bims-celmim Biomed News
on Cellular and mitochondrial metabolism
Issue of 2023–12–24
forty-four papers selected by
Marc Segarra Mondejar, University of Cologne
  1. Mitochondrial metabolism as a dynamic regulatory hub to malignant transformation and anti-cancer drug resistance.
  2. FoxO3a Drives the Metabolic Reprogramming in Tamoxifen-Resistant Breast Cancer Cells Restoring Tamoxifen Sensitivity.
  3. Novel Relationship between Mitofusin 2-Mediated Mitochondrial Hyperfusion, Metabolic Remodeling, and Glycolysis in Pulmonary Arterial Endothelial Cells.
  4. Functional-metabolic coupling in distinct renal cell types coordinates organ-wide physiology and delays premature ageing.
  5. Mitochondrial fatty acid synthesis is an emergent central regulator of mammalian oxidative metabolism.
  6. The Role of Tumor Metabolic Reprogramming in Tumor Immunity.
  7. Disturbances in Nitric Oxide Cycle and Related Molecular Pathways in Clear Cell Renal Cell Carcinoma.
  8. Mitochondrial quality control via organelle and protein degradation.
  9. Mitochondrial quality control pathways sense mitochondrial protein import.
  10. Mitochondrial Quality Control via Mitochondrial Unfolded Protein Response (mtUPR) in Ageing and Neurodegenerative Diseases.
  11. Metabolic transitions regulate global protein fatty acylation.
  12. Liquid chromatography-mass spectrometry-based metabolomics and fluxomics reveals the metabolic alterations in glioma U87MG multicellular tumor spheroids versus two-dimensional cell cultures.
  13. Targeting lipid metabolism in cancer metastasis.
  14. Pyruvate modulation of redox potential controls mouse sperm motility.
  15. Mtfp1 ablation enhances mitochondrial respiration and protects against hepatic steatosis.
  16. Role of Glycolytic and Glutamine Metabolism Reprogramming on the Proliferation, Invasion, and Apoptosis Resistance through Modulation of Signaling Pathways in Glioblastoma.
  17. Reconfiguration of the reductive TCA cycle enables high-level succinic acid production by Yarrowia lipolytica.
  18. Complex II ambiguities-FADH2 in the electron transfer system.
  19. Membranes that make fat: roles of membrane lipids as acyl donors for triglyceride synthesis and organelle function.
  20. FBXL4 mutation-caused mitochondrial DNA depletion syndrome is driven by BNIP3/BNIP3L-dependent excessive mitophagy.
  21. Autophagy of OTUD5 destabilizes GPX4 to confer ferroptosis-dependent kidney injury.
  22. Metabolic Alterations in NADSYN1-Deficient Cells.
  23. Redox and metabolic reprogramming in breast cancer and cancer-associated adipose tissue.
  24. Generation of inducible mitophagy mice.
  25. Degradation of citrate synthase lacking the mitochondrial targeting sequence is inhibited in cells defective in Hsp70/Hsp40 chaperones under heat stress conditions.
  26. Metabolic Interplay in the Tumor Microenvironment: Implications for Immune Function and Anticancer Response.
  27. Nutrient inputs and social metabolic control of T cell fate.
  28. A guide to cell death pathways.
  29. Regulated dynamic subcellular GLUT4 localization revealed by proximal proteome mapping in human muscle cells.
  30. Metabolomics and Microbial Metabolism: Toward a Systematic Understanding.
  31. Targeting NAD+ metabolism: dual roles in cancer treatment.
  32. Blood and Brain Metabolites after Cerebral Ischemia.
  33. Pib2 is a cysteine sensor involved in TORC1 activation in Saccharomyces cerevisiae.
  34. The effect of fructose exposure on amino acid metabolism among Chinese community residents and its possible multi-omics mechanisms.
  35. Mitochondrial dysfunction abrogates dietary lipid processing in enterocytes.
  36. The function of ER-phagy receptors is regulated through phosphorylation-dependent ubiquitination pathways.
  37. Neuron-targeted overexpression of caveolin-1 alleviates diabetes-associated cognitive dysfunction via regulating mitochondrial fission-mitophagy axis.
  38. The Emerging Roles of the Metabolic Regulator G6PD in Human Cancers.
  39. VWCE modulates amino acid-dependent mTOR signaling and coordinates with KICSTOR to recruit GATOR1 to the lysosomes.
  40. S-acylation regulates SQSTM1/p62-mediated selective autophagy.
  41. Analysis of the Mitochondrial Density and Longitudinal Distribution in Rat Live-Skeletal Muscle Fibers by Confocal Microscopy.
  42. Integrated Stress Response (ISR) Pathway: Unraveling Its Role in Cellular Senescence.
  43. Untargeted metabolomics analysis reveals the metabolic disturbances and exacerbation of oxidative stress in recurrent spontaneous abortion.
  44. Lysosomal microautophagy: an emerging dimension in mammalian autophagy.
  1. Biochem Biophys Res Commun. 2023 Dec 17. pii: S0006-291X(23)01476-6. [Epub ahead of print]694 149382
    Mitochondrial metabolism as a dynamic regulatory hub to malignant transformation and anti-cancer drug resistance.
    Manendra Singh Tomar, Ashok Kumar, Ashutosh Shrivastava.
      Glycolysis is the fundamental cellular process that permits cancer cells to convert energy and grow anaerobically. Recent developments in molecular biology have made it evident that mitochondrial respiration is critical to tumor growth and treatment response. As the principal organelle of cellular energy conversion, mitochondria can rapidly alter cellular metabolic processes, thereby fueling malignancies and contributing to treatment resistance. This review emphasizes the significance of mitochondrial biogenesis, turnover, DNA copy number, and mutations in bioenergetic system regulation. Tumorigenesis requires an intricate cascade of metabolic pathways that includes rewiring of the tricarboxylic acid (TCA) cycle, electron transport chain and oxidative phosphorylation, supply of intermediate metabolites of the TCA cycle through amino acids, and the interaction between mitochondria and lipid metabolism. Cancer recurrence or resistance to therapy often results from the cooperation of several cellular defense mechanisms, most of which are connected to mitochondria. Many clinical trials are underway to assess the effectiveness of inhibiting mitochondrial respiration as a potential cancer therapeutic. We aim to summarize innovative strategies and therapeutic targets by conducting a comprehensive review of recent studies on the relationship between mitochondrial metabolism, tumor development and therapeutic resistance.
    Keywords:  Cancer; Drug resistance; Electron transport chain; Metabolism; Mitochondria; Oxidative phosphorylation; TCA cycle
    DOI:  https://doi.org/10.1016/j.bbrc.2023.149382
  2. Cells. 2023 Dec 06. pii: 2777. [Epub ahead of print]12(24):
    FoxO3a Drives the Metabolic Reprogramming in Tamoxifen-Resistant Breast Cancer Cells Restoring Tamoxifen Sensitivity.
    Marco Fiorillo, Elena Ricci, Mariarosa Fava, Camilla Longobucco, Federica Sotgia, Pietro Rizza, Marilena Lanzino, Daniela Bonofiglio, Francesca Luisa Conforti, Stefania Catalano, Ines Barone, Catia Morelli, Saveria Aquila, Michael P Lisanti, Diego Sisci.
      Tamoxifen-resistant breast cancer cells (TamR-BCCs) are characterized by an enhanced metabolic phenotype compared to tamoxifen-sensitive cells. FoxO3a is an important modulator of cell metabolism, and its deregulation has been involved in the acquisition of tamoxifen resistance. Therefore, tetracycline-inducible FoxO3a was overexpressed in TamR-BCCs (TamR/TetOn-AAA), which, together with their control cell line (TamR/TetOn-V), were subjected to seahorse metabolic assays and proteomic analysis. FoxO3a was able to counteract the increased oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) observed in TamR by reducing their energetic activity and glycolytic rate. FoxO3a caused glucose accumulation, very likely by reducing LDH activity and mitigated TamR biosynthetic needs by reducing G6PDH activity and hindering NADPH production via the pentose phosphate pathway (PPP). Proteomic analysis revealed a FoxO3a-dependent marked decrease in the expression of LDH as well as of several enzymes involved in carbohydrate metabolism (e.g., Aldolase A, LDHA and phosphofructokinase) and the analysis of cBioPortal datasets of BC patients evidenced a significant inverse correlation of these proteins and FoxO3a. Interestingly, FoxO3a also increased mitochondrial biogenesis despite reducing mitochondrial functionality by triggering ROS production. Based on these findings, FoxO3a inducing/activating drugs could represent promising tools to be exploited in the management of patients who are refractory to antiestrogen therapy.
    Keywords:  FoxO3a; breast cancer; cancer metabolism; glycolysis; tamoxifen resistance
    DOI:  https://doi.org/10.3390/cells12242777
  3. Int J Mol Sci. 2023 Dec 15. pii: 17533. [Epub ahead of print]24(24):
    Novel Relationship between Mitofusin 2-Mediated Mitochondrial Hyperfusion, Metabolic Remodeling, and Glycolysis in Pulmonary Arterial Endothelial Cells.
    Manivannan Yegambaram, Xutong Sun, Alejandro Garcia Flores, Qing Lu, Jamie Soto, Jaime Richards, Saurabh Aggarwal, Ting Wang, Haiwei Gu, Jeffrey R Fineman, Stephen M Black.
