolic Analysis in Endocrine Disorders and Cancer.
    Aliya Lakhani, Da Hyun Kang, Yea Eun Kang, Junyoung O Park.
      Metabolism is a dynamic network of biochemical reactions that support systemic homeostasis amidst changing nutritional, environmental, and physical activity factors. The circulatory system facilitates metabolite exchange among organs, while the endocrine system finely tunes metabolism through hormone release. Endocrine disorders like obesity, diabetes, and Cushing's syndrome disrupt this balance, contributing to systemic inflammation and global health burdens. They accompany metabolic changes on multiple levels from molecular interactions to individual organs to the whole body. Understanding how metabolic fluxes relate to endocrine disorders illuminates the underlying dysregulation. Cancer is increasingly considered a systemic disorder because it not only affects cells in localized tumors but also the whole body, especially in metastasis. In tumorigenesis, cancer-specific mutations and nutrient availability in the tumor microenvironment reprogram cellular metabolism to meet increased energy and biosynthesis needs. Cancer cachexia results in metabolic changes to other organs like muscle, adipose tissue, and liver. This review explores the interplay between the endocrine system and systems-level metabolism in health and disease. We highlight metabolic fluxes in conditions like obesity, diabetes, Cushing's syndrome, and cancers. Recent advances in metabolomics, fluxomics, and systems biology promise new insights into dynamic metabolism, offering potential biomarkers, therapeutic targets, and personalized medicine.
    Keywords:  Diabetes mellitus; Endocrinology; Metabolism; Obesity; Paraganglioma; Pheochromocytoma; Thyroid neoplasms
    DOI:  https://doi.org/10.3803/EnM.2023.1814
  15. Apoptosis. 2023 Nov 24.
    Cell-specific modulation of mitochondrial respiration and metabolism by the pro-apoptotic Bcl-2 family members Bax and Bak.
    Dana Sovilj, Cristina Daniela Kelemen, Sarka Dvorakova, Renata Zobalova, Helena Raabova, Jan Kriska, Zuzana Hermanova, Tomas Knotek, Miroslava Anderova, Pavel Klener, Vlada Filimonenko, Jiri Neuzil, Ladislav Andera.
      Proteins from the Bcl-2 family play an essential role in the regulation of apoptosis. However, they also possess cell death-unrelated activities that are less well understood. This prompted us to study apoptosis-unrelated activities of the Bax and Bak, pro-apoptotic members of the Bcl-2 family. We prepared Bax/Bak-deficient human cancer cells of different origin and found that while respiration in the glioblastoma U87 Bax/Bak-deficient cells was greatly enhanced, respiration of Bax/Bak-deficient B lymphoma HBL-2 cells was slightly suppressed. Bax/Bak-deficient U87 cells also proliferated faster in culture, formed tumours more rapidly in mice, and showed modulation of metabolism with a considerably increased NAD+/NADH ratio. Follow-up analyses documented increased/decreased expression of mitochondria-encoded subunits of respiratory complexes and stabilization/destabilization of the mitochondrial transcription elongation factor TEFM in Bax/Bak-deficient U87 and HBL-2 cells, respectively. TEFM downregulation using shRNAs attenuated mitochondrial respiration in Bax/Bak-deficient U87 as well as in parental HBL-2 cells. We propose that (post)translational regulation of TEFM levels in Bax/Bak-deficient cells modulates levels of subunits of mitochondrial respiratory complexes that, in turn, contribute to respiration and the accompanying changes in metabolism and proliferation in these cells.
    Keywords:  Bak; Bax; Cell proliferation; Metabolism; Mitochondrial respiration; TEFM
    DOI:  https://doi.org/10.1007/s10495-023-01917-2
  16. EMBO Rep. 2023 Nov 21. e57300
    Microautophagy regulated by STK38 and GABARAPs is essential to repair lysosomes and prevent aging.
    Monami Ogura, Tatsuya Kaminishi, Takayuki Shima, Miku Torigata, Nao Bekku, Keisuke Tabata, Satoshi Minami, Kohei Nishino, Akiko Nezu, Maho Hamasaki, Hidetaka Kosako, Tamotsu Yoshimori, Shuhei Nakamura.
      Lysosomes are degradative organelles and signaling hubs that maintain cell and tissue homeostasis, and lysosomal dysfunction is implicated in aging and reduced longevity. Lysosomes are frequently damaged, but their repair mechanisms remain unclear. Here, we demonstrate that damaged lysosomal membranes are repaired by microautophagy (a process termed "microlysophagy") and identify key regulators of the first and last steps. We reveal the AGC kinase STK38 as a novel microlysophagy regulator. Through phosphorylation of the scaffold protein DOK1, STK38 is specifically required for the lysosomal recruitment of the AAA+ ATPase VPS4, which terminates microlysophagy by promoting the disassembly of ESCRT components. By contrast, microlysophagy initiation involves non-canonical lipidation of ATG8s, especially the GABARAP subfamily, which is required for ESCRT assembly through interaction with ALIX. Depletion of STK38 and GABARAPs accelerates DNA damage-induced cellular senescence in human cells and curtails lifespan in C. elegans, respectively. Thus, microlysophagy is regulated by STK38 and GABARAPs and could be essential for maintaining lysosomal integrity and preventing aging.
    Keywords:  ESCRT; lysosome; microautophagy; non-canonical ATG8 lipidation
    DOI:  https://doi.org/10.15252/embr.202357300
  17. Trends Endocrinol Metab. 2023 Nov 21. pii: S1043-2760(23)00237-0. [Epub ahead of print]
    Cardiac macrophage metabolism in health and disease.
    Benjamin J Kopecky, Kory J Lavine.
      Cardiac macrophages are essential mediators of cardiac development, tissue homeostasis, and response to injury. Cell-intrinsic shifts in metabolism and availability of metabolites regulate macrophage function. The human and mouse heart contain a heterogeneous compilation of cardiac macrophages that are derived from at least two distinct lineages. In this review, we detail the unique functional roles and metabolic profiles of tissue-resident and monocyte-derived cardiac macrophages during embryonic development and adult tissue homeostasis and in response to pathologic and physiologic stressors. We discuss the metabolic preferences of each macrophage lineage and how metabolism influences monocyte fate specification. Finally, we highlight the contribution of cardiac macrophages and derived metabolites on cell-cell communication, metabolic health, and disease pathogenesis.
    Keywords:  HFpEF; cardiac; exercise; infarction; macrophage; metabolism
    DOI:  https://doi.org/10.1016/j.tem.2023.10.011
  18. Cell Metab. 2023 Nov 11. pii: S1550-4131(23)00385-6. [Epub ahead of print]
    The tRNA-GCN2-FBXO22-axis-mediated mTOR ubiquitination senses amino acid insufficiency.
    Meng-Kai Ge, Cheng Zhang, Na Zhang, Ping He, Hai-Yan Cai, Song Li, Shuai Wu, Xi-Li Chu, Yu-Xue Zhang, Hong-Ming Ma, Li Xia, Shuo Yang, Jian-Xiu Yu, Shi-Ying Yao, Xiao-Long Zhou, Bing Su, Guo-Qiang Chen, Shao-Ming Shen.
