bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2024‒01‒07
sixty-one papers selected by
Christian Frezza, Universität zu Köln
  1. Nutrient uptake strategies shift during mouse epiblast development.
  2. Dual regulation of SLC25A39 by AFG3L2 and iron controls mitochondrial glutathione homeostasis.
  3. Glycine homeostasis requires reverse SHMT flux.
  4. Mitochondrial-derived vesicles in metabolism, disease, and aging.
  5. Structural insights into respiratory complex I deficiency and assembly from the mitochondrial disease-related ndufs4-/- mouse.
  6. Blocking methionine catabolism induces senescence and confers vulnerability to GSK3 inhibition in liver cancer.
  7. Show MERCI on mobile mitochondria.
  8. Cutting through stress.
  9. Exquisite exposure: Formaldehyde as a metabolic regulator.
  10. Amino acid intake strategies define pluripotent cell states.
  11. Small intestinal protein sensing pathways regulate food intake and glucose homeostasis.
  12. HKDC1, a target of TFEB, is essential to maintain both mitochondrial and lysosomal homeostasis, preventing cellular senescence.
  13. Regulation of protein O-GlcNAcylation by circadian, metabolic, and cellular signals.
  14. Metabolic reprogramming by histone deacetylase inhibition preferentially targets NRF2-activated tumors.
  15. Metabolic switch regulates lineage plasticity and induces synthetic lethality in triple-negative breast cancer.
  16. Fission-independent compartmentalization of mitochondria during budding yeast cell division.
  17. Histone lactylation couples cellular metabolism with developmental gene regulatory networks.
  18. Serine synthesis via reversed SHMT2 activity drives glycine depletion and acetaminophen hepatotoxicity in MASLD.
  19. MTCH2 cooperates with MFN2 and lysophosphatidic acid synthesis to sustain mitochondrial fusion.
  20. Inhibition of O -GlcNAc transferase activates type I interferon-dependent antitumor immunity by bridging cGAS-STING pathway.
  21. The biology of mitochondrial carrier homolog 2.
  22. Cell cycle arrest induces lipid droplet formation and confers ferroptosis resistance.
  23. The glue that holds us together.
  24. Acylspermidines are conserved mitochondrial sirtuin-dependent metabolites.
  25. ABCG2 is an itaconate exporter that limits antibacterial innate immunity by alleviating TFEB-dependent lysosomal biogenesis.
  26. Hypoxia induces mitochondrial protein lactylation to limit oxidative phosphorylation.
  27. The solute carrier SLC25A17 sustains peroxisomal redox homeostasis in diverse mammalian cell lines.
  28. Somatic mouse models of gastric cancer reveal genotype-specific features of metastatic disease.
  29. Proteolytic activation of fatty acid synthase signals pan-stress resolution.
  30. Translation of non-canonical open reading frames as a cancer cell survival mechanism in childhood medulloblastoma.
  31. Nuclear Hsp104 safeguards the dormant translation machinery during quiescence.
  32. Janus-faced Mitofusin 2 (MFN2): mitochondria-endoplasmic reticulum shaping and tethering functions unveiled.
  33. Mic19 depletion impairs endoplasmic reticulum-mitochondrial contacts and mitochondrial lipid metabolism and triggers liver disease.
  34. FOXO1-mediated lipid metabolism maintains mammalian embryos in dormancy.
  35. Metabolic Adaptation and Cellular Stress Response As Targets for Cancer Therapy.
  36. H2S serves as the immunoregulatory essence of apoptotic cell death.
  37. Intercellular crosstalk shapes purinergic metabolism and signaling in cancer cells.
  38. SARM1 regulates NAD+-linked metabolism and select immune genes in macrophages.
  39. Mitochondrial Dynamics at Different Levels: From Cristae Dynamics to Interorganellar Cross Talk.
  40. Cell metabolism and bone cells.
  41. TAMC-derived creatine sustains glioblastoma growth.
  42. p32 regulates glycometabolism and TCA cycle to inhibit ccRCC progression via copper-induced DLAT lipoylation oligomerization.
  43. Vitamin B12 produced by gut bacteria modulates cholinergic signalling.
  44. EGFR-activated myofibroblasts promote metastasis of pancreatic cancer.
  45. Large-scale column-free purification of bovine F-ATP synthase.
  46. Cell competition and cancer from Drosophila to mammals.
  47. Targeting serine/glycine metabolism improves radiotherapy response in non-small cell lung cancer.
  48. KRAS allelic imbalance drives tumour initiation yet suppresses metastasis in colorectal cancer in vivo.
  49. IKKε and TBK1 prevent RIPK1 dependent and independent inflammation.
  50. Epidermal tyrosine catabolism is crucial for metabolic homeostasis and survival against high-protein diets in Drosophila.
  51. Over-expression of N-acetylaspartate synthase exacerbates pathological energetic deficit and accelerates cognitive decline in the 5xFAD mouse.
  52. The polyketide to fatty acid transition in the evolution of animal lipid metabolism.
  53. Lysosomal TBK1 Responds to Amino Acid Availability to Relieve Rab7-Dependent mTORC1 Inhibition.
  54. Mutant p53 gains oncogenic functions through a chromosomal instability-induced cytosolic DNA response.
  55. Circadian rhythm regulation in the immune system.
  56. Fatty acid synthesis suppresses dietary polyunsaturated fatty acid use.
  57. CHCHD4-TRIAP1 regulation of innate immune signaling mediates skeletal muscle adaptation to exercise.
  58. Deciphering the metabolic heterogeneity of hematopoietic stem cells with single-cell resolution.
  59. Mitochondrial isocitrate dehydrogenase impedes CAR T cell function by restraining antioxidant metabolism and histone acetylation.
  60. OXCT1 functions as a succinyltransferase, contributing to hepatocellular carcinoma via succinylating LACTB.
  61. Dietary approaches for exploiting metabolic vulnerabilities in cancer.
  1. Nat Metab. 2024 Jan 03.
    Nutrient uptake strategies shift during mouse epiblast development.
      
    DOI:  https://doi.org/10.1038/s42255-023-00941-5
  2. Mol Cell. 2023 Dec 20. pii: S1097-2765(23)01027-4. [Epub ahead of print]
    Dual regulation of SLC25A39 by AFG3L2 and iron controls mitochondrial glutathione homeostasis.
    Xiaojian Shi, Marisa DeCiucis, Kariona A Grabinska, Jean Kanyo, Adam Liu, Tukiet T Lam, Hongying Shen.
      Organelle transporters define metabolic compartmentalization, and how this metabolite transport process can be modulated is poorly explored. Here, we discovered that human SLC25A39, a mitochondrial transporter critical for mitochondrial glutathione uptake, is a short-lived protein under dual regulation at the protein level. Co-immunoprecipitation mass spectrometry and CRISPR knockout (KO) in mammalian cells identified that mitochondrial m-AAA protease AFG3L2 is responsible for degrading SLC25A39 through the matrix loop 1. SLC25A39 senses mitochondrial iron-sulfur cluster using four matrix cysteine residues and inhibits its degradation. SLC25A39 protein regulation is robust in developing and mature neurons. This dual transporter regulation, by protein quality control and metabolic sensing, allows modulating mitochondrial glutathione level in response to iron homeostasis, opening avenues for exploring regulation of metabolic compartmentalization. Neuronal SLC25A39 regulation connects mitochondrial protein quality control, glutathione, and iron homeostasis, which were previously unrelated biochemical features in neurodegeneration.
    Keywords:  AFG3L2; SLC25A39; glutathione; iron; mitochondrial transporter; protein quality control
    DOI:  https://doi.org/10.1016/j.molcel.2023.12.008
  3. Cell Metab. 2024 Jan 02. pii: S1550-4131(23)00452-7. [Epub ahead of print]36(1): 103-115.e4
    Glycine homeostasis requires reverse SHMT flux.
    Matthew J McBride, Craig J Hunter, Zhaoyue Zhang, Tara TeSlaa, Xincheng Xu, Gregory S Ducker, Joshua D Rabinowitz.
      The folate-dependent enzyme serine hydroxymethyltransferase (SHMT) reversibly converts serine into glycine and a tetrahydrofolate-bound one-carbon unit. Such one-carbon unit production plays a critical role in development, the immune system, and cancer. Using rodent models, here we show that the whole-body SHMT flux acts to net consume rather than produce glycine. Pharmacological inhibition of whole-body SHMT1/2 and genetic knockout of liver SHMT2 elevated circulating glycine levels up to eight-fold. Stable-isotope tracing revealed that the liver converts glycine to serine, which is then converted by serine dehydratase into pyruvate and burned in the tricarboxylic acid cycle. In response to diets deficient in serine and glycine, de novo biosynthetic flux was unaltered, but SHMT2- and serine-dehydratase-mediated catabolic flux was lower. Thus, glucose-derived serine synthesis is largely insensitive to systemic demand. Instead, circulating serine and glycine homeostasis is maintained through variable consumption, with liver SHMT2 a major glycine-consuming enzyme.
    Keywords:  SHMT; amino acid metabolism; folate cycle; glycine; hepatic clearance; homeostasis; serine
    DOI:  https://doi.org/10.1016/j.cmet.2023.12.001
  4. Cell Metab. 2024 Jan 02. pii: S1550-4131(23)00446-1. [Epub ahead of print]36(1): 21-35
    Mitochondrial-derived vesicles in metabolism, disease, and aging.
    Tim König, Heidi M McBride.
      Mitochondria are central hubs of cellular metabolism and are tightly connected to signaling pathways. The dynamic plasticity of mitochondria to fuse, divide, and contact other organelles to flux metabolites is central to their function. To ensure bona fide functionality and signaling interconnectivity, diverse molecular mechanisms evolved. An ancient and long-overlooked mechanism is the generation of mitochondrial-derived vesicles (MDVs) that shuttle selected mitochondrial cargoes to target organelles. Just recently, we gained significant insight into the mechanisms and functions of MDV transport, ranging from their role in mitochondrial quality control to immune signaling, thus demonstrating unexpected and diverse physiological aspects of MDV transport. This review highlights the origin of MDVs, their biogenesis, and their cargo selection, with a specific focus on the contribution of MDV transport to signaling across cell and organ barriers. Additionally, the implications of MDVs in peroxisome biogenesis, neurodegeneration, metabolism, aging, and cancer are discussed.
    DOI:  https://doi.org/10.1016/j.cmet.2023.11.014
  5. EMBO J. 2024 Jan 02.
    Structural insights into respiratory complex I deficiency and assembly from the mitochondrial disease-related ndufs4-/- mouse.
    Zhan Yin, Ahmed-Noor A Agip, Hannah R Bridges, Judy Hirst.
      Respiratory complex I (NADH:ubiquinone oxidoreductase) is essential for cellular energy production and NAD+ homeostasis. Complex I mutations cause neuromuscular, mitochondrial diseases, such as Leigh Syndrome, but their molecular-level consequences remain poorly understood. Here, we use a popular complex I-linked mitochondrial disease model, the ndufs4-/- mouse, to define the structural, biochemical, and functional consequences of the absence of subunit NDUFS4. Cryo-EM analyses of the complex I from ndufs4-/- mouse hearts revealed a loose association of the NADH-dehydrogenase module, and discrete classes containing either assembly factor NDUFAF2 or subunit NDUFS6. Subunit NDUFA12, which replaces its paralogue NDUFAF2 in mature complex I, is absent from all classes, compounding the deletion of NDUFS4 and preventing maturation of an NDUFS4-free enzyme. We propose that NDUFAF2 recruits the NADH-dehydrogenase module during assembly of the complex. Taken together, the findings provide new molecular-level understanding of the ndufs4-/- mouse model and complex I-linked mitochondrial disease.
