bims-celmim Biomed News
on Cellular and mitochondrial metabolism
Issue of 2023‒08‒27
forty-four papers selected by
Marc Segarra Mondejar, University of Cologne
  1. Alterations of Oligodendrocyte and Myelin Energy Metabolism in Multiple Sclerosis.
  2. Mitochondrial Reactive Oxygen Species Formation Determines ACSL4/LPCAT2-Mediated Ferroptosis.
  3. Role of Mitochondria-ER Contact Sites in Mitophagy.
  4. Energy (and Reactive Oxygen Species Generation) Saving Distribution of Mitochondria for the Activation of ATP Production in Skeletal Muscle.
  5. Clinical Significance of Carnitine in the Treatment of Cancer: From Traffic to the Regulation.
  6. AMPKα1 Deficiency in Astrocytes from a Rat Model of ALS Is Associated with an Altered Metabolic Resilience.
  7. ROS induced lipid peroxidation and their role in ferroptosis.
  8. An integrated view of lipid metabolism in ferroptosis revisited via lipidomic analysis.
  9. Healthy mitochondrial DNA in balanced mitochondrial dynamics: A potential marker for neuro‑aging prediction (Review).
  10. Genetics of enzymatic dysfunctions in metabolic disorders and cancer.
  11. The Role of Swelling in the Regulation of OPA1-Mediated Mitochondrial Function in the Heart In Vitro.
  12. Mitochondrial Transfer Between Cell Crosstalk - An Emerging Role in Mitochondrial Quality Control.
  13. Post-translational modifications and protein quality control of mitochondrial channels and transporters.
  14. Lipocalin-2 induces mitochondrial dysfunction in renal tubular cells via mTOR pathway activation.
  15. Synergistic ROS generation and directional overloading of endogenous calcium induce mitochondrial dysfunction in living cells.
  16. A big picture of the mitochondria-mediated signals: From mitochondria to organism.
  17. Pyruvate Dehydrogenase-Dependent Metabolic Programming Affects the Oligodendrocyte Maturation and Remyelination.
  18. Hypometabolism, Alzheimer's Disease, and Possible Therapeutic Targets: An Overview.
  19. Relationship between ferroptosis and mitophagy in renal fibrosis: a systematic review.
  20. The molecular basis of nutrient sensing and signalling by mTORC1 in metabolism regulation and disease.
  21. Mechanisms of Modulation of Mitochondrial Architecture.
  22. Fatty acid availability controls autophagy and associated cell functions.
  23. Regulation of Mitochondrial Respiration by Hydrogen Sulfide.
  24. Fatty Acid-Activated Proton Transport by Bisaryl Anion Transporters Depolarises Mitochondria and Reduces the Viability of MDA-MB-231 Breast Cancer Cells.
  25. Activated Lymphocyte-Derived DNA Drives Glucose Metabolic Adaptation for Inducing Macrophage Inflammatory Response in Systemic Lupus Erythematosus.
  26. OPA1, a molecular regulator of dilated cardiomyopathy.
  27. Circulating Sphingolipids and Glucose Homeostasis: An Update.
  28. Ferroptosis and mitochondrial dysfunction in acute central nervous system injury.
  29. Metabolic Profile of Alzheimer's Disease: Is 10-Hydroxy-2-decenoic Acid a Pertinent Metabolic Adjuster?
  30. NDUFA4 promotes the progression of head and neck paraganglioma by inhibiting ferroptosis.
  31. Exogenous H2S alleviates senescence of glomerular mesangial cells through up-regulating mitophagy by activation of AMPK-ULK1-PINK1-parkin pathway in mice.
  32. PDHA1 Alleviates Myocardial Ischemia-Reperfusion Injury by Improving Myocardial Insulin Resistance During Cardiopulmonary Bypass Surgery in Rats.
  33. Hexosamine Biosynthetic Pathway and O-GlcNAc cycling of Glucose Metabolism in Brain Function and Disease.
  34. Current Insight on the Role of Glucokinase and Glucokinase Regulatory Protein in Diabetes.
  35. The pentose phosphate pathway in health and disease.
  36. High-intensity aerobic, but not resistance or combined, exercise training improves both cardiometabolic health and skeletal muscle mitochondrial dynamics.
  37. The Unfolded Protein Response: A Double-Edged Sword for Brain Health.
  38. Mitochondrial heterogeneity in diseases.
  39. Mitochondrial Metabolism: A New Dimension of Personalized Oncology.
  40. Autophagy is regulated by endoplasmic reticulum calcium homeostasis and sphingolipid metabolism.
  41. Metabolic Reprogramming toward Aerobic Glycolysis and the Gut Microbiota Involved in the Brain Amyloid Pathology.
  42. The actin binding protein profilin 1 is critical for mitochondria function.
  43. The m6A modification-mediated OGDHL exerts a tumor suppressor role in ccRCC by downregulating FASN to inhibit lipid synthesis and ERK signaling.
  44. Amino acids contribute to adaptive thermogenesis. New insights into the mechanisms of action of recent drugs for metabolic disorders are emerging.