      Mammalian target of rapamycin complex 1 (mTORC1) monitors cellular amino acid changes for function, but the molecular mediators of this process remain to be fully defined. Here, we report that depletion of cellular amino acids, either alone or in combination, leads to the ubiquitination of mTOR, which inhibits mTORC1 kinase activity by preventing substrate recruitment. Mechanistically, amino acid depletion causes accumulation of uncharged tRNAs, thereby stimulating GCN2 to phosphorylate FBXO22, which in turn accrues in the cytoplasm and ubiquitinates mTOR at Lys2066 in a K27-linked manner. Accordingly, mutation of mTOR Lys2066 abolished mTOR ubiquitination in response to amino acid depletion, rendering mTOR insensitive to amino acid starvation both in vitro and in vivo. Collectively, these data reveal a novel mechanism of amino acid sensing by mTORC1 via a previously unknown GCN2-FBXO22-mTOR pathway that is uniquely controlled by uncharged tRNAs.
    Keywords:  FBXO22; GCN2; amino acids; mTOR; mTORC1; ubiquitination; uncharged tRNA
    DOI:  https://doi.org/10.1016/j.cmet.2023.10.016
  19. Trends Cancer. 2023 Nov 23. pii: S2405-8033(23)00230-3. [Epub ahead of print]
    Learning from circadian rhythm to transform cancer prevention, prognosis, and survivorship care.
    Xiaoyan Zhu, Geraldine Maier, Satchidananda Panda.
      Circadian timekeeping mechanisms and cell cycle regulation share thematic biological principles in responding to signals, repairing cellular damage, coordinating metabolism, and allocating cellular resources for optimal function. Recent studies show interactions between cell cycle regulators and circadian clock components, offering insights into potential cancer treatment approaches. Understanding circadian control of metabolism informs timing for therapies to reduce adverse effects and enhance treatment efficacy. Circadian adaptability to lifestyle factors, such as activity, sleep, and nutrition sheds light on their impact on cancer. Leveraging circadian regulatory mechanisms for cancer prevention and care is vital, as most risk stems from modifiable lifestyles. Monitoring circadian factors aids risk assessment and targeted interventions across the cancer care continuum.
    Keywords:  cancer risk; chronotherapy; circadian clock; circadian rhythm; circadian rhythm disruption; lifestyle
    DOI:  https://doi.org/10.1016/j.trecan.2023.11.002
  20. bioRxiv. 2023 Nov 07. pii: 2023.11.07.566074. [Epub ahead of print]
    Mitochondrial One-Carbon Metabolism is Required for TGF-β-Induced Glycine Synthesis and Collagen Protein Production.
    Angelo Y Meliton, Rengül Cetin-Atalay, Yufeng Tian, Jennifer C Houpy Szafran, Kun Woo D Shin, Takugo Cho, Kaitlyn A Sun, Parker S Woods, Obada R Shamaa, Bohao Chen, Alexander Muir, Gökhan M Mutlu, Robert B Hamanaka.
      A hallmark of Idiopathic Pulmonary Fibrosis is the TGF-β-dependent activation of lung fibroblasts, leading to excessive deposition of collagen proteins and progressive scarring. We have previously shown that synthesis of collagen by lung fibroblasts requires de novo synthesis of glycine, the most abundant amino acid in collagen protein. TGF-β upregulates the expression of the enzymes of the de novo serine/glycine synthesis pathway in lung fibroblasts through mTORC1 and ATF4- dependent transcriptional programs. SHMT2, the final enzyme of the de novo serine/glycine synthesis pathway, transfers a one-carbon unit from serine to tetrahydrofolate (THF), producing glycine and 5,10-methylene-THF (meTHF). meTHF is converted back to THF in the mitochondrial one-carbon (1C) pathway through the sequential actions of MTHFD2 (which converts meTHF to 10-formyl-THF), and either MTHFD1L, which produces formate, or ALDH1L2, which produces CO 2 . It is unknown how the mitochondrial 1C pathway contributes to glycine biosynthesis or collagen protein production in fibroblasts, or fibrosis in vivo . Here, we demonstrate that TGF-β induces the expression of MTHFD2 , MTHFD1L , and ALDH1L2 in human lung fibroblasts. MTHFD2 expression was required for TGF-β-induced cellular glycine accumulation and collagen protein production. Combined knockdown of both MTHFD1L and ALDH1L2 also inhibited glycine accumulation and collagen protein production downstream of TGF-β; however knockdown of either protein alone had no inhibitory effect, suggesting that lung fibroblasts can utilize either enzyme to regenerate THF. Pharmacologic inhibition of MTHFD2 recapitulated the effects of MTHFD2 knockdown in lung fibroblasts and ameliorated fibrotic responses after intratracheal bleomycin instillation in vivo . Our results provide insight into the metabolic requirements of lung fibroblasts and provide support for continued development of MTHFD2 inhibitors for the treatment of IPF and other fibrotic diseases.
    DOI:  https://doi.org/10.1101/2023.11.07.566074
  21. Nat Metab. 2023 Nov 23.
    Adipose cDC1s contribute to obesity-associated inflammation through STING-dependent IL-12 production.
    Andrew D Hildreth, Eddie T Padilla, Meha Gupta, Yung Yu Wong, Ryan Sun, Akshara R Legala, Timothy E O'Sullivan.
      Obesity is associated with chronic low-grade white adipose tissue (WAT) inflammation that can contribute to the development of insulin resistance in mammals. Previous studies have identified interleukin (IL)-12 as a critical upstream regulator of WAT inflammation and metabolic dysfunction during obesity. However, the cell types and mechanisms that initiate WAT IL-12 production remain unclear. Here we show that conventional type 1 dendritic cells (cDC1s) are the cellular source of WAT IL-12 during obesity through analysis of mouse and human WAT single-cell transcriptomic datasets, IL-12 reporter mice and IL-12p70 protein levels by enzyme-linked immunosorbent assay. We demonstrate that cDC1s contribute to obesity-associated inflammation by increasing group 1 innate lymphocyte interferon-γ production and inflammatory macrophage accumulation. Inducible depletion of cDC1s increased WAT insulin sensitivity and systemic glucose tolerance during diet-induced obesity. Mechanistically, endocytosis of apoptotic bodies containing self-DNA by WAT cDC1s drives stimulator of interferon genes (STING)-dependent IL-12 production. Together, these results suggest that WAT cDC1s act as critical regulators of adipose tissue inflammation and metabolic dysfunction during obesity.
    DOI:  https://doi.org/10.1038/s42255-023-00934-4
  22. Cancer Immunol Res. 2023 Nov 21.
    A metabolic axis of immune intractability.
    Dominique C Hinshaw, Meet Patel, Lalita A Shevde.