    Keywords:  Complex I; Cryo-EM; Leigh Syndrome; Mitochondria; NADH:Ubiquinone Oxidoreductase
    DOI:  https://doi.org/10.1038/s44318-023-00001-4
  6. Nat Cancer. 2024 Jan 02.
    Blocking methionine catabolism induces senescence and confers vulnerability to GSK3 inhibition in liver cancer.
    Fuming Li, Pingyu Liu, Wen Mi, Liucheng Li, Nicole M Anderson, Nicholas P Lesner, Michelle Burrows, Jacqueline Plesset, Ariana Majer, Guanlin Wang, Jinyang Li, Lingzhi Zhu, Brian Keith, M Celeste Simon.
      Availability of the essential amino acid methionine affects cellular metabolism and growth, and dietary methionine restriction has been implicated as a cancer therapeutic strategy. Nevertheless, how liver cancer cells respond to methionine deprivation and underlying mechanisms remain unclear. Here we find that human liver cancer cells undergo irreversible cell cycle arrest upon methionine deprivation in vitro. Blocking methionine adenosyl transferase 2A (MAT2A)-dependent methionine catabolism induces cell cycle arrest and DNA damage in liver cancer cells, resulting in cellular senescence. A pharmacological screen further identified GSK3 inhibitors as senolytics that selectively kill MAT2A-inhibited senescent liver cancer cells. Importantly, combined treatment with MAT2A and GSK3 inhibitors therapeutically blunts liver tumor growth in vitro and in vivo across multiple models. Together, methionine catabolism is essential for liver tumor growth, and its inhibition can be exploited as an improved pro-senescence strategy for combination with senolytic agents to treat liver cancer.
    DOI:  https://doi.org/10.1038/s43018-023-00671-3
  7. Cell Metab. 2024 Jan 02. pii: S1550-4131(23)00468-0. [Epub ahead of print]36(1): 5-7
    Show MERCI on mobile mitochondria.
    Jelle van den Ameele, Patrick F Chinnery.
      There is emerging evidence that mitochondria can move between cells, particularly from immune cells into cancers. Recent work from Zhang et al. in Cancer Cell employs single-cell RNA- and mitochondrial DNA-sequencing in co-culture experiments and patient tumor samples to detect mitochondrial transfer. However, the mechanisms, scale, and implications remain uncertain.
    DOI:  https://doi.org/10.1016/j.cmet.2023.12.017
  8. Nat Metab. 2024 Jan 02.
    Cutting through stress.
    Luis A Jasper, Meng C Wang.
      
    DOI:  https://doi.org/10.1038/s42255-023-00946-0
  9. Mol Cell. 2024 Jan 04. pii: S1097-2765(23)01025-0. [Epub ahead of print]84(1): 20-22
    Exquisite exposure: Formaldehyde as a metabolic regulator.
    Gabriela Ramirez-Hernandez, Nora Kory.
      Throughout life, whether through external consumption or internal production, we are exposed to different reactive metabolites considered toxic to the body. Pham et al.1 uncover metabolic regulation by one such harmful metabolite: formaldehyde.
    DOI:  https://doi.org/10.1016/j.molcel.2023.12.006
  10. Nat Metab. 2024 Jan 03.
    Amino acid intake strategies define pluripotent cell states.
    Pavlina K Todorova, Benjamin T Jackson, Vidur Garg, Katrina I Paras, Julia S Brunner, Anna E Bridgeman, Yanyang Chen, Sanjeethan C Baksh, Jielin Yan, Anna-Katerina Hadjantonakis, Lydia W S Finley.
      Mammalian preimplantation development is associated with marked metabolic robustness, and embryos can develop under a wide variety of nutrient conditions, including even the complete absence of soluble amino acids. Here we show that mouse embryonic stem cells (ESCs) capture the unique metabolic state of preimplantation embryos and proliferate in the absence of several essential amino acids. Amino acid independence is enabled by constitutive uptake of exogenous protein through macropinocytosis, alongside a robust lysosomal digestive system. Following transition to more committed states, ESCs reduce digestion of extracellular protein and instead become reliant on exogenous amino acids. Accordingly, amino acid withdrawal selects for ESCs that mimic the preimplantation epiblast. More broadly, we find that all lineages of preimplantation blastocysts exhibit constitutive macropinocytic protein uptake and digestion. Taken together, these results highlight exogenous protein uptake and digestion as an intrinsic feature of preimplantation development and provide insight into the catabolic strategies that enable embryos to sustain viability before implantation.
    DOI:  https://doi.org/10.1038/s42255-023-00940-6
  11. Nat Metab. 2024 Jan 02.
    Small intestinal protein sensing pathways regulate food intake and glucose homeostasis.
      
    DOI:  https://doi.org/10.1038/s42255-023-00947-z
  12. Proc Natl Acad Sci U S A. 2024 Jan 09. 121(2): e2306454120
    HKDC1, a target of TFEB, is essential to maintain both mitochondrial and lysosomal homeostasis, preventing cellular senescence.
    Mengying Cui, Koji Yamano, Kenichi Yamamoto, Hitomi Yamamoto-Imoto, Satoshi Minami, Takeshi Yamamoto, Sho Matsui, Tatsuya Kaminishi, Takayuki Shima, Monami Ogura, Megumi Tsuchiya, Kohei Nishino, Brian T Layden, Hisakazu Kato, Hidesato Ogawa, Shinya Oki, Yukinori Okada, Yoshitaka Isaka, Hidetaka Kosako, Noriyuki Matsuda, Tamotsu Yoshimori, Shuhei Nakamura.
      Mitochondrial and lysosomal functions are intimately linked and are critical for cellular homeostasis, as evidenced by the fact that cellular senescence, aging, and multiple prominent diseases are associated with concomitant dysfunction of both organelles. However, it is not well understood how the two important organelles are regulated. Transcription factor EB (TFEB) is the master regulator of lysosomal function and is also implicated in regulating mitochondrial function; however, the mechanism underlying the maintenance of both organelles remains to be fully elucidated. Here, by comprehensive transcriptome analysis and subsequent chromatin immunoprecipitation-qPCR, we identified hexokinase domain containing 1 (HKDC1), which is known to function in the glycolysis pathway as a direct TFEB target. Moreover, HKDC1 was upregulated in both mitochondrial and lysosomal stress in a TFEB-dependent manner, and its function was critical for the maintenance of both organelles under stress conditions. Mechanistically, the TFEB-HKDC1 axis was essential for PINK1 (PTEN-induced kinase 1)/Parkin-dependent mitophagy via its initial step, PINK1 stabilization. In addition, the functions of HKDC1 and voltage-dependent anion channels, with which HKDC1 interacts, were essential for the clearance of damaged lysosomes and maintaining mitochondria-lysosome contact. Interestingly, HKDC1 regulated mitophagy and lysosomal repair independently of its prospective function in glycolysis. Furthermore, loss function of HKDC1 accelerated DNA damage-induced cellular senescence with the accumulation of hyperfused mitochondria and damaged lysosomes. Our results show that HKDC1, a factor downstream of TFEB, maintains both mitochondrial and lysosomal homeostasis, which is critical to prevent cellular senescence.
    Keywords:  HKDC1; TFEB; cellular senescence; mitochondria–lysosome contact; mitophagy
    DOI:  https://doi.org/10.1073/pnas.2306454120
  13. J Biol Chem. 2023 Dec 28. pii: S0021-9258(23)02645-5. [Epub ahead of print] 105616
    Regulation of protein O-GlcNAcylation by circadian, metabolic, and cellular signals.
    Xianhui Liu, Yao D Cai, Joanna C Chiu.
      O-linked β-N-acetylglucosamine (O-GlcNAcylation) is a dynamic post-translational modification that regulates thousands of proteins and almost all cellular processes. Aberrant O-GlcNAcylation has been associated with numerous diseases, including cancer, neurodegenerative diseases, cardiovascular diseases, and type 2 diabetes. O-GlcNAcylation is highly nutrient sensitive since it is dependent on UDP-GlcNAc, the end product of the hexosamine biosynthetic pathway (HBP). We previously observed daily rhythmicity of protein O-GlcNAcylation in a Drosophila model that is sensitive to timing of food consumption. We showed that the circadian clock plays a key role in regulating daily O-GlcNAcylation rhythms given its control of feeding-fasting cycle and hence nutrient availability. Interestingly, we reported that the circadian clock also modulates daily O-GlcNAcylation rhythm by regulating molecular mechanisms beyond the regulation of food consumption time. A large body of work now indicates that O-GlcNAcylation is likely a generalized cellular status effector as it responds to various cellular signals and conditions, such as ER stress, apoptosis, and infection. In this review, we summarize the metabolic regulation of protein O-GlcNAcylation through nutrient availability, HBP enzymes and O-GlcNAc processing enzymes. We discuss the emerging roles of circadian clocks in regulating daily O-GlcNAcylation rhythm. Finally, we provide an overview of other cellular signals or conditions that impact O-GlcNAcylation. Many of these cellular pathways are themselves regulated by the clock and/or metabolism. Our review highlights the importance of maintaining optimal O-GlcNAc rhythm by restricting eating activity to the active period under physiological conditions and provide insights into potential therapeutic targets of O-GlcNAc homeostasis under pathological conditions.
    Keywords:  Circadian clock; Drosophila melanogaster; O-GlcNAc processing enzymes; OGA; OGT; glutamine fructose-6-phosphate aminotransferase; hexosamine biosynthetic pathway; metabolism; signal transduction
    DOI:  https://doi.org/10.1016/j.jbc.2023.105616
  14. Cell Rep. 2023 Dec 30. pii: S2211-1247(23)01640-6. [Epub ahead of print]43(1): 113629
    Metabolic reprogramming by histone deacetylase inhibition preferentially targets NRF2-activated tumors.
    Dimitris Karagiannis, Warren Wu, Albert Li, Makiko Hayashi, Xiao Chen, Michaela Yip, Vaibhav Mangipudy, Xinjing Xu, Francisco J Sánchez-Rivera, Yadira M Soto-Feliciano, Jiangbin Ye, Thales Papagiannakopoulos, Chao Lu.
      The interplay between metabolism and chromatin signaling is implicated in cancer progression. However, whether and how metabolic reprogramming in tumors generates chromatin vulnerabilities remain unclear. Lung adenocarcinoma (LUAD) tumors frequently harbor aberrant activation of the NRF2 antioxidant pathway, which drives aggressive and chemo-resistant disease. Using a chromatin-focused CRISPR screen, we report that NRF2 activation sensitizes LUAD cells to genetic and chemical inhibition of class I histone deacetylases (HDACs). This association is observed across cultured cells, mouse models, and patient-derived xenografts. Integrative epigenomic, transcriptomic, and metabolomic analysis demonstrates that HDAC inhibition causes widespread redistribution of H4ac and its reader protein, which transcriptionally downregulates metabolic enzymes. This results in reduced flux into amino acid metabolism and de novo nucleotide synthesis pathways that are preferentially required for the survival of NRF2-active cancer cells. Together, our findings suggest NRF2 activation as a potential biomarker for effective repurposing of HDAC inhibitors to treat solid tumors.
    Keywords:  CP: Cancer; HDAC inhibitors; NRF2 pathway; cancer epigenetics; cancer metabolism; cancer targeted therapy; epigenetic reprogramming; lung cancer
    DOI:  https://doi.org/10.1016/j.celrep.2023.113629
  15. Cell Metab. 2024 Jan 02. pii: S1550-4131(23)00455-2. [Epub ahead of print]36(1): 193-208.e8
    Metabolic switch regulates lineage plasticity and induces synthetic lethality in triple-negative breast cancer.