  1. Int J Mol Sci. 2023 Aug 18. pii: 12912. [Epub ahead of print]24(16):
    Alterations of Oligodendrocyte and Myelin Energy Metabolism in Multiple Sclerosis.
    Eneritz López-Muguruza, Carlos Matute.
      Multiple sclerosis (MS) is a complex autoimmune disease of the central nervous system (CNS), characterized by demyelination and neurodegeneration. Oligodendrocytes play a vital role in maintaining the integrity of myelin, the protective sheath around nerve fibres essential for efficient signal transmission. However, in MS, oligodendrocytes become dysfunctional, leading to myelin damage and axonal degeneration. Emerging evidence suggests that metabolic changes, including mitochondrial dysfunction and alterations in glucose and lipid metabolism, contribute significantly to the pathogenesis of MS. Mitochondrial dysfunction is observed in both immune cells and oligodendrocytes within the CNS of MS patients. Impaired mitochondrial function leads to energy deficits, affecting crucial processes such as impulse transmission and axonal transport, ultimately contributing to neurodegeneration. Moreover, mitochondrial dysfunction is linked to the generation of reactive oxygen species (ROS), exacerbating myelin damage and inflammation. Altered glucose metabolism affects the energy supply required for oligodendrocyte function and myelin synthesis. Dysregulated lipid metabolism results in changes to the composition of myelin, affecting its stability and integrity. Importantly, low levels of polyunsaturated fatty acids in MS are associated with upregulated lipid metabolism and enhanced glucose catabolism. Understanding the intricate relationship between these mechanisms is crucial for developing targeted therapies to preserve myelin and promote neurological recovery in individuals with MS. Addressing these metabolic aspects may offer new insights into potential therapeutic strategies to halt disease progression and improve the quality of life for MS patients.
    Keywords:  axonal damage; demyelination; dysmyelination; lipids; mitochondria; neurodegeneration; progressive multiple sclerosis; remyelination; repair
    DOI:  https://doi.org/10.3390/ijms241612912
  2. Antioxidants (Basel). 2023 Aug 09. pii: 1590. [Epub ahead of print]12(8):
    Mitochondrial Reactive Oxygen Species Formation Determines ACSL4/LPCAT2-Mediated Ferroptosis.
    Melanie Merkel, Bjarne Goebel, Moritz Boll, Aasha Adhikari, Viktoria Maurer, Dieter Steinhilber, Carsten Culmsee.
      Ferroptosis is a form of oxidative cell death that is characterized by enhanced lipid peroxidation and mitochondrial impairment. The enzymes acyl-CoA synthetase long-chain family member 4 (ACSL4) and lysophosphatidylcholine acyltransferase (LPCAT) play an essential role in the biosynthesis of polyunsaturated fatty acid (PUFA)-containing phospholipids, thereby providing the substrates for lipid peroxidation and promoting ferroptosis. To examine the impact of mitochondria in ACSL4/LPCAT2-driven ferroptosis, HEK293T cells overexpressing ACSL4 and LPCAT2 (OE) or empty vector controls (LV) were exposed to 1S, 3R-RSL3 (RSL3) for induction of ferroptosis. The ACSL4/LPCAT2 overexpression resulted in higher sensitivity against RSL3-induced cell death compared to LV-transfected controls. Moreover, mitochondrial parameters such as mitochondrial reactive oxygen species (ROS) formation, mitochondrial membrane potential, and mitochondrial respiration deteriorated in the OE cells, supporting the conclusion that mitochondria play a significant role in ACSL4/LPCAT2-driven ferroptosis. This was further confirmed through the protection of OE cells against RSL3-mediated cell death by the mitochondrial ROS scavenger mitoquinone (MitoQ), which exerted protection via antioxidative properties rather than through previously reported metabolic effects. Our findings implicate that mitochondrial ROS production and the accompanying organelle disintegration are essential for mediating oxidative cell death initiated through lipid peroxidation in ferroptosis.
    Keywords:  ACSL4; GPx4; HEK293T cells; LPCAT2; RSL3; ferroptosis; lipid peroxidation; mitochondria; mitochondrial ROS; mitoquinone
    DOI:  https://doi.org/10.3390/antiox12081590
  3. Biomolecules. 2023 Jul 31. pii: 1198. [Epub ahead of print]13(8):
    Role of Mitochondria-ER Contact Sites in Mitophagy.
    Alina Rühmkorf, Angelika Bettina Harbauer.
      Mitochondria are often referred to as the "powerhouse" of the cell. However, this organelle has many more functions than simply satisfying the cells' metabolic needs. Mitochondria are involved in calcium homeostasis and lipid metabolism, and they also regulate apoptotic processes. Many of these functions require contact with the ER, which is mediated by several tether proteins located on the respective organellar surfaces, enabling the formation of mitochondria-ER contact sites (MERCS). Upon damage, mitochondria produce reactive oxygen species (ROS) that can harm the surrounding cell. To circumvent toxicity and to maintain a functional pool of healthy organelles, damaged and excess mitochondria can be targeted for degradation via mitophagy, a form of selective autophagy. Defects in mitochondria-ER tethers and the accumulation of damaged mitochondria are found in several neurodegenerative diseases, including Parkinson's disease and amyotrophic lateral sclerosis, which argues that the interplay between the two organelles is vital for neuronal health. This review provides an overview of the different mechanisms of mitochondrial quality control that are implicated with the different mitochondria-ER tether proteins, and also provides a novel perspective on how MERCS are involved in mediating mitophagy upon mitochondrial damage.