      Immune cells in the tumor niche robustly influence disease progression. Remarkably, in cancer, developmental pathways are re-enacted. Many parallels between immune regulation of embryonic development and immune regulation of tumor progression can be drawn, with evidence clearly supporting an immune-suppressive microenvironment in both situations. In these ecosystems, metabolic and bioenergetic circuits guide and regulate immune cell differentiation, plasticity, and functional properties of suppressive and inflammatory immune subsets. As such, there is an emerging pattern of intersection across the dynamic process of ontogeny and the ever-evolving tumor neighborhood. In this article, we focus on the convergence of immune programming during ontogeny and in the tumor microenvironment. Exemplifying dysregulation of Hedgehog (Hh) activity, a key player during ontogeny, we highlight a critical convergence of these fields and the metabolic axis of the nutrient sensing hexosamine biosynthetic pathway (HBP) that integrates glucose, glutamine, amino acids, acetyl CoA, and uridine-5'-triphosphate (UTP), culminating in the synthesis of UDP-GlcNAc, a metabolite that functions as a metabolic and bioenergetic sensor. We discuss an emerging pattern of immune regulation, orchestrated by O-GlcNAcylation of key transcriptional regulators, spurring suppressive activity of dysfunctional immune cells in the tumor microenvironment.
    DOI:  https://doi.org/10.1158/2326-6066.CIR-23-0433
  23. Sci Adv. 2023 11 24. 9(47): eadj6409
    Longitudinal dynamics of the tumor hypoxia response: From enzyme activity to biological phenotype.
    Sandy Che-Eun S Lee, Andrea Hye An Pyo, Marianne Koritzinsky.
      Poor oxygenation (hypoxia) is a common spatially heterogeneous feature of human tumors. Biological responses to tumor hypoxia are orchestrated by the decreased activity of oxygen-dependent enzymes. The affinity of these enzymes for oxygen positions them along a continuum of oxygen sensing that defines their roles in launching reactive and adaptive cellular responses. These responses encompass regulation of all steps in the central dogma, with rapid perturbation of the metabolome and proteome followed by more persistent reprogramming of the transcriptome and epigenome. Core hypoxia response genes and pathways are commonly regulated at multiple inflection points, fine-tuning the dependencies on oxygen concentration and hypoxia duration. Ultimately, shifts in the activity of oxygen-sensing enzymes directly or indirectly endow cells with intrinsic hypoxia tolerance and drive processes that are associated with aggressive phenotypes in cancer including angiogenesis, migration, invasion, immune evasion, epithelial mesenchymal transition, and stemness.
    DOI:  https://doi.org/10.1126/sciadv.adj6409
  24. bioRxiv. 2023 Nov 11. pii: 2023.11.07.566063. [Epub ahead of print]
    2D and 3D multiplexed subcellular profiling of nuclear instability in human cancer.
    Shannon Coy, Brian Cheng, Jong Suk Lee, Rumana Rashid, Lindsay Browning, Yilin Xu, Sankha S Chakrabarty, Clarence Yapp, Sabrina Chan, Juliann B Tefft, Emily Scott, Alexander Spektor, Keith L Ligon, Gregory J Baker, David Pellman, Peter K Sorger, Sandro Santagata.
      Nuclear atypia, including altered nuclear size, contour, and chromatin organization, is ubiquitous in cancer cells. Atypical primary nuclei and micronuclei can rupture during interphase; however, the frequency, causes, and consequences of nuclear rupture are unknown in most cancers. We demonstrate that nuclear envelope rupture is surprisingly common in many human cancers, particularly glioblastoma. Using highly-multiplexed 2D and super-resolution 3D-imaging of glioblastoma tissues and patient-derived xenografts and cells, we link primary nuclear rupture with reduced lamin A/C and micronuclear rupture with reduced lamin B1. Moreover, ruptured glioblastoma cells activate cGAS-STING-signaling involved in innate immunity. We observe that local patterning of cell states influences tumor spatial organization and is linked to both lamin expression and rupture frequency, with neural-progenitor-cell-like states exhibiting the lowest lamin A/C levels and greatest susceptibility to primary nuclear rupture. Our study reveals that nuclear instability is a core feature of cancer, and links nuclear integrity, cell state, and immune signaling.
    DOI:  https://doi.org/10.1101/2023.11.07.566063
  25. Sci Adv. 2023 11 24. 9(47): eadi1867
    HILPS, a long noncoding RNA essential for global oxygen sensing in humans.
    Zhi Chen, Chan Chen, Lei Xiao, Rongfu Tu, Miaomiao Yu, Donghai Wang, Wenqian Kang, Meng Han, Hao Huang, Hudan Liu, Bing Zhao, Guoliang Qing.
      Adaptation to low levels of oxygen (hypoxia) is a universal biological feature across metazoans. However, the unique mechanisms how different species sense oxygen deprivation remain unresolved. Here, we functionally characterize a novel long noncoding RNA (lncRNA), LOC105369301, which we termed hypoxia-induced lncRNA for polo-like kinase 1 (PLK1) stabilization (HILPS). HILPS exhibits appreciable basal expression exclusively in a wide variety of human normal and cancer cells and is robustly induced by hypoxia-inducible factor 1α (HIF1α). HILPS binds to PLK1 and sequesters it from proteasomal degradation. Stabilized PLK1 directly phosphorylates HIF1α and enhances its stability, constituting a positive feed-forward circuit that reinforces oxygen sensing by HIF1α. HILPS depletion triggers catastrophic adaptation defect during hypoxia in both normal and cancer cells. These findings introduce a mechanism that underlies the HIF1α identity deeply interconnected with PLK1 integrity and identify the HILPS-PLK1-HIF1α pathway as a unique oxygen-sensing axis in the regulation of human physiological and pathogenic processes.
    DOI:  https://doi.org/10.1126/sciadv.adi1867
  26. Pflugers Arch. 2023 Nov 24.
    What can we learn about acid-base transporters in cancer from studying somatic mutations in their genes?
    Bobby White, Pawel Swietach.
      Acidosis is a chemical signature of the tumour microenvironment that challenges intracellular pH homeostasis. The orchestrated activity of acid-base transporters of the solute-linked carrier (SLC) family is critical for removing the end-products of fermentative metabolism (lactate/H+) and maintaining a favourably alkaline cytoplasm. Given the critical role of pH homeostasis in enabling cellular activities, mutations in relevant SLC genes may impact the oncogenic process, emerging as negatively or positively selected, or as driver or passenger mutations. To address this, we performed a pan-cancer analysis of The Cancer Genome Atlas simple nucleotide variation data for acid/base-transporting SLCs (ABT-SLCs). Somatic mutation patterns of monocarboxylate transporters (MCTs) were consistent with their proposed essentiality in facilitating lactate/H+ efflux. Among all cancers, tumours of uterine corpus endometrial cancer carried more ABT-SLC somatic mutations than expected from median tumour mutation burden. Among these, somatic mutations in SLC4A3 had features consistent with meaningful consequences on cellular fitness. Definitive evidence for ABT-SLCs as 'cancer essential' or 'driver genes' will have to consider microenvironmental context in genomic sequencing because bulk approaches are insensitive to pH heterogeneity within tumours. Moreover, genomic analyses must be validated with phenotypic outcomes (i.e. SLC-carried flux) to appreciate the opportunities for targeting acid-base transport in cancers.
    Keywords:  Acidosis; Cancer evolution; Glycolysis; Solute-linked carrier; Somatic mutation; pH regulation
    DOI:  https://doi.org/10.1007/s00424-023-02876-y
  27. Sci Rep. 2023 Nov 23. 13(1): 20567
    Nucleotide excision repair deficiency is a targetable therapeutic vulnerability in clear cell renal cell carcinoma.