    Yingsheng Zhang, Meng-Ju Wu, Wan-Chi Lu, Yi-Chuan Li, Chun Ju Chang, Jer-Yen Yang.
      Metabolic reprogramming is key for cancer development, yet the mechanism that sustains triple-negative breast cancer (TNBC) cell growth despite deficient pyruvate kinase M2 (PKM2) and tumor glycolysis remains to be determined. Here, we find that deficiency in tumor glycolysis activates a metabolic switch from glycolysis to fatty acid β-oxidation (FAO) to fuel TNBC growth. We show that, in TNBC cells, PKM2 directly interacts with histone methyltransferase EZH2 to coordinately mediate epigenetic silencing of a carnitine transporter, SLC16A9. Inhibition of PKM2 leads to impaired EZH2 recruitment to SLC16A9, and in turn de-represses SLC16A9 expression to increase intracellular carnitine influx, programming TNBC cells to an FAO-dependent and luminal-like cell state. Together, these findings reveal a new metabolic switch that drives TNBC from a metabolically heterogeneous-lineage plastic cell state to an FAO-dependent-lineage committed cell state, where dual targeting of EZH2 and FAO induces potent synthetic lethality in TNBC.
    Keywords:  EZH2; PKM2; SLC16A9; induced synthetic lethality; lineage plasticity; metabolic reprogramming
    DOI:  https://doi.org/10.1016/j.cmet.2023.12.003
  16. J Cell Biol. 2024 Mar 04. pii: e202211048. [Epub ahead of print]223(3):
    Fission-independent compartmentalization of mitochondria during budding yeast cell division.
    Saori R Yoshii, Yves Barral.
      Lateral diffusion barriers compartmentalize membranes to generate polarity or asymmetrically partition membrane-associated macromolecules. Budding yeasts assemble such barriers in the endoplasmic reticulum (ER) and the outer nuclear envelope at the bud neck to retain aging factors in the mother cell and generate naïve and rejuvenated daughter cells. However, little is known about whether other organelles are similarly compartmentalized. Here, we show that the membranes of mitochondria are laterally compartmentalized at the bud neck and near the cell poles. The barriers in the inner mitochondrial membrane are constitutive, whereas those in the outer membrane form in response to stresses. The strength of mitochondrial diffusion barriers is regulated positively by spatial cues from the septin axis and negatively by retrograde (RTG) signaling. These data indicate that mitochondria are compartmentalized in a fission-independent manner. We propose that these diffusion barriers promote mitochondrial polarity and contribute to mitochondrial quality control.
    DOI:  https://doi.org/10.1083/jcb.202211048
  17. Nat Commun. 2024 Jan 02. 15(1): 90
    Histone lactylation couples cellular metabolism with developmental gene regulatory networks.
    Fjodor Merkuri, Megan Rothstein, Marcos Simoes-Costa.
      Embryonic cells exhibit diverse metabolic states. Recent studies have demonstrated that metabolic reprogramming drives changes in cell identity by affecting gene expression. However, the connection between cellular metabolism and gene expression remains poorly understood. Here we report that glycolysis-regulated histone lactylation couples the metabolic state of embryonic cells with chromatin organization and gene regulatory network (GRN) activation. We found that lactylation marks genomic regions of glycolytic embryonic tissues, like the neural crest (NC) and pre-somitic mesoderm. Histone lactylation occurs in the loci of NC genes as these cells upregulate glycolysis. This process promotes the accessibility of active enhancers and the deployment of the NC GRN. Reducing the deposition of the mark by targeting LDHA/B leads to the downregulation of NC genes and the impairment of cell migration. The deposition of lactyl-CoA on histones at NC enhancers is supported by a mechanism that involves transcription factors SOX9 and YAP/TEAD. These findings define an epigenetic mechanism that integrates cellular metabolism with the GRNs that orchestrate embryonic development.
    DOI:  https://doi.org/10.1038/s41467-023-44121-1
  18. Cell Metab. 2024 Jan 02. pii: S1550-4131(23)00464-3. [Epub ahead of print]36(1): 116-129.e7
    Serine synthesis via reversed SHMT2 activity drives glycine depletion and acetaminophen hepatotoxicity in MASLD.
    Alia Ghrayeb, Alexandra C Finney, Bella Agranovich, Daniel Peled, Sumit Kumar Anand, M Peyton McKinney, Mahasen Sarji, Dongshan Yang, Natan Weissman, Shani Drucker, Sara Isabel Fernandes, Jonatan Fernández-García, Kyle Mahan, Zaid Abassi, Lin Tan, Philip L Lorenzi, James Traylor, Jifeng Zhang, Ifat Abramovich, Y Eugene Chen, Oren Rom, Inbal Mor, Eyal Gottlieb.
      Metabolic dysfunction-associated steatotic liver disease (MASLD) affects one-third of the global population. Understanding the metabolic pathways involved can provide insights into disease progression and treatment. Untargeted metabolomics of livers from mice with early-stage steatosis uncovered decreased methylated metabolites, suggesting altered one-carbon metabolism. The levels of glycine, a central component of one-carbon metabolism, were lower in mice with hepatic steatosis, consistent with clinical evidence. Stable-isotope tracing demonstrated that increased serine synthesis from glycine via reverse serine hydroxymethyltransferase (SHMT) is the underlying cause for decreased glycine in steatotic livers. Consequently, limited glycine availability in steatotic livers impaired glutathione synthesis under acetaminophen-induced oxidative stress, enhancing acute hepatotoxicity. Glycine supplementation or hepatocyte-specific ablation of the mitochondrial SHMT2 isoform in mice with hepatic steatosis mitigated acetaminophen-induced hepatotoxicity by supporting de novo glutathione synthesis. Thus, early metabolic changes in MASLD that limit glycine availability sensitize mice to xenobiotics even at the reversible stage of this disease.
    Keywords:  MASLD; SHMT; acetaminophen hepatotoxicity; glutathione; glycine; one-carbon metabolism; xenobiotic
    DOI:  https://doi.org/10.1016/j.cmet.2023.12.013
  19. EMBO Rep. 2023 Dec 14.
    MTCH2 cooperates with MFN2 and lysophosphatidic acid synthesis to sustain mitochondrial fusion.
    Andres Goldman, Michael Mullokandov, Yehudit Zaltsman, Limor Regev, Smadar Levin-Zaidman, Atan Gross.
      Fusion of the outer mitochondrial membrane (OMM) is regulated by mitofusin 1 (MFN1) and 2 (MFN2), yet the differential contribution of each of these proteins is less understood. Mitochondrial carrier homolog 2 (MTCH2) also plays a role in mitochondrial fusion, but its exact function remains unresolved. MTCH2 overexpression enforces MFN2-independent mitochondrial fusion, proposedly by modulating the phospholipid lysophosphatidic acid (LPA), which is synthesized by glycerol-phosphate acyl transferases (GPATs) in the endoplasmic reticulum (ER) and the OMM. Here we report that MTCH2 requires MFN1 to enforce mitochondrial fusion and that fragmentation caused by loss of MTCH2 can be specifically counterbalanced by overexpression of MFN2 but not MFN1, partially independent of its GTPase activity and mitochondrial localization. Pharmacological inhibition of GPATs (GPATi) or silencing ER-resident GPATs suppresses MFN2's ability to compensate for the loss of MTCH2. Loss of either MTCH2, MFN2, or GPATi does not impair stress-induced mitochondrial fusion, whereas the combined loss of MTCH2 and GPATi or the combined loss of MTCH2 and MFN2 does. Taken together, we unmask two cooperative mechanisms that sustain mitochondrial fusion.
    Keywords:  LPA; MFN2; MTCH2; Mitochondria-ER Communication; Mitochondrial Fusion
    DOI:  https://doi.org/10.1038/s44319-023-00009-1
  20. bioRxiv. 2023 Dec 15. pii: 2023.12.14.571787. [Epub ahead of print]
    Inhibition of O -GlcNAc transferase activates type I interferon-dependent antitumor immunity by bridging cGAS-STING pathway.
    Jianwen Chen, Bao Zhao, Tianliang Li, Hong Dong, Xiang Cheng, Wang Gong, Jing Wang, Junran Zhang, Gang Xin, Yanbao Yu, Yu L Lei, Jennifer D Black, Zihai Li, Haitao Wen.
      The O -GlcNAc transferase (OGT) is an essential enzyme that mediates protein O -GlcNAcylation, a unique form of posttranslational modification of many nuclear and cytosolic proteins. Recent studies observed increased OGT and O -GlcNAcylation levels in a broad range of human cancer tissues compared to adjacent normal tissues, indicating a universal effect of OGT in promoting tumorigenesis. Here, we show that OGT is essential for tumor growth in immunocompetent hosts by repressing the cyclic GMP-AMP synthase (cGAS)-dependent DNA sensing pathway. We found that deletion of OGT ( Ogt -/- ) caused a marked reduction in tumor growth in both syngeneic tumor models and a genetic colorectal cancer (CRC) model induced by mutation of the Apc gene ( Apc min ). Pharmacological inhibition or genetic deletion of OGT induced a robust genomic instability (GIN), leading to cGAS-dependent production of the type I interferon (IFN-I) and IFN-stimulated genes (ISGs). As a result, deletion of Cgas or Sting from Ogt -/- cancer cells restored tumor growth, and this correlated with impaired CD8 + T cell-mediated antitumor immunity. Mechanistically, we found that OGT-dependent cleavage of host cell factor C1 (HCF-1) is required for the avoidance of GIN and IFN-I production in tumors. In summary, our results identify OGT-mediated genomic stability and activate cGAS-STING pathway as an important tumor cell-intrinsic mechanism to repress antitumor immunity.
    DOI:  https://doi.org/10.1101/2023.12.14.571787
  21. Mitochondrion. 2023 Dec 27. pii: S1567-7249(23)00117-4. [Epub ahead of print]75 101837
    The biology of mitochondrial carrier homolog 2.
    Xiaohe Zheng, Binxiang Chu.
      The mitochondrial carrier system is in charge of small molecule transport between the mitochondria and the cytoplasm as well as being an integral portion of the core mitochondrial function. One member of the mitochondrial carrier family of proteins, mitochondrial carrier homolog 2 (MTCH2), is characterized as a critical mitochondrial outer membrane protein insertase participating in mitochondrial homeostasis. Accumulating evidence demonstrate that MTCH2 is integrally linked to cell death and mitochondrial metabolism, and its genetic alterations cause a variety of disease phenotypes, ranging from obesity, Alzheimer's disease, and tumor. To provide a comprehensive insight into the current understanding of MTCH2, we present a detailed description of the physiopathological functions of MTCH2, ranging from apoptosis, mitochondrial dynamics, and metabolic homeostasis regulation. Moreover, we summarized the impact of MTCH2 in human diseases, and highlighted tumors, to assess the role of MTCH2 mutations or variable expression on pathogenesis and target therapeutic options.
    Keywords:  Apoptosis; Lipid metabolism; MTCH2; Mitochondria; Tumor
    DOI:  https://doi.org/10.1016/j.mito.2023.101837
  22. Nat Commun. 2024 Jan 02. 15(1): 79
    Cell cycle arrest induces lipid droplet formation and confers ferroptosis resistance.
    Hyemin Lee, Amber Horbath, Lavanya Kondiparthi, Jitendra Kumar Meena, Guang Lei, Shayani Dasgupta, Xiaoguang Liu, Li Zhuang, Pranavi Koppula, Mi Li, Iqbal Mahmud, Bo Wei, Philip L Lorenzi, Khandan Keyomarsi, Masha V Poyurovsky, Kellen Olszewski, Boyi Gan.