    Keywords:  mitochondria; mitophagy; organellar contact sites
    DOI:  https://doi.org/10.3390/biom13081198
  4. Antioxidants (Basel). 2023 Aug 17. pii: 1624. [Epub ahead of print]12(8):
    Energy (and Reactive Oxygen Species Generation) Saving Distribution of Mitochondria for the Activation of ATP Production in Skeletal Muscle.
    Alejandra Espinosa, Mariana Casas, Enrique Jaimovich.
      Exercise produces oxidants from a variety of intracellular sources, including NADPH oxidases (NOX) and mitochondria. Exercise-derived reactive oxygen species (ROS) are beneficial, and the amount and location of these ROS is important to avoid muscle damage associated with oxidative stress. We discuss here some of the evidence that involves ROS production associated with skeletal muscle contraction and the potential oxidative stress associated with muscle contraction. We also discuss the potential role of H2O2 produced after NOX activation in the regulation of glucose transport in skeletal muscle. Finally, we propose a model based on evidence for the role of different populations of mitochondria in skeletal muscle in the regulation of ATP production upon exercise. The subsarcolemmal population of mitochondria has the enzymatic and metabolic components to establish a high mitochondrial membrane potential when fissioned at rest but lacks the capacity to produce ATP. Calcium entry into the mitochondria will further increase the metabolic input. Upon exercise, subsarcolemmal mitochondria will fuse to intermyofibrillar mitochondria and will transfer the mitochondria membrane potential to them. These mitochondria are rich in ATP synthase and will subsequentially produce the ATP needed for muscle contraction in long-term exercise. These events will optimize energy use and minimize mitochondria ROS production.
    Keywords:  ATP production; MCU; mitochondria dynamics; mitochondrial network
    DOI:  https://doi.org/10.3390/antiox12081624
  5. Oxid Med Cell Longev. 2023 ;2023 9328344
    Clinical Significance of Carnitine in the Treatment of Cancer: From Traffic to the Regulation.
    Raheleh Farahzadi, Mohammad Saeid Hejazi, Ommoleila Molavi, Elahe Pishgahzadeh, Soheila Montazersaheb, Sevda Jafari.
      Metabolic reprogramming is a common hallmark of cancer cells. Cancer cells exhibit metabolic flexibility to maintain high proliferation and survival rates. In other words, adaptation of cellular demand is essential for tumorigenesis, since a diverse supply of nutrients is required to accommodate tumor growth and progression. Diversity of carbon substrates fueling cancer cells indicate metabolic heterogeneity, even in tumors sharing the same clinical diagnosis. In addition to the alteration of glucose and amino acid metabolism in cancer cells, there is evidence that cancer cells can alter lipid metabolism. Some tumors rely on fatty acid oxidation (FAO) as the primary energy source; hence, cancer cells overexpress the enzymes involved in FAO. Carnitine is an essential cofactor in the lipid metabolic pathways. It is crucial in facilitating the transport of long-chain fatty acids into the mitochondria for β-oxidation. This role and others played by carnitine, especially its antioxidant function in cellular processes, emphasize the fine regulation of carnitine traffic within tissues and subcellular compartments. The biological activity of carnitine is orchestrated by specific membrane transporters that mediate the transfer of carnitine and its derivatives across the cell membrane. The concerted function of carnitine transporters creates a collaborative network that is relevant to metabolic reprogramming in cancer cells. Here, the molecular mechanisms relevant to the role and expression of carnitine transporters are discussed, providing insights into cancer treatment.
    DOI:  https://doi.org/10.1155/2023/9328344
  6. Biomolecules. 2023 Jul 28. pii: 1183. [Epub ahead of print]13(8):
    AMPKα1 Deficiency in Astrocytes from a Rat Model of ALS Is Associated with an Altered Metabolic Resilience.
    Inês Belo do Nascimento, Gamze Ates, Nathalie Desmet, Pauline Beckers, Ann Massie, Emmanuel Hermans.
      Alterations in the activity of the regulator of cell metabolism AMP-activated protein kinase (AMPK) have been reported in motor neurons from patients and animal models of amyotrophic lateral sclerosis (ALS). Considering the key role played by astrocytes in modulating energy metabolism in the nervous system and their compromised support towards neurons in ALS, we examined whether a putative alteration in AMPK expression/activity impacted astrocytic functions such as their metabolic plasticity and glutamate handling capacity. We found a reduced expression of AMPK mRNA in primary cultures of astrocytes derived from transgenic rats carrying an ALS-associated mutated superoxide dismutase (hSOD1G93A). The activation of AMPK after glucose deprivation was reduced in hSOD1G93A astrocytes compared to non-transgenic. This was accompanied by a lower increase in ATP levels and increased vulnerability to this insult, although the ATP production rate did not differ between the two cell types. Furthermore, soliciting the activity of glutamate transporters was found to induce similar AMPK activity in these cells. However, manipulation of AMPK activity did not influence glutamate transport. Together, these results suggest that the altered AMPK responsiveness in ALS might be context dependent and may compromise the metabolic adaptation of astrocytes in response to specific cellular stress.
