bims-celmim Biomed News
on Cellular and mitochondrial metabolism
Issue of 2023‒09‒17
forty-one papers selected by
Marc Segarra Mondejar, University of Cologne
  1. Branched-chain keto-acid dehydrogenase kinase regulates vascular permeability and angiogenesis to facilitate tumor metastasis in renal cell carcinoma.
  2. Mitochondrial degradation: Mitophagy and beyond.
  3. SIRT1 activation promotes energy homeostasis and reprograms liver cancer metabolism.
  4. Exosome-mediated metabolic reprogramming: Implications in esophageal carcinoma progression and tumor microenvironment remodeling.
  5. Paraptosis: a non-classical paradigm of cell death for cancer therapy.
  6. Metabolic reprogramming: unveiling the therapeutic potential of targeted therapies against kidney disease.
  7. Understanding the Neuronal Synapse and Challenges Associated with the Mitochondrial Dysfunction in Mild Cognitive Impairment and Alzheimer's Disease.
  8. Fatty acid challenge shifts cellular energy metabolism in a substrate-specific manner in primary bovine neonatal hepatocytes.
  9. A nucleotide diphosphate kinase mediates tethering between mitochondria prior to fusion.
  10. Prefoldin 2 contributes to mitochondrial morphology and function.
  11. Skeletal muscle mitochondria in strength athletes: meeting energy needs with mitochondrial morphological changes.
  12. Sirtuin-3 activates the mitochondrial unfolded protein response and reduces cerebral ischemia/reperfusion injury.
  13. Outer mitochondrial membrane E3 Ub ligase MARCH5 controls mitochondrial steps in peroxisome biogenesis.
  14. Role of Human Monocarboxylate Transporter 1 (hMCT1) and 4 (hMCT4) in Tumor Cells and the Tumor Microenvironment.
  15. Ultrastructural features mirror metabolic derangement in human endothelial cells exposed to high glucose.
  16. Mitochondrial GTP metabolism controls reproductive aging in C. elegans.
  17. Mitochondrial membrane potential acts as a retrograde signal to regulate cell cycle progression.
  18. Endoplasmic reticulum stress: molecular mechanism and therapeutic targets.
  19. Characterization of chemoresistant human non-small cell lung cancer cells by metabolic and lipidomic profiling.
  20. The Role of Pyroptosis and Autophagy in the Nervous System.
  21. Mitophagy involved the biological processes of hormones.
  22. Responsive calcium-derived nanoassemblies induce mitochondrial disorder to promote tumor calcification.
  23. Oncogenic KRASG12D reprograms lipid metabolism by upregulating SLC25A1 to drive pancreatic tumorigenesis.
  24. LPS induces SGPP2 to participate metabolic reprogramming in endothelial cells.
  25. Cholesterol reprograms glucose and lipid metabolism to promote proliferation in colon cancer cells.
  26. MMD collaborates with ACSL4 and MBOAT7 to promote polyunsaturated phosphatidylinositol remodeling and susceptibility to ferroptosis.
  27. ADGRL1 is a glucose receptor involved in mediating energy and glucose homeostasis.
  28. Mitochondrial dysfunction in neurodegenerative disorders: Potential therapeutic application of mitochondrial transfer to central nervous system-residing cells.
  29. GSK-3α aggravates inflammation, metabolic derangement, and cardiac injury post-ischemia/reperfusion.
  30. Deubiquitinase USP19 modulates apoptotic calcium release and endoplasmic reticulum stress by deubiquitinating BAG6 in triple negative breast cancer.
  31. The citrate transporters SLC13A5 and SLC25A1 elicit different metabolic responses and phenotypes in the mouse.
  32. Nrf2 depletion in the context of loss-of-function Keap1 leads to mitolysosome accumulation.
  33. Redox state and altered pyruvate metabolism contribute to a dose-dependent metformin-induced lactate production of human myotubes.
  34. Metabolic signatures and potential biomarkers for the diagnosis and treatment of colon cancer cachexia.
  35. Seasonal light hours modulate peripheral clocks and energy metabolism in mice.
  36. A multi-signal mitochondria-targeted fluorescent probe for simultaneously distinguishing biothiols and realtime visualizing its metabolism in cancer cells and tumor models.
  37. Emerging Role of Ferroptosis in Breast Cancer: Characteristics, Therapy, and Translational Implications for the Present and Future.
  38. NRF2 signaling in cytoprotection and metabolism.
  39. The Role of Stroma in Cancer Metabolism.
  40. Tumor microenvironmental nutrients, cellular responses, and cancer.
  41. Serine starvation silences estrogen receptor signaling through histone hypoacetylation.
  1. Cancer Sci. 2023 Sep 16.
    Branched-chain keto-acid dehydrogenase kinase regulates vascular permeability and angiogenesis to facilitate tumor metastasis in renal cell carcinoma.
    Kunao Yang, Chunlan Xu, Huimin Sun, Zuodong Xuan, Yankuo Liu, Jinxin Li, Yang Bai, Zeyuan Zheng, Yue Zhao, Zhiyuan Shi, Jianzhong Zheng, Chen Shao.
      Branched-chain keto-acid dehydrogenase kinase (BCKDK) is the rate-limiting enzyme of branched-chain amino acid (BCAA) metabolism. In the last six years, BCKDK has been used as a kinase to promote tumor proliferation and metastasis. Renal cell carcinoma (RCC) is a highly vascularized tumor. A high degree of vascularization promotes tumor metastasis. Our objective is to explore the relationship between BCKDK and RCC metastasis and its specific mechanism. In our study, BCKDK is highly expressed in renal clear cell carcinoma and promotes the migration of clear cell renal cell carcinoma (ccRCC). Exosomes from ccRCC cells can promote vascular permeability and angiogenesis, especially when BCKDK is overexpressed in ccRCC cells. BCKDK can also augment the miR-125a-5p expression in ccRCC cells and derived exosomes, thereby decreasing the downstream target protein VE-cadherin level, weakening adhesion junction expression, increasing vascular permeability, and promoting angiogenesis in HUVECs. The novel BCKDK/Exosome-miR-125a-5p/VE-cadherin axis regulates intercellular communication between ccRCC cells and HUVECs. BCKDK plays a critical role in renal cancer metastasis, may be used as a molecular marker of metastatic ccRCC, and even may become a potential target of clinical anti-vascular therapy for ccRCC.
    Keywords:  BCKDK; clear cell renal cell carcinoma; exosome; microRNA; vascular permeability
    DOI:  https://doi.org/10.1111/cas.15956
  2. Mol Cell. 2023 Sep 07. pii: S1097-2765(23)00656-1. [Epub ahead of print]
    Mitochondrial degradation: Mitophagy and beyond.
    Louise Uoselis, Thanh Ngoc Nguyen, Michael Lazarou.
      Mitochondria are central hubs of cellular metabolism that also play key roles in signaling and disease. It is therefore fundamentally important that mitochondrial quality and activity are tightly regulated. Mitochondrial degradation pathways contribute to quality control of mitochondrial networks and can also regulate the metabolic profile of mitochondria to ensure cellular homeostasis. Here, we cover the many and varied ways in which cells degrade or remove their unwanted mitochondria, ranging from mitophagy to mitochondrial extrusion. The molecular signals driving these varied pathways are discussed, including the cellular and physiological contexts under which the different degradation pathways are engaged.
    Keywords:  MDV; PINK1; Parkin; degradation; mitochondria; mitochondrial quality control; mitophagy; proteasome; selective autophagy; ubiquitin
    DOI:  https://doi.org/10.1016/j.molcel.2023.08.021
  3. J Transl Med. 2023 Sep 15. 21(1): 627
    SIRT1 activation promotes energy homeostasis and reprograms liver cancer metabolism.
    Benluvankar Varghese, Ugo Chianese, Lucia Capasso, Veronica Sian, Paola Bontempo, Mariarosaria Conte, Rosaria Benedetti, Lucia Altucci, Vincenzo Carafa, Angela Nebbioso.
      BACKGROUND: Cancer cells are characterized by uncontrolled cell proliferation and impaired bioenergetics. Sirtuins are a family of highly conserved enzymes that play a fundamental role in energy metabolism regulation. SIRT1, in particular, drives many physiological stress responses and metabolic pathways following nutrient deprivation. We previously showed that SIRT1 activation using SCIC2.1 was able to attenuate genotoxic response and senescence. Here, we report that in hepatocellular carcinoma (HCC) cells under glucose-deprived conditions, SCIC2.1 treatment induced overexpression of SIRT1, SIRT3, and SIRT6, modulating metabolic response.METHODS: Flow cytometry was used to analyze the cell cycle. The MTT assay and xCELLigence system were used to measure cell viability and proliferation. In vitro enzymatic assays were carried out as directed by the manufacturer, and the absorbance was measured with an automated Infinite M1000 reader. Western blotting and immunoprecipitation were used to evaluate the expression of various proteins described in this study. The relative expression of genes was studied using real-time PCR. We employed a Seahorse XF24 Analyzer to determine the metabolic state of the cells. Oil Red O staining was used to measure lipid accumulation.
    RESULTS: SCIC2.1 significantly promoted mitochondrial biogenesis via the AMPK-p53-PGC1α pathway and enhanced mitochondrial ATP production under glucose deprivation. SIRT1 inhibition by Ex-527 further supported our hypothesis that metabolic effects are dependent on SIRT1 activation. Interestingly, SCIC2.1 reprogrammed glucose metabolism and fatty acid oxidation for bioenergetic circuits by repressing de novo lipogenesis. In addition, SCIC2.1-mediated SIRT1 activation strongly modulated antioxidant response through SIRT3 activation, and p53-dependent stress response via indirect recruitment of SIRT6.
