bims-celmim Biomed News
on Cellular and mitochondrial metabolism
Issue of 2023‒10‒01
forty-six papers selected by
Marc Segarra Mondejar, University of Cologne
  1. Mitochondrial Dynamics and Insulin Secretion.
  2. Pyruvate Kinase Activity Regulates Cystine Starvation Induced Ferroptosis through Malic Enzyme 1 in Pancreatic Cancer Cells.
  3. The Mitochondrial Calcium Uniporter (MCU): Molecular Identity and Role in Human Diseases.
  4. TMEM135 links peroxisomes to the regulation of brown fat mitochondrial fission and energy homeostasis.
  5. Glutamine regulates the cellular proliferation and cell cycle progression by modulating the mTOR mediated protein levels of β-TrCP.
  6. Insights into the regulation of mitochondrial functions by PKA-mediated phosphorylation.
  7. The Dual Role of Autophagy in Postischemic Brain Neurodegeneration of Alzheimer's Disease Proteinopathy.
  8. Mitochondrial Artificial K+ Channel Construction Using MPTPP@5F8 Nanoparticles for Overcoming Cancer Drug Resistance via Disrupting Cellular Ion Homeostasis.
  9. mTORC1 Regulates the Metabolic Switch of Postnatal Cardiomyocytes During Regeneration.
  10. Plasma cell differentiation, antibody quality, and initial germinal center B cell population depend on glucose influx rate.
  11. Extracellular Vimentin Alters Energy Metabolism And Induces Adipocyte Hypertrophy.
  12. Control of Mitochondrial Electron Transport Chain Flux and Apoptosis by Retinoic Acid: Raman Imaging In Vitro Human Bronchial and Lung Cancerous Cells.
  13. Fundamental Neurochemistry Review: Microglial immunometabolism in traumatic brain injury.
  14. NSD2 methylates AROS to promote SIRT1 activation and regulates fatty acid metabolism-mediated cancer radiotherapy.
  15. Proteome census upon nutrient stress reveals Golgiphagy membrane receptors.
  16. Cancer cells reprogram to metastatic state through the acquisition of platelet mitochondria.
  17. Mitochondrial Calcium Overload Plays a Causal Role in Oxidative Stress in the Failing Heart.
  18. The potential of targeting cuproptosis in the treatment of kidney renal clear cell carcinoma.
  19. Defective quality control autophagy in Hyperhomocysteinemia promotes ER stress and consequent neuronal apoptosis through proteotoxicity.
  20. Mitochondria and Brain Disease: A Comprehensive Review of Pathological Mechanisms and Therapeutic Opportunities.
  21. The Warburg effect alters amino acid homeostasis in human retinal endothelial cells: implication for proliferative diabetic retinopathy.
  22. NRF2, a Superstar of Ferroptosis.
  23. All-optical spatiotemporal mapping of ROS dynamics across mitochondrial microdomains in situ.
  24. Choline metabolism underpins macrophage IL-4 polarization and RELMα up-regulation in helminth infection.
  25. Orai inhibition modulates pulmonary ILC2 metabolism and alleviates airway hyperreactivity in murine and humanized models.
  26. Aspartic Acid in Health and Disease.
  27. Mitochondrial proteome research: the road ahead.
  28. Arachidonic acid metabolism in health and disease.
  29. The bisphosphonates alendronate and zoledronate induce adaptations of aerobic metabolism in permanent human endothelial cells.
  30. Roles of Stress Response in Autophagy Processes and Aging-Related Diseases.
  31. Acetyl-CoA synthetase 2 promotes diabetic renal tubular injury in mice by rewiring fatty acid metabolism through SIRT1/ChREBP pathway.
  32. Early fate decision for mitochondrially encoded proteins by a molecular triage.
  33. Regulators of mitonuclear balance link mitochondrial metabolism to mtDNA expression.
  34. Sodium-dependent glucose transporter 2 inhibition and the atrial antiremodelling effects in HFrEF patients.
  35. Pyruvate kinase M2 regulates kidney fibrosis through pericyte glycolysis during the progression from acute kidney injury to chronic kidney disease.
  36. Lactate: A Theranostic Biomarker for Metabolic Psychiatry?
  37. TRPV1 Channels Are New Players in the Reticulum-Mitochondria Ca2+ Coupling in a Rat Cardiomyoblast Cell Line.
  38. Metabolic hallmarks for purine nucleotide biosynthesis in small-cell lung carcinoma.
  39. Monocarboxylate transporter 4 protects against myocardial ischemia/reperfusion injury by inducing oxidative phosphorylation/glycolysis interconversion and inhibiting oxidative stress.
  40. Mitochondrial-Derived Vesicles: The Good, the Bad, and the Ugly.
  41. The Illustration of Altered Glucose Dependency in Drug-Resistant Cancer Cells.
  42. Metabolic and cell cycle shift induced by the deletion of Dnm1l attenuates the dissolution of pluripotency in mouse embryonic stem cells.
  43. Oncometabolite D-2-hydroxyglutarate-dependent metabolic reprogramming induces skeletal muscle atrophy during cancer cachexia.
  44. Current Advances in Mitochondrial Targeted Interventions in Alzheimer's Disease.
  45. Identification of pyroptosis-related subtypes and comprehensive analysis of characteristics of the tumor microenvironment infiltration in clear cell renal cell carcinoma.
  46. A common East-Asian ALDH2 mutation causes metabolic disorders and the therapeutic effect of ALDH2 activators.
  1. Int J Mol Sci. 2023 Sep 07. pii: 13782. [Epub ahead of print]24(18):
    Mitochondrial Dynamics and Insulin Secretion.
    Uma D Kabra, Martin Jastroch.
      Mitochondria are involved in the regulation of cellular energy metabolism, calcium homeostasis, and apoptosis. For mitochondrial quality control, dynamic processes, such as mitochondrial fission and fusion, are necessary to maintain shape and function. Disturbances of mitochondrial dynamics lead to dysfunctional mitochondria, which contribute to the development and progression of numerous diseases, including Type 2 Diabetes (T2D). Compelling evidence has been put forward that mitochondrial dynamics play a significant role in the metabolism-secretion coupling of pancreatic β cells. The disruption of mitochondrial dynamics is linked to defects in energy production and increased apoptosis, ultimately impairing insulin secretion and β cell death. This review provides an overview of molecular mechanisms controlling mitochondrial dynamics, their dysfunction in pancreatic β cells, and pharmaceutical agents targeting mitochondrial dynamic proteins, such as mitochondrial division inhibitor-1 (mdivi-1), dynasore, P110, and 15-oxospiramilactone (S3).
    Keywords:  diabetes; fission; fusion; glucose-stimulated insulin secretion; mitochondrial dynamics; pancreatic beta cell
    DOI:  https://doi.org/10.3390/ijms241813782
  2. bioRxiv. 2023 Sep 17. pii: 2023.09.15.557984. [Epub ahead of print]
    Pyruvate Kinase Activity Regulates Cystine Starvation Induced Ferroptosis through Malic Enzyme 1 in Pancreatic Cancer Cells.
    Elliot Ensink, Tessa Jordan, Hyllana C D Medeiros, Galloway Thurston, Anmol Pardal, Lei Yu, Sophia Y Lunt.
      Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with high mortality and limited efficacious therapeutic options. PDAC cells undergo metabolic alterations to survive within a nutrient-depleted tumor microenvironment. One critical metabolic shift in PDAC cells occurs through altered isoform expression of the glycolytic enzyme, pyruvate kinase (PK). Pancreatic cancer cells preferentially upregulate pyruvate kinase muscle isoform 2 isoform (PKM2). PKM2 expression reprograms many metabolic pathways, but little is known about its impact on cystine metabolism. Cystine metabolism is critical for supporting survival through its role in defense against ferroptosis, a non-apoptotic iron-dependent form of cell death characterized by unchecked lipid peroxidation. To improve our understanding of the role of PKM2 in cystine metabolism and ferroptosis in PDAC, we generated PKM2 knockout (KO) human PDAC cells. Fascinatingly, PKM2KO cells demonstrate a remarkable resistance to cystine starvation mediated ferroptosis. This resistance to ferroptosis is caused by decreased PK activity, rather than an isoform-specific effect. We further utilized stable isotope tracing to evaluate the impact of glucose and glutamine reprogramming in PKM2KO cells. PKM2KO cells depend on glutamine metabolism to support antioxidant defenses against lipid peroxidation, primarily by increased glutamine flux through the malate aspartate shuttle and utilization of ME1 to produce NADPH. Ferroptosis can be synergistically induced by the combination of PKM2 activation and inhibition of the cystine/glutamate antiporter in vitro . Proof-of-concept in vivo experiments demonstrate the efficacy of this mechanism as a novel treatment strategy for PDAC.Highlights: PKM2KO in pancreatic ductal adenocarcinoma (PDAC) cells produces enhanced defense against cystine starvation induced ferroptosis.Pharmacologic activation of pyruvate kinase (PK) activity promotes ferroptosis under cystine starvation, while inhibition promotes ferroptosis survival in PDAC cells.Decrease in PK activity reprograms glutamine metabolism to increase use of malic enzyme 1 and promote survival under cystine starvation in PDAC cells. Cystine starvation and activation of pyruvate kinase synergistically decreases progression of pancreatic cancer in vivo .
    DOI:  https://doi.org/10.1101/2023.09.15.557984
  3. Biomolecules. 2023 Aug 25. pii: 1304. [Epub ahead of print]13(9):
    The Mitochondrial Calcium Uniporter (MCU): Molecular Identity and Role in Human Diseases.
    Donato D'Angelo, Rosario Rizzuto.
      Calcium (Ca2+) ions act as a second messenger, regulating several cell functions. Mitochondria are critical organelles for the regulation of intracellular Ca2+. Mitochondrial calcium (mtCa2+) uptake is ensured by the presence in the inner mitochondrial membrane (IMM) of the mitochondrial calcium uniporter (MCU) complex, a macromolecular structure composed of pore-forming and regulatory subunits. MtCa2+ uptake plays a crucial role in the regulation of oxidative metabolism and cell death. A lot of evidence demonstrates that the dysregulation of mtCa2+ homeostasis can have serious pathological outcomes. In this review, we briefly discuss the molecular structure and the function of the MCU complex and then we focus our attention on human diseases in which a dysfunction in mtCa2+ has been shown.
    Keywords:  MCU; cancer; cardiovascular diseases; metabolic diseases; mitochondrial Ca2+ signaling; neurodegenerative disorders; skeletal muscle diseases
    DOI:  https://doi.org/10.3390/biom13091304
  4. Nat Commun. 2023 Sep 29. 14(1): 6099
    TMEM135 links peroxisomes to the regulation of brown fat mitochondrial fission and energy homeostasis.
    Donghua Hu, Min Tan, Dongliang Lu, Brian Kleiboeker, Xuejing Liu, Hongsuk Park, Alexxai V Kravitz, Kooresh I Shoghi, Yu-Hua Tseng, Babak Razani, Akihiro Ikeda, Irfan J Lodhi.