      The disruption of mitochondrial dynamics has been identified in cardiovascular diseases, including pulmonary hypertension (PH), ischemia-reperfusion injury, heart failure, and cardiomyopathy. Mitofusin 2 (Mfn2) is abundantly expressed in heart and pulmonary vasculature cells at the outer mitochondrial membrane to modulate fusion. Previously, we have reported reduced levels of Mfn2 and fragmented mitochondria in pulmonary arterial endothelial cells (PAECs) isolated from a sheep model of PH induced by pulmonary over-circulation and restoring Mfn2 normalized mitochondrial function. In this study, we assessed the effect of increased expression of Mfn2 on mitochondrial metabolism, bioenergetics, reactive oxygen species production, and mitochondrial membrane potential in control PAECs. Using an adenoviral expression system to overexpress Mfn2 in PAECs and utilizing 13C labeled substrates, we assessed the levels of TCA cycle metabolites. We identified increased pyruvate and lactate production in cells, revealing a glycolytic phenotype (Warburg phenotype). Mfn2 overexpression decreased the mitochondrial ATP production rate, increased the rate of glycolytic ATP production, and disrupted mitochondrial bioenergetics. The increase in glycolysis was linked to increased hypoxia-inducible factor 1α (HIF-1α) protein levels, elevated mitochondrial reactive oxygen species (mt-ROS), and decreased mitochondrial membrane potential. Our data suggest that disrupting the mitochondrial fusion/fission balance to favor hyperfusion leads to a metabolic shift that promotes aerobic glycolysis. Thus, therapies designed to increase mitochondrial fusion should be approached with caution.
    Keywords:  glycolysis; metabolomics; mitochondrial function; mitofusin; pulmonary hypertension
    DOI:  https://doi.org/10.3390/ijms242417533
  4. Nat Commun. 2023 Dec 18. 14(1): 8405
    Functional-metabolic coupling in distinct renal cell types coordinates organ-wide physiology and delays premature ageing.
    Jack Holcombe, Helen Weavers.
      Precise coupling between cellular physiology and metabolism is emerging as a vital relationship underpinning tissue health and longevity. Nevertheless, functional-metabolic coupling within heterogenous microenvironments in vivo remains poorly understood due to tissue complexity and metabolic plasticity. Here, we establish the Drosophila renal system as a paradigm for linking mechanistic analysis of metabolism, at single-cell resolution, to organ-wide physiology. Kidneys are amongst the most energetically-demanding organs, yet exactly how individual cell types fine-tune metabolism to meet their diverse, unique physiologies over the life-course remains unclear. Integrating live-imaging of metabolite and organelle dynamics with spatio-temporal genetic perturbation within intact functional tissue, we uncover distinct cellular metabolic signatures essential to support renal physiology and healthy ageing. Cell type-specific programming of glucose handling, PPP-mediated glutathione regeneration and FA β-oxidation via dynamic lipid-peroxisomal networks, downstream of differential ERR receptor activity, precisely match cellular energetic demands whilst limiting damage and premature senescence; however, their dramatic dysregulation may underlie age-related renal dysfunction.
    DOI:  https://doi.org/10.1038/s41467-023-44098-x
  5. Cell Metab. 2023 Dec 14. pii: S1550-4131(23)00449-7. [Epub ahead of print]
    Mitochondrial fatty acid synthesis is an emergent central regulator of mammalian oxidative metabolism.
    Riley J Wedan, Jacob Z Longenecker, Sara M Nowinski.
      Contrary to their well-known functions in nutrient breakdown, mitochondria are also important biosynthetic hubs and express an evolutionarily conserved mitochondrial fatty acid synthesis (mtFAS) pathway. mtFAS builds lipoic acid and longer saturated fatty acids, but its exact products, their ultimate destination in cells, and the cellular significance of the pathway are all active research questions. Moreover, why mitochondria need mtFAS despite their well-defined ability to import fatty acids is still unclear. The identification of patients with inborn errors of metabolism in mtFAS genes has sparked fresh research interest in the pathway. New mammalian models have provided insights into how mtFAS coordinates many aspects of oxidative mitochondrial metabolism and raise questions about its role in diseases such as obesity, diabetes, and heart failure. In this review, we discuss the products of mtFAS, their function, and the consequences of mtFAS impairment across models and in metabolic disease.
    Keywords:  fatty acids; inborn errors of metabolism; lipid metabolism; lipids; mitochondria; mitochondrial fatty acid synthesis; mouse models; mtFAS
    DOI:  https://doi.org/10.1016/j.cmet.2023.11.017
  6. Int J Mol Sci. 2023 Dec 13. pii: 17422. [Epub ahead of print]24(24):
    The Role of Tumor Metabolic Reprogramming in Tumor Immunity.
    Xianhong Zhang, Weiguo Song, Yue Gao, Yu Zhang, Yuqi Zhao, Shuailin Hao, Ting Ni.
      The occurrence and development of tumors require the metabolic reprogramming of cancer cells, namely the alteration of flux in an autonomous manner via various metabolic pathways to meet increased bioenergetic and biosynthetic demands. Tumor cells consume large quantities of nutrients and produce related metabolites via their metabolism; this leads to the remodeling of the tumor microenvironment (TME) to better support tumor growth. During TME remodeling, the immune cell metabolism and antitumor immune activity are affected. This further leads to the escape of tumor cells from immune surveillance and therefore to abnormal proliferation. This review summarizes the regulatory functions associated with the abnormal biosynthesis and activity of metabolic signaling molecules during the process of tumor metabolic reprogramming. In addition, we provide a comprehensive description of the competition between immune cells and tumor cells for nutrients in the TME, as well as the metabolites required for tumor metabolism, the metabolic signaling pathways involved, and the functionality of the immune cells. Finally, we summarize current research targeted at the development of tumor immunotherapy. We aim to provide new concepts for future investigations of the mechanisms underlying the metabolic reprogramming of tumors and explore the association of these mechanisms with tumor immunity.
    Keywords:  immune cells; tumor immunity; tumor metabolism; tumor microenvironment; tumor therapy
    DOI:  https://doi.org/10.3390/ijms242417422
  7. Cancers (Basel). 2023 Dec 11. pii: 5797. [Epub ahead of print]15(24):
    Disturbances in Nitric Oxide Cycle and Related Molecular Pathways in Clear Cell Renal Cell Carcinoma.
    Corina Daniela Ene, Mircea Tampa, Simona Roxana Georgescu, Clara Matei, Iulia Maria Teodora Leulescu, Claudia Ioana Dogaru, Mircea Nicolae Penescu, Ilinca Nicolae.
      It is important to note that maintaining adequate levels of nitric oxide (NO), the turnover, and the oxidation level of nitrogen are essential for the optimal progression of cellular processes, and alterations in the NO cycle indicate a crucial step in the onset and progression of multiple diseases. Cellular accumulation of NO and reactive nitrogen species in many types of tumour cells is expressed by an increased susceptibility to oxidative stress in the tumour microenvironment. Clear cell renal cell carcinoma (ccRCC) is a progressive metabolic disease in which tumour cells can adapt to metabolic reprogramming to enhance NO production in the tumour space. Understanding the factors governing NO biosynthesis metabolites in ccRCC represents a relevant, valuable approach to studying NO-based anticancer therapy. Exploring the molecular processes mediated by NO, related disturbances in molecular pathways, and NO-mediated signalling pathways in ccRCC could have significant therapeutic implications in managing and treating this condition.
    Keywords:  ccRCC; nitric oxide; signalling
    DOI:  https://doi.org/10.3390/cancers15245797
  8. J Biochem. 2023 Dec 15. pii: mvad106. [Epub ahead of print]
    Mitochondrial quality control via organelle and protein degradation.
    Koji Yamano, Hiroki Kinefuchi, Waka Kojima.
      Mitochondria are essential eukaryotic organelles that produce ATP as well as synthesize various macromolecules. They also participate in signaling pathways such as the innate immune response and apoptosis. These diverse functions are performed by >1000 different mitochondrial proteins. Although mitochondria are continuously exposed to potentially damaging conditions such as reactive oxygen species, proteases/peptidases localized in different mitochondrial sub-compartments, termed mitoproteases, maintain mitochondrial quality and integrity. In addition to processing incoming precursors and degrading damaged proteins, mitoproteases also regulate metabolic reactions, mitochondrial protein half-lives, and gene transcription. Impaired mitoprotease function is associated with various pathologies. In this review, we highlight recent advances in our understanding of mitochondrial quality control regulated by autophagy, ubiquitin-proteasomes, and mitoproteases.
    Keywords:  autophagy; mitophagy; peptidase; protease; ubiquitin
    DOI:  https://doi.org/10.1093/jb/mvad106
  9. Trends Endocrinol Metab. 2023 Dec 15. pii: S1043-2760(23)00243-6. [Epub ahead of print]
    Mitochondrial quality control pathways sense mitochondrial protein import.
    Laurie P Lee-Glover, Timothy E Shutt.
      Mitochondrial quality control (MQC) mechanisms are required to maintain a functional proteome, which enables mitochondria to perform a myriad of important cellular functions from oxidative phosphorylation to numerous other metabolic pathways. Mitochondrial protein homeostasis begins with the import of over 1000 nuclear-encoded mitochondrial proteins and the synthesis of 13 mitochondrial DNA-encoded proteins. A network of chaperones and proteases helps to fold new proteins and degrade unnecessary, damaged, or misfolded proteins, whereas more extensive damage can be removed by mitochondrial-derived vesicles (MDVs) or mitochondrial autophagy (mitophagy). Here, focusing on mechanisms in mammalian cells, we review the importance of mitochondrial protein import as a sentinel of mitochondrial function that activates multiple MQC mechanisms when impaired.
    Keywords:  mitochondria; mitochondrial protein import; mitochondrial quality control; mitochondrial unfolded protein response; mitochondrial-derived vesicles; mitophagy
    DOI:  https://doi.org/10.1016/j.tem.2023.11.004
  10. Biomolecules. 2023 Dec 13. pii: 1789. [Epub ahead of print]13(12):
    Mitochondrial Quality Control via Mitochondrial Unfolded Protein Response (mtUPR) in Ageing and Neurodegenerative Diseases.