    CONCLUSION: Our results show that SCIC2.1 is able to promote energy homeostasis, attenuating metabolic stress under glucose deprivation via activation of SIRT1. These findings shed light on the metabolic action of SIRT1 in the pathogenesis of HCC and may help determine future therapies for this and, possibly, other metabolic diseases.
    Keywords:  Energy metabolism; Liver cancer; PGC1α; SCIC2.1; SIRT1; Stress response
    DOI:  https://doi.org/10.1186/s12967-023-04440-9
  4. Cytokine Growth Factor Rev. 2023 Aug 30. pii: S1359-6101(23)00056-4. [Epub ahead of print]
    Exosome-mediated metabolic reprogramming: Implications in esophageal carcinoma progression and tumor microenvironment remodeling.
    Yong Xi, Yaxing Shen, Lijie Chen, Lijie Tan, Weiyu Shen, Xing Niu.
      Esophageal carcinoma is among the most fatal malignancies with increasing incidence globally. Tumor onset and progression can be driven by metabolic reprogramming, especially during esophageal carcinoma development. Exosomes, a subset of extracellular vesicles, display an average size of ∼100 nanometers, containing multifarious components (nucleic acids, proteins, lipids, etc.). An increasing number of studies have shown that exosomes are capable of transferring molecules with biological functions into recipient cells, which play crucial roles in esophageal carcinoma progression and tumor microenvironment that is a highly heterogeneous ecosystem through rewriting the metabolic processes in tumor cells and environmental stromal cells. The review introduces the reprogramming of glucose, lipid, amino acid, mitochondrial metabolism in esophageal carcinoma, and summarize current pharmaceutical agents targeting such aberrant metabolism rewiring. We also comprehensively overview the biogenesis and release of exosomes, and recent advances of exosomal cargoes and functions in esophageal carcinoma and their promising clinical application. Moreover, we discuss how exosomes trigger tumor growth, metastasis, drug resistance, and immunosuppression as well as tumor microenvironment remodeling through focusing on their capacity to transfer materials between cells or between cells and tissues and modulate metabolic reprogramming, thus providing a theoretical reference for the design potential pharmaceutical agents targeting these mechanisms. Altogether, our review attempts to fully understand the significance of exosome-based metabolic rewriting in esophageal carcinoma progression and remodeling of the tumor microenvironment, bringing novel insights into the prevention and treatment of esophageal carcinoma in the future.
    Keywords:  Esophageal carcinoma; Exosome; Lipid metabolism; Metabolic reprogramming; Tumor microenvironment; Tumor progression
    DOI:  https://doi.org/10.1016/j.cytogfr.2023.08.010
  5. Acta Pharmacol Sin. 2023 Sep 15.
    Paraptosis: a non-classical paradigm of cell death for cancer therapy.
    Chun-Cao Xu, Yi-Fan Lin, Mu-Yang Huang, Xiao-Lei Zhang, Pei Wang, Ming-Qing Huang, Jin-Jian Lu.
      Due to the sustained proliferative potential of cancer cells, inducing cell death is a potential strategy for cancer therapy. Paraptosis is a mode of cell death characterized by endoplasmic reticulum (ER) and/or mitochondrial swelling and cytoplasmic vacuolization, which is less investigated. Considerable evidence shows that paraptosis can be triggered by various chemical compounds, particularly in cancer cells, thus highlighting the potential application of this non-classical mode of cell death in cancer therapy. Despite these findings, there remain significant gaps in our understanding of the role of paraptosis in cancer. In this review, we summarize the current knowledge on chemical compound-induced paraptosis. The ER and mitochondria are the two major responding organelles in chemical compound-induced paraptosis, which can be triggered by the reduction of protein degradation, disruption of sulfhydryl homeostasis, overload of mitochondrial Ca2+, and increased generation of reactive oxygen species. We also discuss the stumbling blocks to the development of this field and the direction for further research. The rational use of paraptosis might help us develop a new paradigm for cancer therapy.
    Keywords:  ER stress; cancer therapy; endoplasmic reticulum; mitochondria; paraptosis
    DOI:  https://doi.org/10.1038/s41401-023-01159-7
  6. Drug Discov Today. 2023 Sep 08. pii: S1359-6446(23)00281-7. [Epub ahead of print] 103765
    Metabolic reprogramming: unveiling the therapeutic potential of targeted therapies against kidney disease.
    Shubhangi Saxena, Neha Dagar, Vishwadeep Shelke, Maciej Lech, Pragyanshu Khare, Anil Bhanudas Gaikwad.
      As a high-metabolic-rate organ, the kidney exhibits metabolic reprogramming (MR) in various disease states. Given the 860.8 million cases of kidney disease worldwide in 2017, understanding the specific bioenergetic pathways involved and developing targeted interventions are vital needs. The reprogramming of metabolic pathways (glucose metabolism, amino acid metabolism, etc.) has been observed in kidney disease. Therapies targeting these specific pathways have proven to be an efficient approach for retarding kidney disease progression. In this review, we focus on potential pharmacological interventions targeting MR that have advanced through Phase III/IV clinical trials for the management of kidney disease and promising preclinical studies laying the groundwork for future clinical investigations. Teaser: Emphasizing the various metabolic reprogramming pathways and therapies modulating them will aid provision of potential therapeutic options against kidney disease in the near future.
    Keywords:  amino acid metabolism; fatty acid oxidation; glucose metabolism; kidney disease; metabolic reprogramming; therapies
    DOI:  https://doi.org/10.1016/j.drudis.2023.103765
  7. Mitochondrion. 2023 Sep 12. pii: S1567-7249(23)00081-8. [Epub ahead of print]
    Understanding the Neuronal Synapse and Challenges Associated with the Mitochondrial Dysfunction in Mild Cognitive Impairment and Alzheimer's Disease.
    Harkomal Verma, Prabhakar Gangwar, Anuradha Yadav, Bharti Yadav, Rashmi Rao, Sharanjot Kaur, Puneet Kumar, Monisha Dhiman, Giulio Taglialatela, Anil Kumar Mantha.
      Synaptic mitochondria are crucial for maintaining synaptic activity due to their high energy requirements, substantial calcium (Ca2+) fluctuation, and neurotransmitter release at the synapse. To provide a continuous energy supply, neurons use special mechanisms to transport and distribute healthy mitochondria to the synapse while eliminating damaged mitochondria from the synapse. Along the neuron, mitochondrial membrane potential (ψ) gradient exists and is highest in the somal region. Lower ψ in the synaptic region renders mitochondria more vulnerable to oxidative stress-mediated damage. Secondly, mitochondria become susceptible to the release of cytochrome c, and mitochondrial DNA (mtDNA) is not shielded from the reactive oxygen species (ROS) by the histone proteins (unlike nuclear DNA), leading to activation of caspases and pronounced oxidative DNA base damage, which ultimately causes synaptic loss. Both synaptic mitochondrial dysfunction and synaptic failure are crucial factors responsible for Alzheimer's disease (AD). Furthermore, amyloid beta (Aβ) and hyper-phosphorylated Tau, the two leading players of AD, exaggerate the disease-like pathological conditions by reducing the mitochondrial trafficking, blocking the bi-directional transport at the synapse, enhancing the mitochondrial fission via activating the mitochondrial fission proteins, enhancing the swelling of mitochondria by increasing the influx of water through mitochondrial permeability transition pore (mPTP) opening, as well as reduced ATP production by blocking the activity of complex I and complex IV. Mild cognitive impairment (MCI) is also associated with decline in cognitive ability caused by synaptic degradation. This review summarizes the challenges associated with the synaptic mitochondrial dysfunction linked to AD and MCI and the role of phytochemicals in restoring the synaptic activity and rendering neuroprotection in AD.
    Keywords:  Alzheimer's disease; Amyloid beta; DNA base damage; free radicals; hyper-phosphorylated Tau; mitochondria; phytochemicals; synapse
    DOI:  https://doi.org/10.1016/j.mito.2023.09.003
  8. Sci Rep. 2023 Sep 12. 13(1): 15020
    Fatty acid challenge shifts cellular energy metabolism in a substrate-specific manner in primary bovine neonatal hepatocytes.
    T L Chandler, S J Kendall, H M White.
      Adipose tissue mobilization increases circulating fatty acid (FA) concentrations, leads to increased hepatic FA uptake, and influences hepatic metabolism. Our objective was to trace carbon flux through metabolic pathways in primary bovine neonatal hepatocytes challenged with FA, and to examine the effect of FA challenge on oxidative stress. Primary bovine neonatal hepatocytes were isolated from 4 Holstein bull calves and maintained for 24 h before treatment with either 0 or 1 mM FA cocktail. After 21 h, either [1-14C]C16:0 or [2-14C]sodium pyruvate was added to measure complete and incomplete oxidation and cellular glycogen. Cellular and media triglyceride (TG), and glucose and ß-hydroxybutyrate (BHB) export were quantified, as well as reactive oxygen species and cellular glutathione (GSH/GSSH). Fatty acid treatment increased cellular, but not media TG, and although complete oxidation of [1-14C]C16:0 was not affected by FA, BHB export was increased. Reactive oxygen species were increased with FA treatment and GSSH was marginally increased such that the ratio of GSH:GSSG was marginally decreased. Glucose export increased, and cellular glycogen marginally increased with FA treatment while [2-14C]sodium pyruvate oxidation was decreased. These data suggest that FA treatment shifts cellular energy metabolism in a substrate-specific manner, spares pyruvate carbon from oxidation, and stimulates glucose synthesis.