      How cells coordinate cell cycling with cell survival and death remains incompletely understood. Here, we show that cell cycle arrest has a potent suppressive effect on ferroptosis, a form of regulated cell death induced by overwhelming lipid peroxidation at cellular membranes. Mechanistically, cell cycle arrest induces diacylglycerol acyltransferase (DGAT)-dependent lipid droplet formation to sequester excessive polyunsaturated fatty acids (PUFAs) that accumulate in arrested cells in triacylglycerols (TAGs), resulting in ferroptosis suppression. Consequently, DGAT inhibition orchestrates a reshuffling of PUFAs from TAGs to phospholipids and re-sensitizes arrested cells to ferroptosis. We show that some slow-cycling antimitotic drug-resistant cancer cells, such as 5-fluorouracil-resistant cells, have accumulation of lipid droplets and that combined treatment with ferroptosis inducers and DGAT inhibitors effectively suppresses the growth of 5-fluorouracil-resistant tumors by inducing ferroptosis. Together, these results reveal a role for cell cycle arrest in driving ferroptosis resistance and suggest a ferroptosis-inducing therapeutic strategy to target slow-cycling therapy-resistant cancers.
    DOI:  https://doi.org/10.1038/s41467-023-44412-7
  23. Nat Commun. 2024 Jan 04. 15(1): 292
    The glue that holds us together.
      
    DOI:  https://doi.org/10.1038/s41467-023-44476-5
  24. Nat Chem Biol. 2024 Jan 02.
    Acylspermidines are conserved mitochondrial sirtuin-dependent metabolites.
    Bingsen Zhang, James Mullmann, Andreas H Ludewig, Irma R Fernandez, Tyler R Bales, Robert S Weiss, Frank C Schroeder.
      Sirtuins are nicotinamide adenine dinucleotide (NAD+)-dependent protein lysine deacylases regulating metabolism and stress responses; however, characterization of the removed acyl groups and their downstream metabolic fates remains incomplete. Here we employed untargeted comparative metabolomics to reinvestigate mitochondrial sirtuin biochemistry. First, we identified N-glutarylspermidines as metabolites downstream of the mitochondrial sirtuin SIR-2.3 in Caenorhabditis elegans and demonstrated that SIR-2.3 functions as a lysine deglutarylase and that N-glutarylspermidines can be derived from O-glutaryl-ADP-ribose. Subsequent targeted analysis of C. elegans, mouse and human metabolomes revealed a chemically diverse range of N-acylspermidines, and formation of N-succinylspermidines and/or N-glutarylspermidines was observed downstream of mammalian mitochondrial sirtuin SIRT5 in two cell lines, consistent with annotated functions of SIRT5. Finally, N-glutarylspermidines were found to adversely affect C. elegans lifespan and mammalian cell proliferation. Our results indicate that N-acylspermidines are conserved metabolites downstream of mitochondrial sirtuins that facilitate annotation of sirtuin enzymatic activities in vivo and may contribute to sirtuin-dependent phenotypes.
    DOI:  https://doi.org/10.1038/s41589-023-01511-2
  25. Cell Metab. 2024 Jan 02. pii: S1550-4131(23)00465-5. [Epub ahead of print]
    ABCG2 is an itaconate exporter that limits antibacterial innate immunity by alleviating TFEB-dependent lysosomal biogenesis.
    Chao Chen, Zhenxing Zhang, Caiyun Liu, Pengkai Sun, Ping Liu, Xinjian Li.
      Itaconate is a metabolite that synthesized from cis-aconitate in mitochondria and transported into the cytosol to exert multiple regulatory effects in macrophages. However, the mechanism by which itaconate exits from macrophages remains unknown. Using a genetic screen, we reveal that itaconate is exported from cytosol to extracellular space by ATP-binding cassette transporter G2 (ABCG2) in an ATPase-dependent manner in human and mouse macrophages. Elevation of transcription factor TFEB-dependent lysosomal biogenesis and antibacterial innate immunity are observed in inflammatory macrophages with deficiency of ABCG2-mediated itaconate export. Furthermore, deficiency of ABCG2-mediated itaconate export in macrophages promotes antibacterial innate immune defense in a mouse model of S. typhimurium infection. Thus, our findings identify ABCG2-mediated itaconate export as a key regulatory mechanism that limits TFEB-dependent lysosomal biogenesis and antibacterial innate immunity in inflammatory macrophages, implying the potential therapeutic utility of blocking itaconate export in treating human bacterial infections.
    Keywords:  ABCG2; TFEB; exporter; innate immunity; itaconate; lysosomal biogenesis; macrophages
    DOI:  https://doi.org/10.1016/j.cmet.2023.12.015
  26. Cell Res. 2024 Jan;34(1): 13-30
    Hypoxia induces mitochondrial protein lactylation to limit oxidative phosphorylation.
    Yunzi Mao, Jiaojiao Zhang, Qian Zhou, Xiadi He, Zhifang Zheng, Yun Wei, Kaiqiang Zhou, Yan Lin, Haowen Yu, Haihui Zhang, Yineng Zhou, Pengcheng Lin, Baixing Wu, Yiyuan Yuan, Jianyuan Zhao, Wei Xu, Shimin Zhao.
      Oxidative phosphorylation (OXPHOS) consumes oxygen to produce ATP. However, the mechanism that balances OXPHOS activity and intracellular oxygen availability remains elusive. Here, we report that mitochondrial protein lactylation is induced by intracellular hypoxia to constrain OXPHOS. We show that mitochondrial alanyl-tRNA synthetase (AARS2) is a protein lysine lactyltransferase, whose proteasomal degradation is enhanced by proline 377 hydroxylation catalyzed by the oxygen-sensing hydroxylase PHD2. Hypoxia induces AARS2 accumulation to lactylate PDHA1 lysine 336 in the pyruvate dehydrogenase complex and carnitine palmitoyltransferase 2 (CPT2) lysine 457/8, inactivating both enzymes and inhibiting OXPHOS by limiting acetyl-CoA influx from pyruvate and fatty acid oxidation, respectively. PDHA1 and CPT2 lactylation can be reversed by SIRT3 to activate OXPHOS. In mouse muscle cells, lactylation is induced by lactate oxidation-induced intracellular hypoxia during exercise to constrain high-intensity endurance running exhaustion time, which can be increased or decreased by decreasing or increasing lactylation levels, respectively. Our results reveal that mitochondrial protein lactylation integrates intracellular hypoxia and lactate signals to regulate OXPHOS.
    DOI:  https://doi.org/10.1038/s41422-023-00864-6
  27. Free Radic Biol Med. 2023 Dec 29. pii: S0891-5849(23)01191-7. [Epub ahead of print]212 241-254
    The solute carrier SLC25A17 sustains peroxisomal redox homeostasis in diverse mammalian cell lines.
    Cláudio F Costa, Celien Lismont, Serhii Chornyi, Janet Koster, Hongli Li, Mohamed A F Hussein, Paul P Van Veldhoven, Hans R Waterham, Marc Fransen.
      Despite the crucial role of peroxisomes in cellular redox maintenance, little is known about how these organelles transport redox metabolites across their membrane. In this study, we sought to assess potential associations between the cellular redox landscape and the human peroxisomal solute carrier SLC25A17, also known as PMP34. This carrier has been reported to function as a counter-exchanger of adenine-containing cofactors such as coenzyme A (CoA), dephospho-CoA, flavin adenine dinucleotide, nicotinamide adenine dinucleotide (NAD+), adenosine 3',5'-diphosphate, flavin mononucleotide, and adenosine monophosphate. We found that inactivation of SLC25A17 resulted in a shift toward a more reductive state in the glutathione redox couple (GSSG/GSH) across HEK-293 cells, HeLa cells, and SV40-transformed mouse embryonic fibroblasts, with variable impact on the NADPH levels and the NAD+/NADH redox couple. This phenotype could be rescued by the expression of Candida boidinii Pmp47, a putative SLC25A17 orthologue reported to be essential for the metabolism of medium-chain fatty acids in yeast peroxisomes. In addition, we provide evidence that the alterations in the redox state are not caused by changes in peroxisomal antioxidant enzyme expression, catalase activity, H2O2 membrane permeability, or mitochondrial fitness. Furthermore, treating control and ΔSLC25A17 cells with dehydroepiandrosterone, a commonly used glucose-6-phosphate dehydrogenase inhibitor affecting NADPH regeneration, revealed a kinetic disconnection between the peroxisomal and cytosolic glutathione pools. Additionally, these experiments underscored the impact of SLC25A17 loss on peroxisomal NADPH metabolism. The relevance of these findings is discussed in the context of the still ambiguous substrate specificity of SLC25A17 and the recent observation that the mammalian peroxisomal membrane is readily permeable to both GSH and GSSG.
    Keywords:  CoA; Glutathione; Metabolite transport; NADPH; PMP34; Peroxisomes; Redox compartmentalization; SLC25A17
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.12.035
  28. Nat Cancer. 2024 Jan 04.
    Somatic mouse models of gastric cancer reveal genotype-specific features of metastatic disease.
    Josef Leibold, Kaloyan M Tsanov, Corina Amor, Yu-Jui Ho, Francisco J Sánchez-Rivera, Judith Feucht, Timour Baslan, Hsuan-An Chen, Sha Tian, Janelle Simon, Alexandra Wuest, John E Wilkinson, Scott W Lowe.
      Metastatic gastric carcinoma is a highly lethal cancer that responds poorly to conventional and molecularly targeted therapies. Despite its clinical relevance, the mechanisms underlying the behavior and therapeutic response of this disease are poorly understood owing, in part, to a paucity of tractable models. Here we developed methods to somatically introduce different oncogenic lesions directly into the murine gastric epithelium. Genotypic configurations observed in patients produced metastatic gastric cancers that recapitulated the histological, molecular and clinical features of all nonviral molecular subtypes of the human disease. Applying this platform to both wild-type and immunodeficient mice revealed previously unappreciated links between the genotype, organotropism and immune surveillance of metastatic cells, which produced distinct patterns of metastasis that were mirrored in patients. Our results establish a highly portable platform for generating autochthonous cancer models with flexible genotypes and host backgrounds, which can unravel mechanisms of gastric tumorigenesis or test new therapeutic concepts.
    DOI:  https://doi.org/10.1038/s43018-023-00686-w
  29. Nat Metab. 2024 Jan 02.
    Proteolytic activation of fatty acid synthase signals pan-stress resolution.
    Hai Wei, Yi M Weaver, Chendong Yang, Yuan Zhang, Guoli Hu, Courtney M Karner, Matthew Sieber, Ralph J DeBerardinis, Benjamin P Weaver.
      Chronic stress and inflammation are both outcomes and major drivers of many human diseases. Sustained responsiveness despite mitigation suggests a failure to sense resolution of the stressor. Here we show that a proteolytic cleavage event of fatty acid synthase (FASN) activates a global cue for stress resolution in Caenorhabditis elegans. FASN is well established for biosynthesis of the fatty acid palmitate. Our results demonstrate FASN promoting an anti-inflammatory profile apart from palmitate synthesis. Redox-dependent proteolysis of limited amounts of FASN by caspase activates a C-terminal fragment sufficient to downregulate multiple aspects of stress responsiveness, including gene expression, metabolic programs and lipid droplets. The FASN C-terminal fragment signals stress resolution in a cell non-autonomous manner. Consistent with these findings, FASN processing is also seen in well-fed but not fasted male mouse liver. As downregulation of stress responses is critical to health, our findings provide a potential pathway to control diverse aspects of stress responses.