    Keywords:  AMPK; ATP; glutamate transport; metabolic stress
    DOI:  https://doi.org/10.3390/biom13081183
  7. Front Cell Dev Biol. 2023 ;11 1226044
    ROS induced lipid peroxidation and their role in ferroptosis.
    Hiwot Tezera Endale, Winta Tesfaye, Tiget Ayelgn Mengstie.
      Reactive oxygen species (ROS) play a crucial part in the process of cell death, including apoptosis, autophagy, and ferroptosis. ROS involves in the oxidation of lipids and generate 4-hydroxynonenal and other compounds associated with it. Ferroptosis may be facilitated by lipid peroxidation of phospholipid bilayers. In order to offer novel ideas and directions for the investigation of disorders connected to these processes, we evaluate the function of ROS in lipid peroxidation which ultimately leads to ferroptosis as well as proposed crosstalk mechanisms between ferroptosis and other types programmed cell death.
    Keywords:  ROS; apoptosis; autophagy; ferroptosis; lipid peroxidation
    DOI:  https://doi.org/10.3389/fcell.2023.1226044
  8. Exp Mol Med. 2023 Aug 23.
    An integrated view of lipid metabolism in ferroptosis revisited via lipidomic analysis.
    Jong Woo Kim, Ji-Yoon Lee, Mihee Oh, Eun-Woo Lee.
      Ferroptosis is a form of regulated cell death characterized by iron-dependent lipid peroxidation. This process contributes to cellular and tissue damage in various human diseases, such as cardiovascular diseases, neurodegeneration, liver disease, and cancer. Although polyunsaturated fatty acids (PUFAs) in membrane phospholipids are preferentially oxidized, saturated/monounsaturated fatty acids (SFAs/MUFAs) also influence lipid peroxidation and ferroptosis. In this review, we first explain how cells differentially synthesize SFA/MUFAs and PUFAs and how they control fatty acid pools via fatty acid uptake and β-oxidation, impacting ferroptosis. Furthermore, we discuss how fatty acids are stored in different lipids, such as diacyl or ether phospholipids with different head groups; triglycerides; and cholesterols. Moreover, we explain how these fatty acids are released from these molecules. In summary, we provide an integrated view of the diverse and dynamic metabolic processes in the context of ferroptosis by revisiting lipidomic studies. Thus, this review contributes to the development of therapeutic strategies for ferroptosis-related diseases.
    DOI:  https://doi.org/10.1038/s12276-023-01077-y
  9. Biomed Rep. 2023 Sep;19(3): 64
    Healthy mitochondrial DNA in balanced mitochondrial dynamics: A potential marker for neuro‑aging prediction (Review).
    Made Putra Semadhi, Dewi Mulyaty, Eli Halimah, Jutti Levita.
      The mitochondrial genome or mitochondrial DNA (mtDNA) is released as a response to cellular stress. In mitochondrial biogenesis, active communication between the mitochondria genome and nucleus is associated with the mtDNA profile that affects the mitochondrial quality. The present review aimed to assess the molecular mechanism and potential roles of mitochondria in neuro-aging, including the importance of evaluating the health status of mtDNA via mitochondrial dynamics. The normal condition of mitochondria, defined as mitochondrial dynamics, includes persistent changes in morphology due to fission and fusion events and autophagy-mitophagy in the mitochondrial quality control process. The calculated copy number of mtDNA in the mitochondria genome represents cellular health, which can be affected by a long-term imbalance between the production and accumulation of reactive oxygen species in the neuroendocrine system, which leads to an abnormal function of mitochondria and mtDNA damage. Mitochondria health is a new approach to discovering a potential indicator for the health status of the nervous system and several types of neurodegenerative disorders. Mitochondrial dynamics is a key contributor to predicting neuro-aging development, which affects the self-renewal and differentiation of neurons in cell metabolism. Neuro-aging is associated with uncontrolled mitochondrial dynamics, which generates age-associated diseases via various mechanisms and signaling routes that lead to the mtDNA damage that has been associated with neurodegeneration. Future studies on the strategic positioning of mtDNA health profile are needed to detect early neurodegenerative disorders.
    Keywords:  cellular health; mitochondrial DNA; mitochondrial dynamics; neuro-aging
    DOI:  https://doi.org/10.3892/br.2023.1646
  10. Front Oncol. 2023 ;13 1230934
    Genetics of enzymatic dysfunctions in metabolic disorders and cancer.
    Mélanie Mahé, Tiffany J Rios-Fuller, Andrea Karolin, Robert J Schneider.