    DOI:  https://doi.org/10.1038/s41598-023-41919-3
  9. J Cell Biol. 2023 Oct 02. pii: e202309037. [Epub ahead of print]222(10):
    A nucleotide diphosphate kinase mediates tethering between mitochondria prior to fusion.
    Arisa Ikeda, Miho Iijima, Hiromi Sesaki.
      Mitochondrial fusion plays an important role in both their structure and function. In this issue, Su et al. (2023. J. Cell Biol.https://doi.org/10.1083/jcb.202301091) report that a nucleoside diphosphate kinase, NME3, facilitates mitochondrial tethering prior to fusion through its direct membrane-binding and hexamerization but not its kinase activity.
    DOI:  https://doi.org/10.1083/jcb.202309037
  10. BMC Biol. 2023 09 12. 21(1): 193
    Prefoldin 2 contributes to mitochondrial morphology and function.
    Ismail Tahmaz, Somayeh Shahmoradi Ghahe, Monika Stasiak, Kamila P Liput, Katarzyna Jonak, Ulrike Topf.
      BACKGROUND: Prefoldin is an evolutionarily conserved co-chaperone of the tailless complex polypeptide 1 ring complex (TRiC)/chaperonin containing tailless complex 1 (CCT). The prefoldin complex consists of six subunits that are known to transfer newly produced cytoskeletal proteins to TRiC/CCT for folding polypeptides. Prefoldin function was recently linked to the maintenance of protein homeostasis, suggesting a more general function of the co-chaperone during cellular stress conditions. Prefoldin acts in an adenosine triphosphate (ATP)-independent manner, making it a suitable candidate to operate during stress conditions, such as mitochondrial dysfunction. Mitochondrial function depends on the production of mitochondrial proteins in the cytosol. Mechanisms that sustain cytosolic protein homeostasis are vital for the quality control of proteins destined for the organelle and such mechanisms among others include chaperones.RESULTS: We analyzed consequences of the loss of prefoldin subunits on the cell proliferation and survival of Saccharomyces cerevisiae upon exposure to various cellular stress conditions. We found that prefoldin subunits support cell growth under heat stress. Moreover, prefoldin facilitates the growth of cells under respiratory growth conditions. We showed that mitochondrial morphology and abundance of some respiratory chain complexes was supported by the prefoldin 2 (Pfd2/Gim4) subunit. We also found that Pfd2 interacts with Tom70, a receptor of mitochondrial precursor proteins that are targeted into mitochondria.
    CONCLUSIONS: Our findings link the cytosolic prefoldin complex to mitochondrial function. Loss of the prefoldin complex subunit Pfd2 results in adaptive cellular responses on the proteome level under physiological conditions suggesting a continuous need of Pfd2 for maintenance of cellular homeostasis. Within this framework, Pfd2 might support mitochondrial function directly as part of the cytosolic quality control system of mitochondrial proteins or indirectly as a component of the protein homeostasis network.
    Keywords:  Chaperone; Mitochondria; Pfd2/Gim4; Prefoldin; Proteostasis; Tom70
    DOI:  https://doi.org/10.1186/s12915-023-01695-y
  11. J Physiol. 2023 Sep 12.
    Skeletal muscle mitochondria in strength athletes: meeting energy needs with mitochondrial morphological changes.
    Alyse L Lodigiani, Joseph C Morrison.
      
    Keywords:  Olympic weightlifting; mitochondria; mitochondrial morphology; powerlifting; strength training; transmission electron microscopy
    DOI:  https://doi.org/10.1113/JP285345
  12. Int J Biol Sci. 2023 ;19(13): 4327-4339
    Sirtuin-3 activates the mitochondrial unfolded protein response and reduces cerebral ischemia/reperfusion injury.
    Xie Xiaowei, Xu Qian, Zhou Dingzhou.
      Sirtuin-3 (Sirt3) deacetylates several mitochondrial proteins implicated into cerebral ischemia/reperfusion (I/R) injury. The mitochondrial unfolded protein response (UPRmt) favors mitochondrial proteostasis during various stressors. Here, we used Sirt3 transgenic mice and a transient middle cerebral artery occlusion model to evaluate the molecular basis of Sirt3 on the UPRmt during brain post-ischemic dysfunction. The present study illustrated that Sirt3 abundance was suppressed in the brain after brain ischemic abnormalities. Overexpression of Sirt3 in vivo suppressed the infarction size and attenuated neuroinflammation after brain I/R injury. Sirt3 overexpression restored neural viability by reducing mitochondrial ROS synthesis, maintaining the mitochondrial potential and improving mitochondrial adenosine triphosphate synthesis. Sirt3 overexpression protected neuronal mitochondria against brain post-ischemic malfunction via eliciting the UPRmt by the forkhead box O3 (Foxo3)/sphingosine kinase 1 (Sphk1) pathway. Inhibiting either the UPRmt or the Foxo3/Sphk1 pathway relieved the favorable influence of Sirt3 on neural function and mitochondrial behavior. In contrast, Sphk1 overexpression was sufficient to reduce the infarction size, attenuate neuroinflammation, sustain neuronal viability and prevent mitochondrial abnormalities during brain post-ischemia dysfunction. Thus, the UPRmt protects neural viability and mitochondrial homeostasis, and the Sirt3/Foxo3/Sphk1 pathway is a promosing therapeutic candidate for ischemic stroke.
    Keywords:  Foxo3; Sirt3; Sphk1; UPRmt; cerebral I/R injury; mitochondria
    DOI:  https://doi.org/10.7150/ijbs.86614
  13. bioRxiv. 2023 Sep 01. pii: 2023.08.31.555756. [Epub ahead of print]
    Outer mitochondrial membrane E3 Ub ligase MARCH5 controls mitochondrial steps in peroxisome biogenesis.
    Nicolas Verhoeven, Yumiko Oshima, Etienne Cartier, Albert Neutzner, Liron Boyman, Mariusz Karbowski.
      Peroxisome de novo biogenesis requires yet unidentified mitochondrial proteins. We report that the outer mitochondrial membrane (OMM)-associated E3 Ub ligase MARCH5 is vital for generating mitochondria-derived pre-peroxisomes. MARCH5 knockout results in accumulation of immature peroxisomes and lower expression of various peroxisomal proteins. Upon fatty acid-induced peroxisomal biogenesis, MARCH5 redistributes to newly formed peroxisomes; the peroxisomal biogenesis under these conditions is inhibited in MARCH5 knockout cells. MARCH5 activity-deficient mutants are stalled on peroxisomes and induce accumulation of peroxisomes containing high levels of the OMM protein Tom20 (mitochondria-derived pre-peroxisomes). Furthermore, depletion of peroxisome biogenesis factor Pex14 leads to the formation of MARCH5- and Tom20-positive peroxisomes, while no peroxisomes are detected in Pex14/MARCH5 dko cells. Reexpression of WT, but not MARCH5 mutants, restores Tom20-positive pre-peroxisomes in Pex14/MARCH5 dko cells. Thus, MARCH5 acts upstream of Pex14 in mitochondrial steps of peroxisome biogenesis. Our data validate the hybrid, mitochondria-dependent model of peroxisome biogenesis and reveal that MARCH5 is an essential mitochondrial protein in this process.Summary: The authors found that mitochondrial E3 Ub ligase MARCH5 controls the formation of mitochondria-derived pre-peroxisomes. The data support the hybrid, mitochondria-dependent model of peroxisome biogenesis and reveal that MARCH5 is an essential mitochondrial protein in this process.
    DOI:  https://doi.org/10.1101/2023.08.31.555756
  14. Cancer Manag Res. 2023 ;15 957-975
    Role of Human Monocarboxylate Transporter 1 (hMCT1) and 4 (hMCT4) in Tumor Cells and the Tumor Microenvironment.
    Tian Liu, Shangcong Han, Yu Yao, Guiming Zhang.
      In recent years, the abnormal glucose metabolism of tumor cells has attracted increasing attention. Abnormal glucose metabolism is closely related to the occurrence and development of tumors. Monocarboxylate transporters (MCTs) transport the sugar metabolites lactic acid and pyruvate, which affect glucose metabolism and tumor progression in a variety of ways. Thus, research has recently focused on MCTs and their potential functions in cancer. The MCT superfamily consists of 14 members. MCT1 and MCT4 play a crucial role in the maintenance of intracellular pH in tumor cells by transporting monocarboxylic acids (such as lactate, pyruvate and butyrate). MCT1 and MCT4 are highly expressed in a variety of tumor cells and are involved the proliferation, invasion and migration of tumor cells, which are closely related to the prognosis of cancer. Because of their important functions in tumor cells, MCT1 and MCT4 have become potential targets for cancer treatment. In this review, we focus on the structure, function and regulation of MCT1 and MCT4 and discuss the developed inhibitors of MCT1 and MCT4 to provide more comprehensive information that might aid in the development of strategies targeting MCTs in cancer.
    Keywords:  function; monocarboxylate transporter; regulation; tumor; tumor microenvironment
    DOI:  https://doi.org/10.2147/CMAR.S421771
  15. Sci Rep. 2023 Sep 13. 13(1): 15133
    Ultrastructural features mirror metabolic derangement in human endothelial cells exposed to high glucose.
    Roberta Scrimieri, Laura Locatelli, Alessandra Cazzaniga, Roberta Cazzola, Emil Malucelli, Andrea Sorrentino, Stefano Iotti, Jeanette A Maier.