    DOI:  https://doi.org/10.1038/s42255-023-00939-z
  30. Mol Cell. 2023 Dec 29. pii: S1097-2765(23)01022-5. [Epub ahead of print]
    Translation of non-canonical open reading frames as a cancer cell survival mechanism in childhood medulloblastoma.
    Damon A Hofman, Jorge Ruiz-Orera, Ian Yannuzzi, Rakesh Murugesan, Adam Brown, Karl R Clauser, Alexandra L Condurat, Jip T van Dinter, Sem A G Engels, Amy Goodale, Jasper van der Lugt, Tanaz Abid, Li Wang, Kevin N Zhou, Jayne Vogelzang, Keith L Ligon, Timothy N Phoenix, Jennifer A Roth, David E Root, Norbert Hubner, Todd R Golub, Pratiti Bandopadhayay, Sebastiaan van Heesch, John R Prensner.
      A hallmark of high-risk childhood medulloblastoma is the dysregulation of RNA translation. Currently, it is unknown whether medulloblastoma dysregulates the translation of putatively oncogenic non-canonical open reading frames (ORFs). To address this question, we performed ribosome profiling of 32 medulloblastoma tissues and cell lines and observed widespread non-canonical ORF translation. We then developed a stepwise approach using multiple CRISPR-Cas9 screens to elucidate non-canonical ORFs and putative microproteins implicated in medulloblastoma cell survival. We determined that multiple lncRNA-ORFs and upstream ORFs (uORFs) exhibited selective functionality independent of main coding sequences. A microprotein encoded by one of these ORFs, ASNSD1-uORF or ASDURF, was upregulated, associated with MYC-family oncogenes, and promoted medulloblastoma cell survival through engagement with the prefoldin-like chaperone complex. Our findings underscore the fundamental importance of non-canonical ORF translation in medulloblastoma and provide a rationale to include these ORFs in future studies seeking to define new cancer targets.
    Keywords:  CRISPR; Ribo-seq; cancer; gene dependency; lncRNAs; medulloblastoma; non-canonical ORFs; translational regulation; uORF
    DOI:  https://doi.org/10.1016/j.molcel.2023.12.003
  31. Nat Commun. 2024 Jan 05. 15(1): 315
    Nuclear Hsp104 safeguards the dormant translation machinery during quiescence.
    Verena Kohler, Andreas Kohler, Lisa Larsson Berglund, Xinxin Hao, Sarah Gersing, Axel Imhof, Thomas Nyström, Johanna L Höög, Martin Ott, Claes Andréasson, Sabrina Büttner.
      The resilience of cellular proteostasis declines with age, which drives protein aggregation and compromises viability. The nucleus has emerged as a key quality control compartment that handles misfolded proteins produced by the cytosolic protein biosynthesis system. Here, we find that age-associated metabolic cues target the yeast protein disaggregase Hsp104 to the nucleus to maintain a functional nuclear proteome during quiescence. The switch to respiratory metabolism and the accompanying decrease in translation rates direct cytosolic Hsp104 to the nucleus to interact with latent translation initiation factor eIF2 and to suppress protein aggregation. Hindering Hsp104 from entering the nucleus in quiescent cells results in delayed re-entry into the cell cycle due to compromised resumption of protein synthesis. In sum, we report that cytosolic-nuclear partitioning of the Hsp104 disaggregase is a critical mechanism to protect the latent protein synthesis machinery during quiescence in yeast, ensuring the rapid restart of translation once nutrients are replenished.
    DOI:  https://doi.org/10.1038/s41467-023-44538-8
  32. Signal Transduct Target Ther. 2024 Jan 01. 9(1): 4
    Janus-faced Mitofusin 2 (MFN2): mitochondria-endoplasmic reticulum shaping and tethering functions unveiled.
    Camilla Aurora Franchino, Elisa Motori, Matteo Bergami.
      
    DOI:  https://doi.org/10.1038/s41392-023-01730-y
  33. Nat Commun. 2024 Jan 02. 15(1): 168
    Mic19 depletion impairs endoplasmic reticulum-mitochondrial contacts and mitochondrial lipid metabolism and triggers liver disease.
    Jun Dong, Li Chen, Fei Ye, Junhui Tang, Bing Liu, Jiacheng Lin, Pang-Hu Zhou, Bin Lu, Min Wu, Jia-Hong Lu, Jing-Jing He, Simone Engelender, Qingtao Meng, Zhiyin Song, He He.
      Endoplasmic reticulum (ER)-mitochondria contacts are critical for the regulation of lipid transport, synthesis, and metabolism. However, the molecular mechanism and physiological function of endoplasmic reticulum-mitochondrial contacts remain unclear. Here, we show that Mic19, a key subunit of MICOS (mitochondrial contact site and cristae organizing system) complex, regulates ER-mitochondria contacts by the EMC2-SLC25A46-Mic19 axis. Mic19 liver specific knockout (LKO) leads to the reduction of ER-mitochondrial contacts, mitochondrial lipid metabolism disorder, disorganization of mitochondrial cristae and mitochondrial unfolded protein stress response in mouse hepatocytes, impairing liver mitochondrial fatty acid β-oxidation and lipid metabolism, which may spontaneously trigger nonalcoholic steatohepatitis (NASH) and liver fibrosis in mice. Whereas, the re-expression of Mic19 in Mic19 LKO hepatocytes blocks the development of liver disease in mice. In addition, Mic19 overexpression suppresses MCD-induced fatty liver disease. Thus, our findings uncover the EMC2-SLC25A46-Mic19 axis as a pathway regulating ER-mitochondria contacts, and reveal that impairment of ER-mitochondria contacts may be a mechanism associated with the development of NASH and liver fibrosis.
    DOI:  https://doi.org/10.1038/s41467-023-44057-6
  34. Nat Cell Biol. 2024 Jan 04.
    FOXO1-mediated lipid metabolism maintains mammalian embryos in dormancy.
    Vera A van der Weijden, Maximilian Stötzel, Dhanur P Iyer, Beatrix Fauler, Elzbieta Gralinska, Mohammed Shahraz, David Meierhofer, Martin Vingron, Steffen Rulands, Theodore Alexandrov, Thorsten Mielke, Aydan Bulut-Karslioglu.
      Mammalian developmental timing is adjustable in vivo by preserving pre-implantation embryos in a dormant state called diapause. Inhibition of the growth regulator mTOR (mTORi) pauses mouse development in vitro, yet how embryonic dormancy is maintained is not known. Here we show that mouse embryos in diapause are sustained by using lipids as primary energy source. In vitro, supplementation of embryos with the metabolite L-carnitine balances lipid consumption, puts the embryos in deeper dormancy and boosts embryo longevity. We identify FOXO1 as an essential regulator of the energy balance in dormant embryos and propose, through meta-analyses of dormant cell signatures, that it may be a common regulator of dormancy across adult tissues. Our results lift a constraint on in vitro embryo survival and suggest that lipid metabolism may be a critical metabolic transition relevant for longevity and stem cell function across tissues.
    DOI:  https://doi.org/10.1038/s41556-023-01325-3
  35. World J Mens Health. 2024 Jan;42(1): 62-70
    Metabolic Adaptation and Cellular Stress Response As Targets for Cancer Therapy.
    Chang Jun Lee, Haejin Yoon.
      Cancer cells, which divide indefinitely and without control, are frequently exposed to various stress factors but manage to adapt and survive. The mechanisms by which cancer cells maintain cellular homeostasis and exploit stress conditions are not yet clear. Here, we elucidate the roles of diverse cellular metabolism and its regulatory mechanisms, highlighting the essential role of metabolism in cellular composition and signal transduction. Cells respond to various stresses, including DNA damage, energy stress, and oxidative stress, thereby causing metabolic alteration. We provide profound insight into the adaptive mechanisms employed by cancer cells to ensure their survival among internal and external stressors through a comprehensive analysis of the correlation between metabolic alterations and cellular stress. Furthermore, this research establishes a robust framework for the development of innovative therapeutic strategies that specifically target the cellular adaptations of cancer cells.
    Keywords:  Cellular reprogramming; DNA damage; Metabolic disease; Metabolism; Prostatic neoplasms; Stress, physiological
    DOI:  https://doi.org/10.5534/wjmh.230153
  36. Cell Metab. 2024 Jan 02. pii: S1550-4131(23)00457-6. [Epub ahead of print]36(1): 3-5
    H2S serves as the immunoregulatory essence of apoptotic cell death.
    Christopher Hine, András K Ponti, María Ángeles Cáliz-Molina, Alejandro Martín-Montalvo.
      Apoptosis supports tissue homeostasis and prevents immune disorders by removing damaged and functionally aberrant cells. Here, Ou et al. utilized genetic, pharmacological, and proteomic approaches focused on sulfur amino acid catabolism to discover that hydrogen sulfide (H2S) release during apoptosis suppresses Th17 cell differentiation, thus providing therapeutic targets for autoimmune diseases.
    DOI:  https://doi.org/10.1016/j.cmet.2023.12.006
  37. Cell Rep. 2024 Jan 03. pii: S2211-1247(23)01654-6. [Epub ahead of print]43(1): 113643
    Intercellular crosstalk shapes purinergic metabolism and signaling in cancer cells.
    Julia Hesse, Bodo Steckel, Peter Dieterich, Siyar Aydin, Andreas Deussen, Jürgen Schrader.
      CD73-derived adenosine suppresses anti-cancer immunity, and CD73 inhibitors are currently evaluated in several clinical trials. Here, we have assessed enzyme kinetics of all key purinergic ectoenzymes in five cancer cell lines (Hodgkin lymphoma, multiple myeloma, pancreas adenocarcinoma, urinary bladder carcinoma, and glioblastoma) under normoxia and hypoxia. We found that adenosine metabolism varied considerably between individual cancer types. All cell lines investigated exhibited high ecto-adenosine deaminase (ADA) activity, which critically influenced the kinetics of adenosine accumulation. Combining kinetics data with single-cell RNA sequencing data on myeloma and glioblastoma cancerous tissue revealed that purine metabolism is not homogeneously organized, but it differs in a cancer type-specific fashion between malignant cells, stromal cells, and immune cells. Since purine metabolism in cancerous tissue is most likely spatially heterogeneous and differs between the various cell types, diffusion distances in the microenvironment as well as ADA activity may be important variables that influence the level of bioactive adenosine.
    Keywords:  CP: Cancer; NAD; adenosine; adenosine deaminase; glioblastoma; hypoxia; multiple myeloma
    DOI:  https://doi.org/10.1016/j.celrep.2023.113643
  38. J Biol Chem. 2024 Jan 02. pii: S0021-9258(23)02649-2. [Epub ahead of print] 105620
    SARM1 regulates NAD+-linked metabolism and select immune genes in macrophages.
    Katharine A Shanahan, Gavin M Davis, Ciara G Doran, Ryoichi Sugisawa, Gavin P Davey, Andrew G Bowie.
      Sterile alpha and HEAT/Armadillo motif-containing protein (SARM1) was recently described as a NAD+-consuming enzyme, and has previously been shown to regulate immune responses in macrophages. Neuronal SARM1 is known to contribute to axon degeneration due to its NADase activity. However, how SARM1 affects macrophage metabolism has not been explored. Here, we show that macrophages from Sarm1-/- mice display elevated NAD+ concentrations and lower cyclic ADPR, a known product of SARM1-dependent NAD+ catabolism. Further, SARM1-deficient macrophages showed an increase in the reserve capacity of oxidative phosphorylation and glycolysis compared to wild-type cells. Stimulation of macrophages to a pro-inflammatory state by lipopolysaccharide (LPS), revealed that SARM1 restricts the ability of macrophages to upregulate glycolysis and limits the expression of the pro-inflammatory gene Il1b, but boosts expression of anti-inflammatory Il10. In contrast, we show macrophages lacking SARM1 induced to an anti-inflammatory state by IL-4 stimulation display increased oxidative phosphorylation and glycolysis, and reduced expression of the anti-inflammatory gene, Fizz1. Overall, these data show that SARM1 fine-tunes immune gene transcription in macrophages via consumption of NAD+ and altered macrophage metabolism.