      Inherited metabolic disorders arise from mutations in genes involved in the biogenesis, assembly, or activity of metabolic enzymes, leading to enzymatic deficiency and severe metabolic impairments. Metabolic enzymes are essential for the normal functioning of cells and are involved in the production of amino acids, fatty acids and nucleotides, which are essential for cell growth, division and survival. When the activity of metabolic enzymes is disrupted due to mutations or changes in expression levels, it can result in various metabolic disorders that have also been linked to cancer development. However, there remains much to learn regarding the relationship between the dysregulation of metabolic enzymes and metabolic adaptations in cancer cells. In this review, we explore how dysregulated metabolism due to the alteration or change of metabolic enzymes in cancer cells plays a crucial role in tumor development, progression, metastasis and drug resistance. In addition, these changes in metabolism provide cancer cells with a number of advantages, including increased proliferation, resistance to apoptosis and the ability to evade the immune system. The tumor microenvironment, genetic context, and different signaling pathways further influence this interplay between cancer and metabolism. This review aims to explore how the dysregulation of metabolic enzymes in specific pathways, including the urea cycle, glycogen storage, lysosome storage, fatty acid oxidation, and mitochondrial respiration, contributes to the development of metabolic disorders and cancer. Additionally, the review seeks to shed light on why these enzymes represent crucial potential therapeutic targets and biomarkers in various cancer types.
    Keywords:  cancer; enzymatic dysregulation; fatty acid oxidation; glycogen storage; inherited metabolic disorders; lysosome storage; mitochondrial respiration; urea cycle
    DOI:  https://doi.org/10.3389/fonc.2023.1230934
  11. Cells. 2023 Aug 08. pii: 2017. [Epub ahead of print]12(16):
    The Role of Swelling in the Regulation of OPA1-Mediated Mitochondrial Function in the Heart In Vitro.
    Xavier R Chapa-Dubocq, Keishla M Rodríguez-Graciani, Jorge García-Báez, Alyssa Vadovsky, Jason N Bazil, Sabzali Javadov.
      Optic atrophy-1 (OPA1) plays a crucial role in the regulation of mitochondria fusion and participates in maintaining the structural integrity of mitochondrial cristae. Here we elucidate the role of OPA1 cleavage induced by calcium swelling in the presence of Myls22 (an OPA1 GTPase activity inhibitor) and TPEN (an OMA1 inhibitor). The rate of ADP-stimulated respiration was found diminished by both inhibitors, and they did not prevent Ca2+-induced mitochondrial respiratory dysfunction, membrane depolarization, or swelling. L-OPA1 cleavage was stimulated at state 3 respiration; therefore, our data suggest that L-OPA1 cleavage produces S-OPA1 to maintain mitochondrial bioenergetics in response to stress.
    Keywords:  OPA1; calcium retention capacity; heart mitochondria; membrane potential; mitochondrial respiration; mitochondrial swelling
    DOI:  https://doi.org/10.3390/cells12162017
  12. Ageing Res Rev. 2023 Aug 23. pii: S1568-1637(23)00197-6. [Epub ahead of print] 102038
    Mitochondrial Transfer Between Cell Crosstalk - An Emerging Role in Mitochondrial Quality Control.
    Yi Liu, Tinglv Fu, Guorui Li, Boyang Li, Guoqing Luo, Ning Li, Qing Geng.
      Intercellular signaling and component conduction are essential for multicellular organisms' homeostasis, and mitochondrial transcellular transport is a key example of such cellular component exchange. In physiological situations, mitochondrial transfer is linked with biological development, energy coordination, and clearance of harmful components, remarkably playing important roles in maintaining mitochondrial quality. Mitochondria are engaged in many critical biological activities, like oxidative metabolism and biomolecular synthesis, and are exclusively prone to malfunction in pathological processes. Importantly, severe mitochondrial damage will further amplify the defects in the mitochondrial quality control system, which will mobilize more active mitochondrial transfer, replenish exogenous healthy mitochondria, and remove endogenous damaged mitochondria to facilitate disease outcomes. This review explores intercellular mitochondrial transport in cells, its role in cellular mitochondrial quality control, and the linking mechanisms in cellular crosstalk. We also describe advances in therapeutic strategies for diseases that target mitochondrial transfer.
    Keywords:  cell crosstalk; intercellular mitochondrial transfer; mitochondrial quality control; therapy
    DOI:  https://doi.org/10.1016/j.arr.2023.102038
  13. Front Cell Dev Biol. 2023 ;11 1196466
    Post-translational modifications and protein quality control of mitochondrial channels and transporters.
    Ashlesha Kadam, Pooja Jadiya, Dhanendra Tomar.
      Mitochondria play a critical role in energy metabolism and signal transduction, which is tightly regulated by proteins, metabolites, and ion fluxes. Metabolites and ion homeostasis are mainly mediated by channels and transporters present on mitochondrial membranes. Mitochondria comprise two distinct compartments, the outer mitochondrial membrane (OMM) and the inner mitochondrial membrane (IMM), which have differing permeabilities to ions and metabolites. The OMM is semipermeable due to the presence of non-selective molecular pores, while the IMM is highly selective and impermeable due to the presence of specialized channels and transporters which regulate ion and metabolite fluxes. These channels and transporters are modulated by various post-translational modifications (PTMs), including phosphorylation, oxidative modifications, ions, and metabolites binding, glycosylation, acetylation, and others. Additionally, the mitochondrial protein quality control (MPQC) system plays a crucial role in ensuring efficient molecular flux through the mitochondrial membranes by selectively removing mistargeted or defective proteins. Inefficient functioning of the transporters and channels in mitochondria can disrupt cellular homeostasis, leading to the onset of various pathological conditions. In this review, we provide a comprehensive overview of the current understanding of mitochondrial channels and transporters in terms of their functions, PTMs, and quality control mechanisms.