      High glucose-induced endothelial dysfunction is the early event that initiates diabetes-induced vascular disease. Here we employed Cryo Soft X-ray Tomography to obtain three-dimensional maps of high D-glucose-treated endothelial cells and their controls at nanometric spatial resolution. We then correlated ultrastructural differences with metabolic rewiring. While the total mitochondrial mass does not change, high D-glucose promotes mitochondrial fragmentation, as confirmed by the modulation of fission-fusion markers, and dysfunction, as demonstrated by the drop of membrane potential, the decreased oxygen consumption and the increased production of reactive oxygen species. The 3D ultrastructural analysis also indicates the accumulation of lipid droplets in cells cultured in high D-glucose. Indeed, because of the decrease of fatty acid β-oxidation induced by high D-glucose concentration, triglycerides are esterified into fatty acids and then stored into lipid droplets. We propose that the increase of lipid droplets represents an adaptive mechanism to cope with the overload of glucose and associated oxidative stress and metabolic dysregulation.
    DOI:  https://doi.org/10.1038/s41598-023-42333-5
  16. Dev Cell. 2023 Sep 07. pii: S1534-5807(23)00435-5. [Epub ahead of print]
    Mitochondrial GTP metabolism controls reproductive aging in C. elegans.
    Yi-Tang Lee, Marzia Savini, Tao Chen, Jin Yang, Qian Zhao, Lang Ding, Shihong Max Gao, Mumine Senturk, Jessica N Sowa, Jue D Wang, Meng C Wang.
      Healthy mitochondria are critical for reproduction. During aging, both reproductive fitness and mitochondrial homeostasis decline. Mitochondrial metabolism and dynamics are key factors in supporting mitochondrial homeostasis. However, how they are coupled to control reproductive health remains unclear. We report that mitochondrial GTP (mtGTP) metabolism acts through mitochondrial dynamics factors to regulate reproductive aging. We discovered that germline-only inactivation of GTP- but not ATP-specific succinyl-CoA synthetase (SCS) promotes reproductive longevity in Caenorhabditis elegans. We further identified an age-associated increase in mitochondrial clustering surrounding oocyte nuclei, which is attenuated by GTP-specific SCS inactivation. Germline-only induction of mitochondrial fission factors sufficiently promotes mitochondrial dispersion and reproductive longevity. Moreover, we discovered that bacterial inputs affect mtGTP levels and dynamics factors to modulate reproductive aging. These results demonstrate the significance of mtGTP metabolism in regulating oocyte mitochondrial homeostasis and reproductive longevity and identify mitochondrial fission induction as an effective strategy to improve reproductive health.
    Keywords:  GTP metabolism; bacteria-host interaction; gene-environment interaction; mitochondrial distribution; mitochondrial dynamics; oocyte quality control; reproductive aging; succinyl-CoA synthetase; vitamin B12
    DOI:  https://doi.org/10.1016/j.devcel.2023.08.019
  17. Life Sci Alliance. 2023 Dec;pii: e202302091. [Epub ahead of print]6(12):
    Mitochondrial membrane potential acts as a retrograde signal to regulate cell cycle progression.
    Choco Michael Gorospe, Gustavo Carvalho, Alicia Herrera Curbelo, Lisa Marchhart, Isabela C Mendes, Katarzyna Niedźwiecka, Paulina H Wanrooij.
      Mitochondria are central to numerous metabolic pathways whereby mitochondrial dysfunction has a profound impact and can manifest in disease. The consequences of mitochondrial dysfunction can be ameliorated by adaptive responses that rely on crosstalk from the mitochondria to the rest of the cell. Such mito-cellular signalling slows cell cycle progression in mitochondrial DNA-deficient (ρ0) Saccharomyces cerevisiae cells, but the initial trigger of the response has not been thoroughly studied. Here, we show that decreased mitochondrial membrane potential (ΔΨm) acts as the initial signal of mitochondrial stress that delays G1-to-S phase transition in both ρ0 and control cells containing mtDNA. Accordingly, experimentally increasing ΔΨm was sufficient to restore timely cell cycle progression in ρ0 cells. In contrast, cellular levels of oxidative stress did not correlate with the G1-to-S delay. Restored G1-to-S transition in ρ0 cells with a recovered ΔΨm is likely attributable to larger cell size, whereas the timing of G1/S transcription remained delayed. The identification of ΔΨm as a regulator of cell cycle progression may have implications for disease states involving mitochondrial dysfunction.
    DOI:  https://doi.org/10.26508/lsa.202302091
  18. Signal Transduct Target Ther. 2023 Sep 15. 8(1): 352
    Endoplasmic reticulum stress: molecular mechanism and therapeutic targets.
    Xingyi Chen, Chaoran Shi, Meihui He, Siqi Xiong, Xiaobo Xia.
      The endoplasmic reticulum (ER) functions as a quality-control organelle for protein homeostasis, or "proteostasis". The protein quality control systems involve ER-associated degradation, protein chaperons, and autophagy. ER stress is activated when proteostasis is broken with an accumulation of misfolded and unfolded proteins in the ER. ER stress activates an adaptive unfolded protein response to restore proteostasis by initiating protein kinase R-like ER kinase, activating transcription factor 6, and inositol requiring enzyme 1. ER stress is multifaceted, and acts on aspects at the epigenetic level, including transcription and protein processing. Accumulated data indicates its key role in protein homeostasis and other diverse functions involved in various ocular diseases, such as glaucoma, diabetic retinopathy, age-related macular degeneration, retinitis pigmentosa, achromatopsia, cataracts, ocular tumors, ocular surface diseases, and myopia. This review summarizes the molecular mechanisms underlying the aforementioned ocular diseases from an ER stress perspective. Drugs (chemicals, neurotrophic factors, and nanoparticles), gene therapy, and stem cell therapy are used to treat ocular diseases by alleviating ER stress. We delineate the advancement of therapy targeting ER stress to provide new treatment strategies for ocular diseases.
    DOI:  https://doi.org/10.1038/s41392-023-01570-w
  19. Metabolomics. 2023 Sep 10. 19(9): 80
    Characterization of chemoresistant human non-small cell lung cancer cells by metabolic and lipidomic profiling.
    Ji Won Lee, Hwanhui Lee, Yoon Shik Chun, Junyoung Ahn, Jeong Yong Moon, Dae Kyeong Kim, Somi Kim Cho, Hyung-Kyoon Choi.
      INTRODUCTION: Lung cancer is one of the most malignant cancers and the leading cause of cancer-related deaths worldwide, while acquired chemoresistance would represent a major problem in the treatment of non-small cell lung cancer (NSCLC) because of the reduced treatment effect and increased rates of recurrence.METHODS: To establish the chemoresistant NSCLC cells, doxorubicin was treated to A549 cells over 3 months at gradually increasing concentrations from 0.03 to 0.5 µM. Real-time PCR and Western blotting were employed for investigating mRNA and protein expression of the glutathione peroxidase (GPX) protein family and multidrug resistance protein 1 (MRP1) in A549 and A549/CR cells. We also employed gas chromatography mass-spectrometry and nano electrospray ionization mass-spectrometry coupled with multivariate statistical analysis to characterize the unique metabolic and lipidomic profiles of chemoresistant NSCLC cells in order to identify potential therapeutic targets.
    RESULTS: Reactive oxygen species levels were decreased, and mRNA and protein levels of GPX2 and multidrug resistance protein 1 (MRP1) were increased in A549/CR. We identified 87 metabolites and intact lipid species in A549 and A549/CR. Among these metabolites, lactic acid, glutamic acid, glycine, proline, aspartic acid, succinic acid, and ceramide, alongside the PC to PE ratio, and arachidonic acid-containing phospholipids were suggested as characteristic features of chemoresistant NSCLC cells (A549/CR).
    CONCLUSIONS: This study reveals characteristic feature differences between drug-resistance NSCLC cells and their parental cells. We suggest potential therapeutic targets in chemoresistant NSCLC. Our results provide new insight into metabolic and lipidomic alterations in chemoresistant NSCLC. This could be used as fundamental information to develop therapeutic strategies for the treatment of chemoresistant NSCLC patients.
    Keywords:  Chemoresistance; Lipidomic profiling; Metabolic profiling; Non-small cell lung cancer; Potential therapeutic targets
    DOI:  https://doi.org/10.1007/s11306-023-02045-3
  20. Mol Neurobiol. 2023 Sep 12.
    The Role of Pyroptosis and Autophagy in the Nervous System.
    Huijie Zhao, Xiaodi Fu, Yanting Zhang, Chaoran Chen, Honggang Wang.
      Autophagy is a conservative self-degradation system, which includes the two major processes of enveloping abnormal proteins, organelles and other macromolecules, and transferring them into lysosomes for the subsequent degradation. It holds the stability of the intracellular environment under stress. So far, three types of autophagy have been found: microautophagy, chaperone-mediated autophagy and macroautophagy. Many diseases have the pathological process of autophagy dysfunction, such as nervous system diseases. Pyroptosis is one kind of programmed cell death mediated by gasdermin (GSDM). In this process of pyroptosis, the activated caspase-3, caspase-4/5/11, or caspase-1 cleaves GSDM into the N-terminal pore-forming domain (PFD). The oligomer of PFD combines with the cell membrane to form membrane holes, thus leading to pyroptosis. Pyroptosis plays a key role in multiple tissues and organs. Many studies have revealed that autophagy and pyroptosis participate in the nervous system, but the mechanisms need to be fully clarified. Here, we focused on the recent articles on the role and mechanism of pyroptosis and autophagy in the pathological processes of the nervous system.
    Keywords:  Autophagy; NLRP3 inflammasome; Nervous system; Pyroptosis; Traumatically injured spinal cord
    DOI:  https://doi.org/10.1007/s12035-023-03614-2
  21. Biomed Pharmacother. 2023 Sep 11. pii: S0753-3322(23)01266-0. [Epub ahead of print]167 115468
    Mitophagy involved the biological processes of hormones.