    Aurel Prosz, Haohui Duan, Viktoria Tisza, Pranshu Sahgal, Sabine Topka, Gregory T Klus, Judit Börcsök, Zsofia Sztupinszki, Timothy Hanlon, Miklos Diossy, Laura Vizkeleti, Dag Rune Stormoen, Istvan Csabai, Helle Pappot, Joseph Vijai, Kenneth Offit, Thomas Ried, Nilay Sethi, Kent W Mouw, Sandor Spisak, Shailja Pathania, Zoltan Szallasi.
      Due to a demonstrated lack of DNA repair deficiencies, clear cell renal cell carcinoma (ccRCC) has not benefitted from targeted synthetic lethality-based therapies. We investigated whether nucleotide excision repair (NER) deficiency is present in an identifiable subset of ccRCC cases that would render those tumors sensitive to therapy targeting this specific DNA repair pathway aberration. We used functional assays that detect UV-induced 6-4 pyrimidine-pyrimidone photoproducts to quantify NER deficiency in ccRCC cell lines. We also measured sensitivity to irofulven, an experimental cancer therapeutic agent that specifically targets cells with inactivated transcription-coupled nucleotide excision repair (TC-NER). In order to detect NER deficiency in clinical biopsies, we assessed whole exome sequencing data for the presence of an NER deficiency associated mutational signature previously identified in ERCC2 mutant bladder cancer. Functional assays showed NER deficiency in ccRCC cells. Some cell lines showed irofulven sensitivity at a concentration that is well tolerated by patients. Prostaglandin reductase 1 (PTGR1), which activates irofulven, was also associated with this sensitivity. Next generation sequencing data of the cell lines showed NER deficiency-associated mutational signatures. A significant subset of ccRCC patients had the same signature and high PTGR1 expression. ccRCC cell line-based analysis showed that NER deficiency is likely present in this cancer type. Approximately 10% of ccRCC patients in the TCGA cohort showed mutational signatures consistent with ERCC2 inactivation associated NER deficiency and also substantial levels of PTGR1 expression. These patients may be responsive to irofulven, a previously abandoned anticancer agent that has minimal activity in NER-proficient cells.
    DOI:  https://doi.org/10.1038/s41598-023-47946-4
  28. Nat Commun. 2023 Nov 21. 14(1): 7572
    SETD2 deficiency accelerates sphingomyelin accumulation and promotes the development of renal cancer.
    Hanyu Rao, Changwei Liu, Aiting Wang, Chunxiao Ma, Yue Xu, Tianbao Ye, Wenqiong Su, Peijun Zhou, Wei-Qiang Gao, Li Li, Xianting Ding.
      Patients with polycystic kidney disease (PKD) encounter a high risk of clear cell renal cell carcinoma (ccRCC), a malignant tumor with dysregulated lipid metabolism. SET domain-containing 2 (SETD2) has been identified as an important tumor suppressor and an immunosuppressor in ccRCC. However, the role of SETD2 in ccRCC generation in PKD remains largely unexplored. Herein, we perform metabolomics, lipidomics, transcriptomics and proteomics within SETD2 loss induced PKD-ccRCC transition mouse model. Our analyses show that SETD2 loss causes extensive metabolic reprogramming events that eventually results in enhanced sphingomyelin biosynthesis and tumorigenesis. Clinical ccRCC patient specimens further confirm the abnormal metabolic reprogramming and sphingomyelin accumulation. Tumor symptom caused by Setd2 knockout is relieved by myriocin, a selective inhibitor of serine-palmitoyl-transferase and sphingomyelin biosynthesis. Our results reveal that SETD2 deficiency promotes large-scale metabolic reprogramming and sphingomyelin biosynthesis during PKD-ccRCC transition. This study introduces high-quality multi-omics resources and uncovers a regulatory mechanism of SETD2 on lipid metabolism during tumorigenesis.
    DOI:  https://doi.org/10.1038/s41467-023-43378-w
  29. Nucleic Acids Res. 2023 Nov 23. pii: gkad1081. [Epub ahead of print]
    Reactivation of the G1 enhancer landscape underlies core circuitry addiction to SWI/SNF.
    Katerina Cermakova, Ling Tao, Milan Dejmek, Michal Sala, Matthew D Montierth, Yuen San Chan, Ivanshi Patel, Courtney Chambers, Mario Loeza Cabrera, Dane Hoffman, Ronald J Parchem, Wenyi Wang, Radim Nencka, Eveline Barbieri, H Courtney Hodges.
      Several cancer core regulatory circuitries (CRCs) depend on the sustained generation of DNA accessibility by SWI/SNF chromatin remodelers. However, the window when SWI/SNF is acutely essential in these settings has not been identified. Here we used neuroblastoma (NB) cells to model and dissect the relationship between cell-cycle progression and SWI/SNF ATPase activity. We find that SWI/SNF inactivation impairs coordinated occupancy of non-pioneer CRC members at enhancers within 1 hour, rapidly breaking their autoregulation. By precisely timing inhibitor treatment following synchronization, we show that SWI/SNF is dispensable for survival in S and G2/M, but becomes acutely essential only during G1 phase. We furthermore developed a new approach to analyze the oscillating patterns of genome-wide DNA accessibility across the cell cycle, which revealed that SWI/SNF-dependent CRC binding sites are enriched at enhancers with peak accessibility during G1 phase, where they activate genes involved in cell-cycle progression. SWI/SNF inhibition strongly impairs G1-S transition and potentiates the ability of retinoids used clinically to induce cell-cycle exit. Similar cell-cycle effects in diverse SWI/SNF-addicted settings highlight G1-S transition as a common cause of SWI/SNF dependency. Our results illustrate that deeper knowledge of the temporal patterns of enhancer-related dependencies may aid the rational targeting of addicted cancers.
    DOI:  https://doi.org/10.1093/nar/gkad1081
  30. Semin Diagn Pathol. 2023 Nov 08. pii: S0740-2570(23)00097-7. [Epub ahead of print]
    Hereditary succinate dehydrogenase-deficient renal cell carcinoma.
    Joanna Rogala, Ming Zhou.
      Succinate dehydrogenase (SDH), formed by four subunits SDHA, SDHB, SDHC, SDHD, and an assembly factor SDHAF2, functions as a key respiratory enzyme. Biallelic inactivation of genes encoding any of the components, almost always in the presence of a germline mutation, causes loss of function of the entire enzyme complex (so-called SDH deficiency) and subsequent development of SDH-deficient neoplasms which include pheochromocytoma/paraganglioma, gastrointestinal stromal tumor, and renal cell carcinoma (RCC). These tumors may occur in the same patient or kindred. SDH-deficient RCC shows distinctive morphological features with vacuolated eosinophilic cytoplasm due to distinctive cytoplasmatic inclusions containing flocculent material. The diagnosis is confirmed by loss of SDHB on immunohistochemistry with positive internal control. The majority of tumors occur in the setting of germline mutations in one of the SDH genes, most commonly SDHB. The prognosis is excellent for low-grade tumors but worse for high-grade tumors with high-grade nuclei, sarcomatoid change, or coagulative necrosis. Awareness of the morphological features and low-threshold for applying SDHB immunohistochemistry help identify patients with SDH-deficient RCC and hereditary SDH-deficient tumor syndromes. In this review we summarize recent development on the clinical and genetic features, diagnostic approach, and pitfalls of SDH-deficient syndrome, focusing on SDH-deficient renal cell carcinomas.