    Keywords:  MCU; MPQC; MPTP; SLCs; VDAC; mitochondrial channels; mitochondrial transporters; posttranslational modifications
    DOI:  https://doi.org/10.3389/fcell.2023.1196466
  14. Cell Rep. 2023 Aug 24. pii: S2211-1247(23)01043-4. [Epub ahead of print]42(9): 113032
    Lipocalin-2 induces mitochondrial dysfunction in renal tubular cells via mTOR pathway activation.
    Eloïse Marques, Maraiza Alves Teixeira, Clément Nguyen, Fabiola Terzi, Morgan Gallazzini.
      Mitochondrial dysfunction is a critical process in renal epithelial cells upon kidney injury. While its implication in kidney disease progression is established, the mechanisms modulating it remain unclear. Here, we describe the role of Lipocalin-2 (LCN2), a protein expressed in injured tubular cells, in mitochondrial dysfunction. We show that LCN2 expression decreases mitochondrial mass and function and induces mitochondrial fragmentation. Importantly, while LCN2 expression favors DRP1 mitochondrial recruitment, DRP1 inhibition antagonizes LCN2's effect on mitochondrial shape. Remarkably, LCN2 promotes mitochondrial fragmentation independently of its secretion or transport iron activity. Mechanistically, intracellular LCN2 expression increases mTOR activity, and rapamycin inhibits LCN2's effect on mitochondrial shape. In vivo, Lcn2 gene inactivation prevents mTOR activation and mitochondrial length decrease observed upon ischemia-reperfusion-induced kidney injury (IRI) in Lcn2+/+ mice. Our data identify LCN2 as a key regulator of mitochondrial dynamics and further elucidate the mechanisms leading to mitochondrial dysfunction.
    Keywords:  CP: Metabolism; Lipocalin-2; kidney; mTOR pathway; mitochondrial dynamics
    DOI:  https://doi.org/10.1016/j.celrep.2023.113032
  15. Biomaterials. 2023 Aug 17. pii: S0142-9612(23)00292-2. [Epub ahead of print]301 122284
    Synergistic ROS generation and directional overloading of endogenous calcium induce mitochondrial dysfunction in living cells.
    Fengying Shao, Jianyu Han, Zhaoyan Tian, Zhi Wang, Songqin Liu, Yafeng Wu.
      Taking advantage of endogenous Ca2+ to upregulate intramitochondrial Ca2+ level has become a powerful mean for mitochondrial dysfunction-mediated tumor therapy. However, the Ca2+ entered into mitochondria is limited ascribing to the uncontrollability and non-selectivity of endogenous Ca2+ transport. It remains a great challenge to make the maximum use of endogenous Ca2+ to ensure sufficient Ca2+ overloading in mitochondria. Herein, we smartly fabricate an intracellular Ca2+ directional transport channel to selectively transport endogenous Ca2+ from endoplasmic reticulum (ER) to mitochondria based on cascade release nanoplatform ABT-199@liposomes/doxorubicin@FeIII-tannic acid (ABT@Lip/DOX@Fe-TA). In tumor acidic microenvironment, Fe3+ ions are firstly released and reduced by tannic acid (TA) to Fe2+ for ROS generation. Subsequently, under the NIR light irradiation, the released ABT-199 molecules combine with ROS contribute to the formation of IP3R-Grp75-VDAC1 channel between ER and mitochondria, thus Ca2+ ions are directionally delivered and intramitochondrial Ca2+ level is significantly upregulated. The synergetic ROS generation and mitochondrial Ca2+ overloading effectively intensifies mitochondrial dysfunction, thereby achieving efficient tumor inhibition. This work presents a new insight and promising avenue for endogenous Ca2+-involved tumor therapies.
    Keywords:  Ca(2+) directional transport; Cascade release; Mitochondrial Ca(2+) overloading; ROS; Tumor therapy
    DOI:  https://doi.org/10.1016/j.biomaterials.2023.122284
  16. Biochem Biophys Res Commun. 2023 Aug 20. pii: S0006-291X(23)00978-6. [Epub ahead of print]678 45-61
    A big picture of the mitochondria-mediated signals: From mitochondria to organism.
    Neşe Vardar Acar, R Köksal Özgül.
      Mitochondria, well-known for years as the powerhouse and biosynthetic center of the cell, are dynamic signaling organelles beyond their energy production and biosynthesis functions. The metabolic functions of mitochondria, playing an important role in various biological events both in physiological and stress conditions, transform them into important cellular stress sensors. Mitochondria constantly communicate with the rest of the cell and even from other cells to the organism, transmitting stress signals including oxidative and reductive stress or adaptive signals such as mitohormesis. Mitochondrial signal transduction has a vital function in regulating integrity of human genome, organelles, cells, and ultimately organism.