    Yifei Ma, Ying Zheng, Ying Zhou, Ningna Weng, Qing Zhu.
      Mitochondria fulfill vital functions in energy production, maintaining ion balance, and facilitating material metabolism. Mitochondria are sacrificed to protect cells or induce apoptosis when the body is under stress. The regulatory pathways of mitophagy include both ubiquitin-dependent and non-dependent pathways. The involvement of mitophagy has been demonstrated in the onset and progression of numerous diseases, highlighting its significant role. Endocrine hormones are chemical substances secreted by endocrine organs or endocrine cells, which participate in the regulation of physiological functions and internal environmental homeostasis of the body. Imbalances in endocrine hormones contribute to the development of various diseases. However, the precise impact of mitophagy on the physiological and pathological processes involving endocrine hormones remains unclear. This article aims to comprehensively overview recent advancements in understanding the mechanisms through which mitophagy regulates endocrine hormones.
    Keywords:  Autophagy; Endocrine; Hormones; Mitophagy
    DOI:  https://doi.org/10.1016/j.biopha.2023.115468
  22. Chem Sci. 2023 Sep 13. 14(35): 9350-9359
    Responsive calcium-derived nanoassemblies induce mitochondrial disorder to promote tumor calcification.
    Yan Zhao, Xinquan Yu, Weiheng Kong, Rong-Mei Kong, Ensheng Zhang, Lian Xia, Jing Zhang, Fengli Qu, Weihong Tan.
      Physiological calcification of the treated tumor area is considered to be a predictor of good prognosis. Promoting tumor calcification by inducing mitochondrial metabolic disorder and destroying calcium equilibrium has a potential inhibitory effect on tumor proliferation. Here, by promoting calcification by inducing mitochondrial dysfunction combined with triggering a surge of reactive oxygen species, we construct a bioresponsive calcification initiator, termed CaP-AA, using CaHPO4 covalently doped l-ascorbic acid. CaHPO4 releases Ca2+ within the cytoplasm of tumor cells to trigger calcium overload. Meanwhile, exogenous l-ascorbic acid indirectly enhances metabolic balance disruption via pro-oxidant effects. Such Ca2+ overload increases the likelihood of tumor calcification in vivo for tumor inhibition by perturbing mitochondrial homeostasis. The introduction of responsive calcium sources that would, in turn, trigger intratumoral calcification mediated by perturbing mitochondrial homeostasis would be an effective regulatory strategy for tumor therapy.
    DOI:  https://doi.org/10.1039/d3sc02945j
  23. Cancer Res. 2023 Sep 11.
    Oncogenic KRASG12D reprograms lipid metabolism by upregulating SLC25A1 to drive pancreatic tumorigenesis.
    Ruowen Zhang, Xiaogang Peng, James Xianxing Du, Rebecca Boohaker, Igor L Estevao, Brian I Grajeda, Marc B Cox, Igor C Almeida, Weiqin Lu.
      Pancreatic cancer is a highly lethal disease with obesity as one of the risk factors. Oncogenic KRAS mutations are prevalent in pancreatic cancer and can rewire lipid metabolism by altering fatty acid (FA) uptake, FA oxidation (FAO), and lipogenesis. Identification of the underlying mechanisms could lead to improved therapeutic strategies for treating KRAS mutant pancreatic cancer. Here, we observed that KRASG12D upregulated the expression of SLC25A1, a citrate transporter that is a key metabolic switch to mediate FAO, fatty acid synthesis (FAS), glycolysis, and gluconeogenesis. In genetically engineered mouse models and human pancreatic cancer cells, KRASG12D induced SLC25A1 upregulation via GLI1, which directly stimulated SLC25A1 transcription by binding its promoter. The enhanced expression of SLC25A1 increased levels of cytosolic citrate, FAs, and key enzymes in lipid metabolism. In addition, a high-fat diet (HFD) further stimulated the KRASG12D-GLI1-SLC25A1 axis and the associated increase in citrate and FAs. Pharmacological inhibition of SLC25A1 and upstream GLI1 significantly suppressed pancreatic tumorigenesis in KrasG12D/+ mice on a HFD. These results reveal a KRASG12D-GLI1-SLC25A1 regulatory axis with SLC25A1 as an important node that regulates lipid metabolism during pancreatic tumorigenesis, thus indicating an intervention strategy for oncogenic KRAS-driven pancreatic cancer.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-22-2679
  24. Free Radic Biol Med. 2023 Sep 11. pii: S0891-5849(23)00625-1. [Epub ahead of print]
    LPS induces SGPP2 to participate metabolic reprogramming in endothelial cells.
    Xin Yi, Meng-Ling Chang, Zeng-Ding Zhou, Lei Yi, Hao Yuan, Jin Qi, Lei Yi, Jing-Ning Huan, Xiao-Qin Huang.
      Sepsis often causes organ dysfunction and is manifested in increased endothelial cell permeability in blood vessels. Early-stage inflammation is accompanied by metabolic changes, but it is unclear how the metabolic alterations in the endothelial cells following lipopolysaccharide (LPS) stimulation affect endothelial cell function. In this study, the effects of 1 μg/ml of LPS on the metabolism of human umbilical vein endothelial cells (HUVECs) were investigated, and the metabolic changes after LPS stimulation were explained from the perspective of mRNA expression, chromatin openness and metabolic flux. We found changes in the central metabolism of endothelial cells after LPS stimulation, such as enhanced glycolysis function, decreased mitochondrial membrane potential, and increased production of reactive oxygen species (ROS). Sphingolipid metabolic pathways change at the transcriptome level, and sphingosine-1-phosphatase 2 (SGPP2) was upregulated in LPS-stimulated endothelial cells and zebrafish models. Overexpression of SGPP2 improved cell barrier function, enhanced mitochondrial respiration capacity, but also produced oxidative respiration chain uncoupling. In addition, SGPP2 overexpression inhibited the degradation of HIF-1α protein. The molecular and biochemical processes identified in this study are not only beneficial for understanding the metabolic-related mechanisms of LPS-induced endothelial injury, but also for the discovery of general therapeutic targets for inflammation and inflammation-related diseases.
    Keywords:  HUVEC; LPS; Metabolic reprogramming; ROS; Warburg effect
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.09.007
  25. Cancer Metab. 2023 Sep 13. 11(1): 15
    Cholesterol reprograms glucose and lipid metabolism to promote proliferation in colon cancer cells.
    Shyamananda Singh Mayengbam, Abhijeet Singh, Himanshi Yaduvanshi, Firoz Khan Bhati, Bhavana Deshmukh, Dipti Athavale, Pranay L Ramteke, Manoj Kumar Bhat.
      Hypercholesterolemia is often correlated with obesity which is considered a risk factor for various cancers. With the growing population of hypercholesterolemic individuals, there is a need to understand the role of increased circulatory cholesterol or dietary cholesterol intake towards cancer etiology and pathology. Recently, abnormality in the blood cholesterol level of colon cancer patients has been reported. In the present study, we demonstrate that alteration in cholesterol levels (through a high-cholesterol or high-fat diet) increases the incidence of chemical carcinogen-induced colon polyp occurrence and tumor progression in mice. At the cellular level, low-density lipoprotein cholesterol (LDLc) and high-density lipoprotein cholesterol (HDLc) promote colon cancer cell proliferation by tuning the cellular glucose and lipid metabolism. Mechanistically, supplementation of LDLc or HDLc promotes cellular glucose uptake, and utilization, thereby, causing an increase in lactate production by colon cancer cells. Moreover, LDLc or HDLc upregulates aerobic glycolysis, causing an increase in total ATP production through glycolysis, and a decrease in ATP generation by OXPHOS. Interestingly, the shift in the metabolic status towards a more glycolytic phenotype upon the availability of cholesterol supports rapid cell proliferation. Additionally, an alteration in the expression of the molecules involved in cholesterol uptake along with the increase in lipid and cholesterol accumulation was observed in cells supplemented with LDLc or HDLc. These results indicate that colon cancer cells directly utilize the cholesterol associated with LDLc or HDLc. Moreover, targeting glucose metabolism through LDH inhibitor (oxamate) drastically abrogates the cellular proliferation induced by LDLc or HDLc. Collectively, we illustrate the vital role of cholesterol in regulating the cellular glucose and lipid metabolism of cancer cells and its direct effect on the colon tumorigenesis.
    Keywords:  Cholesterol; Colon cancer; Glucose metabolism; HDLc; LDLc; Lipid metabolism
    DOI:  https://doi.org/10.1186/s40170-023-00315-1
  26. Cell Rep. 2023 Sep 07. pii: S2211-1247(23)01034-3. [Epub ahead of print]42(9): 113023
    MMD collaborates with ACSL4 and MBOAT7 to promote polyunsaturated phosphatidylinositol remodeling and susceptibility to ferroptosis.
    Vaishnavi V Phadnis, Jamie Snider, Venkateshwari Varadharajan, Iyappan Ramachandiran, Amy A Deik, Zon Weng Lai, Tenzin Kunchok, Elinor Ng Eaton, Carolin Sebastiany, Anna Lyakisheva, Kyle D Vaccaro, Juliet Allen, Zhong Yao, Victoria Wong, Betty Geng, Kipp Weiskopf, Clary B Clish, J Mark Brown, Igor Stagljar, Robert A Weinberg, Whitney S Henry.