    Paula Cilleros-Holgado, David Gómez-Fernández, Rocío Piñero-Pérez, Jose Manuel Romero-Domínguez, Diana Reche-López, Alejandra López-Cabrera, Mónica Álvarez-Córdoba, Manuel Munuera-Cabeza, Marta Talaverón-Rey, Alejandra Suárez-Carrillo, Ana Romero-González, Jose Antonio Sánchez-Alcázar.
      Mitochondria play a key role in cellular functions, including energy production and oxidative stress regulation. For this reason, maintaining mitochondrial homeostasis and proteostasis (homeostasis of the proteome) is essential for cellular health. Therefore, there are different mitochondrial quality control mechanisms, such as mitochondrial biogenesis, mitochondrial dynamics, mitochondrial-derived vesicles (MDVs), mitophagy, or mitochondrial unfolded protein response (mtUPR). The last item is a stress response that occurs when stress is present within mitochondria and, especially, when the accumulation of unfolded and misfolded proteins in the mitochondrial matrix surpasses the folding capacity of the mitochondrion. In response to this, molecular chaperones and proteases as well as the mitochondrial antioxidant system are activated to restore mitochondrial proteostasis and cellular function. In disease contexts, mtUPR modulation holds therapeutic potential by mitigating mitochondrial dysfunction. In particular, in the case of neurodegenerative diseases, such as primary mitochondrial diseases, Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Amyotrophic Lateral Sclerosis (ALS), or Friedreich's Ataxia (FA), there is a wealth of evidence demonstrating that the modulation of mtUPR helps to reduce neurodegeneration and its associated symptoms in various cellular and animal models. These findings underscore mtUPR's role as a promising therapeutic target in combating these devastating disorders.
    Keywords:  ageing; mitochondria; mitochondrial biogenesis; mitochondrial diseases; mitochondrial dynamics; mitochondrial quality control mechanisms; mitochondrial unfolded protein response (mtUPR); mitophagy; neurodegenerative diseases; therapeutic target
    DOI:  https://doi.org/10.3390/biom13121789
  11. J Biol Chem. 2023 Dec 13. pii: S0021-9258(23)02591-7. [Epub ahead of print] 105563
    Metabolic transitions regulate global protein fatty acylation.
    Manasi Talwadekar, Subhash Khatri, Chinthapalli Balaji, Arnab Chakraborty, Nandini-Pal Basak, Siddhesh Kamat, Ullas Kolthur-Seetharam.
      Intermediary metabolites and flux through various pathways have emerged as key determinants of post-translational modifications. Independently, dynamic fluctuations in their concentrations are known to drive cellular energetics in a bi-directional manner. Notably, intracellular fatty acid pools that drastically change during fed and fasted states act as precursors for both ATP production and fatty acylation of proteins. Protein fatty acylation is well regarded for its role in regulating structure and functions of diverse proteins, however the effect of intracellular concentrations of fatty acids on protein modification is less understood. In this regard, we unequivocally demonstrate that metabolic contexts, viz. fed and fasted states, dictate the extent of global fatty acylation. Moreover, we show that presence or absence of glucose, that influences cellular and mitochondrial uptake/utilization of fatty acids, affects palmitoylation and oleoylation, which is consistent with their intracellular abundance in fed and fasted states. Employing complementary approaches including click-chemistry, lipidomics and imaging, we show the top-down control of cellular metabolic state. Importantly, our results establish the crucial role of mitochondria and retrograde signaling components like SIRT4, AMPK and mTOR in orchestrating protein fatty acylation at a whole cell level. Specifically, pharmacogenetic perturbations that alter either mitochondrial functions and/or retrograde signaling affect protein fatty acylation. Besides illustrating the cross-talk between carbohydrate and lipid metabolism in mediating bulk post-translational modification, our findings also highlight the involvement of mitochondrial energetics.
    Keywords:  Acylation; acyl exchange; free fatty acids; oleate; palmitate; sirtuins
    DOI:  https://doi.org/10.1016/j.jbc.2023.105563
  12. Rapid Commun Mass Spectrom. 2024 Jan 30. 38(2): e9670
    Liquid chromatography-mass spectrometry-based metabolomics and fluxomics reveals the metabolic alterations in glioma U87MG multicellular tumor spheroids versus two-dimensional cell cultures.
    Shanjing Wen, Xinyi Tu, Qingce Zang, Ying Zhu, Limei Li, Ruiping Zhang, Zeper Abliz.
       RATIONALE: Multicellular tumor spheroids (MCTSs) that reconstitute the metabolic characteristics of in vivo tumor tissue may facilitate the discovery of molecular biomarkers and effective anticancer therapies. However, little is known about how cancer cells adapt their metabolic changes in complex three-dimensional (3D) microenvironments. Here, using the two-dimensional (2D) cell model as control, the metabolic phenotypes of glioma U87MG multicellular tumor spheroids were systematically investigated based on static metabolomics and dynamic fluxomics analysis.
    METHODS: A liquid chromatography-mass spectrometry-based global metabolomics and lipidomics approach was adopted to survey the cellular samples from 2D and 3D culture systems, revealing marked molecular differences between them. Then, by means of metabolomic pathway analysis, the metabolic pathways altered in glioma MCTSs were found using 13 C6 -glucose as a tracer to map the metabolic flux of glycolysis, the tricarboxylic acid (TCA) cycle, de novo nucleotide synthesis, and de novo lipid biosynthesis in the MCTS model.
    RESULTS: We found nine metabolic pathways as well as glycerolipid, glycerophospholipid and sphingolipid metabolism to be predominantly altered in glioma MCTSs. The reduced nucleotide metabolism, amino acid metabolism and glutathione metabolism indicated an overall lower cellular activity in MCTSs. Through dynamic fluxomics analysis in the MCTS model, we found that cells cultured in MCTSs exhibited increased glycolysis activity and de novo lipid biosynthesis activity, and decreased the TCA cycle and de novo purine nucleotide biosynthesis activity.
    CONCLUSIONS: Our study highlights specific, altered biochemical pathways in MCTSs, emphasizing dysregulation of energy metabolism and lipid metabolism, and offering novel insight into metabolic events in glioma MCTSs.
    DOI:  https://doi.org/10.1002/rcm.9670
  13. Biochim Biophys Acta Rev Cancer. 2023 Dec 13. pii: S0304-419X(23)00200-7. [Epub ahead of print] 189051
    Targeting lipid metabolism in cancer metastasis.
    Gloria Pascual, Blanca Majem, Salvador Aznar-Benitah.
      This review delves into the most recent research on the metabolic adaptability of cancer cells and examines how their metabolic functions can impact their progression into metastatic forms. We emphasize the growing significance of lipid metabolism and dietary lipids within the tumor microenvironment, underscoring their influence on tumor progression. Additionally, we present an outline of the interplay between metabolic processes and the epigenome of cancer cells, underscoring the importance regarding the metastatic process. Lastly, we examine the potential of targeting metabolism as a therapeutic approach in combating cancer progression, shedding light on innovative drugs/targets currently undergoing preclinical evaluation.
    Keywords:  Epigenetics; Lipid metabolism; Metastasis; Microenvironment; Therapies
    DOI:  https://doi.org/10.1016/j.bbcan.2023.189051
  14. Dev Cell. 2023 Dec 05. pii: S1534-5807(23)00609-3. [Epub ahead of print]
    Pyruvate modulation of redox potential controls mouse sperm motility.
    Cameron A Schmidt, Benjamin J Hale, Debajit Bhowmick, William J Miller, P Darrell Neufer, Christopher B Geyer.
      Sperm gain fertilization competence in the female reproductive tract through a series of biochemical changes and a requisite switch from linear progressive to hyperactive motility. Despite being essential for fertilization, regulation of sperm energy transduction is poorly understood. This knowledge gap confounds interpretation of interspecies variation and limits progress in optimizing sperm selection for assisted reproduction. Here, we developed a model of mouse sperm bioenergetics using metabolic phenotyping data, quantitative microscopy, and spectral flow cytometry. The results define a mechanism of motility regulation by microenvironmental pyruvate. Rather than being consumed as a mitochondrial fuel source, pyruvate stimulates hyperactivation by repressing lactate oxidation and activating glycolysis in the flagellum through provision of nicotinamide adenine dinucleotide (NAD)+. These findings provide evidence that the transitions in motility requisite for sperm competence are governed by changes in the metabolic microenvironment, highlighting the unexplored potential of using catabolite combination to optimize sperm selection for fertilization.
    Keywords:  fertility; fertilization; glycolysis; metabolism; motility; redox potential; sperm
    DOI:  https://doi.org/10.1016/j.devcel.2023.11.011
  15. Nat Commun. 2023 Dec 20. 14(1): 8474
    Mtfp1 ablation enhances mitochondrial respiration and protects against hepatic steatosis.
    Cecilia Patitucci, Juan Diego Hernández-Camacho, Elodie Vimont, Sonny Yde, Thomas Cokelaer, Thibault Chaze, Quentin Giai Gianetto, Mariette Matondo, Anastasia Gazi, Ivan Nemazanyy, David A Stroud, Daniella H Hock, Erminia Donnarumma, Timothy Wai.