    Keywords:  Cellular stress; Mitochondrial crosstalk; Mitochondrial functions; Mitochondrial signaling transduction
    DOI:  https://doi.org/10.1016/j.bbrc.2023.08.032
  17. Mol Neurobiol. 2023 Aug 24.
    Pyruvate Dehydrogenase-Dependent Metabolic Programming Affects the Oligodendrocyte Maturation and Remyelination.
    M Sajad, Insha Zahoor, Faraz Rashid, Mirela Cerghet, Ramandeep Rattan, Shailendra Giri.
      The metabolic needs of the premature/premyelinating oligodendrocytes (pre-OLs) and mature oligodendrocytes (OLs) are distinct. The metabolic control of oligodendrocyte maturation from the pre-OLs to the OLs is not fully understood. Here, we show that the terminal maturation and higher mitochondrial respiration in the OLs is an integrated process controlled through pyruvate dehydrogenase complex (Pdh). Combined bioenergetics and metabolic studies show that OLs show elevated mitochondrial respiration than the pre-OLs. Our signaling studies show that the increased mitochondrial respiration activity in the OLs is mediated by the activation of Pdh due to inhibition of the pyruvate dehydrogenase kinase-1 (Pdhk1) that phosphorylates and inhibits Pdh activity. Accordingly, when Pdhk1 is directly expressed in the pre-OLs, they fail to mature into the OLs. While Pdh converts pyruvate into the acetyl-CoA by its oxidative decarboxylation, our study shows that Pdh-dependent acetyl-CoA generation from pyruvate contributes to the acetylation of the bHLH family transcription factor, oligodendrocyte transcription factor 1 (Olig1) which is known to be involved in the OL maturation. Pdh inhibition via direct expression of Pdhk1 in the pre-OLs blocks the Olig1-acetylation and OL maturation. Using the cuprizone model of demyelination, we show that Pdh is deactivated during the demyelination phase, which is however reversed in the remyelination phase upon cuprizone withdrawal. In addition, Pdh activity status correlates with the Olig1-acetylation status in the cuprizone model. Hence, the Pdh metabolic node activation allows a robust mitochondrial respiration and activation of a molecular program necessary for the terminal maturation of oligodendrocytes. Our findings open a new dialogue in the developmental biology that links cellular development and metabolism. These findings have far-reaching implications in the development of therapies for a variety of demyelinating disorders including multiple sclerosis.
    Keywords:  Metabolism; Multiple sclerosis; OPC maturation; Oligodendrocytes; Pdh; Pdhk1
    DOI:  https://doi.org/10.1007/s12035-023-03546-x
  18. Cells. 2023 Aug 08. pii: 2019. [Epub ahead of print]12(16):
    Hypometabolism, Alzheimer's Disease, and Possible Therapeutic Targets: An Overview.
    Snehal Raut, Aditya Bhalerao, Michael Powers, Minelly Gonzalez, Salvatore Mancuso, Luca Cucullo.
      The brain is a highly dynamic organ that requires a constant energy source to function normally. This energy is mostly supplied by glucose, a simple sugar that serves as the brain's principal fuel source. Glucose transport across the blood-brain barrier (BBB) is primarily controlled via sodium-independent facilitated glucose transport, such as by glucose transporter 1 (GLUT1) and 3 (GLUT3). However, other glucose transporters, including GLUT4 and the sodium-dependent transporters SGLT1 and SGLT6, have been reported in vitro and in vivo. When the BBB endothelial layer is crossed, neurons and astrocytes can absorb the glucose using their GLUT1 and GLUT3 transporters. Glucose then enters the glycolytic pathway and is metabolized into adenosine triphosphate (ATP), which supplies the energy to support cellular functions. The transport and metabolism of glucose in the brain are impacted by several medical conditions, which can cause neurological and neuropsychiatric symptoms. Alzheimer's disease (AD), Parkinson's disease (PD), epilepsy, traumatic brain injury (TBI), schizophrenia, etc., are a few of the most prevalent disorders, characterized by a decline in brain metabolism or hypometabolism early in the course of the disease. Indeed, AD is considered a metabolic disorder related to decreased brain glucose metabolism, involving brain insulin resistance and age-dependent mitochondrial dysfunction. Although the conventional view is that reduced cerebral metabolism is an effect of neuronal loss and consequent brain atrophy, a growing body of evidence points to the opposite, where hypometabolism is prodromal or at least precedes the onset of brain atrophy and the manifestation of clinical symptoms. The underlying processes responsible for these glucose transport and metabolic abnormalities are complicated and remain poorly understood. This review article provides a comprehensive overview of the current understanding of hypometabolism in AD and potential therapeutic targets.
    Keywords:  Alzheimer’s disease; blood–brain barrier; glucose metabolism; glucose transporter; glucose uptake; oxidative stress
    DOI:  https://doi.org/10.3390/cells12162019
  19. J Drug Target. 2023 Aug 23. 1-9
    Relationship between ferroptosis and mitophagy in renal fibrosis: a systematic review.
    Mingyu Zhang, Ziyuan Tong, Yaqing Wang, Wenjing Fu, Yilin Meng, Jiayi Huang, Li Sun.