      Mitochondrial morphology, which is controlled by mitochondrial fission and fusion, is an important regulator of the thermogenic capacity of brown adipocytes. Adipose-specific peroxisome deficiency impairs thermogenesis by inhibiting cold-induced mitochondrial fission due to decreased mitochondrial membrane content of the peroxisome-derived lipids called plasmalogens. Here, we identify TMEM135 as a critical mediator of the peroxisomal regulation of mitochondrial fission and thermogenesis. Adipose-specific TMEM135 knockout in mice blocks mitochondrial fission, impairs thermogenesis, and increases diet-induced obesity and insulin resistance. Conversely, TMEM135 overexpression promotes mitochondrial division, counteracts obesity and insulin resistance, and rescues thermogenesis in peroxisome-deficient mice. Mechanistically, thermogenic stimuli promote association between peroxisomes and mitochondria and plasmalogen-dependent localization of TMEM135 in mitochondria, where it mediates PKA-dependent phosphorylation and mitochondrial retention of the fission factor Drp1. Together, these results reveal a previously unrecognized inter-organelle communication regulating mitochondrial fission and energy homeostasis and identify TMEM135 as a potential target for therapeutic activation of BAT.
    DOI:  https://doi.org/10.1038/s41467-023-41849-8
  5. Cell Cycle. 2023 Sep 28. 1-14
    Glutamine regulates the cellular proliferation and cell cycle progression by modulating the mTOR mediated protein levels of β-TrCP.
    Pushkar Malakar, Didhiti Singha, Debopriyo Choudhury, Sudhanshu Shukla.
      The amino acid glutamine plays an important role in cell growth and proliferation. Reliance on glutamine has long been considered a hallmark of highly proliferating cancer cells. Development of strategies for cancer therapy that primarily target glutamine metabolism has been an active area of research. Glutamine depletion is associated with growth arrest and apoptosis-induced cell death; however, the molecular mechanisms involved in this process are not clearly understood. Here, we show that glutamine depletion activates the energetic stress AMPK pathway and inhibits mTORC1 activity. Furthermore, inhibition of mTORC1 reduces the protein levels of β-TrCP, resulting in aberrant cell cycle progression and reduced proliferation. In agreement with the role of β-TrCP in glutamine metabolism, knockdown of β-TrCP resulted in proliferation and cell cycle defects similar to those observed for glutamine depletion. In summary, our results provide mechanistic insights into the role of glutamine metabolism in regulation of cell growth and proliferation via β-TrCP, uncovering a previously undescribed molecular process involved in glutamine metabolism.
    Keywords:  Glutamine; cell cycle; mTORC1; proliferation; β-TrCP
    DOI:  https://doi.org/10.1080/15384101.2023.2260166
  6. J Biochem. 2023 Sep 29. pii: mvad075. [Epub ahead of print]
    Insights into the regulation of mitochondrial functions by PKA-mediated phosphorylation.
    Shiori Akabane, Toshihiko Oka.
      Cyclic AMP (cAMP) - protein kinase A (PKA) signaling is a highly conserved pathway in eukaryotes and plays a central role in cell signaling cascades in response to environmental changes. Elevated cAMP levels promote the activation of PKA, which phosphorylates various downstream proteins. Many cytosolic and nuclear proteins, such as metabolic enzymes and transcriptional factors, have been identified as substrates for PKA, suggesting that PKA-mediated regulation occurs predominantly in the cytosol. Mitochondrial proteins are also phosphorylated by PKA, and PKA-mediated phosphorylation of mitochondrial proteins is considered to control a variety of mitochondrial functions, including oxidative phosphorylation, protein import, morphology, and quality control. In this review, we outline PKA mitochondrial substrates and summarize the regulation of mitochondrial functions through PKA-mediated phosphorylation.
    Keywords:  PKA; cAMP; mitochondria; phosphorylation
    DOI:  https://doi.org/10.1093/jb/mvad075
  7. Int J Mol Sci. 2023 Sep 07. pii: 13793. [Epub ahead of print]24(18):
    The Dual Role of Autophagy in Postischemic Brain Neurodegeneration of Alzheimer's Disease Proteinopathy.
    Ryszard Pluta.
      Autophagy is a self-defense and self-degrading intracellular system involved in the recycling and elimination of the payload of cytoplasmic redundant components, aggregated or misfolded proteins and intracellular pathogens to maintain cell homeostasis and physiological function. Autophagy is activated in response to metabolic stress or starvation to maintain homeostasis in cells by updating organelles and dysfunctional proteins. In neurodegenerative diseases, such as cerebral ischemia, autophagy is disturbed, e.g., as a result of the pathological accumulation of proteins associated with Alzheimer's disease and their structural changes. Postischemic brain neurodegeneration, such as Alzheimer's disease, is characterized by the accumulation of amyloid and tau protein. After cerebral ischemia, autophagy was found to be activated in neuronal, glial and vascular cells. Some studies have shown the protective properties of autophagy in postischemic brain, while other studies have shown completely opposite properties. Thus, autophagy is now presented as a double-edged sword with possible therapeutic potential in brain ischemia. The exact role and regulatory pathways of autophagy that are involved in cerebral ischemia have not been conclusively elucidated. This review aims to provide a comprehensive look at the advances in the study of autophagy behavior in neuronal, glial and vascular cells for ischemic brain injury. In addition, the importance of autophagy in neurodegeneration after cerebral ischemia has been highlighted. The review also presents the possibility of modulating the autophagy machinery through various compounds on the development of neurodegeneration after cerebral ischemia.
    Keywords:  Alzheimer’s disease proteinopathy; apoptosis; autophagy; brain ischemia; endothelial cells; glial cells; necrosis; neurodegeneration; neurons; recirculation; reperfusion
    DOI:  https://doi.org/10.3390/ijms241813793
  8. Adv Healthc Mater. 2023 Sep 24. e2302012
    Mitochondrial Artificial K+ Channel Construction Using MPTPP@5F8 Nanoparticles for Overcoming Cancer Drug Resistance via Disrupting Cellular Ion Homeostasis.
    Panqin Ma, Zheng Luo, Zhiguo Li, Yuchao Lin, Zibiao Li, Zhen Wu, Changliang Ren, Yun-Long Wu.
      Mitochondrial potassium ion channels have become a promising target for cancer therapy. However, in malignant tumours, their low expression or inhibitory regulation typically leads to undesired cancer therapy, or even induces drug resistance. Herein, we developed an in situ mitochondria-targeted artificial K+ channel construction strategy, with the purpose to trigger cancer cell apoptosis by impairing mitochondrial ion homeostasis. By considering the fact that cancer cells have a lower membrane potential than that of normal cells, our strategy could selectively deliver artificial K+ channel molecule 5F8 to the mitochondria of cancer cells, by using a mitochondria-targeting triphenylphosphine modified block polymer (MPTPP) as a carrier. More importantly, 5F8 could further specifically form a K+ -selective ion channel through the directional assembly of crown ethers on the mitochondrial membrane, thereby inducing mitochondrial K+ influx and disrupting ions homeostasis. Thanks to this design, mitochondrial dysfunction, including decreased mitochondrial membrane potential, reduced ATP synthesis, downregulated anti-apoptotic BCL-2 and MCL-1 protein levels, and increased ROS levels, could further effectively induce the programmed apoptosis of multidrug-resistant cancer cells, no matter in case of pump or non-pump dependent drug resistance. In short, this mitochondria-targeted artificial K+ -selective ion channel construction strategy might be beneficial for potential drug resistance cancer therapy. This article is protected by copyright. All rights reserved.
    Keywords:  Artificial K+ channels; Cancer therapy; Mitochondrial homeostasis; Mitochondrial targeting; Multidrug resistance
    DOI:  https://doi.org/10.1002/adhm.202302012
  9. bioRxiv. 2023 Sep 13. pii: 2023.09.12.557400. [Epub ahead of print]
    mTORC1 Regulates the Metabolic Switch of Postnatal Cardiomyocytes During Regeneration.
    Wyatt G Paltzer, Timothy J Aballo, Jiyoung Bae, Katharine A Hubert, Dakota J Nuttall, Cassidy Perry, Kayla N Wanless, Raya Nahlawi, Ying Ge, Ahmed I Mahmoud.
      The metabolic switch from glycolysis to fatty acid oxidation in postnatal cardiomyocytes contributes to the loss of the cardiac regenerative potential of the mammalian heart. However, the mechanisms that regulate this metabolic switch remain unclear. The protein kinase complex mechanistic target of rapamycin complex 1 (mTORC1) is a central signaling hub that regulates cellular metabolism and protein synthesis, yet its role during mammalian heart regeneration and postnatal metabolic maturation is undefined. Here, we use immunoblotting, rapamycin treatment, myocardial infarction, and global proteomics to define the role of mTORC1 in postnatal heart development and regeneration. Our results demonstrate that the activity of mTORC1 is dynamically regulated between the regenerating and the non-regenerating hearts. Acute inhibition of mTORC1 by rapamycin or everolimus reduces cardiomyocyte proliferation and inhibits neonatal heart regeneration following injury. Our quantitative proteomic analysis demonstrates that transient inhibition of mTORC1 during neonatal heart injury did not reduce protein synthesis, but rather shifts the cardiac proteome of the neonatal injured heart from glycolysis towards fatty acid oxidation. This indicates that mTORC1 inhibition following injury accelerates the postnatal metabolic switch, which promotes metabolic maturation and impedes cardiomyocyte proliferation and heart regeneration. Taken together, our results define an important role for mTORC1 in regulating postnatal cardiac metabolism and may represent a novel target to modulate cardiac metabolism and promote heart regeneration.
    DOI:  https://doi.org/10.1101/2023.09.12.557400
  10. bioRxiv. 2023 Sep 16. pii: 2023.09.13.557599. [Epub ahead of print]
    Plasma cell differentiation, antibody quality, and initial germinal center B cell population depend on glucose influx rate.
    Shawna K Brookens, Sung Hoon Cho, Yeeun Paik, Kaylor Meyer, Ariel L Raybuck, Chloe Park, Dalton L Greenwood, Jeffrey C Rathmell, Mark R Boothby.
      Antibody secretion into sera, selection for higher affinity BCR, and the generation of higher Ab affinities are important elements of immune response optimization, and a core function of germinal center reactions. B cell proliferation requires nutrients to support the anabolism inherent in clonal expansion. Glucose usage by GC B cells has been reported to contribute little to their energy needs, with questions raised as to whether or not glucose uptake or glycolysis increases in GC B cells compared to their naïve precursors. Indeed, metabolism can be highly flexible, such that supply shortage along one pathway may be compensated by increased flux on others. We now show that elimination of the glucose transporter GLUT1 after establishment of a pre-immune B cell repertoire, even after initiation of the GC B cell gene expression program, decreased initial GC B cell population numbers, affinity maturation, and PC outputs. Glucose oxidation was heightened in GC B cells, but this hexose flowed more into the pentose phosphate pathway (PPP), whose activity was important in controlling reactive oxygen (ROS) and ASC production. In modeling how glucose usage by B cells promotes the Ab response, the control of ROS appeared insufficient. Surprisingly, the combination of galactose, which mitigated ROS, with provision of mannose - an efficient precursor to glycosylation - supported robust production of and normal Ab secretion by ASC under glucose-free conditions. Collectively, the findings indicate that GC depend on normal glucose influx, especially in PC production, but reveal an unexpected metabolic flexibility in hexose requirements.KEY POINTS: Glucose influx is critical for GC homeostasis, affinity maturation and the generation of Ab-secreting cells.Plasma cell development uses the Pentose Phosphate Pathway, and hexose sugars maintain redox homeostasis.PCs can develop and achieve robust Ab secretion in the absence of glucose using a combination of hexose alternatives.