      Ferroptosis is a form of regulated cell death with roles in degenerative diseases and cancer. Excessive iron-catalyzed peroxidation of membrane phospholipids, especially those containing the polyunsaturated fatty acid arachidonic acid (AA), is central in driving ferroptosis. Here, we reveal that an understudied Golgi-resident scaffold protein, MMD, promotes susceptibility to ferroptosis in ovarian and renal carcinoma cells in an ACSL4- and MBOAT7-dependent manner. Mechanistically, MMD physically interacts with both ACSL4 and MBOAT7, two enzymes that catalyze sequential steps to incorporate AA in phosphatidylinositol (PI) lipids. Thus, MMD increases the flux of AA into PI, resulting in heightened cellular levels of AA-PI and other AA-containing phospholipid species. This molecular mechanism points to a pro-ferroptotic role for MBOAT7 and AA-PI, with potential therapeutic implications, and reveals that MMD is an important regulator of cellular lipid metabolism.
    Keywords:  ACSL4; CP: Cell biology; MBOAT7; MMD; arachidonic acid; cancer; ferroptosis; lipid metabolism; phosphatidylinositol; polyunsaturated fatty acid; scaffold
    DOI:  https://doi.org/10.1016/j.celrep.2023.113023
  27. Diabetologia. 2023 Sep 15.
    ADGRL1 is a glucose receptor involved in mediating energy and glucose homeostasis.
    Kavaljit H Chhabra, Siresha Bathina, Tumininu S Faniyan, Dennis J Samuel, Muhammad Ummear Raza, Leticia Maria de Souza Cordeiro, Gonzalo Viana Di Prisco, Brady K Atwood, Jorge Robles, Lauren Bainbridge, Autumn Davis.
      AIMS/HYPOTHESIS: The brain is a major consumer of glucose as an energy source and regulates systemic glucose as well as energy balance. Although glucose transporters such as GLUT2 and sodium-glucose cotransporter 2 (SGLT2) are known to regulate glucose homeostasis and metabolism, the identity of a receptor that binds glucose to activate glucose signalling pathways in the brain is unknown. In this study, we aimed to discover a glucose receptor in the mouse hypothalamus.METHODS: Here we used a high molecular mass glucose-biotin polymer to enrich glucose-bound mouse hypothalamic neurons through cell-based affinity chromatography. We then subjected the enriched neurons to proteomic analyses and identified adhesion G-protein coupled receptor 1 (ADGRL1) as a top candidate for a glucose receptor. We validated glucose-ADGRL1 interactions using CHO cells stably expressing human ADGRL1 and ligand-receptor binding assays. We generated and determined the phenotype of global Adgrl1-knockout mice and hypothalamus-specific Adgrl1-deficient mice. We measured the variables related to glucose and energy homeostasis in these mice. We also generated an Adgrl1Cre mouse model to investigate the role of ADGRL1 in sensing glucose using electrophysiology.
    RESULTS: Adgrl1 is highly expressed in the ventromedial nucleus of the hypothalamus (VMH) in mice. Lack of Adgrl1 in the VMH in mice caused fasting hyperinsulinaemia, enhanced glucose-stimulated insulin secretion and insulin resistance. In addition, the Adgrl1-deficient mice had impaired feeding responses to glucose and fasting coupled with abnormal glucose sensing and decreased physical activity before development of obesity and hyperglycaemia. In female mice, ovariectomy was necessary to reveal the contribution of ADGRL1 to energy and glucose homeostasis.
    CONCLUSIONS/INTERPRETATION: Altogether, our findings demonstrate that ADGRL1 binds glucose and is involved in energy as well as glucose homeostasis in a sex-dependent manner. Targeting ADGRL1 may introduce a new class of drugs for the treatment of type 2 diabetes and obesity.
    Keywords:  Diabetes; Glucose receptor; Glucose sensing; Hypothalamus; Mouse models; Obesity
    DOI:  https://doi.org/10.1007/s00125-023-06010-6
  28. J Transl Med. 2023 09 09. 21(1): 613
    Mitochondrial dysfunction in neurodegenerative disorders: Potential therapeutic application of mitochondrial transfer to central nervous system-residing cells.
    Felipe A Bustamante-Barrientos, Noymar Luque-Campos, María Jesús Araya, Eliana Lara-Barba, Javiera de Solminihac, Carolina Pradenas, Luis Molina, Yeimi Herrera-Luna, Yildy Utreras-Mendoza, Roberto Elizondo-Vega, Ana María Vega-Letter, Patricia Luz-Crawford.
      Mitochondrial dysfunction is reiteratively involved in the pathogenesis of diverse neurodegenerative diseases. Current in vitro and in vivo approaches support that mitochondrial dysfunction is branded by several molecular and cellular defects, whose impact at different levels including the calcium and iron homeostasis, energetic balance and/or oxidative stress, makes it difficult to resolve them collectively given their multifactorial nature. Mitochondrial transfer offers an overall solution since it contains the replacement of damage mitochondria by healthy units. Therefore, this review provides an introducing view on the structure and energy-related functions of mitochondria as well as their dynamics. In turn, we summarize current knowledge on how these features are deregulated in different neurodegenerative diseases, including frontotemporal dementia, multiple sclerosis, amyotrophic lateral sclerosis, Friedreich ataxia, Alzheimer´s disease, Parkinson´s disease, and Huntington's disease. Finally, we analyzed current advances in mitochondrial transfer between diverse cell types that actively participate in neurodegenerative processes, and how they might be projected toward developing novel therapeutic strategies.
    DOI:  https://doi.org/10.1186/s12967-023-04493-w
  29. J Mol Med (Berl). 2023 Sep 14.
    GSK-3α aggravates inflammation, metabolic derangement, and cardiac injury post-ischemia/reperfusion.
    Firdos Ahmad, Hezlin Marzook, Anamika Gupta, Aseel Aref, Kiran Patil, Amir Ali Khan, Mohamed A Saleh, Walter J Koch, James R Woodgett, Rizwan Qaisar.
      Reperfusion after acute myocardial infarction further exaggerates cardiac injury and adverse remodeling. Irrespective of cardiac cell types, loss of specifically the α isoform of the protein kinase GSK-3 is protective in chronic cardiac diseases. However, the role of GSK-3α in clinically relevant ischemia/reperfusion (I/R)-induced cardiac injury is unknown. Here, we challenged cardiomyocyte-specific conditional GSK-3α knockout (cKO) and littermate control mice with I/R injury and investigated the underlying molecular mechanism using an in vitro GSK-3α gain-of-function model in AC16 cardiomyocytes post-hypoxia/reoxygenation (H/R). Analysis revealed a significantly lower percentage of infarct area in the cKO vs. control hearts post-I/R. Consistent with in vivo findings, GSK-3α overexpression promoted AC16 cardiomyocyte death post-H/R which was accompanied by an induction of reactive oxygen species (ROS) generation. Consistently, GSK-3α gain-of-function caused mitochondrial dysfunction by significantly suppressing mitochondrial membrane potential. Transcriptomic analysis of GSK-3α overexpressing cardiomyocytes challenged with hypoxia or H/R revealed that NOD-like receptor (NLR), TNF, NF-κB, IL-17, and mitogen-activated protein kinase (MAPK) signaling pathways were among the most upregulated pathways. Glutathione and fatty acid metabolism were among the top downregulated pathways post-H/R. Together, these observations suggest that loss of cardiomyocyte-GSK-3α attenuates cardiac injury post-I/R potentially through limiting the myocardial inflammation, mitochondrial dysfunction, and metabolic derangement. Therefore, selective inhibition of GSK-3α may provide beneficial effects in I/R-induced cardiac injury and remodeling. KEY MESSAGES: GSK-3α promotes cardiac injury post-ischemia/reperfusion (I/R). GSK-3α regulates inflammatory and metabolic pathways post-hypoxia/reoxygenation (H/R). GSK-3α overexpression upregulates NOD-like receptor (NLR), TNF, NF-kB, IL-17, and MAPK signaling pathways in cardiomyocytes post-H/R. GSK-3α downregulates glutathione and fatty acid metabolic pathways in cardiomyocytes post-H/R.
    Keywords:  Cardiac injury; GSK-3α; Inflammation; Ischemia/reperfusion; Metabolism; Mitochondria
    DOI:  https://doi.org/10.1007/s00109-023-02373-w
  30. Clin Transl Med. 2023 Sep;13(9): e1398
    Deubiquitinase USP19 modulates apoptotic calcium release and endoplasmic reticulum stress by deubiquitinating BAG6 in triple negative breast cancer.
    Xiaoqiang Zhang, Xuyu Chen, Fangze Qian, Yanhui Zhu, Gao He, Junzhe Yang, Xian Wu, Hongfei Zhang, Xiafei Yu, Xiaoan Liu.
      BACKGROUND: Triple-negative breast cancer (TNBC), a heterogeneous subtype of breast cancer (BC), had poor prognosis. Endoplasmic reticulum (ER) stress was responsible for cellular processes and played a crucial role in the cell function. ER stress is a complex and dynamic process that can induce abnormal apoptosis and death. However, the underlying mechanism of ER stress involved in TNBC is not well defined.METHODS: We identified ubiquitin-specific protease 19 (USP19) as a TNBC negative regulator for further investigation. The effects of USP19 on BC proliferation were assessed in vitro using proliferation test and cell-cycle assays, while the effects in vivo were examined using a mouse tumorigenicity model. Through in vitro flow cytometric analyses and in vivo TUNEL assays, cell apoptosis was assessed. Proteomics was used to examine the proteins that interact with USP19.