    Keywords:  Deficiency; Mutation; Renal cell carcinoma; Succinate dehydrogenase
    DOI:  https://doi.org/10.1053/j.semdp.2023.11.001
  31. Nat Cell Biol. 2023 Nov 20.
    Quick tips for interpreting cell death experiments.
    Scott J Dixon, Michael J Lee.
      
    DOI:  https://doi.org/10.1038/s41556-023-01288-5
  32. Nat Genet. 2023 Nov 24.
    Age-associated transcriptional stress due to accelerated elongation and increased stalling of RNAPII.
    Antonios Papadakis, Akos Gyenis, Joris Pothof, Jan H J Hoeijmakers, Argyris Papantonis, Andreas Beyer.
      
    DOI:  https://doi.org/10.1038/s41588-023-01601-w
  33. Nat Struct Mol Biol. 2023 Nov 23.
    Intra-promoter switch of transcription initiation sites in proliferation signaling-dependent RNA metabolism.
    Joseph W Wragg, Paige-Louise White, Yavor Hadzhiev, Kasun Wanigasooriya, Agata Stodolna, Louise Tee, Joao D Barros-Silva, Andrew D Beggs, Ferenc Müller.
      Global changes in transcriptional regulation and RNA metabolism are crucial features of cancer development. However, little is known about the role of the core promoter in defining transcript identity and post-transcriptional fates, a potentially crucial layer of transcriptional regulation in cancer. In this study, we use CAGE-seq analysis to uncover widespread use of dual-initiation promoters in which non-canonical, first-base-cytosine (C) transcription initiation occurs alongside first-base-purine initiation across 59 human cancers and healthy tissues. C-initiation is often followed by a 5' terminal oligopyrimidine (5'TOP) sequence, dramatically increasing the range of genes potentially subjected to 5'TOP-associated post-transcriptional regulation. We show selective, dynamic switching between purine and C-initiation site usage, indicating transcription initiation-level regulation in cancers. We additionally detail global metabolic changes in C-initiation transcripts that mark differentiation status, proliferative capacity, radiosensitivity, and response to irradiation and to PI3K-Akt-mTOR and DNA damage pathway-targeted radiosensitization therapies in colorectal cancer organoids and cancer cell lines and tissues.
    DOI:  https://doi.org/10.1038/s41594-023-01156-8
  34. Nat Metab. 2023 Nov 23.
    Anomalous peroxidase activity of cytochrome c is the primary pathogenic target in Barth syndrome.
    Valerian E Kagan, Yulia Y Tyurina, Karolina Mikulska-Ruminska, Deena Damschroder, Eduardo Vieira Neto, Alessia Lasorsa, Alexander A Kapralov, Vladimir A Tyurin, Andrew A Amoscato, Svetlana N Samovich, Austin B Souryavong, Haider H Dar, Abu Ramim, Zhuqing Liang, Pablo Lazcano, Jiajia Ji, Michael W Schmidtke, Kirill Kiselyov, Aybike Korkmaz, Georgy K Vladimirov, Margarita A Artyukhova, Pushpa Rampratap, Laura K Cole, Ammanamanchi Niyatie, Emma-Kate Baker, Jim Peterson, Grant M Hatch, Jeffrey Atkinson, Jerry Vockley, Bernhard Kühn, Robert Wessells, Patrick C A van der Wel, Ivet Bahar, Hülya Bayir, Miriam L Greenberg.
      Barth syndrome (BTHS) is a life-threatening genetic disorder with unknown pathogenicity caused by mutations in TAFAZZIN (TAZ) that affect remodeling of mitochondrial cardiolipin (CL). TAZ deficiency leads to accumulation of mono-lyso-CL (MLCL), which forms a peroxidase complex with cytochrome c (cyt c) capable of oxidizing polyunsaturated fatty acid-containing lipids. We hypothesized that accumulation of MLCL facilitates formation of anomalous MLCL-cyt c peroxidase complexes and peroxidation of polyunsaturated fatty acid phospholipids as the primary BTHS pathogenic mechanism. Using genetic, biochemical/biophysical, redox lipidomic and computational approaches, we reveal mechanisms of peroxidase-competent MLCL-cyt c complexation and increased phospholipid peroxidation in different TAZ-deficient cells and animal models and in pre-transplant biopsies from hearts of patients with BTHS. A specific mitochondria-targeted anti-peroxidase agent inhibited MLCL-cyt c peroxidase activity, prevented phospholipid peroxidation, improved mitochondrial respiration of TAZ-deficient C2C12 myoblasts and restored exercise endurance in a BTHS Drosophila model. Targeting MLCL-cyt c peroxidase offers therapeutic approaches to BTHS treatment.
    DOI:  https://doi.org/10.1038/s42255-023-00926-4
  35. Nature. 2023 Nov 22.
    Epithelial IFNγ signalling and compartmentalized antigen presentation orchestrate gut immunity.
    Ankit Malik, Deepika Sharma, Raúl Aguirre-Gamboa, Shaina McGrath, Sarah Zabala, Christopher Weber, Bana Jabri.
      All nucleated cells express major histocompatibility complex I and interferon-γ (IFNγ) receptor1, but an epithelial cell-specific function of IFNγ signalling or antigen presentation by means of major histocompatibility complex I has not been explored. We show here that on sensing IFNγ, colonic epithelial cells productively present pathogen and self-derived antigens to cognate intra-epithelial T cells, which are critically located at the epithelial barrier. Antigen presentation by the epithelial cells confers extracellular ATPase expression in cognate intra-epithelial T cells, which limits the accumulation of extracellular adenosine triphosphate and consequent activation of the NLRP3 inflammasome in tissue macrophages. By contrast, antigen presentation by the tissue macrophages alongside inflammasome-associated interleukin-1α and interleukin-1β production promotes a pathogenic transformation of CD4+ T cells into granulocyte-macrophage colony-stimulating-factor (GM-CSF)-producing T cells in vivo, which promotes colitis and colorectal cancer. Taken together, our study unravels critical checkpoints requiring IFNγ sensing and antigen presentation by epithelial cells that control the development of pathogenic CD4+ T cell responses in vivo.
    DOI:  https://doi.org/10.1038/s41586-023-06721-1
  36. Radiat Res. 2023 Nov 21.
    Heme Biosynthesis is Crucial for Cell Survival and Mitochondrial OXPHOS after X Irradiation.
    Tomoki Bo, Koen Van Wijk, Osamu Nakajima.