    DOI:  https://doi.org/10.1101/2023.09.13.557599
  11. Diabetes Metab J. 2023 Sep 26.
    Extracellular Vimentin Alters Energy Metabolism And Induces Adipocyte Hypertrophy.
    Ji-Hae Park, Soyeon Kwon, Young Mi Park.
      Background: Previous studies have reported that oxidative stress contributes to obesity characterized by adipocyte hypertrophy. However, mechanism has not been studied extensively. In the current study, we evaluated role of extracellular vimentin secreted by oxidized low-density lipoprotein (oxLDL) in energy metabolism in adipocytes.Methods: We treated 3T3-L1-derived adipocytes with oxLDL and measured vimentin which was secreted in the media. We evaluated changes in uptake of glucose and free fatty acid, expression of molecules functioning in energy metabolism, synthesis of adenosine triphosphate (ATP) and lactate, markers for endoplasmic reticulum (ER) stress and autophagy in adipocytes treated with recombinant vimentin.
    Results: Adipocytes secreted vimentin in response to oxLDL. Microscopic evaluation revealed that vimentin treatment induced increase in adipocyte size and increase in sizes of intracellular lipid droplets with increased intracellular triglyceride. Adipocytes treated with vimentin showed increased uptake of glucose and free fatty acid with increased expression of plasma membrane glucose transporter type 1 (GLUT1), GLUT4, and CD36. Vimentin treatment increased transcription of GLUT1 and hypoxia-inducible factor 1α (Hif-1α) but decreased GLUT4 transcription. Adipose triglyceride lipase (ATGL), peroxisome proliferator-activated receptor γ (PPARγ), sterol regulatory element-binding protein 1 (SREBP1), diacylglycerol O-acyltransferase 1 (DGAT1) and 2 were decreased by vimentin treatment. Markers for ER stress were increased and autophagy was impaired in vimentin-treated adipocytes. No change was observed in synthesis of ATP and lactate in the adipocytes treated with vimentin. Conclusion: We concluded that extracellular vimentin regulates expression of molecules in energy metabolism and promotes adipocyte hypertrophy. Our results show that vimentin functions in the interplay between oxidative stress and metabolism, suggesting a mechanism by which adipocyte hypertrophy is induced in oxidative stress.
    Keywords:  Adipocytes; Fatty acids, nonesterified; Glucose; Glucose transporter type 1; Hypertrophy; Hypoxia-inducible factor 1; Oxidized low density lipoprotein
    DOI:  https://doi.org/10.4093/dmj.2022.0332
  12. Cancers (Basel). 2023 Sep 13. pii: 4535. [Epub ahead of print]15(18):
    Control of Mitochondrial Electron Transport Chain Flux and Apoptosis by Retinoic Acid: Raman Imaging In Vitro Human Bronchial and Lung Cancerous Cells.
    Halina Abramczyk, Jakub Maciej Surmacki.
      The multiple functions of cytochrome c (cyt c) and their regulation in life and death decisions of the mammalian cell go beyond respiration, apoptosis, ROS scavenging, and oxidation of cardiolipine. It has become increasingly evident that cyt c is involved in the propagation of mitogenic signals. It has been proposed that the mitogenic signals occur via the PKCδ-retinoic acid signal complex comprising the protein kinase Cδ, the adapter protein Src homologous collagen homolog (p66Shc), and cyt c. We showed the importance of retinoic acid in regulating cellular processes monitored by the Raman bands of cyt c. To understand the role of retinoids in regulating redox status of cyt c, we recorded the Raman spectra and images of cells receiving redox stimuli by retinoic acid at in vitro cell cultures. For these purposes, we incubated bronchial normal epithelial lung (BEpC) and lung cancer cells (A549) with retinoic acid at concentrations of 1, 10, and 50 µM for 24 and 48 h of incubations. The new role of retinoic acid in a change of the redox status of iron ion in the heme group of cyt c from oxidized Fe3+ to reduced Fe2+ form may have serious consequences on ATPase effectiveness and aborting the activation of the conventional mitochondrial signaling protein-dependent pathways, lack of triggering programmed cell death through apoptosis, and lack of cytokine induction. To explain the effect of retinoids on the redox status of cyt c in the electron transfer chain, we used the quantum chemistry models of retinoid biology. It has been proposed that retinol catalyzes resonance energy transfer (RET) reactions in cyt c. The paper suggests that RET is pivotally important for mitochondrial energy homeostasis by controlling oxidative phosphorylation by switching between activation and inactivation of glycolysis and regulation of electron flux in the electron transport chain. The key role in this process is played by protein kinase C δ (PKCδ), which triggers a signal to the pyruvate dehydrogenase complex. The PKCδ-retinoic acid complex reversibly (at normal physiological conditions) or irreversibly (cancer) responds to the redox potential of cyt c that changes with the electron transfer chain flux.
    Keywords:  Raman imaging; apoptosis; cell signaling; cytochrome c; electron transport chain; human bronchial (BEpC) and lung cancer (A549) cell line; phosphorylation; reactive oxygen species; respiration; retinoic acid
    DOI:  https://doi.org/10.3390/cancers15184535
  13. J Neurochem. 2023 Sep 27.
    Fundamental Neurochemistry Review: Microglial immunometabolism in traumatic brain injury.
    Nathan R Strogulski, Luis V Portela, Brian M Polster, David J Loane.
      Traumatic brain injury (TBI) is a devastating neurological disorder caused by a physical impact to the brain that promotes diffuse damage and chronic neurodegeneration. Key mechanisms believed to support secondary brain injury include mitochondrial dysfunction and chronic neuroinflammation. Microglia and brain-infiltrating macrophages are responsible for neuroinflammatory cytokine and reactive oxygen species (ROS) production after TBI. Their production is associated with loss of homeostatic microglial functions such as immunosurveillance, phagocytosis, and immune resolution. Beyond providing energy support, mitochondrial metabolic pathways reprogram the pro- and anti-inflammatory machinery in immune cells, providing a critical immunometabolic axis capable of regulating immunologic response to noxious stimuli. In the brain, the capacity to adapt to different environmental stimuli derives, in part, from microglia's ability to recognize and respond to changes in extracellular and intracellular metabolite levels. This capacity is met by an equally plastic metabolism, capable of altering immune function. Microglial pro-inflammatory activation is associated with decreased mitochondrial respiration, whereas anti-inflammatory microglial polarization is supported by increased oxidative metabolism. These metabolic adaptations contribute to neuroimmune responses, placing mitochondria as a central regulator of post-traumatic neuroinflammation. Although it is established that profound neurometabolic changes occur following TBI, key questions related to metabolic shifts in microglia remain unresolved. These include (a) the nature of microglial mitochondrial dysfunction after TBI, (b) the hierarchical positions of different metabolic pathways such as glycolysis, pentose phosphate pathway, glutaminolysis, and lipid oxidation during secondary injury and recovery, and (c) how immunometabolism alters microglial phenotypes, culminating in chronic non-resolving neuroinflammation. In this basic neurochemistry review article, we describe the contributions of immunometabolism to TBI, detail primary evidence of mitochondrial dysfunction and metabolic impairments in microglia and macrophages, discuss how major metabolic pathways contribute to post-traumatic neuroinflammation, and set out future directions toward advancing immunometabolic phenotyping in TBI.
    Keywords:  metabolism; microglia; mitochondria; neuroimmunology; traumatic brain injury
    DOI:  https://doi.org/10.1111/jnc.15959
  14. Cell Rep. 2023 Sep 26. pii: S2211-1247(23)01138-5. [Epub ahead of print]42(10): 113126
    NSD2 methylates AROS to promote SIRT1 activation and regulates fatty acid metabolism-mediated cancer radiotherapy.
    Xun Li, Da Song, Yaqi Chen, Changsheng Huang, Anyi Liu, Qi Wu, Xiaowei She, Kangdi Li, Kairui Wan, Chengxin Yu, Cheng Qiu, Lang Liu, Guihua Wang, Feng Xu, Jing Wang, Junbo Hu.
      Fatty acid metabolism plays a critical role in both tumorigenesis and cancer radiotherapy. However, the regulatory mechanism of fatty acid metabolism has not been fully elucidated. NSD2, a histone methyltransferase that catalyzes di-methylation of histone H3 at lysine 36, has been shown to play an essential role in tumorigenesis and cancer progression. Here, we show that NSD2 promotes fatty acid oxidation (FAO) by methylating AROS (active regulator of SIRT1) at lysine 27, facilitating the physical interaction between AROS and SIRT1. The mutation of lysine 27 to arginine weakens the interaction between AROS and SIRT1 and impairs AROS-SIRT1-mediated FAO. Additionally, we examine the effect of NSD2 inhibition on radiotherapy efficacy and find an enhanced effectiveness of radiotherapy. Together, our findings identify a NSD2-dependent methylation regulation pattern of the AROS-SIRT1 axis, suggesting that NSD2 inhibition may be a potential adjunct for tumor radiotherapy.
    Keywords:  AROS methylation; CP: Cancer; CP: Metabolism; NSD2; SIRT1; fatty acid metabolism; radiotherapy
    DOI:  https://doi.org/10.1016/j.celrep.2023.113126
  15. Nature. 2023 Sep 27.
    Proteome census upon nutrient stress reveals Golgiphagy membrane receptors.
    Kelsey L Hickey, Sharan Swarup, Ian R Smith, Julia C Paoli, Enya Miguel Whelan, Joao A Paulo, J Wade Harper.
      During nutrient stress, macroautophagy degrades cellular macromolecules, thereby providing biosynthetic building blocks while simultaneously remodeling the proteome1,2. While machinery responsible for initiation of macroautophagy is well characterized3,4, our understanding of the extent to which individual proteins, protein complexes and organelles are selected for autophagic degradation, and the underlying targeting mechanisms is limited. Here, we use orthogonal proteomic strategies to provide a spatial proteome census of autophagic cargo during nutrient stress in mammalian cells. We find that macroautophagy has selectivity for recycling membrane-bound organelles (principally Golgi and ER). Through autophagic cargo prioritization, we identify a complex of membrane-embedded proteins, YIPF3 and YIPF4, as receptors for Golgiphagy. During nutrient stress, YIPF3 and YIPF4 interact with ATG8s via LIR motifs and are mobilized into autophagosomes that traffic to lysosomes in a process that requires the canonical autophagic machinery. Cells lacking YIPF3 or YIPF4 are selectively defective in elimination of a specific cohort of Golgi membrane proteins during nutrient stress. Moreover, YIPF3/4 play an analogous role in Golgi remodeling during programmed conversion of stem cells to the neuronal lineage in vitro. Collectively, this study reveals prioritization of membrane protein cargo during nutrient stress-dependent proteome remodeling and identifies an unanticipated Golgi remodeling pathway requiring membrane-embedded receptors.