      Hepatic steatosis is the result of imbalanced nutrient delivery and metabolism in the liver and is the first hallmark of Metabolic dysfunction-associated steatotic liver disease (MASLD). MASLD is the most common chronic liver disease and involves the accumulation of excess lipids in hepatocytes, inflammation, and cancer. Mitochondria play central roles in liver metabolism yet the specific mitochondrial functions causally linked to MASLD remain unclear. Here, we identify Mitochondrial Fission Process 1 protein (MTFP1) as a key regulator of mitochondrial and metabolic activity in the liver. Deletion of Mtfp1 in hepatocytes is physiologically benign in mice yet leads to the upregulation of oxidative phosphorylation (OXPHOS) activity and mitochondrial respiration, independently of mitochondrial biogenesis. Consequently, liver-specific knockout mice are protected against high fat diet-induced steatosis and metabolic dysregulation. Additionally, Mtfp1 deletion inhibits mitochondrial permeability transition pore opening in hepatocytes, conferring protection against apoptotic liver damage in vivo and ex vivo. Our work uncovers additional functions of MTFP1 in the liver, positioning this gene as an unexpected regulator of OXPHOS and a therapeutic candidate for MASLD.
    DOI:  https://doi.org/10.1038/s41467-023-44143-9
  16. Int J Mol Sci. 2023 Dec 18. pii: 17633. [Epub ahead of print]24(24):
    Role of Glycolytic and Glutamine Metabolism Reprogramming on the Proliferation, Invasion, and Apoptosis Resistance through Modulation of Signaling Pathways in Glioblastoma.
    Cristina Trejo-Solis, Daniela Silva-Adaya, Norma Serrano-García, Roxana Magaña-Maldonado, Dolores Jimenez-Farfan, Elizabeth Ferreira-Guerrero, Arturo Cruz-Salgado, Rosa Angelica Castillo-Rodriguez.
      Glioma cells exhibit genetic and metabolic alterations that affect the deregulation of several cellular signal transduction pathways, including those related to glucose metabolism. Moreover, oncogenic signaling pathways induce the expression of metabolic genes, increasing the metabolic enzyme activities and thus the critical biosynthetic pathways to generate nucleotides, amino acids, and fatty acids, which provide energy and metabolic intermediates that are essential to accomplish the biosynthetic needs of glioma cells. In this review, we aim to explore how dysregulated metabolic enzymes and their metabolites from primary metabolism pathways in glioblastoma (GBM) such as glycolysis and glutaminolysis modulate anabolic and catabolic metabolic pathways as well as pro-oncogenic signaling and contribute to the formation, survival, growth, and malignancy of glioma cells. Also, we discuss promising therapeutic strategies by targeting the key players in metabolic regulation. Therefore, the knowledge of metabolic reprogramming is necessary to fully understand the biology of malignant gliomas to improve patient survival significantly.
    Keywords:  glioma; glucose; glutamine; metabolism; oncogenic pathways
    DOI:  https://doi.org/10.3390/ijms242417633
  17. Nat Commun. 2023 Dec 20. 14(1): 8480
    Reconfiguration of the reductive TCA cycle enables high-level succinic acid production by Yarrowia lipolytica.
    Zhiyong Cui, Yutao Zhong, Zhijie Sun, Zhennan Jiang, Jingyu Deng, Qian Wang, Jens Nielsen, Jin Hou, Qingsheng Qi.
      Succinic acid (SA) is an important C4-dicarboxylic acid. Microbial production of SA at low pH results in low purification costs and hence good overall process economics. However, redox imbalances limited SA biosynthesis from glucose via the reductive tricarboxylic acid (TCA) cycle in yeast. Here, we engineer the strictly aerobic yeast Yarrowia lipolytica for efficient SA production without pH control. Introduction of the reductive TCA cycle into the cytosol of a succinate dehydrogenase-disrupted yeast strain causes arrested cell growth. Although adaptive laboratory evolution restores cell growth, limited NADH supply restricts SA production. Reconfiguration of the reductive SA biosynthesis pathway in the mitochondria through coupling the oxidative and reductive TCA cycle for NADH regeneration results in improved SA production. In pilot-scale fermentation, the engineered strain produces 111.9 g/L SA with a yield of 0.79 g/g glucose within 62 h. This study paves the way for industrial production of biobased SA.
    DOI:  https://doi.org/10.1038/s41467-023-44245-4
  18. J Biol Chem. 2023 Nov 22. pii: S0021-9258(23)02498-5. [Epub ahead of print]300(1): 105470
    Complex II ambiguities-FADH2 in the electron transfer system.
    Erich Gnaiger.
      The prevailing notion that reduced cofactors NADH and FADH2 transfer electrons from the tricarboxylic acid cycle to the mitochondrial electron transfer system creates ambiguities regarding respiratory Complex II (CII). CII is the only membrane-bound enzyme in the tricarboxylic acid cycle and is part of the electron transfer system of the mitochondrial inner membrane feeding electrons into the coenzyme Q-junction. The succinate dehydrogenase subunit SDHA of CII oxidizes succinate and reduces the covalently bound prosthetic group FAD to FADH2 in the canonical forward tricarboxylic acid cycle. However, several graphical representations of the electron transfer system depict FADH2 in the mitochondrial matrix as a substrate to be oxidized by CII. This leads to the false conclusion that FADH2 from the β-oxidation cycle in fatty acid oxidation feeds electrons into CII. In reality, dehydrogenases of fatty acid oxidation channel electrons to the Q-junction but not through CII. The ambiguities surrounding Complex II in the literature and educational resources call for quality control, to secure scientific standards in current communications of bioenergetics, and ultimately support adequate clinical applications. This review aims to raise awareness of the inherent ambiguity crisis, complementing efforts to address the well-acknowledged issues of credibility and reproducibility.
    Keywords:  Complex II; coenzyme Q; electron transfer system; fatty acid oxidation; flavin adenine dinucleotide; succinate dehydrogenase; tricarboxylic acid cycle
    DOI:  https://doi.org/10.1016/j.jbc.2023.105470
  19. FEBS Lett. 2023 Dec 23.
    Membranes that make fat: roles of membrane lipids as acyl donors for triglyceride synthesis and organelle function.
    Antonio D Barbosa, Symeon Siniossoglou.
      Triglycerides constitute an inert storage form for fatty acids deposited in lipid droplets, and are mobilized to provide metabolic energy or membrane building blocks. The biosynthesis of triglycerides is highly conserved within eukaryotes and normally involves the sequential esterification of activated fatty acids with a glycerol backbone. Some eukaryotes, however, can also use cellular membrane lipids as direct fatty acid donors for triglyceride synthesis. The biological significance of a pathway that generates triglycerides at the expense of organelle membranes has remained elusive. Here we review current knowledge on how cells use membrane lipids as fatty acid donors for triglyceride synthesis, and discuss the hypothesis that a primary function of this pathway is to regulate membrane lipid remodelling and organelle function.
    Keywords:  Lipid droplet; endoplasmic reticulum; fat; membrane; nuclear membrane; phospholipid; triglyceride
    DOI:  https://doi.org/10.1002/1873-3468.14793
  20. Trends Mol Med. 2023 Dec 19. pii: S1471-4914(23)00279-4. [Epub ahead of print]
    FBXL4 mutation-caused mitochondrial DNA depletion syndrome is driven by BNIP3/BNIP3L-dependent excessive mitophagy.
    Kun Gao, Xiayun Xu, Chenji Wang.
      Encephalomyopathic mitochondrial DNA (mtDNA) depletion syndrome 13 (MTDPS13) is an autosomal recessive disorder arising from biallelic F-box and leucine-rich repeat (LRR) protein 4 (FBXL4) gene mutations. Recent advances have shown that excessive BCL2 interacting protein 3 (BNIP3)/ BCL2 interacting protein 3 like (BNIP3L)-dependent mitophagy underlies the molecular pathogenesis of MTDPS13. Here, we provide an overview of these groundbreaking findings and discuss potential therapeutic strategies for this fatal disease.
    Keywords:  BNIP3/BNIP3L; FBXL4; MTDPS13; mitochondria; mitophagy; ubiquitination
    DOI:  https://doi.org/10.1016/j.molmed.2023.11.017
  21. Nat Commun. 2023 Dec 18. 14(1): 8393
    Autophagy of OTUD5 destabilizes GPX4 to confer ferroptosis-dependent kidney injury.
    Li-Kai Chu, Xu Cao, Lin Wan, Qiang Diao, Yu Zhu, Yu Kan, Li-Li Ye, Yi-Ming Mao, Xing-Qiang Dong, Qian-Wei Xiong, Ming-Cui Fu, Ting Zhang, Hui-Ting Zhou, Shi-Zhong Cai, Zhou-Rui Ma, Ssu-Wei Hsu, Reen Wu, Ching-Hsien Chen, Xiang-Ming Yan, Jun Liu.
      Ferroptosis is an iron-dependent programmed cell death associated with severe kidney diseases, linked to decreased glutathione peroxidase 4 (GPX4). However, the spatial distribution of renal GPX4-mediated ferroptosis and the molecular events causing GPX4 reduction during ischemia-reperfusion (I/R) remain largely unknown. Using spatial transcriptomics, we identify that GPX4 is situated at the interface of the inner cortex and outer medulla, a hyperactive ferroptosis site post-I/R injury. We further discover OTU deubiquitinase 5 (OTUD5) as a GPX4-binding protein that confers ferroptosis resistance by stabilizing GPX4. During I/R, ferroptosis is induced by mTORC1-mediated autophagy, causing OTUD5 degradation and subsequent GPX4 decay. Functionally, OTUD5 deletion intensifies renal tubular cell ferroptosis and exacerbates acute kidney injury, while AAV-mediated OTUD5 delivery mitigates ferroptosis and promotes renal function recovery from I/R injury. Overall, this study highlights a new autophagy-dependent ferroptosis module: hypoxia/ischemia-induced OTUD5 autophagy triggers GPX4 degradation, offering a potential therapeutic avenue for I/R-related kidney diseases.
    DOI:  https://doi.org/10.1038/s41467-023-44228-5
  22. Metabolites. 2023 Dec 12. pii: 1196. [Epub ahead of print]13(12):
    Metabolic Alterations in NADSYN1-Deficient Cells.