    Keywords:  NAD(+); NADase; SARM1; cADPR; cytokine induction; macrophages; metabolism
    DOI:  https://doi.org/10.1016/j.jbc.2023.105620
  39. Annu Rev Biophys. 2024 Jan 02.
    Mitochondrial Dynamics at Different Levels: From Cristae Dynamics to Interorganellar Cross Talk.
    Arun Kumar Kondadi, Andreas S Reichert.
      Mitochondria are essential organelles performing important cellular functions ranging from bioenergetics and metabolism to apoptotic signaling and immune responses. They are highly dynamic at different structural and functional levels. Mitochondria have been shown to constantly undergo fusion and fission processes and dynamically interact with other organelles such as the endoplasmic reticulum, peroxisomes, and lipid droplets. The field of mitochondrial dynamics has evolved hand in hand with technological achievements including advanced fluorescence super-resolution nanoscopy. Dynamic remodeling of the cristae membrane within individual mitochondria, discovered very recently, opens up a further exciting layer of mitochondrial dynamics. In this review, we discuss mitochondrial dynamics at the following levels: (a) within an individual mitochondrion, (b) among mitochondria, and (c) between mitochondria and other organelles. Although the three tiers of mitochondrial dynamics have in the past been classified in a hierarchical manner, they are functionally connected and must act in a coordinated manner to maintain cellular functions and thus prevent various human diseases. Expected final online publication date for the Annual Review of Biophysics, Volume 53 is May 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
    DOI:  https://doi.org/10.1146/annurev-biophys-030822-020736
  40. Bone Rep. 2023 Dec;19 101719
    Cell metabolism and bone cells.
    Ernestina Schipani, Geert Carmeliet.
      
    DOI:  https://doi.org/10.1016/j.bonr.2023.101719
  41. Cell Metab. 2024 Jan 02. pii: S1550-4131(23)00463-1. [Epub ahead of print]36(1): 1-3
    TAMC-derived creatine sustains glioblastoma growth.
    Huiwen Yan, Pengcheng Bu.
      Tumor-associated myeloid cells (TAMCs) are the predominant immune population in glioblastoma (GBM), but the definite role of TAMCs in GBM tumorigenicity remains uncertain. In this issue of Cell Metabolism, Rashidi et al. identify a specific population of TAMCs surrounding hypoxic regions of GBM. These TAMCs provide creatine to nearby tumor cells to promote GBM progression.
    DOI:  https://doi.org/10.1016/j.cmet.2023.12.012
  42. Int J Biol Sci. 2024 ;20(2): 516-536
    p32 regulates glycometabolism and TCA cycle to inhibit ccRCC progression via copper-induced DLAT lipoylation oligomerization.
    Shaoping Tian, Rui Wang, Yiting Wang, Ruibing Chen, Tianyu Lin, Xuesong Xiao, Xinyu Liu, Justin Eze Ideozu, Hua Geng, Yong Wang, Dan Yue.
      A key player in mitochondrial respiration, p32, often referred to as C1QBP, is mostly found in the mitochondrial matrix. Previously, we showed that p32 interacts with DLAT in the mitochondria. Here, we found that p32 expression was reduced in ccRCC and suppressed progression and metastasis in ccRCC animal models. We observed that increasing p32 expression led to an increase in oxidative phosphorylation by interacting with DLAT, thus, regulating the activation of the pyruvate dehydrogenase complex (PDHc). Mechanistically, reduced p32 expression, in concert with DLAT, suppresses PDHc activity and the TCA cycle. Furthermore, our research discovered that p32 has a direct binding affinity for copper, facilitating the copper-induced oligomerization of lipo-DLAT specifically in ccRCC cells. This finding reveals an innovative function of the p32/DLAT/copper complex in regulating glycometabolism and the TCA cycle in ccRCC. Importantly, our research provides important new understandings of the underlying molecular processes causing the abnormal mitochondrial metabolism linked to this cancer.
    Keywords:  Clear cell renal cell carcinoma; Copper; DLAT; glycometabolism; p32; tricarboxylic acid cycle
    DOI:  https://doi.org/10.7150/ijbs.84399
  43. Nat Cell Biol. 2024 Jan 02.
    Vitamin B12 produced by gut bacteria modulates cholinergic signalling.
    Woo Kyu Kang, Jeremy T Florman, Antonia Araya, Bennett W Fox, Andrea Thackeray, Frank C Schroeder, Albertha J M Walhout, Mark J Alkema.
      A growing body of evidence indicates that gut microbiota influence brain function and behaviour. However, the molecular basis of how gut bacteria modulate host nervous system function is largely unknown. Here we show that vitamin B12-producing bacteria that colonize the intestine can modulate excitatory cholinergic signalling and behaviour in the host Caenorhabditis elegans. Here we demonstrate that vitamin B12 reduces cholinergic signalling in the nervous system through rewiring of the methionine (Met)/S-adenosylmethionine cycle in the intestine. We identify a conserved metabolic crosstalk between the methionine/S-adenosylmethionine cycle and the choline-oxidation pathway. In addition, we show that metabolic rewiring of these pathways by vitamin B12 reduces cholinergic signalling by limiting the availability of free choline required by neurons to synthesize acetylcholine. Our study reveals a gut-brain communication pathway by which enteric bacteria modulate host behaviour and may affect neurological health.
    DOI:  https://doi.org/10.1038/s41556-023-01299-2
  44. Cancer Cell. 2023 Dec 19. pii: S1535-6108(23)00430-0. [Epub ahead of print]
    EGFR-activated myofibroblasts promote metastasis of pancreatic cancer.
    Gianluca Mucciolo, Joaquín Araos Henríquez, Muntadher Jihad, Sara Pinto Teles, Judhell S Manansala, Wenlong Li, Sally Ashworth, Eloise G Lloyd, Priscilla S W Cheng, Weike Luo, Akanksha Anand, Ashley Sawle, Anna Piskorz, Giulia Biffi.
      Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis. Cancer-associated fibroblasts (CAFs) are recognized potential therapeutic targets, but poor understanding of these heterogeneous cell populations has limited the development of effective treatment strategies. We previously identified transforming growth factor beta (TGF-β) as a main driver of myofibroblastic CAFs (myCAFs). Here, we show that epidermal growth factor receptor/Erb-B2 receptor (EGFR/ERBB2) signaling is induced by TGF-β in myCAFs through an autocrine process mediated by amphiregulin. Inhibition of this EGFR/ERBB2-signaling network in PDAC organoid-derived cultures and mouse models differentially impacts distinct CAF subtypes, providing insights into mechanisms underpinning their heterogeneity. Remarkably, EGFR-activated myCAFs promote PDAC metastasis in mice, unmasking functional significance in myCAF heterogeneity. Finally, analyses of other cancer datasets suggest that these processes might operate in other malignancies. These data provide functional relevance to myCAF heterogeneity and identify a candidate target for preventing tumor invasion in PDAC.
    Keywords:  Amphiregulin; EGFR/ERBB2 signaling; TGF-β signaling; cancer-associated fibroblasts; metastasis; myCAFs; pancreatic cancer; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.ccell.2023.12.002
  45. J Biol Chem. 2023 Dec 28. pii: S0021-9258(23)02632-7. [Epub ahead of print] 105603
    Large-scale column-free purification of bovine F-ATP synthase.
    Chimari Jiko, Yukio Morimoto, Tomitake Tsukihara, Christoph Gerle.
      Mammalian F-ATP synthase is central to mitochondrial bioenergetics and is present in the inner mitochondrial membrane in a dynamic oligomeric state of higher oligomers, tetramers, dimers and monomers. In vitro investigations of mammalian F-ATP synthase are often limited by the ability to purify the oligomeric forms present in vivo at a quantity, stability and purity that meets the demand of the planned experiment. We developed a purification approach for the isolation of bovine F-ATP synthase from heart muscle mitochondria that uses a combination of buffer conditions favoring IF1 binding and sucrose density gradient ultracentrifugation to yield stable complexes at high purity in the milligram range. By tuning the glyco-diosgenin (GDN) to lauryl maltose neopentyl glycol (LMNG) ratio in a final gradient, fractions that are either enriched in tetrameric or monomeric F-ATP synthase can be obtained. It is expected that this large-scale column-free purification strategy broadens the spectrum of in vitro investigation on mammalian F-ATP synthase.
    Keywords:  F-ATP synthase oligomer; bioenergetics; gradient centrifugation; membrane protein; mitochondria; purification; rotary ATPase; supercomplex
    DOI:  https://doi.org/10.1016/j.jbc.2023.105603
  46. Oncogenesis. 2024 Jan 03. 13(1): 1
    Cell competition and cancer from Drosophila to mammals.
    Bojie Cong, Ross L Cagan.
      Throughout an individual's life, somatic cells acquire cancer-associated mutations. A fraction of these mutations trigger tumour formation, a phenomenon partly driven by the interplay of mutant and wild-type cell clones competing for dominance; conversely, other mutations function against tumour initiation. This mechanism of 'cell competition', can shift clone dynamics by evaluating the relative status of clonal populations, promoting 'winners' and eliminating 'losers'. This review examines the role of cell competition in the context of tumorigenesis, tumour progression and therapeutic intervention.
    DOI:  https://doi.org/10.1038/s41389-023-00505-y
  47. Br J Cancer. 2023 Dec 30.
    Targeting serine/glycine metabolism improves radiotherapy response in non-small cell lung cancer.
    Anaís Sánchez-Castillo, Elien Heylen, Judith Hounjet, Kim G Savelkouls, Natasja G Lieuwes, Rianne Biemans, Ludwig J Dubois, Kobe Reynders, Kasper M Rouschop, Rianne D W Vaes, Kim De Keersmaecker, Maarten Lambrecht, Lizza E L Hendriks, Dirk K M De Ruysscher, Marc Vooijs, Kim R Kampen.
      BACKGROUND: Lung cancer is the most lethal cancer, and 85% of cases are classified as non-small cell lung cancer (NSCLC). Metabolic rewiring is a cancer hallmark that causes treatment resistance, and lacks insights into serine/glycine pathway adaptations upon radiotherapy.METHODS: We analyzed radiotherapy responses using mass-spectrometry-based metabolomics in NSCLC patient's plasma and cell lines. Efficacy of serine/glycine conversion inhibitor sertraline with radiotherapy was investigated by proliferation, clonogenic and spheroid assays, and in vivo using a serine/glycine dependent NSCLC mouse model by assessment of tumor growth, metabolite and cytokine levels, and immune signatures.
    RESULTS: Serine/glycine pathway metabolites were significantly consumed in response to radiotherapy in NSCLC patients and cell models. Combining sertraline with radiotherapy impaired NSCLC proliferation, clonogenicity and stem cell self-renewal capacity. In vivo, NSCLC tumor growth was reduced solely in the sertraline plus radiotherapy combination treatment group. Tumor weights linked to systemic serine/glycine pathway metabolite levels, and were inhibited in the combination therapy group. Interestingly, combination therapy reshaped the tumor microenvironment via cytokines associated with natural killer cells, supported by eradication of immune checkpoint galectin-1 and elevated granzyme B levels.
    CONCLUSION: Our findings highlight that targeting serine/glycine metabolism using sertraline restricts cancer cell recovery from radiotherapy and provides tumor control through immunomodulation in NSCLC.