    DOI:  https://doi.org/10.1038/s41586-023-06657-6
  16. Cell Rep. 2023 Sep 19. pii: S2211-1247(23)01159-2. [Epub ahead of print]42(9): 113147
    Cancer cells reprogram to metastatic state through the acquisition of platelet mitochondria.
    Wenkan Zhang, Hao Zhou, Hengyuan Li, Haochen Mou, Eloy Yinwang, Yucheng Xue, Shengdong Wang, Yongxing Zhang, Zenan Wang, Tao Chen, Hangxiang Sun, Fangqian Wang, Jiahao Zhang, Xupeng Chai, Shixin Chen, Binghao Li, Changqing Zhang, Junjie Gao, Zhaoming Ye.
      Metastasis is the major cause of cancer deaths, and cancer cells evolve to adapt to various tumor microenvironments, which hinders the treatment of tumor metastasis. Platelets play critical roles in tumor development, especially during metastasis. Here, we elucidate the role of platelet mitochondria in tumor metastasis. Cancer cells are reprogrammed to a metastatic state through the acquisition of platelet mitochondria via the PINK1/Parkin-Mfn2 pathway. Furthermore, platelet mitochondria regulate the GSH/GSSG ratio and reactive oxygen species (ROS) in cancer cells to promote lung metastasis of osteosarcoma. Impairing platelet mitochondrial function has proven to be an efficient approach to impair metastasis, providing a direction for osteosarcoma therapy. Our findings demonstrate mitochondrial transfer between platelets and cancer cells and suggest a role for platelet mitochondria in tumor metastasis.
    Keywords:  CP: Cancer; CP: Cell biology; glutathione; metabolic reprogram; mitochondria transfer; osteosarcoma metastasis; oxidative stress; platelets
    DOI:  https://doi.org/10.1016/j.celrep.2023.113147
  17. Biomolecules. 2023 Sep 19. pii: 1409. [Epub ahead of print]13(9):
    Mitochondrial Calcium Overload Plays a Causal Role in Oxidative Stress in the Failing Heart.
    Haikel Dridi, Gaetano Santulli, Laith Bahlouli, Marco C Miotto, Gunnar Weninger, Andrew R Marks.
      Heart failure is a serious global health challenge, affecting more than 6.2 million people in the United States and is projected to reach over 8 million by 2030. Independent of etiology, failing hearts share common features, including defective calcium (Ca2+) handling, mitochondrial Ca2+ overload, and oxidative stress. In cardiomyocytes, Ca2+ not only regulates excitation-contraction coupling, but also mitochondrial metabolism and oxidative stress signaling, thereby controlling the function and actual destiny of the cell. Understanding the mechanisms of mitochondrial Ca2+ uptake and the molecular pathways involved in the regulation of increased mitochondrial Ca2+ influx is an ongoing challenge in order to identify novel therapeutic targets to alleviate the burden of heart failure. In this review, we discuss the mechanisms underlying altered mitochondrial Ca2+ handling in heart failure and the potential therapeutic strategies.
    Keywords:  calcium; heart failure; mitochondria
    DOI:  https://doi.org/10.3390/biom13091409
  18. Biomed Pharmacother. 2023 Sep 25. pii: S0753-3322(23)01320-3. [Epub ahead of print]167 115522
    The potential of targeting cuproptosis in the treatment of kidney renal clear cell carcinoma.
    Guojie Lei, Lusheng Tang, Yanhua Yu, Wenxia Bian, Lingyan Yu, Junyu Zhou, Yanchun Li, Ying Wang, Jing Du.
      Renal cell carcinoma (RCC) is one of the top ten malignancies and tumor-related causes of death worldwide. The most common histologic subtype is kidney renal clear cell carcinoma (KIRC), accounting for approximately 75% of all RCC cases. Early resection is considered the basic treatment for patients with KIRC. However, approximately 30% of these patients experience recurrence post-operation. Cuproptosis, an autonomous mechanism for controlling cell death, encompasses various molecular mechanisms and multiple cellular metabolic pathways. These pathways mainly include copper metabolic signaling pathways, mitochondrial metabolism signaling pathways, and lipoic acid pathway signaling pathways. Recent evidence shows that cuproptosis is identified as a key cell death modality that plays a meaningful role in tumor progression. However, there is no published systematic review that summarizes the correlation between cuproptosis and KIRC, despite the fact that investigations on cuproptosis and the pathogenesis of KIRC have increased in past years. Researchers have discovered that exogenous copper infusion accelerates the dysfunction of mitochondrial dysfunction and suppresses KIRC cells by inducing cuproptosis. The levels of tricarboxylic acid cycle proteins, lipoic acid protein, copper, and ferredoxin 1 (FDX1) were dysregulated in KIRC cells, and the prognosis of patients with high FDX1 expression is better than that of patients with low expression. Cuproptosis played an indispensable role in the regulation of tumor microenvironment features, tumor progression, and long-term prognosis of KIRC. In this review, we summarized the systemic and cellular metabolic processes of copper and the copper-related signaling pathways, highlighting the potential targets related to cuproptosis for KIRC treatment.
    Keywords:  Cell death; Cuproptosis; Kidney renal clear cell carcinoma; Therapeutic target
    DOI:  https://doi.org/10.1016/j.biopha.2023.115522
  19. Cell Commun Signal. 2023 09 25. 21(1): 258
    Defective quality control autophagy in Hyperhomocysteinemia promotes ER stress and consequent neuronal apoptosis through proteotoxicity.
    Bhavneet Kaur, Pradeep Kumar Sharma, Barun Chatterjee, Bhawana Bissa, Vasugi Nattarayan, Soundhar Ramasamy, Ajay Bhat, Megha Lal, Sarbani Samaddar, Sourav Banerjee, Soumya Sinha Roy.
      Homocysteine (Hcy), produced physiologically in all cells, is an intermediate metabolite of methionine and cysteine metabolism. Hyperhomocysteinemia (HHcy) resulting from an in-born error of metabolism that leads to accumulation of high levels of Hcy, is associated with vascular damage, neurodegeneration and cognitive decline. Using a HHcy model in neuronal cells, primary cortical neurons and transgenic zebrafish, we demonstrate diminished autophagy and Hcy-induced neurotoxicity associated with mitochondrial dysfunction, fragmentation and apoptosis. We find this mitochondrial dysfunction is due to Hcy-induced proteotoxicity leading to ER stress. We show this sustained proteotoxicity originates from the perturbation of upstream autophagic pathways through an aberrant activation of mTOR and that protetoxic stress act as a feedforward cues to aggravate a sustained ER stress that culminate to mitochondrial apoptosis in HHcy model systems. Using chemical chaperones to mitigate sustained ER stress, Hcy-induced proteotoxicity and consequent neurotoxicity were rescued. We also rescue neuronal lethality by activation of autophagy and thereby reducing proteotoxicity and ER stress. Our findings pave the way to devise new strategies for the treatment of neural and cognitive pathologies reported in HHcy, by either activation of upstream autophagy or by suppression of downstream ER stress. Video Abstract.
    Keywords:  Apoptosis; Autophagy; CBS; Endoplasmic reticulum; Homocysteine; Hyperhomocysteinemia; Mitochondria; Neuron
    DOI:  https://doi.org/10.1186/s12964-023-01288-w
  20. Biomedicines. 2023 Sep 07. pii: 2488. [Epub ahead of print]11(9):
    Mitochondria and Brain Disease: A Comprehensive Review of Pathological Mechanisms and Therapeutic Opportunities.
    Vicente Javier Clemente-Suárez, Laura Redondo-Flórez, Ana Isabel Beltrán-Velasco, Domingo Jesús Ramos-Campo, Pedro Belinchón-deMiguel, Ismael Martinez-Guardado, Athanasios A Dalamitros, Rodrigo Yáñez-Sepúlveda, Alexandra Martín-Rodríguez, José Francisco Tornero-Aguilera.
      Mitochondria play a vital role in maintaining cellular energy homeostasis, regulating apoptosis, and controlling redox signaling. Dysfunction of mitochondria has been implicated in the pathogenesis of various brain diseases, including neurodegenerative disorders, stroke, and psychiatric illnesses. This review paper provides a comprehensive overview of the intricate relationship between mitochondria and brain disease, focusing on the underlying pathological mechanisms and exploring potential therapeutic opportunities. The review covers key topics such as mitochondrial DNA mutations, impaired oxidative phosphorylation, mitochondrial dynamics, calcium dysregulation, and reactive oxygen species generation in the context of brain disease. Additionally, it discusses emerging strategies targeting mitochondrial dysfunction, including mitochondrial protective agents, metabolic modulators, and gene therapy approaches. By critically analysing the existing literature and recent advancements, this review aims to enhance our understanding of the multifaceted role of mitochondria in brain disease and shed light on novel therapeutic interventions.
    Keywords:  brain disease; mitochondria; mitochondrial DNA mutations; mitochondrial dynamics; mitochondrial protective agents; neurodegenerative disorders; oxidative phosphorylation; reactive oxygen species
    DOI:  https://doi.org/10.3390/biomedicines11092488
  21. Sci Rep. 2023 09 25. 13(1): 15973
    The Warburg effect alters amino acid homeostasis in human retinal endothelial cells: implication for proliferative diabetic retinopathy.
    Andrew Gregory, Thangal Yumnamcha, Mohamed Shawky, Shaimaa Eltanani, Armaan Naghdi, Bing X Ross, Xihui Lin, Ahmed S Ibrahim.
      Proliferative diabetic retinopathy (PDR) remains a leading cause of blindness despite progress in screening and treatment. Recently, the Warburg effect, a metabolic alteration affecting amino acid (AA) metabolism in proliferating cells, has drawn attention regarding its role in PDR. This study aimed to investigate the impact of the Warburg effect on AA metabolism in human retinal endothelial cells (HRECs) subjected to PDR-associated risk factors and validate the findings in patients with PDR. In vitro experiments exposed HRECs to high glucose (HG) and/or hypoxia (Hyp), known inducers of the Warburg effect. The HG + Hyp group of HRECs exhibited significant differences in non-essential AAs with aliphatic non-polar side chains, mainly driven by elevated glycine concentrations. Pathway enrichment analysis revealed several glycine metabolism-related pathways significantly altered due to the Warburg effect induced by HG + Hyp. Crucially, vitreous humor samples from PDR patients displayed higher glycine levels compared to non-diabetic and diabetic patients without PDR. The odds ratio for PDR patients with glycine levels above the cut-off of 0.0836 µM was 28 (p = 0.03) compared to non-PDR controls. In conclusion, this study provides mechanistic insights into how a specific Warburg effect subtype contributes to glycine accumulation in PDR and supports glycine's potential as a biomarker for PDR pathogenesis.