      Heme is an essential component of the hemoproteins involved in the mitochondrial electron transport chain (ETC). Cancer cells have been reported to display high heme levels and increased activity of heme-containing proteins. Consistently, inhibition of heme biosynthesis by the ALAD inhibitor succinylacetone (SA) has been shown to reduce tumor cell survival. These observations indicate that heme biosynthesis is essential for cancer cell proliferation. X irradiation has been shown to increase mitochondrial mass, membrane potential, oxygen consumption, reactive oxygen species (ROS) production, and ATP synthesis. This finding suggests that radiation activates mitochondrial oxidative phosphorylation (OXPHOS). However, although heme is an essential component of the mitochondrial ETC, whether radiation influences heme biosynthesis remains unclear. In this study, we evaluated heme biosynthesis activity after X irradiation and examined the effects of heme biosynthesis inhibition by SA on cellular radiosensitivity and mitochondrial OXPHOS function. We demonstrated that X irradiation significantly increased ALAS1 mRNA levels and cellular heme content. Inhibition of heme biosynthesis by SA significantly decreased cellular heme content and sensitized cancer cells to radiation. We also showed that SA reduced cellular ATP levels, mitochondrial membrane potential, and mitochondrial ROS production, suggesting mitochondrial OXPHOS dysfunction. SA decreased the expression of mitochondrial heme-related proteins COX2 and cytochrome c but did not influence COX1 and VDAC expression. These results indicate that inhibition of heme biosynthesis decreased mitochondrial ETC protein expression and OXPHOS activity, which triggered cellular ATP depletion and radiosensitization after X irradiation. In summary, heme biosynthesis is upregulated by X irradiation and is essential for mitochondrial OXPHOS and cell survival.
    DOI:  https://doi.org/10.1667/RADE-23-00035.1
  37. J Biol Chem. 2023 Nov 22. pii: S0021-9258(23)02520-6. [Epub ahead of print] 105492
    Combined inhibition of MTAP and MAT2a mimics synthetic lethality in tumor models via PRMT5 inhibition.
    Gabriel T Bedard, Nord Gilaj, Karina Peregrina, Isabella Brew, Elena Tosti, Karl Shaffer, Peter C Tyler, Winfried Edelmann, Leonard H Augenlicht, Vern L Schramm.
      Homozygous 5'-methylthioadenosine phosphorylase (MTAP) deletions occur in approximately 15% of human cancers. Co-deletion of MTAP and methionine adenosyltransferase 2 alpha (MAT2a) induces a synthetic lethal phenotype involving protein arginine methyltransferase 5 (PRMT5) inhibition. MAT2a inhibitors are now in clinical trials for genotypic MTAP-/- cancers, however the MTAP-/- genotype represents fewer than 2% of human colorectal cancers (CRCs), limiting the utility of MAT2a inhibitors in these and other MTAP+/+ cancers. Methylthio-DADMe-Immucilin-A (MTDIA) is a picomolar transition state analogue inhibitor of MTAP that renders cells enzymatically MTAP-deficient to induce the MTAP-/- phenotype. Here we demonstrate that MTDIA and MAT2a inhibitor AG-270 combination therapy mimics synthetic lethality in MTAP+/+ CRC cell lines with similar effects in mouse xenografts and without adverse histology on normal tissues. Combination treatment is synergistic with a 104-fold increase in drug potency for inhibition of CRC cell growth in culture. Combined MTDIA and AG-270 decreased S-adenosyl-L-methionine (SAM) and increased 5'-methylthioadenosine (MTA) in cells. The increased intracellular MTA:SAM ratio inhibits PRMT5 activity, leading to cellular arrest and apoptotic cell death by causing MDM4 alternative splicing and p53 activation. Combination MTDIA and AG-270 treatment differs from direct inhibition of PRMT5 by GSK3326595 by avoiding toxicity caused by cell death in the normal gut epithelium induced by the PRMT5 inhibitor. The combination of MTAP and MAT2a inhibitors expands this synthetic lethal approach to include MTAP+/+ cancers, especially the remaining 98% of CRCs without the MTAP-/- genotype.
    Keywords:  S-adenosyl-L-methionine; arginine methylation; cancer metabolism; cancer therapeutics; colorectal cancer; methionine salvage pathway
    DOI:  https://doi.org/10.1016/j.jbc.2023.105492
  38. Nature. 2023 Nov 22.
    Trans-vaccenic acid reprograms CD8+ T cells and anti-tumour immunity.
    Hao Fan, Siyuan Xia, Junhong Xiang, Yuancheng Li, Matthew O Ross, Seon Ah Lim, Fan Yang, Jiayi Tu, Lishi Xie, Urszula Dougherty, Freya Q Zhang, Zhong Zheng, Rukang Zhang, Rong Wu, Lei Dong, Rui Su, Xiufen Chen, Thomas Althaus, Peter A Riedell, Patrick B Jonker, Alexander Muir, Gregory B Lesinski, Sarwish Rafiq, Madhav V Dhodapkar, Wendy Stock, Olatoyosi Odenike, Anand A Patel, Joseph Opferman, Takemasa Tsuji, Junko Matsuzaki, Hardik Shah, Brandon Faubert, Shannon E Elf, Brian Layden, B Marc Bissonnette, Yu-Ying He, Justin Kline, Hui Mao, Kunle Odunsi, Xue Gao, Hongbo Chi, Chuan He, Jing Chen.
      Diet-derived nutrients are inextricably linked to human physiology by providing energy and biosynthetic building blocks and by functioning as regulatory molecules. However, the mechanisms by which circulating nutrients in the human body influence specific physiological processes remain largely unknown. Here we use a blood nutrient compound library-based screening approach to demonstrate that dietary trans-vaccenic acid (TVA) directly promotes effector CD8+ T cell function and anti-tumour immunity in vivo. TVA is the predominant form of trans-fatty acids enriched in human milk, but the human body cannot produce TVA endogenously1. Circulating TVA in humans is mainly from ruminant-derived foods including beef, lamb and dairy products such as milk and butter2,3, but only around 19% or 12% of dietary TVA is converted to rumenic acid by humans or mice, respectively4,5. Mechanistically, TVA inactivates the cell-surface receptor GPR43, an immunomodulatory G protein-coupled receptor activated by its short-chain fatty acid ligands6-8. TVA thus antagonizes the short-chain fatty acid agonists of GPR43, leading to activation of the cAMP-PKA-CREB axis for enhanced CD8+ T cell function. These findings reveal that diet-derived TVA represents a mechanism for host-extrinsic reprogramming of CD8+ T cells as opposed to the intrahost gut microbiota-derived short-chain fatty acids. TVA thus has translational potential for the treatment of tumours.
    DOI:  https://doi.org/10.1038/s41586-023-06749-3
  39. Cell Metab. 2023 Nov 16. pii: S1550-4131(23)00386-8. [Epub ahead of print]
    Adipo-glial signaling mediates metabolic adaptation in peripheral nerve regeneration.
    Venkat Krishnan Sundaram, Vlad Schütza, Nele H Schröter, Aline Backhaus, Annika Bilsing, Lisa Joneck, Anna Seelbach, Clara Mutschler, Jose A Gomez-Sanchez, Erik Schäffner, Eva Ernst Sánchez, Dagmar Akkermann, Christina Paul, Nancy Schwagarus, Silvana Müller, Angela Odle, Gwen Childs, David Ewers, Theresa Kungl, Maren Sitte, Gabriela Salinas, Michael W Sereda, Klaus-Armin Nave, Markus H Schwab, Mario Ost, Peter Arthur-Farraj, Ruth M Stassart, Robert Fledrich.