    Nils W F Meijer, Johan Gerrits, Susan Zwakenberg, Fried J T Zwartkruis, Nanda M Verhoeven-Duif, Judith J M Jans.
      NAD synthetase 1 (encoded by the gene NADSYN1) is a cytosolic enzyme that catalyzes the final step in the biosynthesis of nicotinamide adenine dinucleotide (NAD+) from tryptophan and nicotinic acid. NADSYN1 deficiency has recently been added to the spectrum of congenital NAD+ deficiency disorders. To gain insight into the metabolic consequences of NADSYN1 deficiency, the encoding gene was disrupted in A549 and HEK293T cells, and the metabolome was profiled in the presence of different NAD+ precursors, including tryptophan, nicotinamide and nicotinic acid. We demonstrate that when precursors of the NAD+ salvage pathway in the form of nicotinamide become limiting, NADSYN1 deficiency results in a decline in intracellular NAD+ levels even in the presence of other potential NAD+ sources such as tryptophan and nicotinic acid. As a consequence, alterations in 122 and 69 metabolites are observed in NADSYN1-deficient A549 and HEK293T cells compared to the wild-type cell line (FC > 2 and p < 0.05). We thus show that NADSYN1 deficiency results in a metabolic phenotype characterized by alterations in glycolysis, the TCA cycle, the pentose phosphate pathway, and the polyol pathway.
    Keywords:  NAD+ deficiency; NAD+ salvage pathway; NADSYN1; Preiss–Handler pathway; de novo NAD+ synthesis pathway; glycolysis; metabolomics; pentose phosphate pathway; polyol pathway
    DOI:  https://doi.org/10.3390/metabo13121196
  23. FEBS Lett. 2023 Dec 23.
    Redox and metabolic reprogramming in breast cancer and cancer-associated adipose tissue.
    Tamara Zakic, Vanja Pekovic-Vaughan, Aleksandra Cvoro, Aleksandra Korac, Aleksandra Jankovic, Bato Korac.
      Redox and metabolic processes are tightly coupled in both physiological and pathological conditions. In cancer, their integration occurs at multiple levels and is characterised by synchronised reprogramming both in the tumour tissue and its specific but heterogeneous microenvironment. In breast cancer, the principal microenvironment is the cancer-associated adipose tissue (CAAT). Understanding how the redox-metabolic reprogramming becomes coordinated in human breast cancer is imperative both for cancer prevention and for the establishment of new therapeutic approaches. This review aims to provide an overview of the current knowledge of the redox profiles and regulation of intermediary metabolism in breast cancer whilst considering the tumour and CAAT of breast cancer as a unique Warburg's pseudo-organ. As cancer is now recognised as a systemic metabolic disease, we have paid particular attention to the cell-specific redox-metabolic reprogramming and the roles of estrogen receptors and circadian rhythms, as well as their crosstalk in the development, growth, progression, and prognosis of breast cancer.
    Keywords:  adipose tissue; breast cancer; circadian rhythms; estrogen; redox-metabolic reprogramming; tumour microenvironment
    DOI:  https://doi.org/10.1002/1873-3468.14794
  24. Genes Cells. 2023 Dec 22.
    Generation of inducible mitophagy mice.
    Toshiyuki Nishiji, Atsushi Hoshino, Yuki Uchio, Satoaki Matoba.
      Mitophagy is programmed selective autophagy of mitochondria and is important for mitochondrial quality control and cellular homeostasis. Mitochondrial dysfunction and impaired mitophagy are closely associated with various diseases, including heart failure and diabetes. To better understand the pathophysiological role of mitophagy, we generated doxycycline-inducible mitophagy mice using a synthetic mitophagy adaptor protein consisting of an outer mitochondrial membrane targeting sequence and an engineered LIR. To evaluate the activation of mitophagy upon doxycycline treatment, we also generated mitophagy reporter mito-QC mice in which mitochondria tandemly express mCherry and GFP, and only GFP signals are lost in acidic lysosomes subjected to mitophagy. With the ROSA26 promoter-driven rtTA, mitophagy was observed at least in heart, liver, and skeletal muscle. We investigated the relationship between mitophagy activation and pressure overload heart failure or high fat diet-induced obesity. Unexpectedly, we were unable to confirm the protective effect of mitophagy in these two pathological models. Further titration of the level of mitophagy induction is required to demonstrate the potency of the protective effects of mitophagy in disease models.
    Keywords:  bioengineering; heart failure; mitophagy
    DOI:  https://doi.org/10.1111/gtc.13091
  25. FEMS Yeast Res. 2023 Dec 21. pii: foad054. [Epub ahead of print]
    Degradation of citrate synthase lacking the mitochondrial targeting sequence is inhibited in cells defective in Hsp70/Hsp40 chaperones under heat stress conditions.
    Mayuko Hayashi, Tomoyuki Kawarasaki, Kunio Nakatsukasa.
      Most nucleus-encoded mitochondrial precursor proteins are synthesized in the cytosol and imported into mitochondria in a post-translational manner. In recent years, the quality control mechanisms of non-imported mitochondrial proteins have been intensively studied. In a previous study, we established that in budding yeast a mutant form of citrate synthase 1 (N∆Cit1) that lacks the N-terminal mitochondrial targeting sequence and therefore mislocalizes to the cytosol is targeted for proteasomal degradation by the SCFUcc1 ubiquitin ligase complex. Here, we show that Hsp70 and Hsp40 chaperones (Ssa1 and Ydj1 in yeast, respectively) are required for N∆Cit1 degradation under heat stress conditions. In the absence of Hsp70 function, a portion of N∆Cit1-GFP formed insoluble aggregates and cytosolic foci. However, the extent of ubiquitination of N∆Cit1 was unaffected, implying that Hsp70/Hsp40 chaperones are involved in the post-ubiquitination step of N∆Cit1 degradation. Intriguingly, degradation of cytosolic/peroxisomal gluconeogenic citrate synthase (Cit2), an endogenous substrate for SCFUcc1-mediated proteasomal degradation, was not highly dependent on Hsp70 even under heat stress conditions. These results suggest that mitochondrial citrate synthase is thermally vulnerable in the cytosol, where Hsp70/Hsp40 chaperones are required to facilitate its degradation.
    Keywords:   Saccharomyces cerevisiae ; Hsp70; TCA cycle; citrate synthase; degradation; glyoxylate cycle; ubiquitin-proteasome system
    DOI:  https://doi.org/10.1093/femsyr/foad054
  26. Curr Issues Mol Biol. 2023 Dec 05. 45(12): 9753-9767
    Metabolic Interplay in the Tumor Microenvironment: Implications for Immune Function and Anticancer Response.
    Reem Youssef, Rohan Maniar, Jaffar Khan, Hector Mesa.
      Malignant tumors exhibit rapid growth and high metabolic rates, similar to embryonic stem cells, and depend on aerobic glycolysis, known as the "Warburg effect". This understanding has enabled the use of radiolabeled glucose analogs in tumor staging and therapeutic response assessment via PET scans. Traditional treatments like chemotherapy and radiotherapy target rapidly dividing cells, causing significant toxicity. Despite immunotherapy's impact on solid tumor treatment, gaps remain, leading to research on cancer cell evasion of immune response and immune tolerance induction via interactions with the tumor microenvironment (TME). The TME, consisting of immune cells, fibroblasts, vessels, and the extracellular matrix, regulates tumor progression and therapy responses. TME-targeted therapies aim to transform this environment from supporting tumor growth to impeding it and fostering an effective immune response. This review examines the metabolic disparities between immune cells and cancer cells, their impact on immune function and therapeutic targeting, the TME components, and the complex interplay between cancer cells and nontumoral cells. The success of TME-targeted therapies highlights their potential to achieve better cancer control or even a cure.
    Keywords:  immunotherapy; oncometabolites; tumor microenvironment
    DOI:  https://doi.org/10.3390/cimb45120609
  27. Cell Metab. 2023 Dec 12. pii: S1550-4131(23)00460-6. [Epub ahead of print]
    Nutrient inputs and social metabolic control of T cell fate.
    Zachary A Bacigalupa, Madelyn D Landis, Jeffrey C Rathmell.
      Cells in multicellular organisms experience diverse neighbors, signals, and evolving physical environments that drive functional and metabolic demands. To maintain proper development and homeostasis while avoiding inappropriate cell proliferation or death, individual cells interact with their neighbors via "social" cues to share and partition available nutrients. Metabolic signals also contribute to cell fate by providing biochemical links between cell-extrinsic signals and available resources. In addition to metabolic checkpoints that sense nutrients and directly supply molecular intermediates for biosynthetic pathways, many metabolites directly signal or provide the basis for post-translational modifications of target proteins and chromatin. In this review, we survey the landscape of T cell nutrient sensing and metabolic signaling that supports proper immunity while avoiding immunodeficiency or autoimmunity. The integration of cell-extrinsic microenvironmental cues with cell-intrinsic metabolic signaling provides a social metabolic control model to integrate cell signaling, metabolism, and fate.
    Keywords:  T cells; epigenetics; immunometabolism; metabolic signaling; social control model
    DOI:  https://doi.org/10.1016/j.cmet.2023.12.009
  28. Nat Rev Mol Cell Biol. 2023 Dec 18.
    A guide to cell death pathways.
    Junying Yuan, Dimitry Ofengeim.