    DOI:  https://doi.org/10.1038/s41598-023-43022-z
  22. Antioxidants (Basel). 2023 Sep 08. pii: 1739. [Epub ahead of print]12(9):
    NRF2, a Superstar of Ferroptosis.
    Ruihan Yan, Bingyi Lin, Wenwei Jin, Ling Tang, Shuming Hu, Rong Cai.
      Ferroptosis is an iron-dependent and lipid peroxidation-driven cell death cascade, occurring when there is an imbalance of redox homeostasis in the cell. Nuclear factor erythroid 2-related factor 2 (NFE2L2, also known as NRF2) is key for cellular antioxidant responses, which promotes downstream genes transcription by binding to their antioxidant response elements (AREs). Numerous studies suggest that NRF2 assumes an extremely important role in the regulation of ferroptosis, for its various functions in iron, lipid, and amino acid metabolism, and so on. Many pathological states are relevant to ferroptosis. Abnormal suppression of ferroptosis is found in many cases of cancer, promoting their progression and metastasis. While during tissue damages, ferroptosis is recurrently promoted, resulting in a large number of cell deaths and even dysfunctions of the corresponding organs. Therefore, targeting NRF2-related signaling pathways, to induce or inhibit ferroptosis, has become a great potential therapy for combating cancers, as well as preventing neurodegenerative and ischemic diseases. In this review, a brief overview of the research process of ferroptosis over the past decade will be presented. In particular, the mechanisms of ferroptosis and a focus on the regulation of ferroptosis by NRF2 will be discussed. Finally, the review will briefly list some clinical applications of targeting the NRF2 signaling pathway in the treatment of diseases.
    Keywords:  NRF2; antioxidant; ferroptosis; metabolism
    DOI:  https://doi.org/10.3390/antiox12091739
  23. Nat Commun. 2023 Sep 27. 14(1): 6036
    All-optical spatiotemporal mapping of ROS dynamics across mitochondrial microdomains in situ.
    Shon A Koren, Nada Ahmed Selim, Lizbeth De la Rosa, Jacob Horn, M Arsalan Farooqi, Alicia Y Wei, Annika Müller-Eigner, Jacen Emerson, Gail V W Johnson, Andrew P Wojtovich.
      Hydrogen peroxide (H2O2) functions as a second messenger to signal metabolic distress through highly compartmentalized production in mitochondria. The dynamics of reactive oxygen species (ROS) generation and diffusion between mitochondrial compartments and into the cytosol govern oxidative stress responses and pathology, though these processes remain poorly understood. Here, we couple the H2O2 biosensor, HyPer7, with optogenetic stimulation of the ROS-generating protein KillerRed targeted into multiple mitochondrial microdomains. Single mitochondrial photogeneration of H2O2 demonstrates the spatiotemporal dynamics of ROS diffusion and transient hyperfusion of mitochondria due to ROS. This transient hyperfusion phenotype required mitochondrial fusion but not fission machinery. Measurement of microdomain-specific H2O2 diffusion kinetics reveals directionally selective diffusion through mitochondrial microdomains. All-optical generation and detection of physiologically-relevant concentrations of H2O2 between mitochondrial compartments provide a map of mitochondrial H2O2 diffusion dynamics in situ as a framework to understand the role of ROS in health and disease.
    DOI:  https://doi.org/10.1038/s41467-023-41682-z
  24. PLoS Pathog. 2023 Sep 25. 19(9): e1011658
    Choline metabolism underpins macrophage IL-4 polarization and RELMα up-regulation in helminth infection.
    Peyman Ghorbani, Sang Yong Kim, Tyler K T Smith, Lucía Minarrieta, Victoria Robert-Gostlin, Marisa K Kilgour, Maja Ilijevska, Irina Alecu, Shayne A Snider, Kaitlyn D Margison, Julia R C Nunes, Daniel Woo, Ciara Pember, Conor O'Dwyer, Julie Ouellette, Pavel Kotchetkov, Julie St-Pierre, Steffany A L Bennett, Baptiste Lacoste, Alexandre Blais, Meera G Nair, Morgan D Fullerton.
      Type 2 cytokines like IL-4 are hallmarks of helminth infection and activate macrophages to limit immunopathology and mediate helminth clearance. In addition to cytokines, nutrients and metabolites critically influence macrophage polarization. Choline is an essential nutrient known to support normal macrophage responses to lipopolysaccharide; however, its function in macrophages polarized by type 2 cytokines is unknown. Using murine IL-4-polarized macrophages, targeted lipidomics revealed significantly elevated levels of phosphatidylcholine, with select changes to other choline-containing lipid species. These changes were supported by the coordinated upregulation of choline transport compared to naïve macrophages. Pharmacological inhibition of choline metabolism significantly suppressed several mitochondrial transcripts and dramatically inhibited select IL-4-responsive transcripts, most notably, Retnla. We further confirmed that blocking choline metabolism diminished IL-4-induced RELMα (encoded by Retnla) protein content and secretion and caused a dramatic reprogramming toward glycolytic metabolism. To better understand the physiological implications of these observations, naïve or mice infected with the intestinal helminth Heligmosomoides polygyrus were treated with the choline kinase α inhibitor, RSM-932A, to limit choline metabolism in vivo. Pharmacological inhibition of choline metabolism lowered RELMα expression across cell-types and tissues and led to the disappearance of peritoneal macrophages and B-1 lymphocytes and an influx of infiltrating monocytes. The impaired macrophage activation was associated with some loss in optimal immunity to H. polygyrus, with increased egg burden. Together, these data demonstrate that choline metabolism is required for macrophage RELMα induction, metabolic programming, and peritoneal immune homeostasis, which could have important implications in the context of other models of infection or cancer immunity.
    DOI:  https://doi.org/10.1371/journal.ppat.1011658
  25. Nat Commun. 2023 Sep 26. 14(1): 5989
    Orai inhibition modulates pulmonary ILC2 metabolism and alleviates airway hyperreactivity in murine and humanized models.
    Emily Howard, Benjamin P Hurrell, Doumet Georges Helou, Pedram Shafiei-Jahani, Spyridon Hasiakos, Jacob Painter, Sonal Srikanth, Yousang Gwack, Omid Akbari.
      Ca2+ entry via Ca2+ release-activated Ca2+ (CRAC) channels is a predominant mechanism of intracellular Ca2+ elevation in immune cells. Here we show the immunoregulatory role of CRAC channel components Orai1 and Orai2 in Group 2 innate lymphoid cells (ILC2s), that play crucial roles in the induction of type 2 inflammation. We find that blocking or genetic ablation of Orai1 and Orai2 downregulates ILC2 effector function and cytokine production, consequently ameliorating the development of ILC2-mediated airway inflammation in multiple murine models. Mechanistically, ILC2 metabolic and mitochondrial homeostasis are inhibited and lead to the upregulation of reactive oxygen species production. We confirm our findings in human ILC2s, as blocking Orai1 and Orai2 prevents the development of airway hyperreactivity in humanized mice. Our findings have a broad impact on the basic understanding of Ca2+ signaling in ILC2 biology, providing potential insights into the development of therapies for the treatment of allergic and atopic inflammatory diseases.
    DOI:  https://doi.org/10.1038/s41467-023-41065-4
  26. Nutrients. 2023 Sep 17. pii: 4023. [Epub ahead of print]15(18):
    Aspartic Acid in Health and Disease.
    Milan Holeček.
      Aspartic acid exists in L- and D-isoforms (L-Asp and D-Asp). Most L-Asp is synthesized by mitochondrial aspartate aminotransferase from oxaloacetate and glutamate acquired by glutamine deamidation, particularly in the liver and tumor cells, and transamination of branched-chain amino acids (BCAAs), particularly in muscles. The main source of D-Asp is the racemization of L-Asp. L-Asp transported via aspartate-glutamate carrier to the cytosol is used in protein and nucleotide synthesis, gluconeogenesis, urea, and purine-nucleotide cycles, and neurotransmission and via the malate-aspartate shuttle maintains NADH delivery to mitochondria and redox balance. L-Asp released from neurons connects with the glutamate-glutamine cycle and ensures glycolysis and ammonia detoxification in astrocytes. D-Asp has a role in brain development and hypothalamus regulation. The hereditary disorders in L-Asp metabolism include citrullinemia, asparagine synthetase deficiency, Canavan disease, and dicarboxylic aminoaciduria. L-Asp plays a role in the pathogenesis of psychiatric and neurologic disorders and alterations in BCAA levels in diabetes and hyperammonemia. Further research is needed to examine the targeting of L-Asp metabolism as a strategy to fight cancer, the use of L-Asp as a dietary supplement, and the risks of increased L-Asp consumption. The role of D-Asp in the brain warrants studies on its therapeutic potential in psychiatric and neurologic disorders.
    Keywords:  aspartame; aspartate and cell-to-cell interactions; branched-chain amino acids; gluconeogenesis; glutamate–glutamine cycle; malate–aspartate shuttle; neurotransmission; oxaloacetate; purine-nucleotide cycle; urea cycle
    DOI:  https://doi.org/10.3390/nu15184023
  27. Nat Rev Mol Cell Biol. 2023 Sep 29.
    Mitochondrial proteome research: the road ahead.
    Zakery N Baker, Patrick Forny, David J Pagliarini.
      Mitochondria are multifaceted organelles with key roles in anabolic and catabolic metabolism, bioenergetics, cellular signalling and nutrient sensing, and programmed cell death processes. Their diverse functions are enabled by a sophisticated set of protein components encoded by the nuclear and mitochondrial genomes. The extent and complexity of the mitochondrial proteome remained unclear for decades. This began to change 20 years ago when, driven by the emergence of mass spectrometry-based proteomics, the first draft mitochondrial proteomes were established. In the ensuing decades, further technological and computational advances helped to refine these 'maps', with current estimates of the core mammalian mitochondrial proteome ranging from 1,000 to 1,500 proteins. The creation of these compendia provided a systemic view of an organelle previously studied primarily in a reductionist fashion and has accelerated both basic scientific discovery and the diagnosis and treatment of human disease. Yet numerous challenges remain in understanding mitochondrial biology and translating this knowledge into the medical context. In this Roadmap, we propose a path forward for refining the mitochondrial protein map to enhance its discovery and therapeutic potential. We discuss how emerging technologies can assist the detection of new mitochondrial proteins, reveal their patterns of expression across diverse tissues and cell types, and provide key information on proteoforms. We highlight the power of an enhanced map for systematically defining the functions of its members. Finally, we examine the utility of an expanded, functionally annotated mitochondrial proteome in a translational setting for aiding both diagnosis of mitochondrial disease and targeting of mitochondria for treatment.
    DOI:  https://doi.org/10.1038/s41580-023-00650-7
  28. MedComm (2020). 2023 Oct;4(5): e363
    Arachidonic acid metabolism in health and disease.