    RESULTS: Multiple in vitro and in vivo tests showed that USP19 decreases TNBC cell growth while increasing apoptosis. Then, we demonstrated that USP19 interacts with deubiquitinates and subsequently stabilises family molecular chaperone regulator 6 (BAG6). BAG6 can boost B-cell lymphoma 2 (BCL2) ubiquitination and degradation, thereby raising ER calcium (Ca2+ ) levels and causing ER stress. We also found that the N6 -methyladenosine (m6 A) "writer" methyltransferase-like 14 (METTL14) increased global m6 A modification.
    CONCLUSIONS: Our study reveals that USP19 elevates the intracellular Ca2+ concentration to alter ER stress via regulation of BAG6 and BCL2 stability and may be a viable therapeutic target for TNBC therapy.
    Keywords:  BAG6; Bcl-2; TNBC; USP19; endoplasmic reticulum stress; m6A
    DOI:  https://doi.org/10.1002/ctm2.1398
  31. Commun Biol. 2023 09 09. 6(1): 926
    The citrate transporters SLC13A5 and SLC25A1 elicit different metabolic responses and phenotypes in the mouse.
    Gonzalo Fernandez-Fuente, Katherine A Overmyer, Alexis J Lawton, Ildiko Kasza, Samantha L Shapiro, Patricia Gallego-Muñoz, Joshua J Coon, John M Denu, Caroline M Alexander, Luigi Puglielli.
      Cytosolic citrate is imported from the mitochondria by SLC25A1, and from the extracellular milieu by SLC13A5. In the cytosol, citrate is used by ACLY to generate acetyl-CoA, which can then be exported to the endoplasmic reticulum (ER) by SLC33A1. Here, we report the generation of mice with systemic overexpression (sTg) of SLC25A1 or SLC13A5. Both animals displayed increased cytosolic levels of citrate and acetyl-CoA; however, SLC13A5 sTg mice developed a progeria-like phenotype with premature death, while SLC25A1 sTg mice did not. Analysis of the metabolic profile revealed widespread differences. Furthermore, SLC13A5 sTg mice displayed increased engagement of the ER acetylation machinery through SLC33A1, while SLC25A1 sTg mice did not. In conclusion, our findings point to different biological responses to SLC13A5- or SLC25A1-mediated import of citrate and suggest that the directionality of the citrate/acetyl-CoA pathway can transduce different signals.
    DOI:  https://doi.org/10.1038/s42003-023-05311-1
  32. Free Radic Biol Med. 2023 Sep 13. pii: S0891-5849(23)00627-5. [Epub ahead of print]
    Nrf2 depletion in the context of loss-of-function Keap1 leads to mitolysosome accumulation.
    Sharadha Dayalan Naidu, Plamena R Angelova, Elena V Knatko, Chiara Leonardi, Miroslav Novak, Laureano de la Vega, Ian G Ganley, Andrey Y Abramov, Albena T Dinkova-Kostova.
      Transcription factor nuclear factor erythroid 2 p45-related factor 2 (Nrf2) is the principal determinant of the cellular redox homeostasis, contributing to mitochondrial function, integrity and bioenergetics. The main negative regulator of Nrf2 is Kelch-like ECH associated protein 1 (Keap1), a substrate adaptor for Cul3/Rbx1 ubiquitin ligase, which continuously targets Nrf2 for ubiquitination and proteasomal degradation. Loss-of-function mutations in Keap1 occur frequently in lung cancer, leading to constitutive Nrf2 activation. We used the human lung cancer cell line A549 and its CRISPR/Cas9-generated homozygous Nrf2-knockout (Nrf2-KO) counterpart to assess the role of Nrf2 on mitochondrial health. To confirm that the observed effects of Nrf2 deficiency are not due to clonal selection or long-term adaptation to the absence of Nrf2, we also depleted Nrf2 by siRNA (siNFE2L2), thus creating populations of Nrf2-knockdown (Nrf2-KD) A549 cells. Nrf2 deficiency decreased mitochondrial respiration, but increased the mitochondrial membrane potential, mass, DNA content, and the number of mitolysosomes. The proportion of ATG7 and ATG3 within their respective LC3B conjugates was increased in Nrf2-deficient cells with mutant Keap1, whereas the formation of new autophagosomes was not affected. Thus, in lung cancer cells with loss-of-function Keap1, Nrf2 facilitates mitolysosome degradation thereby ensuring timely clearance of damaged mitochondria.
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.09.009
  33. Am J Physiol Cell Physiol. 2023 Sep 11.
    Redox state and altered pyruvate metabolism contribute to a dose-dependent metformin-induced lactate production of human myotubes.
    Jennifer Maurer, Xinjie Zhao, Martin Irmler, Anders Gudiksen, Nanna S Pilmark, Qi Li, Thomas Goj, Johannes Beckers, Martin Hrabě de Angelis, Andreas Birkenfeld, Andreas Peter, Rainer Lehmann, Henriette Pilegaard, Kristian Karstoft, Guowang Xu, Cora Weigert.
      Metformin-induced glycolysis and lactate production can lead to acidosis as a life-threatening side effect, but slight increases in blood lactate levels in a physiological range were also reported in metformin-treated patients. However, how metformin increases systemic lactate concentrations is only partly understood. Because human skeletal muscle has a high capacity to produce lactate, the aim was to elucidate the dose-dependent regulation of metformin-induced lactate production and the potential contribution of skeletal muscle to blood lactate levels under metformin treatment. This was examined by using metformin treatment (16-776 μM) of primary human myotubes and by 17 days of metformin treatment in humans. As from 78 µM, metformin induced lactate production and secretion and glucose consumption. Investigating the cellular redox state by mitochondrial respirometry, we found metformin to inhibit the respiratory chain complex I (776 µM, p < 0.01) along with decreasing the [NAD+]:[NADH] ratio (776 µM, p < 0.001). RNA sequencing and phospho-immunoblot data indicate inhibition of pyruvate oxidation mediated through phosphorylation of the pyruvate dehydrogenase (PDH) complex (39 µM, p < 0.01). On the other hand, in human skeletal muscle, phosphorylation of PDH was not altered by metformin. Nonetheless, blood lactate levels were increased under metformin treatment (p < 0.05). In conclusion, the findings suggest that metformin-induced inhibition of pyruvate oxidation combined with altered cellular redox state, shifts the equilibrium of the lactate dehydrogenase (LDH) reaction leading to a dose-dependent lactate production in primary human myotubes.
    Keywords:  Lactate; Metformin; Pyruvate dehydrogenase complex; Respiration; Skeletal Muscle
    DOI:  https://doi.org/10.1152/ajpcell.00186.2023
  34. Acta Biochim Biophys Sin (Shanghai). 2023 Sep 14.
    Metabolic signatures and potential biomarkers for the diagnosis and treatment of colon cancer cachexia.
    Xu Qiu, Ruohan Lu, Qiqing He, Shu Chen, Caihua Huang, Donghai Lin.
      Cancer cachexia (CAC) is a debilitating condition that often arises from noncachexia cancer (NCAC), with distinct metabolic characteristics and medical treatments. However, the metabolic changes and underlying molecular mechanisms during cachexia progression remain poorly understood. Understanding the progression of CAC is crucial for developing diagnostic approaches to distinguish between CAC and NCAC stages, facilitating appropriate treatment for cancer patients. In this study, we establish a mouse model of colon CAC and categorize the mice into three groups: CAC, NCAC and normal control (NOR). By performing nuclear magnetic resonance (NMR)-based metabolomic profiling on mouse sera, we elucidate the metabolic properties of these groups. Our findings unveil significant differences in the metabolic profiles among the CAC, NCAC and NOR groups, highlighting significant impairments in energy metabolism and amino acid metabolism during cachexia progression. Additionally, we observe the elevated serum levels of lysine and acetate during the transition from the NCAC to CAC stages. Using multivariate ROC analysis, we identify lysine and acetate as potential biomarkers for distinguishing between CAC and NCAC stages. These biomarkers hold promise for the diagnosis of CAC from noncachexia cancer. Our study provides novel insights into the metabolic mechanisms underlying cachexia progression and offers valuable avenues for the diagnosis and treatment of CAC in clinical settings.
    Keywords:  NMR-based metabolomics; biomarker; cancer cachexia; metabolic profile; serum
    DOI:  https://doi.org/10.3724/abbs.2023151
  35. Cell Metab. 2023 Sep 01. pii: S1550-4131(23)00300-5. [Epub ahead of print]
    Seasonal light hours modulate peripheral clocks and energy metabolism in mice.
    Lewin Small, Leonidas S Lundell, Jo Iversen, Amy M Ehrlich, Morten Dall, Astrid L Basse, Emilie Dalbram, Ann N Hansen, Jonas T Treebak, Romain Barrès, Juleen R Zierath.
      Except for latitudes close to the equator, seasonal variation in light hours can change dramatically between summer and winter. Yet investigations into the interplay between energy metabolism and circadian rhythms typically use a 12 h light:12 h dark photoperiod corresponding to the light duration at the equator. We hypothesized that altering the seasonal photoperiod affects both the rhythmicity of peripheral tissue clocks and energy homeostasis. Mice were housed at photoperiods representing either light hours in summer, winter, or the equinox. Mice housed at a winter photoperiod exhibited an increase in the amplitude of rhythmic lipid metabolism and a modest reduction in fat mass and liver triglyceride content. Comparing melatonin-proficient and -deficient mice, the effect of seasonal light on energy metabolism was largely driven by differences in the rhythmicity of food intake and not melatonin. Together, these data indicate that seasonal light impacts energy metabolism by modulating the timing of eating.
    Keywords:  circadian biology; energy homeostasis; glucose metabolism; hormones; integrative physiology; obesity; transcriptomics
    DOI:  https://doi.org/10.1016/j.cmet.2023.08.005
  36. Talanta. 2023 Sep 09. pii: S0039-9140(23)00855-X. [Epub ahead of print]267 125104
    A multi-signal mitochondria-targeted fluorescent probe for simultaneously distinguishing biothiols and realtime visualizing its metabolism in cancer cells and tumor models.