    DOI:  https://doi.org/10.1038/s41416-023-02553-y
  48. Nat Commun. 2024 Jan 02. 15(1): 100
    KRAS allelic imbalance drives tumour initiation yet suppresses metastasis in colorectal cancer in vivo.
    Arafath K Najumudeen, Sigrid K Fey, Laura M Millett, Catriona A Ford, Kathryn Gilroy, Nuray Gunduz, Rachel A Ridgway, Eve Anderson, Douglas Strathdee, William Clark, Colin Nixon, Jennifer P Morton, Andrew D Campbell, Owen J Sansom.
      Oncogenic KRAS mutations are well-described functionally and are known to drive tumorigenesis. Recent reports describe a significant prevalence of KRAS allelic imbalances or gene dosage changes in human cancers, including loss of the wild-type allele in KRAS mutant cancers. However, the role of wild-type KRAS in tumorigenesis and therapeutic response remains elusive. We report an in vivo murine model of colorectal cancer featuring deletion of wild-type Kras in the context of oncogenic Kras. Deletion of wild-type Kras exacerbates oncogenic KRAS signalling through MAPK and thus drives tumour initiation. Absence of wild-type Kras potentiates the oncogenic effect of KRASG12D, while incidentally inducing sensitivity to inhibition of MEK1/2. Importantly, loss of the wild-type allele in aggressive models of KRASG12D-driven CRC significantly alters tumour progression, and suppresses metastasis through modulation of the immune microenvironment. This study highlights the critical role for wild-type Kras upon tumour initiation, progression and therapeutic response in Kras mutant CRC.
    DOI:  https://doi.org/10.1038/s41467-023-44342-4
  49. Nat Commun. 2024 Jan 02. 15(1): 130
    IKKε and TBK1 prevent RIPK1 dependent and independent inflammation.
    Remzi Onur Eren, Göksu Gökberk Kaya, Robin Schwarzer, Manolis Pasparakis.
      TBK1 and IKKε regulate multiple cellular processes including anti-viral type-I interferon responses, metabolism and TNF receptor signaling. However, the relative contributions and potentially redundant functions of IKKε and TBK1 in cell death, inflammation and tissue homeostasis remain poorly understood. Here we show that IKKε compensates for the loss of TBK1 kinase activity to prevent RIPK1-dependent and -independent inflammation in mice. Combined inhibition of IKKε and TBK1 kinase activities caused embryonic lethality that was rescued by heterozygous expression of kinase-inactive RIPK1. Adult mice expressing kinase-inactive versions of IKKε and TBK1 developed systemic inflammation that was induced by both RIPK1-dependent and -independent mechanisms. Combined inhibition of IKKε and TBK1 kinase activities in myeloid cells induced RIPK1-dependent cell death and systemic inflammation mediated by IL-1 family cytokines. Tissue-specific studies showed that IKKε and TBK1 were required to prevent cell death and inflammation in the intestine but were dispensable for liver and skin homeostasis. Together, these findings revealed that IKKε and TBK1 exhibit tissue-specific functions that are important to prevent cell death and inflammation and maintain tissue homeostasis.
    DOI:  https://doi.org/10.1038/s41467-023-44372-y
  50. Development. 2024 Jan 01. pii: dev202372. [Epub ahead of print]151(1):
    Epidermal tyrosine catabolism is crucial for metabolic homeostasis and survival against high-protein diets in Drosophila.
    Hina Kosakamoto, Masayuki Miura, Fumiaki Obata.
      The insect epidermis forms the exoskeleton and determines the body size of an organism. How the epidermis acts as a metabolic regulator to adapt to changes in dietary protein availability remains elusive. Here, we show that the Drosophila epidermis regulates tyrosine (Tyr) catabolism in response to dietary protein levels, thereby promoting metabolic homeostasis. The gene expression profile of the Drosophila larval body wall reveals that enzymes involved in the Tyr degradation pathway, including 4-hydroxyphenylpyruvate dioxygenase (Hpd), are upregulated by increased protein intake. Hpd is specifically expressed in the epidermis and is dynamically regulated by the internal Tyr levels. Whereas basal Hpd expression is maintained by insulin/IGF-1 signalling, Hpd induction on high-protein diet requires activation of the AMP-activated protein kinase (AMPK)-forkhead box O subfamily (FoxO) axis. Impairment of the FoxO-mediated Hpd induction in the epidermis leads to aberrant increases in internal Tyr and its metabolites, disrupting larval development on high-protein diets. Taken together, our findings uncover a crucial role of the epidermis as a metabolic regulator in coping with an unfavourable dietary environment.
    Keywords:   Drosophila melanogaster ; AMPK; Epidermal metabolism; FoxO; High-protein diet; Insulin/IGF-1 signalling; Tyrosine
    DOI:  https://doi.org/10.1242/dev.202372
  51. J Neurochem. 2024 Jan 05.
    Over-expression of N-acetylaspartate synthase exacerbates pathological energetic deficit and accelerates cognitive decline in the 5xFAD mouse.
    Jeremy S Francis, Quy Nguyen, Vladimir Markov, Paola Leone.
      N-acetylaspartate (NAA) is an abundant central nervous system amino acid derivative that is tightly coupled to mitochondria and energy metabolism in neurons. A reduced NAA signature is a prominent early pathological biomarker in multiple neurodegenerative diseases and becomes progressively more pronounced as disease advances. Because NAA synthesis requires aspartate drawn directly from mitochondria, we argued that this process is in direct competition with oxidative phosphorylation for substrate and that sustained high levels of NAA synthesis would be incompatible with pathological energy crisis. We show here that over-expression of the rate-limiting NAA synthetic enzyme in the hippocampus of the 5x familial Alzheimer's disease (5xFAD) mouse results in an exaggerated pathological ATP deficit and accelerated cognitive decline. Over-expression of NAA synthase did not increase amyloid burden or result in cell loss but did significantly deplete mitochondrial aspartate and impair the ability of mitochondria to oxidize glutamate for adenosine triphosphate (ATP) synthesis. These results define NAA as a sink for energetic substrate and suggest initial pathological reductions in NAA are part of a response to energetic crisis designed to preserve substrate bioavailability for mitochondrial ATP synthesis.
    Keywords:  N-acetylaspartate; Neurodegenerative disease; metabolic decline
    DOI:  https://doi.org/10.1111/jnc.16044
  52. Nat Commun. 2024 Jan 03. 15(1): 236
    The polyketide to fatty acid transition in the evolution of animal lipid metabolism.
    Zhenjian Lin, Feng Li, Patrick J Krug, Eric W Schmidt.
      Animals synthesize simple lipids using a distinct fatty acid synthase (FAS) related to the type I polyketide synthase (PKS) enzymes that produce complex specialized metabolites. The evolutionary origin of the animal FAS and its relationship to the diversity of PKSs remain unclear despite the critical role of lipid synthesis in cellular metabolism. Recently, an animal FAS-like PKS (AFPK) was identified in sacoglossan molluscs. Here, we explore the phylogenetic distribution of AFPKs and other PKS and FAS enzymes across the tree of life. We found AFPKs widely distributed in arthropods and molluscs (>6300 newly described AFPK sequences). The AFPKs form a clade with the animal FAS, providing an evolutionary link bridging the type I PKSs and the animal FAS. We found molluscan AFPK diversification correlated with shell loss, suggesting AFPKs provide a chemical defense. Arthropods have few or no PKSs, but our results indicate AFPKs contributed to their ecological and evolutionary success by facilitating branched hydrocarbon and pheromone biosynthesis. Although animal metabolism is well studied, surprising new metabolic enzyme classes such as AFPKs await discovery.
    DOI:  https://doi.org/10.1038/s41467-023-44497-0
  53. bioRxiv. 2023 Dec 17. pii: 2023.12.16.571979. [Epub ahead of print]
    Lysosomal TBK1 Responds to Amino Acid Availability to Relieve Rab7-Dependent mTORC1 Inhibition.
    Gabriel Talaia, Amanda Bentley-DeSousa, Shawn M Ferguson.
      Lysosomes play a pivotal role in coordinating macromolecule degradation and regulating cell growth and metabolism. Despite substantial progress in identifying lysosomal signaling proteins, understanding the pathways that synchronize lysosome functions with changing cellular demands remains incomplete. This study uncovers a role for TANK-binding kinase 1 (TBK1), well known for its role in innate immunity and organelle quality control, in modulating lysosomal responsiveness to nutrients. Specifically, we identify a pool of TBK1 that is recruited to lysosomes in response to elevated amino acid levels. At lysosomes, this TBK1 phosphorylates Rab7 on serine 72. This is critical for alleviating Rab7-mediated inhibition of amino acid-dependent mTORC1 activation. Furthermore, a TBK1 mutant (E696K) associated with amyotrophic lateral sclerosis and frontotemporal dementia constitutively accumulates at lysosomes, resulting in elevated Rab7 phosphorylation and increased mTORC1 activation. This data establishes the lysosome as a site of amino acid regulated TBK1 signaling that is crucial for efficient mTORC1 activation. This lysosomal pool of TBK1 has broader implications for lysosome homeostasis, and its dysregulation could contribute to the pathogenesis of ALS-FTD.
    DOI:  https://doi.org/10.1101/2023.12.16.571979
  54. Nat Commun. 2024 Jan 02. 15(1): 180
    Mutant p53 gains oncogenic functions through a chromosomal instability-induced cytosolic DNA response.
    Mei Zhao, Tianxiao Wang, Frederico O Gleber-Netto, Zhen Chen, Daniel J McGrail, Javier A Gomez, Wutong Ju, Mayur A Gadhikar, Wencai Ma, Li Shen, Qi Wang, Ximing Tang, Sen Pathak, Maria Gabriela Raso, Jared K Burks, Shiaw-Yih Lin, Jing Wang, Asha S Multani, Curtis R Pickering, Junjie Chen, Jeffrey N Myers, Ge Zhou.
      Inactivating TP53 mutations leads to a loss of function of p53, but can also often result in oncogenic gain-of-function (GOF) of mutant p53 (mutp53) proteins which promotes tumor development and progression. The GOF activities of TP53 mutations are well documented, but the mechanisms involved remain poorly understood. Here, we study the mutp53 interactome and find that by targeting minichromosome maintenance complex components (MCMs), GOF mutp53 predisposes cells to replication stress and chromosomal instability (CIN), leading to a tumor cell-autonomous and cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING)-dependent cytosolic DNA response that activates downstream non-canonical nuclear factor kappa light chain enhancer of activated B cell (NC-NF-κB) signaling. Consequently, GOF mutp53-MCMs-CIN-cytosolic DNA-cGAS-STING-NC-NF-κB signaling promotes tumor cell metastasis and an immunosuppressive tumor microenvironment through antagonizing interferon signaling and regulating genes associated with pro-tumorigenic inflammation. Our findings have important implications for understanding not only the GOF activities of TP53 mutations but also the genome-guardian role of p53 and its inactivation during tumor development and progression.
    DOI:  https://doi.org/10.1038/s41467-023-44239-2
  55. Immunology. 2023 Dec 30.
    Circadian rhythm regulation in the immune system.
    Jun Ding, Pengyu Chen, Chunjian Qi.