    Yiran Zhang, Yingxiang Liu, Jin Sun, Wei Zhang, Zheng Guo, Qiong Ma.
      Arachidonic acid (AA), an n-6 essential fatty acid, is a major component of mammalian cells and can be released by phospholipase A2. Accumulating evidence indicates that AA plays essential biochemical roles, as it is the direct precursor of bioactive lipid metabolites of eicosanoids such as prostaglandins, leukotrienes, and epoxyeicosatrienoic acid obtained from three distinct enzymatic metabolic pathways: the cyclooxygenase pathway, lipoxygenase pathway, and cytochrome P450 pathway. AA metabolism is involved not only in cell differentiation, tissue development, and organ function but also in the progression of diseases, such as hepatic fibrosis, neurodegeneration, obesity, diabetes, and cancers. These eicosanoids are generally considered proinflammatory molecules, as they can trigger oxidative stress and stimulate the immune response. Therefore, interventions in AA metabolic pathways are effective ways to manage inflammatory-related diseases in the clinic. Currently, inhibitors targeting enzymes related to AA metabolic pathways are an important area of drug discovery. Moreover, many advances have also been made in clinical studies of AA metabolic inhibitors in combination with chemotherapy and immunotherapy. Herein, we review the discovery of AA and focus on AA metabolism in relation to health and diseases. Furthermore, inhibitors targeting AA metabolism are summarized, and potential clinical applications are discussed.
    Keywords:  arachidonic acid; bioactive lipid metabolites; organ homeostasis; targeted therapy
    DOI:  https://doi.org/10.1002/mco2.363
  29. Sci Rep. 2023 Sep 27. 13(1): 16205
    The bisphosphonates alendronate and zoledronate induce adaptations of aerobic metabolism in permanent human endothelial cells.
    Adrianna Budzinska, Lukasz Galganski, Wieslawa Jarmuszkiewicz.
      Nitrogen-containing bisphosphonates (NBPs), compounds that are widely used in the treatment of bone disorders, may cause side effects related to endothelial dysfunction. The aim of our study was to investigate the effects of chronic 6-day exposure to two common bone-preserving drugs, alendronate and zoledronate, on endothelial function and oxidative metabolism of cultured human endothelial cells (EA.hy926). NBPs reduced cell viability, induced oxidative stress and a pro-inflammatory state and downregulated the prenylation-dependent ERK1/2 signaling pathway in endothelial cells. In addition, NBPs induced increased anaerobic respiration and slightly increased oxidative mitochondrial capacity, affecting mitochondrial turnover through reduced mitochondrial fission. Moreover, by blocking the mevalonate pathway, NBPs caused a significant decrease in the level of coenzyme Q10, thereby depriving endothelial cells of an important antioxidant and mitochondrial electron carrier. This resulted in increased formation of reactive oxygen species (ROS), upregulation of antioxidant enzymes, and impairment of mitochondrial respiratory function. A general decrease in mitochondrial respiration occurred with stronger reducing fuels (pyruvate and glutamate) in NBP-treated intact endothelial cells, and significantly reduced phosphorylating respiration was observed during the oxidation of succinate and especially malate in NBP-treated permeabilized endothelial cells. The observed changes in oxidative metabolism caused a decrease in ATP levels and an increase in oxygen levels in NBP-treated cells. Thus, NBPs modulate the energy metabolism of endothelial cells, leading to alterations in the cellular energy state, coenzyme Q10 redox balance, mitochondrial respiratory function, and mitochondrial turnover.
    DOI:  https://doi.org/10.1038/s41598-023-43377-3
  30. Int J Mol Sci. 2023 Sep 07. pii: 13804. [Epub ahead of print]24(18):
    Roles of Stress Response in Autophagy Processes and Aging-Related Diseases.
    Yoshihisa Watanabe, Katsutoshi Taguchi, Masaki Tanaka.
      The heat shock factor 1 (HSF1)-mediated stress response pathway and autophagy processes play important roles in the maintenance of proteostasis. Autophagy processes are subdivided into three subtypes: macroautophagy, chaperone-mediated autophagy (CMA), and microautophagy. Recently, molecular chaperones and co-factors were shown to be involved in the selective degradation of substrates by these three autophagy processes. This evidence suggests that autophagy processes are regulated in a coordinated manner by the HSF1-mediated stress response pathway. Recently, various studies have demonstrated that proteostasis pathways including HSF1 and autophagy are implicated in longevity. Furthermore, they serve as therapeutic targets for aging-related diseases such as cancer and neurodegenerative diseases. In the future, these studies will underpin the development of therapies against various diseases.
    Keywords:  aging; chaperone-mediated autophagy; macroautophagy; microautophagy; proteostasis network; stress response
    DOI:  https://doi.org/10.3390/ijms241813804
  31. Acta Pharmacol Sin. 2023 Sep 28.
    Acetyl-CoA synthetase 2 promotes diabetic renal tubular injury in mice by rewiring fatty acid metabolism through SIRT1/ChREBP pathway.
    Jian Lu, Xue-Qi Li, Pei-Pei Chen, Jia-Xiu Zhang, Liang Li, Gui-Hua Wang, Xiao-Qi Liu, Chun-Ming Jiang, Kun-Ling Ma.
      Diabetic nephropathy (DN) is characterized by chronic low-grade renal inflammatory responses, which greatly contribute to disease progression. Abnormal glucose metabolism disrupts renal lipid metabolism, leading to lipid accumulation, nephrotoxicity, and subsequent aseptic renal interstitial inflammation. In this study, we investigated the mechanisms underlying the renal inflammation in diabetes, driven by glucose-lipid metabolic rearrangement with a focus on the role of acetyl-CoA synthetase 2 (ACSS2) in lipid accumulation and renal tubular injury. Diabetic models were established in mice by the injection of streptozotocin and in human renal tubular epithelial HK-2 cells cultured under a high glucose (HG, 30 mmol/L) condition. We showed that the expression levels of ACSS2 were significantly increased in renal tubular epithelial cells (RTECs) from the diabetic mice and human diabetic kidney biopsy samples, and ACSS2 was co-localized with the pro-inflammatory cytokine IL-1β in RTECs. Diabetic ACSS2-deficient mice exhibited reduced renal tubular injury and inflammatory responses. Similarly, ACSS2 knockdown or inhibition of ACSS2 by ACSS2i (10 µmol/L) in HK-2 cells significantly ameliorated HG-induced inflammation, mitochondrial stress, and fatty acid synthesis. Molecular docking revealed that ACSS2 interacted with Sirtuin 1 (SIRT1). In HG-treated HK-2 cells, we demonstrated that ACSS2 suppressed SIRT1 expression and activated fatty acid synthesis by modulating SIRT1-carbohydrate responsive element binding protein (ChREBP) activity, leading to mitochondrial oxidative stress and inflammation. We conclude that ACSS2 promotes mitochondrial oxidative stress and renal tubular inflammation in DN by regulating the SIRT1-ChREBP pathway. This highlights the potential therapeutic value of pharmacological inhibition of ACSS2 for alleviating renal inflammation and dysregulation of fatty acid metabolic homeostasis in DN. Metabolic inflammation in the renal region, driven by lipid metabolism disorder, is a key factor in renal injury in diabetic nephropathy (DN). Acetyl-CoA synthetase 2 (ACSS2) is abundantly expressed in renal tubular epithelial cells (RTECs) and highly upregulated in diabetic kidneys. Deleting ACSS2 reduces renal fatty acid accumulation and markers of renal tubular injury in diabetic mice. We demonstrate that ACSS2 deletion inhibits ChREBP-mediated fatty acid lipogenesis, mitochondrial oxidative stress, and inflammatory response in RTECs, which play a major role in the progression of diabetic renal tubular injury in the kidney. These findings support the potential use of ACSS2 inhibitors in treating patients with DN.
    Keywords:  Acetyl-CoA synthetase 2; ChREBP; SIRT1; diabetic nephropathy; fatty acid metabolism; renal tubular cell
    DOI:  https://doi.org/10.1038/s41401-023-01160-0
  32. Mol Cell. 2023 Sep 21. pii: S1097-2765(23)00696-2. [Epub ahead of print]
    Early fate decision for mitochondrially encoded proteins by a molecular triage.
    Andreas Kohler, Andreas Carlström, Hendrik Nolte, Verena Kohler, Sung-Jun Jung, Sagar Sridhara, Takashi Tatsuta, Jens Berndtsson, Thomas Langer, Martin Ott.
      Folding of newly synthesized proteins poses challenges for a functional proteome. Dedicated protein quality control (PQC) systems either promote the folding of nascent polypeptides at ribosomes or, if this fails, ensure their degradation. Although well studied for cytosolic protein biogenesis, it is not understood how these processes work for mitochondrially encoded proteins, key subunits of the oxidative phosphorylation (OXPHOS) system. Here, we identify dedicated hubs in proximity to mitoribosomal tunnel exits coordinating mitochondrial protein biogenesis and quality control. Conserved prohibitin (PHB)/m-AAA protease supercomplexes and the availability of assembly chaperones determine the fate of newly synthesized proteins by molecular triaging. The localization of these competing activities in the vicinity of the mitoribosomal tunnel exit allows for a prompt decision on whether newly synthesized proteins are fed into OXPHOS assembly or are degraded.
    Keywords:  assembly factors; complex assembly; m-AAA protease; mitochondria; mitoribosome; prohibitin; protein biogenesis; protein quality control; respiratory chain; translation
    DOI:  https://doi.org/10.1016/j.molcel.2023.09.001
  33. Nat Cell Biol. 2023 Sep 28.
    Regulators of mitonuclear balance link mitochondrial metabolism to mtDNA expression.
    Nicholas J Kramer, Gyan Prakash, R Stefan Isaac, Karine Choquet, Iliana Soto, Boryana Petrova, Hope E Merens, Naama Kanarek, L Stirling Churchman.
      Mitochondrial oxidative phosphorylation (OXPHOS) complexes are assembled from proteins encoded by both nuclear and mitochondrial DNA. These dual-origin enzymes pose a complex gene regulatory challenge for cells requiring coordinated gene expression across organelles. To identify genes involved in dual-origin protein complex synthesis, we performed fluorescence-activated cell-sorting-based genome-wide screens analysing mutant cells with unbalanced levels of mitochondrial- and nuclear-encoded subunits of Complex IV. We identified genes involved in OXPHOS biogenesis, including two uncharacterized genes: PREPL and NME6. We found that PREPL specifically impacts Complex IV biogenesis by acting at the intersection of mitochondrial lipid metabolism and protein synthesis, whereas NME6, an uncharacterized nucleoside diphosphate kinase, controls OXPHOS biogenesis through multiple mechanisms reliant on its NDPK domain. Firstly, NME6 forms a complex with RCC1L, which together perform nucleoside diphosphate kinase activity to maintain local mitochondrial pyrimidine triphosphate levels essential for mitochondrial RNA abundance. Secondly, NME6 modulates the activity of mitoribosome regulatory complexes, altering mitoribosome assembly and mitochondrial RNA pseudouridylation. Taken together, we propose that NME6 acts as a link between compartmentalized mitochondrial metabolites and mitochondrial gene expression.