      The peripheral nervous system harbors a remarkable potential to regenerate after acute nerve trauma. Full functional recovery, however, is rare and critically depends on peripheral nerve Schwann cells that orchestrate breakdown and resynthesis of myelin and, at the same time, support axonal regrowth. How Schwann cells meet the high metabolic demand required for nerve repair remains poorly understood. We here report that nerve injury induces adipocyte to glial signaling and identify the adipokine leptin as an upstream regulator of glial metabolic adaptation in regeneration. Signal integration by leptin receptors in Schwann cells ensures efficient peripheral nerve repair by adjusting injury-specific catabolic processes in regenerating nerves, including myelin autophagy and mitochondrial respiration. Our findings propose a model according to which acute nerve injury triggers a therapeutically targetable intercellular crosstalk that modulates glial metabolism to provide sufficient energy for successful nerve repair.
    Keywords:  Schwann cell; adipocytes; energy metabolism; leptin; leptin receptor; metabolic adaptation; mitochondrial respiration; myelin autophagy; myelinophagy; nerve repair; oxidative phosphorylation; peripheral nerve injury; regeneration; remyelination
    DOI:  https://doi.org/10.1016/j.cmet.2023.10.017
  40. J Biol Chem. 2023 Nov 20. pii: S0021-9258(23)02513-9. [Epub ahead of print] 105485
    Metabolic reprogramming driven by EZH2 inhibition depends on cell-matrix interactions.
    Teresa W-M Fan, Jahid M M Islam, Richard M Higashi, Penghui Lin, Christine F Brainson, Andrew N Lane.
      EZH2 (Enhancer of Zeste Homolog 2), a subunit of Polycomb Repressive Complex 2 (PRC2), catalyzes the trimethylation of histone H3 at lysine 27 (H3K27me3), which represses expression of genes. It also has PRC2-independent functions, including transcriptional coactivation of oncogenes, and is frequently overexpressed in lung cancers. Clinically, EZH2 inhibition can be achieved with the FDA-approved drug EPZ-6438 (tazemetostat). To realize the full potential of EZH2 blockade, it is critical to understand how cell-cell/cell-matrix interactions present in three-dimensional (3D) tissue and cell culture systems influences this blockade in terms of growth-related metabolic functions. Here, we show that EZH2 suppression reduced growth of human lung adenocarcinoma A549 cells in two-dimensional (2D) cultures but stimulated growth in 3D culture. To understand the metabolic underpinnings, we employed [13C6]-glucose Stable Isotope-Resolved Metabolomics (SIRM) to determine the effect of EZH2 suppression on metabolic networks in 2D versus 3D A549 cultures. The Krebs cycle, neoribogenesis, γ-aminobutyrate (GAB) metabolism, and salvage synthesis of purine nucleotides were activated by EZH2 suppression in 3D spheroids but not in 2D cells, consistent with the growth effect. Using simultaneous 2H7-glucose + 13C5,15N2-Gln tracers and EPZ-6438 inhibition of H3 trimethylation, we delineated the effects on the Krebs cycle, γ-aminobutyrate metabolism, gluconeogenesis, and purine salvage to be PRC2 dependent. Furthermore, the growth/metabolic effects differed for mouse Matrigel versus self-produced A549 extracellular matrix. Thus, our findings highlight the importance of the presence and nature of extracellular matrix in studying the function of EZH2 and its inhibitors in cancer cells for modeling the in vivo outcomes.
    Keywords:  EZH2; Stable Isotope-Resolved Metabolomics; extracellular matrix; glucose/glutamine metabolism; spheroids
    DOI:  https://doi.org/10.1016/j.jbc.2023.105485
  41. Blood. 2023 Nov 22. pii: blood.2023019964. [Epub ahead of print]
    The lifelong natural history of clonal hematopoiesis and its links to myeloid malignancy.
    Margarete A Fabre, George S Vassiliou.
      The study of somatic mutations and the associated clonal mosaicism across the human body has transformed our understanding of ageing and its links to cancer. In proliferative human tissues, stem cells compete for dominance and those with an advantage expand clonally in relation to their peers. In the hematopoietic system, such expansion is termed clonal hematopoiesis (CH). The forces driving competition, namely heterogeneity of the hematopoietic stem cell (HSC) pool and attrition of the HSC environment, become increasingly prominent with age. As a result, CH becomes progressively more common through life, to the point of becoming essentially ubiquitous. We are beginning to unravel the specific intra- and extra-cellular factors underpinning clonal behavior, with somatic mutations in specific driver genes, inflammation, telomere maintenance, extraneous exposures and inherited genetic variation among the important players. The inevitability of CH with age, combined with its unequivocal links to myeloid cancers, poses a scientific and clinical challenge. Specifically, we need to decipher the factors determining clonal behavior and to develop prognostic tools to identify those at high risk of malignant progression, for whom preventive interventions may be warranted. Here, we discuss how recent advances in our understanding of the natural history of CH have provided important insights into these processes and helped define future avenues of investigation.
    DOI:  https://doi.org/10.1182/blood.2023019964
  42. Cell Rep. 2023 Nov 22. pii: S2211-1247(23)01495-X. [Epub ahead of print]42(12): 113483
    Circadian clock factors regulate the first condensation reaction of fatty acid synthesis in Arabidopsis.
    Sang-Chul Kim, Kristen N Edgeworth, Dmitri A Nusinow, Xuemin Wang.
      The circadian clock regulates temporal metabolic activities, but how it affects lipid metabolism is poorly understood. Here, we show that the central clock regulators LATE ELONGATED HYPOCOTYL (LHY) and CIRCADIAN CLOCK ASSOCIATED 1 (CCA1) regulate the initial step of fatty acid (FA) biosynthesis in Arabidopsis. Triacylglycerol (TAG) accumulation in seeds was increased in LHY-overexpressing (LHY-OE) and decreased in lhycca1 plants. Metabolic tracking of lipids in developing seeds indicated that LHY enhanced FA synthesis. Transcript analysis revealed that the expression of genes involved in FA synthesis, including the one encoding β-ketoacyl-ACP synthase III (KASIII), was oppositely changed in developing seeds of LHY/CCA1-OEs and lhycca1. Chromatin immunoprecipitation, electrophoretic mobility shift, and transactivation assays indicated that LHY bound and activated the promoter of KASIII. Furthermore, phosphatidic acid, a metabolic precursor to TAG, inhibited LHY binding to KASIII promoter elements. Our data show a regulatory mechanism for plant lipid biosynthesis by the molecular clock.
    Keywords:  Arabidopsis; CP: Plants; Clock regulation of lipid metabolism; LHY/CCA1; Lipid-clock interconnection; b-ketoacyl-ACP synthase III (KASIII); circadian clock; fatty acid synthesis; lipid signaling; phosphatidic acid; seed oil; transcriptional regulation
    DOI:  https://doi.org/10.1016/j.celrep.2023.113483
  43. Metabolites. 2023 Nov 11. pii: 1145. [Epub ahead of print]13(11):
    Modeling Red Blood Cell Metabolism in the Omics Era.
    Alicia Key, Zachary Haiman, Bernhard O Palsson, Angelo D'Alessandro.