      Circadian rhythms are a ubiquitous feature in nearly all living organisms, representing oscillatory patterns with a 24-h cycle that are widespread across various physiological processes. Circadian rhythms regulate a multitude of physiological systems, including the immune system. At the molecular level, most immune cells autonomously express clock-regulating genes, which play critical roles in regulating immune cell functions. These functions encompass migration, phagocytic activity, immune cell metabolism (such as mitochondrial structural function and metabolism), signalling pathway activation, inflammatory responses, innate immune recognition, and adaptive immune processes (including vaccine responses and pathogen clearance). The endogenous circadian clock orchestrates multifaceted rhythmicity within the immune system, optimizing immune surveillance and responsiveness; this bears significant implications for maintaining immune homeostasis and resilience against diseases. This work provides an overview of circadian rhythm regulation within the immune system.
    Keywords:  circadian regulatory factors; circadian rhythms; immune cell functions; immune system
    DOI:  https://doi.org/10.1111/imm.13747
  56. Nat Commun. 2024 Jan 02. 15(1): 45
    Fatty acid synthesis suppresses dietary polyunsaturated fatty acid use.
    Anna Worthmann, Julius Ridder, Sharlaine Y L Piel, Ioannis Evangelakos, Melina Musfeldt, Hannah Voß, Marie O'Farrell, Alexander W Fischer, Sangeeta Adak, Monica Sundd, Hasibullah Siffeti, Friederike Haumann, Katja Kloth, Tatjana Bierhals, Markus Heine, Paul Pertzborn, Mira Pauly, Julia-Josefine Scholz, Suman Kundu, Marceline M Fuh, Axel Neu, Klaus Tödter, Maja Hempel, Uwe Knippschild, Clay F Semenkovich, Hartmut Schlüter, Joerg Heeren, Ludger Scheja, Christian Kubisch, Christian Schlein.
      Dietary polyunsaturated fatty acids (PUFA) are increasingly recognized for their health benefits, whereas a high production of endogenous fatty acids - a process called de novo lipogenesis (DNL) - is closely linked to metabolic diseases. Determinants of PUFA incorporation into complex lipids are insufficiently understood and may influence the onset and progression of metabolic diseases. Here we show that fatty acid synthase (FASN), the key enzyme of DNL, critically determines the use of dietary PUFA in mice and humans. Moreover, the combination of FASN inhibition and PUFA-supplementation decreases liver triacylglycerols (TAG) in mice fed with high-fat diet. Mechanistically, FASN inhibition causes higher PUFA uptake via the lysophosphatidylcholine transporter MFSD2A, and a diacylglycerol O-acyltransferase 2 (DGAT2)-dependent incorporation of PUFA into TAG. Overall, the outcome of PUFA supplementation may depend on the degree of endogenous DNL and combining PUFA supplementation and FASN inhibition might be a promising approach to target metabolic disease.
    DOI:  https://doi.org/10.1038/s41467-023-44364-y
  57. Cell Rep. 2023 Dec 28. pii: S2211-1247(23)01637-6. [Epub ahead of print]43(1): 113626
    CHCHD4-TRIAP1 regulation of innate immune signaling mediates skeletal muscle adaptation to exercise.
    Jin Ma, Ping-Yuan Wang, Jie Zhuang, Annie Y Son, Alexander K Karius, Abu Mohammad Syed, Masahiro Nishi, Zhichao Wu, Mateus P Mori, Young-Chae Kim, Paul M Hwang.
      Exercise training can stimulate the formation of fatty-acid-oxidizing slow-twitch skeletal muscle fibers, which are inversely correlated with obesity, but the molecular mechanism underlying this transformation requires further elucidation. Here, we report that the downregulation of the mitochondrial disulfide relay carrier CHCHD4 by exercise training decreases the import of TP53-regulated inhibitor of apoptosis 1 (TRIAP1) into mitochondria, which can reduce cardiolipin levels and promote VDAC oligomerization in skeletal muscle. VDAC oligomerization, known to facilitate mtDNA release, can activate cGAS-STING/NFKB innate immune signaling and downregulate MyoD in skeletal muscle, thereby promoting the formation of oxidative slow-twitch fibers. In mice, CHCHD4 haploinsufficiency is sufficient to activate this pathway, leading to increased oxidative muscle fibers and decreased fat accumulation with aging. The identification of a specific mediator regulating muscle fiber transformation provides an opportunity to understand further the molecular underpinnings of complex metabolic conditions such as obesity and could have therapeutic implications.
    Keywords:  CHCHD4; CP: Immunology; MyoD; TRIAP1; VDAC; cardiolipin; exercise adaptation; innate immune signaling; mitochondria; mtDNA; skeletal muscle
    DOI:  https://doi.org/10.1016/j.celrep.2023.113626
  58. Cell Metab. 2024 Jan 02. pii: S1550-4131(23)00456-4. [Epub ahead of print]36(1): 209-221.e6
    Deciphering the metabolic heterogeneity of hematopoietic stem cells with single-cell resolution.
    Jing Cao, Qi Jason Yao, Jiao Wu, Xiaonan Chen, Lin Huang, Wanshan Liu, Kun Qian, Jing-Jing Wan, Bo O Zhou.
      Metabolic status is crucial for stem cell functions; however, the metabolic heterogeneity of endogenous stem cells has never been directly assessed. Here, we develop a platform for high-throughput single-cell metabolomics (hi-scMet) of hematopoietic stem cells (HSCs). By combining flow cytometric isolation and nanoparticle-enhanced laser desorption/ionization mass spectrometry, we routinely detected >100 features from single cells. We mapped the single-cell metabolomes of all hematopoietic cell populations and HSC subpopulations with different division times, detecting 33 features whose levels exhibited trending changes during HSC proliferation. We found progressive activation of the oxidative pentose phosphate pathway (OxiPPP) from dormant to active HSCs. Genetic or pharmacological interference with OxiPPP increased reactive oxygen species level in HSCs, reducing HSC self-renewal upon oxidative stress. Together, our work uncovers the metabolic dynamics during HSC proliferation, reveals a role of OxiPPP for HSC activation, and illustrates the utility of hi-scMet in dissecting metabolic heterogeneity of immunophenotypically defined cell populations.
    Keywords:  6-phosphogluconic acid; HSC; MALDI-MS; hematopoietic stem cell; hi-scMet; metabolism; metabolomic heterogeneity; nanoparticle; pentose phosphate pathway; single-cell metabolomics
    DOI:  https://doi.org/10.1016/j.cmet.2023.12.005
  59. Cell Metab. 2024 Jan 02. pii: S1550-4131(23)00461-8. [Epub ahead of print]36(1): 176-192.e10
    Mitochondrial isocitrate dehydrogenase impedes CAR T cell function by restraining antioxidant metabolism and histone acetylation.
    Xiaohui Si, Mi Shao, Xinyi Teng, Yue Huang, Ye Meng, Longyuan Wu, Jieping Wei, Lianxuan Liu, Tianning Gu, Junzhe Song, Ruirui Jing, Xingyuan Zhai, Xin Guo, Delin Kong, Xiujian Wang, Bohan Cai, Ying Shen, Zhaoru Zhang, Dongrui Wang, Yongxian Hu, Pengxu Qian, Gang Xiao, He Huang.
      The efficacy of chimeric antigen receptor (CAR) T cell therapy is hampered by relapse in hematologic malignancies and by hyporesponsiveness in solid tumors. Long-lived memory CAR T cells are critical for improving tumor clearance and long-term protection. However, during rapid ex vivo expansion or in vivo tumor eradication, metabolic shifts and inhibitory signals lead to terminal differentiation and exhaustion of CAR T cells. Through a mitochondria-related compound screening, we find that the FDA-approved isocitrate dehydrogenase 2 (IDH2) inhibitor enasidenib enhances memory CAR T cell formation and sustains anti-leukemic cytotoxicity in vivo. Mechanistically, IDH2 impedes metabolic fitness of CAR T cells by restraining glucose utilization via the pentose phosphate pathway, which alleviates oxidative stress, particularly in nutrient-restricted conditions. In addition, IDH2 limits cytosolic acetyl-CoA levels to prevent histone acetylation that promotes memory cell formation. In combination with pharmacological IDH2 inhibition, CAR T cell therapy is demonstrated to have superior efficacy in a pre-clinical model.
    Keywords:  chimeric antigen receptor T cell; enasidenib; exhaustion; histone acetylation; isocitrate dehydrogenase 2; memory T cell formation; nutrient-restricted conditions; pentose phosphate pathway
    DOI:  https://doi.org/10.1016/j.cmet.2023.12.010
  60. Mol Cell. 2023 Dec 28. pii: S1097-2765(23)01019-5. [Epub ahead of print]
    OXCT1 functions as a succinyltransferase, contributing to hepatocellular carcinoma via succinylating LACTB.
    Wenhao Ma, Yuchen Sun, Ronghui Yan, Pinggen Zhang, Shengqi Shen, Hui Lu, Zilong Zhou, Zetan Jiang, Ling Ye, Qiankun Mao, Nanchi Xiong, Weidong Jia, Linchong Sun, Ping Gao, Huafeng Zhang.
      Metabolic reprogramming is an important feature of cancers that has been closely linked to post-translational protein modification (PTM). Lysine succinylation is a recently identified PTM involved in regulating protein functions, whereas its regulatory mechanism and possible roles in tumor progression remain unclear. Here, we show that OXCT1, an enzyme catalyzing ketone body oxidation, functions as a lysine succinyltransferase to contribute to tumor progression. Mechanistically, we find that OXCT1 functions as a succinyltransferase, with residue G424 essential for this activity. We also identified serine beta-lactamase-like protein (LACTB) as a main target of OXCT1-mediated succinylation. Extensive succinylation of LACTB K284 inhibits its proteolytic activity, resulting in increased mitochondrial membrane potential and respiration, ultimately leading to hepatocellular carcinoma (HCC) progression. In summary, this study establishes lysine succinyltransferase function of OXCT1 and highlights a link between HCC prognosis and LACTB K284 succinylation, suggesting a potentially valuable biomarker and therapeutic target for further development.
    Keywords:  LACTB; OXCT1; hepatocellular carcinoma; succinylation
    DOI:  https://doi.org/10.1016/j.molcel.2023.11.042
  61. Biochim Biophys Acta Rev Cancer. 2023 Dec 27. pii: S0304-419X(23)00211-1. [Epub ahead of print] 189062
    Dietary approaches for exploiting metabolic vulnerabilities in cancer.
    Otília Menyhárt, Balázs Győrffy.
      Renewed interest in tumor metabolism sparked an enthusiasm for dietary interventions to prevent and treat cancer. Changes in diet impact circulating nutrient levels in the plasma and the tumor microenvironment, and preclinical studies suggest that dietary approaches, including caloric and nutrient restrictions, can modulate tumor initiation, progression, and metastasis. Cancers are heterogeneous in their metabolic dependencies and preferred energy sources and can be addicted to glucose, fructose, amino acids, or lipids for survival and growth. This dependence is influenced by tumor type, anatomical location, tissue of origin, aberrant signaling, and the microenvironment. This review summarizes nutrient dependencies and the related signaling pathway activations that provide targets for nutritional interventions. We examine popular dietary approaches used as adjuvants to anticancer therapies, encompassing caloric restrictions, including time-restricted feeding, intermittent fasting, fasting-mimicking diets (FMDs), and nutrient restrictions, notably the ketogenic diet. Despite promising results, much of the knowledge on dietary restrictions comes from in vitro and animal studies, which may not accurately reflect real-life situations. Further research is needed to determine the optimal duration, timing, safety, and efficacy of dietary restrictions for different cancers and treatments. In addition, well-designed human trials are necessary to establish the link between specific metabolic vulnerabilities and targeted dietary interventions. However, low patient compliance in clinical trials remains a significant challenge.
    Keywords:  Caloric restriction; Dietary intervention; Fasting-mimicking diet; Ketogenic diet; cancer metabolism
    DOI:  https://doi.org/10.1016/j.bbcan.2023.189062
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