    DOI:  https://doi.org/10.1038/s41556-023-01244-3
  34. J Cardiovasc Med (Hagerstown). 2023 Nov 01. 24(11): 838-839
    Sodium-dependent glucose transporter 2 inhibition and the atrial antiremodelling effects in HFrEF patients.
    Paolo N Marino.
      
    DOI:  https://doi.org/10.2459/JCM.0000000000001547
  35. Cell Prolif. 2023 Sep 25. e13548
    Pyruvate kinase M2 regulates kidney fibrosis through pericyte glycolysis during the progression from acute kidney injury to chronic kidney disease.
    Yulan Chen, Xueyuan Bai, Jianwen Chen, Mengjie Huang, Quan Hong, Qing Ouyang, Xuefeng Sun, Yan Zhang, Jiaona Liu, Xu Wang, Lingling Wu, Xiangmei Chen.
      We aimed to investigate the role of renal pericyte pyruvate kinase M2 (PKM2) in the progression of acute kidney injury (AKI) to chronic kidney disease (CKD). The role of PKM2 in renal pericyte-myofibroblast transdifferentiation was investigated in an AKI-CKD mouse model. Platelet growth factor receptor beta (PDGFRβ)-iCreERT2; tdTomato mice were used for renal pericyte tracing. Western blotting and immunofluorescence staining were used to examine protein expression. An 5-ethynyl-2'-deoxyuridine assay was used to measure renal pericyte proliferation. A scratch cell migration assay was used to analyse cell migration. Seahorse experiments were used to examine glycolytic rates. Enzyme-linked immunoassay was used to measure pyruvate kinase enzymatic activity and lactate concentrations. The PKM2 nuclear translocation inhibitors Shikonin and TEPP-46 were used to alter pericyte transdifferentiation. In AKI-CKD, renal pericytes proliferated and transdifferentiated into myofibroblasts and PKM2 is highly expressed in renal pericytes. Shikonin and TEPP-46 inhibited pericyte proliferation, migration, and pericyte-myofibroblast transdifferentiation by reducing nuclear PKM2 entry. In the nucleus, PKM2 promoted downstream lactate dehydrogenase A (LDHA) and glucose transporter 1 (GLUT1) transcription, which are critical for glycolysis. Therefore, PKM2 regulates pericyte glycolytic and lactate production, which regulates renal pericyte-myofibroblast transdifferentiation. PKM2-regulated renal pericyte-myofibroblast transdifferentiation by regulating downstream LDHA and GLUT1 transcription and lactate production. Reducing nuclear PKM2 import can reduce renal pericytes-myofibroblasts transdifferentiation, providing new ideas for AKI-CKD treatment.
    DOI:  https://doi.org/10.1111/cpr.13548
  36. Antioxidants (Basel). 2023 Aug 22. pii: 1656. [Epub ahead of print]12(9):
    Lactate: A Theranostic Biomarker for Metabolic Psychiatry?
    Edward Caddye, Julien Pineau, Joshua Reyniers, Itamar Ronen, Alessandro Colasanti.
      Alterations in neurometabolism and mitochondria are implicated in the pathophysiology of psychiatric conditions such as mood disorders and schizophrenia. Thus, developing objective biomarkers related to brain mitochondrial function is crucial for the development of interventions, such as central nervous system penetrating agents that target brain health. Lactate, a major circulatory fuel source that can be produced and utilized by the brain and body, is presented as a theranostic biomarker for neurometabolic dysfunction in psychiatric conditions. This concept is based on three key properties of lactate that make it an intriguing metabolic intermediate with implications for this field: Firstly, the lactate response to various stimuli, including physiological or psychological stress, represents a quantifiable and dynamic marker that reflects metabolic and mitochondrial health. Second, lactate concentration in the brain is tightly regulated according to the sleep-wake cycle, the dysregulation of which is implicated in both metabolic and mood disorders. Third, lactate universally integrates arousal behaviours, pH, cellular metabolism, redox states, oxidative stress, and inflammation, and can signal and encode this information via intra- and extracellular pathways in the brain. In this review, we expand on the above properties of lactate and discuss the methodological developments and rationale for the use of functional magnetic resonance spectroscopy for in vivo monitoring of brain lactate. We conclude that accurate and dynamic assessment of brain lactate responses might contribute to the development of novel and personalized therapies that improve mitochondrial health in psychiatric disorders and other conditions associated with neurometabolic dysfunction.
    Keywords:  brain; imaging; lactate; metabolic psychiatry; mitochondria; neurometabolism; redox
    DOI:  https://doi.org/10.3390/antiox12091656
  37. Cells. 2023 09 20. pii: 2322. [Epub ahead of print]12(18):
    TRPV1 Channels Are New Players in the Reticulum-Mitochondria Ca2+ Coupling in a Rat Cardiomyoblast Cell Line.
    Nolwenn Tessier, Mallory Ducrozet, Maya Dia, Sally Badawi, Christophe Chouabe, Claire Crola Da Silva, Michel Ovize, Gabriel Bidaux, Fabien Van Coppenolle, Sylvie Ducreux.
      The Ca2+ release in microdomains formed by intercompartmental contacts, such as mitochondria-associated endoplasmic reticulum membranes (MAMs), encodes a signal that contributes to Ca2+ homeostasis and cell fate control. However, the composition and function of MAMs remain to be fully defined. Here, we focused on the transient receptor potential vanilloid 1 (TRPV1), a Ca2+-permeable ion channel and a polymodal nociceptor. We found TRPV1 channels in the reticular membrane, including some at MAMs, in a rat cardiomyoblast cell line (SV40-transformed H9c2) by Western blotting, immunostaining, cell fractionation, and proximity ligation assay. We used chemical and genetic probes to perform Ca2+ imaging in four cellular compartments: the endoplasmic reticulum (ER), cytoplasm, mitochondrial matrix, and mitochondrial surface. Our results showed that the ER Ca2+ released through TRPV1 channels is detected at the mitochondrial outer membrane and transferred to the mitochondria. Finally, we observed that prolonged TRPV1 modulation for 30 min alters the intracellular Ca2+ equilibrium and influences the MAM structure or the hypoxia/reoxygenation-induced cell death. Thus, our study provides the first evidence that TRPV1 channels contribute to MAM Ca2+ exchanges.
    Keywords:  Ca2+ homeostasis; ER–mitochondria contact sites; H9c2; TRP channels; TRPV1; hypoxia–reoxygenation
    DOI:  https://doi.org/10.3390/cells12182322
  38. Mol Cancer Res. 2023 Sep 29.
    Metabolic hallmarks for purine nucleotide biosynthesis in small-cell lung carcinoma.
    Sho Tabata, Shigeki Umemura, Miyu Narita, Hibiki Udagawa, Takamasa Ishikawa, Masahiro Tsuboi, Koichi Goto, Genichiro Ishii, Katsuya Tsuchihara, Atsushi Ochiai, Susumu S Kobayashi, Tomoyoshi Soga, Hideki Makinoshima.
      Small-cell lung cancer (SCLC) has a poor prognosis, emphasizing the necessity for developing new therapies. The de novo synthesis pathway of purine nucleotides, which is involved in the malignant growth of SCLC, has emerged as a novel therapeutic target. Purine nucleotides are supplied by two pathways: de novo and salvage. However, the role of the salvage pathway in SCLC and the differences in utilization and crosstalk between the two pathways remain largely unclear. Here, we found that deletion of the HPRT1 gene, which codes for the rate-limiting enzyme of the purine salvage pathway, significantly suppressed tumor growth in vivo in several SCLC cells. We also demonstrated that HPRT1 expression confers resistance to lemetrexol (LMX), an inhibitor of the purine de novo pathway. Interestingly, HPRT1-knockout had less effect on SCLC SBC-5 cells, which are more sensitive to LMX than other SCLC cell lines, suggesting that a preference for either the purine de novo or salvage pathway occurs in SCLC. Furthermore, metabolome analysis of HPRT1-knockout cells revealed increased intermediates in the pentose phosphate pathway and elevated metabolic flux in the purine de novo pathway, indicating compensated metabolism between the de novo and salvage pathways in purine nucleotide biosynthesis. These results suggest that HPRT1 has therapeutic implications in SCLC and provide fundamental insights into the regulation of purine nucleotide biosynthesis. Implications: SCLC tumors preferentially utilize either the de novo or salvage pathway in purine nucleotide biosynthesis, and HPRT1 has therapeutic implications in SCLC.
    DOI:  https://doi.org/10.1158/1541-7786.MCR-23-0386
  39. Clin Exp Pharmacol Physiol. 2023 Sep 28.
    Monocarboxylate transporter 4 protects against myocardial ischemia/reperfusion injury by inducing oxidative phosphorylation/glycolysis interconversion and inhibiting oxidative stress.
    Qiao Pan, Xiaobo Xie, Qingxia Yuan.
      Myocardial ischemia/reperfusion (I/R) injury is the primary cause of heart damage in the treatment of myocardial infarction, and the imbalance of the energy metabolism in the pathogenesis of myocardial I/R is one of the main triggers of cardiac dysfunction. Monocarboxylate transporter 4 (MCT4) is a key transporter of lactate, which plays a vital role in cellular metabolism. The present study investigated the role and underlying mechanism of MCT4 in myocardial I/R injury. The results of this study showed that MCT4 was upregulated during oxygen-glucose deprivation (OGD) and restored after reoxygenation in cardiomyocytes HL-1. Interestingly, the overexpression of MCT4 increased cell viability and decreased apoptosis of OGD/R-induced HL-1 cells. Furthermore, MCT4 boosted glucose uptake and lactate levels and promoted protein expression of glycolysis regulator LDHA, while also impeding oxidative phosphorylation (OXPHOS) regulators C-MYC and NDUFB8 in OGD/R-induced HL-1 cells. A reduction in reactive oxygen species and oxidative stress markers malonaldehyde and superoxide dismutase was also observed within the OGD/R stimulated HL-1 cells. Additionally, the in vivo exogenous application of MCT4 restored cardiac function, as demonstrated by the reduced infarct size and decreased myocardial apoptosis in I/R rats. OXPHOS and oxidative stress declined, while glycolysis was activated when the I/R mice were injected with AAV-MCT4. Our findings indicate that MCT4 could exert a cardioprotective effect after myocardial I/R injury by inducing OXPHOS/glycolysis interconversion and inhibiting oxidative stress.
    Keywords:  MCT4; OXPHOS/glycolysis; ischemia/reperfusion; myocardial infarction; oxidative stress
    DOI:  https://doi.org/10.1111/1440-1681.13821
  40. Int J Mol Sci. 2023 Sep 08. pii: 13835. [Epub ahead of print]24(18):
    Mitochondrial-Derived Vesicles: The Good, the Bad, and the Ugly.