      Regulated cell death mediated by dedicated molecular machines, known as programmed cell death, plays important roles in health and disease. Apoptosis, necroptosis and pyroptosis are three such programmed cell death modalities. The caspase family of cysteine proteases serve as key regulators of programmed cell death. During apoptosis, a cascade of caspase activation mediates signal transduction and cellular destruction, whereas pyroptosis occurs when activated caspases cleave gasdermins, which can then form pores in the plasma membrane. Necroptosis, a form of caspase-independent programmed necrosis mediated by RIPK3 and MLKL, is inhibited by caspase-8-mediated cleavage of RIPK1. Disruption of cellular homeostatic mechanisms that are essential for cell survival, such as normal ionic and redox balance and lysosomal flux, can also induce cell death without invoking programmed cell death mechanisms. Excitotoxicity, ferroptosis and lysosomal cell death are examples of such cell death modes. In this Review, we provide an overview of the major cell death mechanisms, highlighting the latest insights into their complex regulation and execution, and their relevance to human diseases.
    DOI:  https://doi.org/10.1038/s41580-023-00689-6
  29. J Cell Sci. 2023 Dec 01. pii: jcs261454. [Epub ahead of print]136(23):
    Regulated dynamic subcellular GLUT4 localization revealed by proximal proteome mapping in human muscle cells.
    Anuttoma Ray, Jennifer Wen, Lucie Yammine, Jeff Culver, Isabella Supardi Parida, Jeonifer Garren, Liang Xue, Katherine Hales, Qing Xiang, Morris J Birnbaum, Bei B Zhang, Mara Monetti, Timothy E McGraw.
      Regulation of glucose transport, which is central for control of whole-body metabolism, is determined by the amount of GLUT4 glucose transporter (also known as SLC2A4) in the plasma membrane (PM) of fat and muscle cells. Physiologic signals [such as activated insulin receptor or AMP-activated protein kinase (AMPK)] increase PM GLUT4. Here, we show that the distribution of GLUT4 between the PM and interior of human muscle cells is dynamically maintained, and that AMPK promotes PM redistribution of GLUT4 by regulating exocytosis and endocytosis. Stimulation of exocytosis by AMPK is mediated by Rab10 and the Rab GTPase-activating protein TBC1D4. APEX2 proximity mapping reveals that GLUT4 traverses both PM-proximal and PM-distal compartments in unstimulated muscle cells, further supporting retention of GLUT4 by a constitutive retrieval mechanism. AMPK-stimulated translocation involves GLUT4 redistribution among the same compartments traversed in unstimulated cells, with a significant recruitment of GLUT4 from the Golgi and trans-Golgi network compartments. Our comprehensive proximal protein mapping provides an integrated, high-density, whole-cell accounting of the localization of GLUT4 at a resolution of ∼20 nm that serves as a structural framework for understanding the molecular mechanisms regulating GLUT4 trafficking downstream of different signaling inputs in a physiologically relevant cell type.
    Keywords:  AMPK regulation of GLUT4; GLUT4 trafficking; GLUT4-proximal proteome; Human muscle cells
    DOI:  https://doi.org/10.1242/jcs.261454
  30. Annu Rev Biophys. 2023 Dec 18.
    Metabolomics and Microbial Metabolism: Toward a Systematic Understanding.
    Duncan Holbrook-Smith, Julian Trouillon, Uwe Sauer.
      Over the past decades, our understanding of microbial metabolism has increased dramatically. Metabolomics, a family of techniques that are used to measure the quantities of small molecules in biological samples, has been central to these efforts. Advances in analytical chemistry have made it possible to measure the relative and absolute concentrations of more and more compounds with increasing levels of certainty. In this review, we highlight how metabolomics has contributed to understanding microbial metabolism and in what ways it can still be deployed to expand our systematic understanding of metabolism. To that end, we explain how metabolomics was used to (a) characterize network topologies of metabolism and its regulation networks, (b) elucidate the control of metabolic function, and (c) understand the molecular basis of higher-order phenomena. We also discuss areas of inquiry where technological advances should continue to increase the impact of metabolomics, as well as areas where our understanding is bottlenecked by other factors such as the availability of statistical and modeling frameworks that can extract biological meaning from metabolomics data. 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-030722-021957
  31. Front Immunol. 2023 ;14 1269896
    Targeting NAD+ metabolism: dual roles in cancer treatment.
    Jiaxin Yong, Songqing Cai, Zhaolei Zeng.
      Nicotinamide adenine dinucleotide (NAD+) is indispensable for various oxidation-reduction reactions in mammalian cells, particularly during energy production. Malignant cells increase the expression levels of NAD+ biosynthesis enzymes for rapid proliferation and biomass production. Furthermore, mounting proof has indicated that NAD-degrading enzymes (NADases) play a role in creating the immunosuppressive tumor microenvironment (TME). Interestingly, both inhibiting NAD+ synthesis and targeting NADase have positive implications for cancer treatment. Here we summarize the detrimental outcomes of increased NAD+ production, the functions of NAD+ metabolic enzymes in creating an immunosuppressive TME, and discuss the progress and clinical translational potential of inhibitors for NAD+ synthesis and therapies targeting NADase.
    Keywords:  CD38; NAD+ metabolism; NAMPT inhibitor; cancer immunotherapy; cancer treatment; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2023.1269896
  32. Int J Mol Sci. 2023 Dec 09. pii: 17302. [Epub ahead of print]24(24):
    Blood and Brain Metabolites after Cerebral Ischemia.
    Eva Baranovicova, Dagmar Kalenska, Peter Kaplan, Maria Kovalska, Zuzana Tatarkova, Jan Lehotsky.
      The study of an organism's response to cerebral ischemia at different levels is essential to understanding the mechanism of the injury and protection. A great interest is devoted to finding the links between quantitative metabolic changes and post-ischemic damage. This work aims to summarize the outcomes of the most studied metabolites in brain tissue-lactate, glutamine, GABA (4-aminobutyric acid), glutamate, and NAA (N-acetyl aspartate)-regarding their biological function in physiological conditions and their role after cerebral ischemia/reperfusion. We focused on ischemic damage and post-ischemic recovery in both experimental-including our results-as well as clinical studies. We discuss the role of blood glucose in view of the diverse impact of hyperglycemia, whether experimentally induced, caused by insulin resistance, or developed as a stress response to the cerebral ischemic event. Additionally, based on our and other studies, we analyze and critically discuss post-ischemic alterations in energy metabolites and the elevation of blood ketone bodies observed in the studies on rodents. To complete the schema, we discuss alterations in blood plasma circulating amino acids after cerebral ischemia. So far, no fundamental brain or blood metabolite(s) has been recognized as a relevant biological marker with the feasibility to determine the post-ischemic outcome or extent of ischemic damage. However, studies from our group on rats subjected to protective ischemic preconditioning showed that these animals did not develop post-ischemic hyperglycemia and manifested a decreased metabolic infringement and faster metabolomic recovery. The metabolomic approach is an additional tool for understanding damaging and/or restorative processes within the affected brain region reflected in the blood to uncover the response of the whole organism via interorgan metabolic communications to the stressful cerebral ischemic challenge.
    Keywords:  animal models; blood; cerebral ischemia; cerebral microdialysis; metabolites; stroke; tissues
    DOI:  https://doi.org/10.3390/ijms242417302
  33. Cell Rep. 2023 Dec 20. pii: S2211-1247(23)01611-X. [Epub ahead of print]43(1): 113599
    Pib2 is a cysteine sensor involved in TORC1 activation in Saccharomyces cerevisiae.
    Qingzhong Zeng, Yasuhiro Araki, Takeshi Noda.
      Target of rapamycin complex 1 (TORC1) is a master regulator that monitors the availability of various amino acids to promote cell growth in Saccharomyces cerevisiae. It is activated via two distinct upstream pathways: the Gtr pathway, which corresponds to mammalian Rag, and the Pib2 pathway. This study shows that Ser3 was phosphorylated exclusively in a Pib2-dependent manner. Using Ser3 as an indicator of TORC1 activity, together with the established TORC1 substrate Sch9, we investigated which pathways were employed by individual amino acids. Different amino acids exhibited different dependencies on the Gtr and Pib2 pathways. Cysteine was most dependent on the Pib2 pathway and increased the interaction between TORC1 and Pib2 in vivo and in vitro. Moreover, cysteine directly bound to Pib2 via W632 and F635, two critical residues in the T(ail) motif that are necessary to activate TORC1. These results indicate that Pib2 functions as a sensor for cysteine in TORC1 regulation.
    Keywords:  CP: Molecular biology; Cysteine; Pib2; TORC1; mTORC1
    DOI:  https://doi.org/10.1016/j.celrep.2023.113599
  34. Sci Rep. 2023 Dec 19. 13(1): 22704
    The effect of fructose exposure on amino acid metabolism among Chinese community residents and its possible multi-omics mechanisms.
    Ouyan Rang, Xinru Qin, Yonghong Tang, Lin Cao, Guojuan Li, Xiaocheng Liu, Jing Zhong, Mu Wang.
      The consumption of fructose has increased dramaticly during the last few decades, inducing a great increase in the risk of intrahepatic lipid accumulation, hypertriglyceridemia, hyperuricemia and cancer. However, the underlying mechanism has not yet been fully elucidated. Amino acid metabolism may play an important role in the process of the diseases caused by fructose, but there is still a lack of corresponding evidence. In present study, we provide an evidence of how fructose affects amino acids metabolism in 1895 ordinary residents in Chinese community using UPLC-QqQMS based amino acid targeted metabolomics and the underlying mechanism of fructose exposure how interferes with amino acid metabolism related genes and acetylated modification of proteome in the liver of rats model. We found people with high fructose exposure had higher levels of Asa, EtN, Asp, and Glu, and lower levels of 1MHis, PEtN, Arg, Gln, GABA, Aad, Hyl and Cys. The further mechanism study displayed amino acid metabolic genes of Aspa, Cndp1, Dbt, Dmgdh, and toxic metabolites such as N-acetylethanolamines accumulation, interference of urea cycle, as well as acetylated modification of key enzymes in glutamine metabolic network and glutamine derived NEAAs synthesis pathway in liver may play important roles in fructose caused reprogramming in amino acid metabolism. This research provides novel insights of the mechanism of amino acid metabolic disorder caused by fructose and supplies new targets for clinical therapy.