      Red blood cells (RBCs) are abundant (more than 80% of the total cells in the human body), yet relatively simple, as they lack nuclei and organelles, including mitochondria. Since the earliest days of biochemistry, the accessibility of blood and RBCs made them an ideal matrix for the characterization of metabolism. Because of this, investigations into RBC metabolism are of extreme relevance for research and diagnostic purposes in scientific and clinical endeavors. The relative simplicity of RBCs has made them an eligible model for the development of reconstruction maps of eukaryotic cell metabolism since the early days of systems biology. Computational models hold the potential to deepen knowledge of RBC metabolism, but also and foremost to predict in silico RBC metabolic behaviors in response to environmental stimuli. Here, we review now classic concepts on RBC metabolism, prior work in systems biology of unicellular organisms, and how this work paved the way for the development of reconstruction models of RBC metabolism. Translationally, we discuss how the fields of metabolomics and systems biology have generated evidence to advance our understanding of the RBC storage lesion, a process of decline in storage quality that impacts over a hundred million blood units transfused every year.
    Keywords:  erythrocytes; genome-scale metabolic models; metabolomics; omics; personalized medicine; red blood cells; systems biology; transfusion
    DOI:  https://doi.org/10.3390/metabo13111145
  44. Adv Sci (Weinh). 2023 Nov 21. e2303664
    Extracellular Delivery of Functional Mitochondria Rescues the Dysfunction of CD4+ T Cells in Aging.
    Colwyn A Headley, Shalini Gautam, Angelica Olmo-Fontanez, Andreu Garcia-Vilanova, Varun Dwivedi, Anwari Akhter, Alyssa Schami, Kevin Chiem, Russell Ault, Hao Zhang, Hong Cai, Alison Whigham, Jennifer Delgado, Amberlee Hicks, Philip S Tsao, Jonathan Gelfond, Luis Martinez-Sobrido, Yufeng Wang, Jordi B Torrelles, Joanne Turner.
      Mitochondrial dysfunction alters cellular metabolism, increases tissue oxidative stress, and may be principal to the dysregulated signaling and function of CD4+ T lymphocytes in the elderly. In this proof of principle study, it is investigated whether the transfer of functional mitochondria into CD4+ T cells that are isolated from old mice (aged CD4+ T cells), can abrogate aging-associated mitochondrial dysfunction, and improve the aged CD4+ T cell functionality. The results show that the delivery of exogenous mitochondria to aged non-activated CD4+ T cells led to significant mitochondrial proteome alterations highlighted by improved aerobic metabolism and decreased cellular mitoROS. Additionally, mito-transferred aged CD4+ T cells showed improvements in activation-induced TCR-signaling kinetics displaying markers of activation (CD25), increased IL-2 production, enhanced proliferation ex vivo. Importantly, immune deficient mouse models (RAG-KO) showed that adoptive transfer of mito-transferred naive aged CD4+ T cells, protected recipient mice from influenza A and Mycobacterium tuberculosis infections. These findings support mitochondria as targets of therapeutic intervention in aging.
    Keywords:  CD4+ T cells; adaptive immunity; aging immunology; immunometabolism; mitochondrial dysfunction
    DOI:  https://doi.org/10.1002/advs.202303664
  45. Cell Death Differ. 2023 Nov 24.
    LUBAC is required for RIG-I sensing of RNA viruses.
    Helena C Teague, Charlotte Lefevre, Eva Rieser, Lina Wolfram, Diego de Miguel, Daniel Patricio de Oliveira, Marisa Oliveira, Daniel S Mansur, Nerea Irigoyen, Henning Walczak, Brian J Ferguson.
      The ability of cells to mount an interferon response to virus infections depends on intracellular nucleic acid sensing pattern recognition receptors (PRRs). RIG-I is an intracellular PRR that binds short double-stranded viral RNAs to trigger MAVS-dependent signalling. The RIG-I/MAVS signalling complex requires the coordinated activity of multiple kinases and E3 ubiquitin ligases to activate the transcription factors that drive type I and type III interferon production from infected cells. The linear ubiquitin chain assembly complex (LUBAC) regulates the activity of multiple receptor signalling pathways in both ligase-dependent and -independent ways. Here, we show that the three proteins that constitute LUBAC have separate functions in regulating RIG-I signalling. Both HOIP, the E3 ligase capable of generating M1-ubiquitin chains, and LUBAC accessory protein HOIL-1 are required for viral RNA sensing by RIG-I. The third LUBAC component, SHARPIN, is not required for RIG-I signalling. These data cement the role of LUBAC as a positive regulator of RIG-I signalling and as an important component of antiviral innate immune responses.
    DOI:  https://doi.org/10.1038/s41418-023-01233-x
  46. Free Radic Biol Med. 2023 Nov 16. pii: S0891-5849(23)01101-2. [Epub ahead of print]
    Mitochondrial hyperfusion induces metabolic remodeling in lung endothelial cells by modifying the activities of electron transport chain complexes I and III.
    Manivannan Yegambaram, Xutong Sun, Qing Lu, Yan Jin, Wojciech Ornatowski, Jamie Soto, Saurabh Aggarwal, Ting Wang, Kim Tieu, Haiwei Gu, Jeffrey R Fineman, Stephen M Black.
       OBJECTIVE: Pulmonary hypertension (PH) is a progressive disease with vascular remodeling as a critical structural alteration. We have previously shown that metabolic reprogramming is an early initiating mechanism in animal models of PH. This metabolic dysregulation has been linked to remodeling the mitochondrial network to favor fission. However, whether the mitochondrial fission/fusion balance underlies the metabolic reprogramming found early in PH development is unknown.
    METHODS: Utilizing a rat early model of PH, in conjunction with cultured pulmonary endothelial cells (PECs), we utilized metabolic flux assays, Seahorse Bioassays, measurements of electron transport chain (ETC) complex activity, fluorescent microscopy, and molecular approaches to investigate the link between the disruption of mitochondrial dynamics and the early metabolic changes that occur in PH.
    RESULTS: We observed increased fusion mediators, including Mfn1, Mfn2, and Opa1, and unchanged fission mediators, including Drp1 and Fis1, in a two-week monocrotaline-induced PH animal model (early-stage PH). We were able to establish a connection between increases in fusion mediator Mfn1 and metabolic reprogramming. Using an adenoviral expression system to enhance Mfn1 levels in pulmonary endothelial cells and utilizing 13C-glucose labeled substrate, we found increased production of 13C lactate and decreased TCA cycle metabolites, revealing a Warburg phenotype. The use of a 13C5-glutamine substrate showed evidence that hyperfusion also induces oxidative carboxylation. The increase in glycolysis was linked to increased hypoxia-inducible factor 1α (HIF-1α) protein levels secondary to the disruption of cellular bioenergetics and higher levels of mitochondrial reactive oxygen species (mt-ROS). The elevation in mt-ROS correlated with attenuated ETC complexes I and III activities. Utilizing a mitochondrial-targeted antioxidant to suppress mt-ROS, limited HIF-1α protein levels, which reduced cellular glycolysis and reestablished mitochondrial membrane potential.
    CONCLUSIONS: Our data connects mitochondrial fusion-mediated mt-ROS to the Warburg phenotype in early-stage PH development.
    Keywords:  Glycolysis; Metabolomics; Mitochondrial function; Mitofusin; Pulmonary hypertension
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.11.008
  47. Nat Genet. 2023 Nov 23.
    Is clonal hematopoiesis 'mostly harmless'?
      
    DOI:  https://doi.org/10.1038/s41588-023-01556-y
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