    Anna Picca, Flora Guerra, Riccardo Calvani, Hélio José Coelho-Júnior, Francesco Landi, Cecilia Bucci, Emanuele Marzetti.
      Mitophagy is crucial for maintaining mitochondrial quality. However, its assessment in vivo is challenging. The endosomal-lysosomal system is a more accessible pathway through which subtypes of extracellular vesicles (EVs), which also contain mitochondrial constituents, are released for disposal. The inclusion of mitochondrial components into EVs occurs in the setting of mild mitochondrial damage and during impairment of lysosomal function. By releasing mitochondrial-derived vesicles (MDVs), cells limit the unload of mitochondrial damage-associated molecular patterns with proinflammatory activity. Both positive and negative effects of EVs on recipient cells have been described. Whether this is due to the production of EVs other than those containing mitochondria, such as MDVs, holding specific biological functions is currently unknown. Evidence on the existence of different MDV subtypes has been produced. However, their characterization is not always pursued, which would be relevant to exploring the dynamics of mitochondrial quality control in health and disease. Furthermore, MDV classification may be instrumental in understanding their biological roles and promoting their implementation as biomarkers in clinical studies.
    Keywords:  damage-associated molecular patterns (DAMPs); endosomal–lysosomal system; exosomes; extracellular vesicles; inflammation; mitochondrial DNA; mitochondrial quality control; mitophagy; mitovesicles; oxidative stress
    DOI:  https://doi.org/10.3390/ijms241813835
  41. Int J Mol Sci. 2023 Sep 11. pii: 13928. [Epub ahead of print]24(18):
    The Illustration of Altered Glucose Dependency in Drug-Resistant Cancer Cells.
    Kausik Bishayee, Seung-Hee Lee, Yong Soo Park.
      A chemotherapeutic approach is crucial in malignancy management, which is often challenging due to the development of chemoresistance. Over time, chemo-resistant cancer cells rapidly repopulate and metastasize, increasing the recurrence rate in cancer patients. Targeting these destined cancer cells is more troublesome for clinicians, as they share biology and molecular cross-talks with normal cells. However, the recent insights into the metabolic profiles of chemo-resistant cancer cells surprisingly illustrated the activation of distinct pathways compared with chemo-sensitive or primary cancer cells. These distinct metabolic dynamics are vital and contribute to the shift from chemo-sensitivity to chemo-resistance in cancer. This review will discuss the important metabolic alterations in cancer cells that lead to drug resistance.
    Keywords:  OXPHOS; Warburg pathway; drug resistance; metabolic reprogramming; pentose phosphate pathway
    DOI:  https://doi.org/10.3390/ijms241813928
  42. Cell Mol Life Sci. 2023 Sep 25. 80(10): 302
    Metabolic and cell cycle shift induced by the deletion of Dnm1l attenuates the dissolution of pluripotency in mouse embryonic stem cells.
    Bong Jong Seo, Seung Bin Na, Joonhyuk Choi, Byeongyong Ahn, Omer Habib, Chankyu Park, Kwonho Hong, Jeong Tae Do.
      Mitochondria are versatile organelles that continuously change their morphology via fission and fusion. However, the detailed functions of mitochondrial dynamics-related genes in pluripotent stem cells remain largely unclear. Here, we aimed to determine the effects on energy metabolism and differentiation ability of mouse embryonic stem cells (ESCs) following deletion of the mitochondrial fission-related gene Dnml1. Resultant Dnm1l-/- ESCs maintained major pluripotency characteristics. However, Dnm1l-/- ESCs showed several phenotypic changes, including the inhibition of differentiation ability (dissolution of pluripotency). Notably, Dnm1l-/- ESCs maintained the expression of the pluripotency marker Oct4 and undifferentiated colony types upon differentiation induction. RNA sequencing analysis revealed that the most frequently differentially expressed genes were enriched in the glutathione metabolic pathway. Our data suggested that differentiation inhibition of Dnm1l-/- ESCs was primarily due to metabolic shift from glycolysis to OXPHOS, G2/M phase retardation, and high level of Nanog and 2-cell-specific gene expression.
    Keywords:  Cellular metabolism; Dynamin 1 like (Dnm1l); Embryonic stem cells (ESCs); Mitochondrial fission; Pluripotency
    DOI:  https://doi.org/10.1007/s00018-023-04962-x
  43. Commun Biol. 2023 Sep 23. 6(1): 977
    Oncometabolite D-2-hydroxyglutarate-dependent metabolic reprogramming induces skeletal muscle atrophy during cancer cachexia.
    Xinting Zhu, Juan Hao, Hong Zhang, Mengyi Chi, Yaxian Wang, Jinlu Huang, Rong Xu, Zhao Xincai, Bo Xin, Xipeng Sun, Jianping Zhang, Shumin Zhou, Dongdong Cheng, Ting Yuan, Jun Ding, Shuier Zheng, Cheng Guo, Quanjun Yang.
      Cancer cachexia is characterized by weight loss and skeletal muscle wasting. Based on the up-regulation of catabolism and down-regulation of anabolism, here we showed genetic mutation-mediated metabolic reprogramming in the progression of cancer cachexia by screening for metabolites and investigating their direct effect on muscle atrophy. Treatment with 93 μM D-2-hydroxyglutarate (D2HG) resulted in reduced myotube width and increased expression of E3 ubiquitin ligases. Isocitrate Dehydrogenase 1 (IDH1) mutant patients had higher D2HG than non-mutant patients. In the in vivo murine cancer cachexia model, mutant IDH1 in CT26 cancer cells accelerated cachexia progression and worsened overall survival. Transcriptomics and metabolomics revealed a distinct D2HG-induced metabolic imbalance. Treatment with the IDH1 inhibitor ivosidenib delayed the progression of cancer cachexia in murine GL261 glioma model and CT26 colorectal carcinoma models. These data demonstrate the contribution of IDH1 mutation mediated D2HG accumulation to the progression of cancer cachexia and highlight the individualized treatment of IDH1 mutation associated cancer cachexia.
    DOI:  https://doi.org/10.1038/s42003-023-05366-0
  44. Biomedicines. 2023 Aug 22. pii: 2331. [Epub ahead of print]11(9):
    Current Advances in Mitochondrial Targeted Interventions in Alzheimer's Disease.
    Tiago Sousa, Paula I Moreira, Susana Cardoso.
      Alzheimer's disease is the most prevalent neurodegenerative disorder and affects the lives not only of those who are diagnosed but also of their caregivers. Despite the enormous social, economic and political burden, AD remains a disease without an effective treatment and with several failed attempts to modify the disease course. The fact that AD clinical diagnosis is most often performed at a stage at which the underlying pathological events are in an advanced and conceivably irremediable state strongly hampers treatment attempts. This raises the awareness of the need to identify and characterize the early brain changes in AD, in order to identify possible novel therapeutic targets to circumvent AD's cascade of events. One of the most auspicious targets is mitochondria, powerful organelles found in nearly all cells of the body. A vast body of literature has shown that mitochondria from AD patients and model organisms of the disease differ from their non-AD counterparts. In view of this evidence, preserving and/or restoring mitochondria's health and function can represent the primary means to achieve advances to tackle AD. In this review, we will briefly assess and summarize the previous and latest evidence of mitochondria dysfunction in AD. A particular focus will be given to the recent updates and advances in the strategy options aimed to target faulty mitochondria in AD.
    Keywords:  Alzheimer’s disease; glucose metabolism dysregulation; mitochondria; mitochondrial-directed approaches; oxidative stress
    DOI:  https://doi.org/10.3390/biomedicines11092331
  45. Sci Rep. 2023 09 25. 13(1): 16055
    Identification of pyroptosis-related subtypes and comprehensive analysis of characteristics of the tumor microenvironment infiltration in clear cell renal cell carcinoma.
    Jiayi Zeng, Ping Zhu, Yanlin Tang, Changzheng Zhang, Chujin Ye, Shouyu Cheng, Kaiwen Tian, Bowen Yang, Weinan Zeng, Yanjun Liu, Zhiyong Xian, Yuming Yu.
      Pyroptosis is a kind of programmed cell death triggered by the inflammasome. Growing evidence has revealed the crucial utility of pyroptosis in tumors. However, the potential mechanism of pyroptosis in clear cell renal cell carcinoma (ccRCC) is still unclear. In this research, we systematically analyze the genetic and transcriptional alterations of pyroptosis-related genes (PRGs) in ccRCC, identify pyroptosis-related subtypes, analyze the clinical and microenvironmental differences among different subtypes, develop a corresponding prognostic model to predict the prognosis of patients, and interpret the effect of pyroptosis on ccRCC microenvironment. This study provides a new perspective for a comprehensive understanding of the role of pyroptosis in ccRCC and its impact on the immune microenvironment, and a reliable scoring system was established to predict patients' prognosis.
    DOI:  https://doi.org/10.1038/s41598-023-43023-y
  46. Nat Commun. 2023 Sep 25. 14(1): 5971
    A common East-Asian ALDH2 mutation causes metabolic disorders and the therapeutic effect of ALDH2 activators.
    Yi-Cheng Chang, Hsiao-Lin Lee, Wenjin Yang, Meng-Lun Hsieh, Cai-Cin Liu, Tung-Yuan Lee, Jing-Yong Huang, Jiun-Yi Nong, Fu-An Li, Hsiao-Li Chuang, Zhi-Zhong Ding, Wei-Lun Su, Li-Yun Chueh, Yi-Ting Tsai, Che-Hong Chen, Daria Mochly-Rosen, Lee-Ming Chuang.
      Obesity and type 2 diabetes have reached pandemic proportion. ALDH2 (acetaldehyde dehydrogenase 2, mitochondrial) is the key metabolizing enzyme of acetaldehyde and other toxic aldehydes, such as 4-hydroxynonenal. A missense Glu504Lys mutation of the ALDH2 gene is prevalent in 560 million East Asians, resulting in reduced ALDH2 enzymatic activity. We find that male Aldh2 knock-in mice mimicking human Glu504Lys mutation were prone to develop diet-induced obesity, glucose intolerance, insulin resistance, and fatty liver due to reduced adaptive thermogenesis and energy expenditure. We find reduced activity of ALDH2 of the brown adipose tissue from the male Aldh2 homozygous knock-in mice. Proteomic analyses of the brown adipose tissue from the male Aldh2 knock-in mice identifies increased 4-hydroxynonenal-adducted proteins involved in mitochondrial fatty acid oxidation and electron transport chain, leading to markedly decreased fatty acid oxidation rate and mitochondrial respiration of brown adipose tissue, which is essential for adaptive thermogenesis and energy expenditure. AD-9308 is a water-soluble, potent, and highly selective ALDH2 activator. AD-9308 treatment ameliorates diet-induced obesity and fatty liver, and improves glucose homeostasis in both male Aldh2 wild-type and knock-in mice. Our data highlight the therapeutic potential of reducing toxic aldehyde levels by activating ALDH2 for metabolic diseases.
    DOI:  https://doi.org/10.1038/s41467-023-41570-6
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