    DOI:  https://doi.org/10.1038/s41598-023-50069-5
  35. Nature. 2023 Dec 20.
    Mitochondrial dysfunction abrogates dietary lipid processing in enterocytes.
    Chrysanthi Moschandrea, Vangelis Kondylis, Ioannis Evangelakos, Marija Herholz, Farina Schneider, Christina Schmidt, Ming Yang, Sandra Ehret, Markus Heine, Michelle Y Jaeckstein, Karolina Szczepanowska, Robin Schwarzer, Linda Baumann, Theresa Bock, Efterpi Nikitopoulou, Susanne Brodesser, Marcus Krüger, Christian Frezza, Joerg Heeren, Aleksandra Trifunovic, Manolis Pasparakis.
      Digested dietary fats are taken up by enterocytes where they are assembled into pre-chylomicrons in the endoplasmic reticulum followed by transport to the Golgi for maturation and subsequent secretion to the circulation1. The role of mitochondria in dietary lipid processing is unclear. Here we show that mitochondrial dysfunction in enterocytes inhibits chylomicron production and the transport of dietary lipids to peripheral organs. Mice with specific ablation of the mitochondrial aspartyl-tRNA synthetase DARS2 (ref. 2), the respiratory chain subunit SDHA3 or the assembly factor COX10 (ref. 4) in intestinal epithelial cells showed accumulation of large lipid droplets (LDs) in enterocytes of the proximal small intestine and failed to thrive. Feeding a fat-free diet suppressed the build-up of LDs in DARS2-deficient enterocytes, which shows that the accumulating lipids derive mostly from digested fat. Furthermore, metabolic tracing studies revealed an impaired transport of dietary lipids to peripheral organs in mice lacking DARS2 in intestinal epithelial cells. DARS2 deficiency caused a distinct lack of mature chylomicrons concomitant with a progressive dispersal of the Golgi apparatus in proximal enterocytes. This finding suggests that mitochondrial dysfunction results in impaired trafficking of chylomicrons from the endoplasmic reticulum to the Golgi, which in turn leads to storage of dietary lipids in large cytoplasmic LDs. Taken together, these results reveal a role for mitochondria in dietary lipid transport in enterocytes, which might be relevant for understanding the intestinal defects observed in patients with mitochondrial disorders5.
    DOI:  https://doi.org/10.1038/s41586-023-06857-0
  36. Nat Commun. 2023 Dec 15. 14(1): 8364
    The function of ER-phagy receptors is regulated through phosphorylation-dependent ubiquitination pathways.
    Rayene Berkane, Hung Ho-Xuan, Marius Glogger, Pablo Sanz-Martinez, Lorène Brunello, Tristan Glaesner, Santosh Kumar Kuncha, Katharina Holzhüter, Sara Cano-Franco, Viviana Buonomo, Paloma Cabrerizo-Poveda, Ashwin Balakrishnan, Georg Tascher, Koraljka Husnjak, Thomas Juretschke, Mohit Misra, Alexis González, Volker Dötsch, Paolo Grumati, Mike Heilemann, Alexandra Stolz.
      Selective autophagy of the endoplasmic reticulum (ER), known as ER-phagy, is an important regulator of ER remodeling and essential to maintain cellular homeostasis during environmental changes. We recently showed that members of the FAM134 family play a critical role during stress-induced ER-phagy. However, the mechanisms on how they are activated remain largely unknown. In this study, we analyze phosphorylation of FAM134 as a trigger of FAM134-driven ER-phagy upon mTOR (mechanistic target of rapamycin) inhibition. An unbiased screen of kinase inhibitors reveals CK2 to be essential for FAM134B- and FAM134C-driven ER-phagy after mTOR inhibition. Furthermore, we provide evidence that ER-phagy receptors are regulated by ubiquitination events and that treatment with E1 inhibitor suppresses Torin1-induced ER-phagy flux. Using super-resolution microscopy, we show that CK2 activity is essential for the formation of high-density FAM134B and FAM134C clusters. In addition, dense clustering of FAM134B and FAM134C requires phosphorylation-dependent ubiquitination of FAM134B and FAM134C. Treatment with the CK2 inhibitor SGC-CK2-1 or mutation of FAM134B and FAM134C phosphosites prevents ubiquitination of FAM134 proteins, formation of high-density clusters, as well as Torin1-induced ER-phagy flux. Therefore, we propose that CK2-dependent phosphorylation of ER-phagy receptors precedes ubiquitin-dependent activation of ER-phagy flux.
    DOI:  https://doi.org/10.1038/s41467-023-44101-5
  37. Cell Commun Signal. 2023 Dec 15. 21(1): 357
    Neuron-targeted overexpression of caveolin-1 alleviates diabetes-associated cognitive dysfunction via regulating mitochondrial fission-mitophagy axis.
    Wenxin Tang, Chaoying Yan, Shuxuan He, Mengyu Du, Bo Cheng, Bin Deng, Shan Zhu, Yansong Li, Qiang Wang.
       BACKGROUND: Type 2 diabetes mellitus (T2DM) induced diabetes-associated cognitive dysfunction (DACD) that seriously affects the self-management of T2DM patients, is currently one of the most severe T2DM-associated complications, but the mechanistic basis remains unclear. Mitochondria are highly dynamic organelles, whose function refers to a broad spectrum of features such as mitochondrial dynamics, mitophagy and so on. Mitochondrial abnormalities have emerged as key determinants for cognitive function, the relationship between DACD and mitochondria is not well understood.
    METHODS: Here, we explored the underlying mechanism of mitochondrial dysfunction of T2DM mice and HT22 cells treated with high glucose/palmitic acid (HG/Pal) focusing on the mitochondrial fission-mitophagy axis with drug injection, western blotting, Immunofluorescence, and electron microscopy. We further explored the potential role of caveolin-1 (cav-1) in T2DM induced mitochondrial dysfunction and synaptic alteration through viral transduction.
    RESULTS: As previously reported, T2DM condition significantly prompted hippocampal mitochondrial fission, whereas mitophagy was blocked rather than increasing, which was accompanied by dysfunctional mitochondria and impaired neuronal function. By contrast, Mdivi-1 (mitochondrial division inhibitor) and urolithin A (mitophagy activator) ameliorated mitochondrial and neuronal function and thereafter lead to cognitive improvement by inhibiting excessive mitochondrial fission and giving rise to mitophagy, respectively. We have previously shown that cav-1 can significantly improve DACD by inhibiting ferroptosis. Here, we further demonstrated that cav-1 could not only inhibit mitochondrial fission via the interaction with GSK3β to modulate Drp1 pathway, but also rescue mitophagy through interacting with AMPK to activate PINK1/Parkin and ULK1-dependent signlings.
    CONCLUSIONS: Overall, our data for the first time point to a mitochondrial fission-mitophagy axis as a driver of neuronal dysfunction in a phenotype that was exaggerated by T2DM, and the protective role of cav-1 in DACD. Graphic Summary Illustration. In T2DM, excessive mitochondrial fission and impaired mitophagy conspire to an altered mitochondrial morphology and mitochondrial dysfunction, with a consequent neuronal damage, overall suggesting an unbalanced mitochondrial fission-mitophagy axis. Upon cav-1 overexpression, GSK3β and AMPK are phosphorylated respectively to activate Drp1 and mitophagy-related pathways (PINK1 and ULKI), ultimately inhibits mitochondrial fission and enhances mitophagy. In the meantime, the mitochondrial morphology and neuronal function are rescued, indicating the protective role of cav-1 on mitochondrial fission-mitophagy axis. Video Abstract.
    Keywords:  Caveolin-1; Diabetes-associated cognitive dysfunction; Mitochondrial fission; Mitophagy
    DOI:  https://doi.org/10.1186/s12964-023-01328-5
  38. Int J Mol Sci. 2023 Dec 07. pii: 17238. [Epub ahead of print]24(24):
    The Emerging Roles of the Metabolic Regulator G6PD in Human Cancers.
    Alfar Ahamed, Rendy Hosea, Shourong Wu, Vivi Kasim.
      Metabolic reprogramming, especially reprogrammed glucose metabolism, is a well-known cancer hallmark related to various characteristics of tumor cells, including proliferation, survival, metastasis, and drug resistance. Glucose-6-phosphate dehydrogenase (G6PD) is the first and rate-limiting enzyme of the pentose phosphate pathway (PPP), a branch of glycolysis, that converts glucose-6-phosphate (G6P) into 6-phosphogluconolactone (6PGL). Furthermore, PPP produces ribose-5-phosphate (R5P), which provides sugar-phosphate backbones for nucleotide synthesis as well as nicotinamide adenine dinucleotide phosphate (NADPH), an important cellular reductant. Several studies have shown enhanced G6PD expression and PPP flux in various tumor cells, as well as their correlation with tumor progression through cancer hallmark regulation, especially reprogramming cellular metabolism, sustaining proliferative signaling, resisting cell death, and activating invasion and metastasis. Inhibiting G6PD could suppress tumor cell proliferation, promote cell death, reverse chemoresistance, and inhibit metastasis, suggesting the potential of G6PD as a target for anti-tumor therapeutic strategies. Indeed, while challenges-including side effects-still remain, small-molecule G6PD inhibitors showing potential anti-tumor effect either when used alone or in combination with other anti-tumor drugs have been developed. This review provides an overview of the structural significance of G6PD, its role in and regulation of tumor development and progression, and the strategies explored in relation to G6PD-targeted therapy.