    Jinshuai Lan, Li Liu, Zhe Li, Ruifeng Zeng, Lixia Chen, Yitian He, Hai Wei, Yue Ding, Tong Zhang.
      Biothiols and its metabolite SO2 derivatives play vital roles in various physiological processes. Although a few probes have been designed for monitoring the metabolism of biothiols, developing multi-signal fluorescent probes with practicability for simultaneously distinguishing biothiols (GSH, Cys and Hcy) and real-time visualizing SO2 derivatives is an enormous challenge. To better visualize biothiols metabolism in vitro and vivo, we developed a novel multi-signal NIR fluorescent probe (probe 2) with mitochondria-targeted for distinguishing biothiols and its metabolism, based on an ICT-PET synergetic mechanism. Probe 2 with dual recognition sites distinguishing detected Cys/Hcy (Red-Green), GSH (Green) and SO32- (Blue) via three channels. First probe 2 distinguished Cys and GSH to estimate main biothiols in living cells through the ratio changes of two well-defined emission bands (Red-Green), and then imaged its metabolite SO2 with ratiometric fluorescence (Red-Blue), eliminating the interference by different biothiols. Notably, probe 2 exhibits satisfactory sensitivity (detection limit: 0.21, 0.13, 0.14 and 3.06 μM for Cys, Hcy, GSH and SO32-, respectively), high selectivity, reliability at physiological pH, and rapid fluorescence response (within 10 min). Given these advantages, probe 2 has been successfully applied to the real-time monitor GSH metabolic process in MCF-7 cells and biothiols metabolism in breast cancer, suggesting biothiols metabolic changes might be a diagnostic indicator during cancer treatment. So probe 2 is a convenient and efficient tool for understanding the physiological functions of biothiols and its metabolism.
    Keywords:  Bioimaging; Biothiols; Fluorescent probe; Metabolism; Mitochondria; Sulfur dioxide
    DOI:  https://doi.org/10.1016/j.talanta.2023.125104
  37. Curr Mol Med. 2023 Sep 13.
    Emerging Role of Ferroptosis in Breast Cancer: Characteristics, Therapy, and Translational Implications for the Present and Future.
    Suman Kumar Ray, Sukhes Mukherjee.
      Ferroptosis is a nonapoptotic, iron-dependent form of cell death that can be actuated in disease cells by expected improvements and manufactured specialists. Different studies have recently resurrected the role of this newly discovered cell death pathway and demonstrated its efficacy in treating breast cancer. Breast cancer is the most well-known type of cancer among women worldwide. Despite many years of research focusing on cell death in breast cancer, counting apoptosis, clinical treatment leftovers are difficult due to the high likelihood of recurrence. Ferroptosis is defined by a lack of lipid peroxide repair capacity by phospholipid hydroperoxides GPX4, accessibility of redox-active iron, and followed oxidation of polyunsaturated fatty acids acid-containing phospholipids signalling, amino acid and iron metabolism, ferritinophagy, epithelial-to-mesenchymal transition, cell adhesion, and mevalonate and phospholipid biosynthesis can all be factors that influence ferroptosis susceptibility. Ferroptosis, an iron-dependent controlled cell death caused by excessive lipid peroxidation, has been entwined in breast cancer development and therapeutic response for the past decade. Advances in enhancing clinical drugs targeting ferroptosis are developing silver linings to treat breast cancer. Ferroptosis is influenced by metabolism and the expression of certain genes, making it a prospective therapeutic target for monitoring malignant growth and an appealing target for precision cancer medication disclosure. In the coming years, research into biomarkers to follow ferroptosis in patients with breast cancer and the course of events and the subsequent use of novel ferroptosis-based treatments will be captious. We present a fundamental analysis of the actual understanding of molecular mechanisms along with regulatory networks associated with ferroptosis, expected physiological functions in growth concealment, ferroptosis-associated differentially expressed genes, treatment targeting potential, and recent advances in the development of therapeutic strategies in this review.
    Keywords:  Ferroptosis; apoptosis; biomarkers; breast cancer; ferritinophagy; precision medicine
    DOI:  https://doi.org/10.2174/1566524023666230913105735
  38. Br J Pharmacol. 2023 Sep 15.
    NRF2 signaling in cytoprotection and metabolism.
    Shohei Murakami, Yusuke Kusano, Keito Okazaki, Takaaki Akaike, Hozumi Motohashi.
      The KEAP1-NRF2 system plays a central role in cytoprotection and defense mechanisms against oxidative stress. Because KEAP1 serves as a biosensor for electrophiles by using its reactive thiols and because NRF2 is a transcriptional factor regulating genes involved in the sulfur-mediated redox reactions, the KEAP1-NRF2 system has been regarded as a sulfur-utilizing cytoprotective mechanism. NRF2 is a key regulator of cytoprotective genes, such as antioxidant and detoxification genes, and also to possess potent anti-inflammatory activity. NRF2 has been recently focused as a regulator for the cellular metabolism and mitochondrial function. Particularly, the NRF2-mediated regulatory mechanisms of metabolites and mitochondria has been considered diverse but has not been fully clarified yet. This review article provides an overview of the molecular mechanisms that regulate NRF2 signaling and its cytoprotective roles, and also highlights NRF2 contribution to the cellular metabolism, particularly in the context of mitochondrial function and newly found sulfur metabolism.
    DOI:  https://doi.org/10.1111/bph.16246
  39. Cold Spring Harb Perspect Med. 2023 Sep 11. pii: a041540. [Epub ahead of print]
    The Role of Stroma in Cancer Metabolism.
    Alec C Kimmelman, Mara H Sherman.
      The altered metabolism of tumor cells is a well-known hallmark of cancer and is driven by multiple factors such as mutations in oncogenes and tumor suppressor genes, the origin of the tissue where the tumor arises, and the microenvironment of the tumor. These metabolic changes support the growth of cancer cells by providing energy and the necessary building blocks to sustain proliferation. Targeting these metabolic alterations therapeutically is a potential strategy to treat cancer, but it is challenging due to the metabolic plasticity of tumors. Cancer cells have developed ways to scavenge nutrients through autophagy and macropinocytosis and can also form metabolic networks with stromal cells in the tumor microenvironment. Understanding the role of the tumor microenvironment in tumor metabolism is crucial for effective therapeutic targeting. This review will discuss tumor metabolism and the contribution of the stroma in supporting tumor growth through metabolic interactions.
    DOI:  https://doi.org/10.1101/cshperspect.a041540
  40. Cell Chem Biol. 2023 Sep 01. pii: S2451-9456(23)00281-7. [Epub ahead of print]
    Tumor microenvironmental nutrients, cellular responses, and cancer.
    Graham P Lobel, Yanqing Jiang, M Celeste Simon.
      Over the last two decades, the rapidly expanding field of tumor metabolism has enhanced our knowledge of the impact of nutrient availability on metabolic reprogramming in cancer. Apart from established roles in cancer cells themselves, various nutrients, metabolic enzymes, and stress responses are key to the activities of tumor microenvironmental immune, fibroblastic, endothelial, and other cell types that support malignant transformation. In this article, we review our current understanding of how nutrient availability affects metabolic pathways and responses in both cancer and "stromal" cells, by dissecting major examples and their regulation of cellular activity. Understanding the relationship of nutrient availability to cellular behaviors in the tumor ecosystem will broaden the horizon of exploiting novel therapeutic vulnerabilities in cancer.
    Keywords:  Cancer metabolism; cancer therapeutics; cancer-associated fibroblasts; immune cell metabolism; nutrient exchange; stress responses; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.chembiol.2023.08.011
  41. Proc Natl Acad Sci U S A. 2023 Sep 19. 120(38): e2302489120
    Serine starvation silences estrogen receptor signaling through histone hypoacetylation.
    Albert M Li, Bo He, Dimitris Karagiannis, Yang Li, Haowen Jiang, Preethi Srinivasan, Yaniel Ramirez, Meng-Ning Zhou, Christina Curtis, Joshua J Gruber, Chao Lu, Erinn B Rankin, Jiangbin Ye.
      Loss of estrogen receptor (ER) pathway activity promotes breast cancer progression, yet how this occurs remains poorly understood. Here, we show that serine starvation, a metabolic stress often found in breast cancer, represses estrogen receptor alpha (ERα) signaling by reprogramming glucose metabolism and epigenetics. Using isotope tracing and time-resolved metabolomic analyses, we demonstrate that serine is required to maintain glucose flux through glycolysis and the TCA cycle to support acetyl-CoA generation for histone acetylation. Consequently, limiting serine depletes histone H3 lysine 27 acetylation (H3K27ac), particularly at the promoter region of ER pathway genes including the gene encoding ERα, ESR1. Mechanistically, serine starvation impairs acetyl-CoA-dependent gene expression by inhibiting the entry of glycolytic carbon into the TCA cycle and down-regulating the mitochondrial citrate exporter SLC25A1, a critical enzyme in the production of nucleocytosolic acetyl-CoA from glucose. Consistent with this model, total H3K27ac and ERα expression are suppressed by SLC25A1 inhibition and restored by acetate, an alternate source of acetyl-CoA, in serine-free conditions. We thus uncover an unexpected role for serine in sustaining ER signaling through the regulation of acetyl-CoA metabolism.
    Keywords:  SLC25A1; breast cancer; estrogen receptor; histone acetylation; serine metabolism
    DOI:  https://doi.org/10.1073/pnas.2302489120
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