    Keywords:  anti-tumor therapy; drug resistance; glucose-6-phosphate dehydrogenase (G6PD); pentose phosphate pathway (PPP); tumor cell proliferation; tumor metabolism
    DOI:  https://doi.org/10.3390/ijms242417238
  39. Nat Commun. 2023 Dec 20. 14(1): 8464
    VWCE modulates amino acid-dependent mTOR signaling and coordinates with KICSTOR to recruit GATOR1 to the lysosomes.
    Tianyu Zhao, Yuanyuan Guan, Chenchen Xu, Dong Wang, Jialiang Guan, Ying Liu.
      The mechanistic target of rapamycin complex 1 (mTORC1) is a crucial regulator of cell growth. It senses nutrient signals and adjusts cellular metabolism accordingly. Deregulation of mTORC1 has been associated with metabolic diseases, cancer, and aging. Amino acid signals are transduced to mTORC1 through sensor proteins and two protein complexes named GATOR1 and GATOR2. In this study, we identify VWCE (von Willebrand factor C and EGF domains) as a negative regulator of amino acid-dependent mTORC1 signaling. Knockdown of VWCE promotes mTORC1 activity even in the absence of amino acids. VWCE interacts with the KICSTOR complex to facilitate the recruitment of GATOR1 to the lysosomes. Bioinformatic analysis reveals that expression of VWCE is reduced in prostate cancer. More importantly, overexpression of VWCE inhibits the development of prostate cancer. Therefore, VWCE may serve as a potential therapeutic target for the treatment of prostate cancers.
    DOI:  https://doi.org/10.1038/s41467-023-44241-8
  40. Autophagy. 2023 Dec 20.
    S-acylation regulates SQSTM1/p62-mediated selective autophagy.
    Xue Huang, Lu Liu, Jia Yao, Changhai Lin, Tingxiu Xiang, Aimin Yang.
      Macroautophagy/autophagy is a highly conserved metabolic process that degrades intracellular components and recycles bioenergetic substrates. SQSTM1/p62 (sequestosome 1) is a classical autophagy receptor that participates in selective autophagy to eliminate abnormal intracellular components and recycle bioenergetic substrates. In autophagy, SQSTM1 recruits ubiquitinated substrates to form SQSTM1 droplets and delivers these cargoes to phagophores, the precursors to autophagosomes. Recently, we reported a previously unidentified SQSTM1 S-acylation, which is catalyzed by S-acyltransferase ZDHHC19 and reversed by LYPLA1/APT1. S-acylation of SQSTM1 enhances the affinity of SQSTM1 droplets with the phagophore membrane, thereby promoting efficient autophagic degradation of ubiquitinated substrates. Our study uncovers the role of the S-acylation-deacylation cycle in regulating SQSTM1-mediated selective autophagy.
    Keywords:  Autophagosome; SQSTM1; s-acylation; selective autophagy
    DOI:  https://doi.org/10.1080/15548627.2023.2297623
  41. J Vis Exp. 2023 Dec 01.
    Analysis of the Mitochondrial Density and Longitudinal Distribution in Rat Live-Skeletal Muscle Fibers by Confocal Microscopy.
    Perla Pérez-Treviño, Bianca Nieblas, Selma Romina López-Vaquera, Noemí García.
      The mitochondrion is an organelle that can be elongated, fragmented, and renovated according to the metabolic requirements of the cells. The remodeling of the mitochondrial network allows healthy mitochondria to meet cellular demands; however, the loss of this capacity has been related to the development or progression of different pathologies. In skeletal muscle, mitochondrial density and distribution changes are observed in physiological and pathological conditions such as exercise, aging, and obesity, among others. Therefore, the study of the mitochondrial network may provide a better understanding of mechanisms related to those conditions. Here, a protocol for mitochondria imaging of live-skeletal muscle fibers from rats is described. Fibers are manually dissected in a relaxing solution and incubated with a fluorescent live-cell imaging indicator of mitochondria (tetramethylrhodamine ethyl ester, TMRE). The mitochondria signal is recorded by confocal microscopy using the XYZ scan mode to obtain confocal images of the intermyofibrillar mitochondrial (IMF) network. After that, the confocal images are processed by thresholding and binarization. The binarized confocal image accounts for the positive pixels for mitochondria, which are then counted to obtain the mitochondrial density. The mitochondrial network in skeletal muscle is characterized by a high density of IMF population, which has a periodic longitudinal distribution similar to that of T-tubules (TT). The Fast Fourier Transform (FFT) is a standard analysis technique performed to evaluate the distribution of TT that allows finding the distribution frequency and the level of their organization. In this protocol, the implementation of the FFT algorithm is described for the analysis of the longitudinal mitochondrial distribution in skeletal muscle.
    DOI:  https://doi.org/10.3791/65306
  42. Int J Mol Sci. 2023 Dec 13. pii: 17423. [Epub ahead of print]24(24):
    Integrated Stress Response (ISR) Pathway: Unraveling Its Role in Cellular Senescence.
    Alexander Kalinin, Ekaterina Zubkova, Mikhail Menshikov.
      Cellular senescence is a complex process characterized by irreversible cell cycle arrest. Senescent cells accumulate with age, promoting disease development, yet the absence of specific markers hampers the development of selective anti-senescence drugs. The integrated stress response (ISR), an evolutionarily highly conserved signaling network activated in response to stress, globally downregulates protein translation while initiating the translation of specific protein sets including transcription factors. We propose that ISR signaling plays a central role in controlling senescence, given that senescence is considered a form of cellular stress. Exploring the intricate relationship between the ISR pathway and cellular senescence, we emphasize its potential as a regulatory mechanism in senescence and cellular metabolism. The ISR emerges as a master regulator of cellular metabolism during stress, activating autophagy and the mitochondrial unfolded protein response, crucial for maintaining mitochondrial quality and efficiency. Our review comprehensively examines ISR molecular mechanisms, focusing on ATF4-interacting partners, ISR modulators, and their impact on senescence-related conditions. By shedding light on the intricate relationship between ISR and cellular senescence, we aim to inspire future research directions and advance the development of targeted anti-senescence therapies based on ISR modulation.
    Keywords:  ATF4; ISR; Nrf2; SASP; cellular mechanisms; metabolism; senescence; stress response
    DOI:  https://doi.org/10.3390/ijms242417423
  43. PLoS One. 2023 ;18(12): e0296122
    Untargeted metabolomics analysis reveals the metabolic disturbances and exacerbation of oxidative stress in recurrent spontaneous abortion.
    AiNing Wu, YanHui Zhao, RongXin Yu, JianXing Zhou, Ya Tuo.
       BACKGROUND: Recurrent spontaneous abortion (RSA) is characterized by the occurrence of two or more consecutive spontaneous abortions, with a rising prevalence among pregnant women and significant implications for their physical and mental well-being. The multifaceted etiology of RSA has posed challenges in unraveling the molecular mechanisms underlying that underlie its pathogenesis. Oxidative stress and immune response have been identified as pivotal factors in the development of its condition.
    METHODS: Eleven serum samples from healthy pregnant women and 17 from RSA were subjected to liquid chromatography/mass spectrometry (LC-MS) analysis. Multivariate statistical analysis was employed to excavate system-level characterization of the serum metabolome. The measurement of seven oxidative stress products, namely superoxide dismutase (SOD), catalase (CAT), malonaldehyde (MDA), glutathione (GPx), glutathione peroxidase (GSH), oxidized glutathione (GSSG), heme oxygenase (HO-1), was carried out using ELISA.
    RESULTS: Through the monitoring of metabolic and lipid alternations during RSA events, we have identified 816 biomarkers that were implicated in various metabolic pathways, including glutathione metabolism, phosphonate and phosphinate metabolism, nucleotide metabolism, sphingolipid metabolism, lysine degradation and purine metabolism, etc. These pathways have been found to be closely associated with the progression of the disease. Our finding indicated that the levels of MDA and HO-1 were elevated in the RSA group compared to the control group, whereas SOD, CAT and GPx exhibited a contrary pattern. However, no slight difference was observed in GSH and GSSG levels between the RSA group and the control group.
    CONCLUSION: The manifestation of RSA elicited discernible temporal alternations in the serum metabolome and biochemical markers linked to the metabolic pathways of oxidative stress and immune response. Our investigation furnished a more comprehensive analytical framework encompassing metabolites and enzymes associated with oxidative stress. This inquiry furnished a more nuanced comprehension of the pathogenesis of RSA and established the ground work for prognostication and prophylaxis.
    DOI:  https://doi.org/10.1371/journal.pone.0296122
  44. Trends Cell Biol. 2023 Dec 15. pii: S0962-8924(23)00238-6. [Epub ahead of print]
    Lysosomal microautophagy: an emerging dimension in mammalian autophagy.
    Yoshihiko Kuchitsu, Tomohiko Taguchi.
      Autophagy is a self-catabolic process through which cellular components are delivered to lysosomes for degradation. There are three types of autophagy, i.e., macroautophagy, chaperone-mediated autophagy (CMA), and microautophagy. In macroautophagy, a portion of the cytoplasm is wrapped by the autophagosome, which then fuses with lysosomes and delivers the engulfed cytoplasm for degradation. In CMA, the translocation of cytosolic substrates to the lysosomal lumen is directly across the limiting membrane of lysosomes. In microautophagy, lytic organelles, including endosomes or lysosomes, take up a portion of the cytoplasm directly. Although macroautophagy has been investigated extensively, microautophagy has received much less attention. Nonetheless, it has become evident that microautophagy plays a variety of cellular roles from yeast to mammals. Here we review the very recent updates of microautophagy. In particular, we focus on the feature of the degradative substrates and the molecular machinery that mediates microautophagy.
    Keywords:  ESCRT complex; K63-linked ubiquitination; lysosome; microautophagy; vacuole
    DOI:  https://doi.org/10.1016/j.tcb.2023.11.005
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