      Renal fibrosis, characterised by glomerulosclerosis and tubulointerstitial fibrosis, is a typical pathological alteration in the progression of chronic kidney disease (CKD) to end-stage renal disease (ESRD). However, the limited and expensive options for treating renal fibrosis place a heavy financial burden on patients and healthcare systems. Therefore, it is significant to find an effective treatment for renal fibrosis. Ferroptosis, a non-traditional form of cell death, has been found to play an important role in acute kidney injury (AKI), tumours, neurodegenerative diseases, and so on. Moreover, a growing body of research suggests that ferroptosis might be a potential target of renal fibrosis. Meanwhile, mitophagy is a type of selective autophagy that can selectively degrade damaged or dysfunctional mitochondria as a form of mitochondrial quality control, reducing the production of reactive oxygen species (ROS), the accumulation of which is the main cause of renal fibrosis. Additionally, as a receptor of mitophagy, NIX can release beclin1 to induce mitophagy, which can also bind to solute carrier family 7 member 11 (SLC7A11) to block the activity of cystine/glutamate antitransporter (system Xc-) and inhibit ferroptosis, thereby suggesting a link between mitophagy and ferroptosis. However, there have been only limited studies on the relationship among mitophagy, ferroptosis and renal fibrosis. In this paper, we review the mechanisms of mitophagy, and describe how ferroptosis and mitophagy are related to renal fibrosis in an effort to identify potential novel targets for the treatment of renal fibrosis.
    Keywords:  Mitophagy; ferroptosis; mechanism; relationship; renal fibrosis
    DOI:  https://doi.org/10.1080/1061186X.2023.2250574
  20. Nat Rev Mol Cell Biol. 2023 Aug 23.
    The molecular basis of nutrient sensing and signalling by mTORC1 in metabolism regulation and disease.
    Claire Goul, Roberta Peruzzo, Roberto Zoncu.
      The Ser/Thr kinase mechanistic target of rapamycin (mTOR) is a central regulator of cellular metabolism. As part of mTOR complex 1 (mTORC1), mTOR integrates signals such as the levels of nutrients, growth factors, energy sources and oxygen, and triggers responses that either boost anabolism or suppress catabolism. mTORC1 signalling has wide-ranging consequences for the growth and homeostasis of key tissues and organs, and its dysregulated activity promotes cancer, type 2 diabetes, neurodegeneration and other age-related disorders. How mTORC1 integrates numerous upstream cues and translates them into specific downstream responses is an outstanding question with major implications for our understanding of physiology and disease mechanisms. In this Review, we discuss recent structural and functional insights into the molecular architecture of mTORC1 and its lysosomal partners, which have greatly increased our mechanistic understanding of nutrient-dependent mTORC1 regulation. We also discuss the emerging involvement of aberrant nutrient-mTORC1 signalling in multiple diseases.
    DOI:  https://doi.org/10.1038/s41580-023-00641-8
  21. Biomolecules. 2023 Aug 07. pii: 1225. [Epub ahead of print]13(8):
    Mechanisms of Modulation of Mitochondrial Architecture.
    Juan Pablo Muñoz, Fernanda Luisa Basei, María Laura Rojas, David Galvis, Antonio Zorzano.
      Mitochondrial network architecture plays a critical role in cellular physiology. Indeed, alterations in the shape of mitochondria upon exposure to cellular stress can cause the dysfunction of these organelles. In this scenario, mitochondrial dynamics proteins and the phospholipid composition of the mitochondrial membrane are key for fine-tuning the modulation of mitochondrial architecture. In addition, several factors including post-translational modifications such as the phosphorylation, acetylation, SUMOylation, and o-GlcNAcylation of mitochondrial dynamics proteins contribute to shaping the plasticity of this architecture. In this regard, several studies have evidenced that, upon metabolic stress, mitochondrial dynamics proteins are post-translationally modified, leading to the alteration of mitochondrial architecture. Interestingly, several proteins that sustain the mitochondrial lipid composition also modulate mitochondrial morphology and organelle communication. In this context, pharmacological studies have revealed that the modulation of mitochondrial shape and function emerges as a potential therapeutic strategy for metabolic diseases. Here, we review the factors that modulate mitochondrial architecture.
    Keywords:  lipids; membrane contact sites (MCSs); metabolic disease; metabolism; mitochondria; mitochondrial dynamics; pharmacology; post-translational modification; tethers
    DOI:  https://doi.org/10.3390/biom13081225
  22. Autophagy. 2023 Aug 21. 1-2
    Fatty acid availability controls autophagy and associated cell functions.
    Leslie A Rowland, Michael P Czech.
      Macroautophagy/autophagy requires enormous membrane expansions during concerted actions of transient autophagic vesicles and lysosomes, yet the source of the membrane lipids is poorly understood. Recent work in adipocytes has now pinpointed the de novo lipogenesis pathway as the preferred source of fatty acids for phospholipid in autophagic membrane synthesis, as loss of FASN (fatty acid synthase) disrupts autophagic flux and lysosome function in vivo and in vitro. These data indicate fatty acid synthesis channels lipid for membrane expansions, whereas fatty acids from circulating lipoproteins provide for adipose lipid storage. Importantly, autophagy blockade upon loss of fatty acids promotes a strong thermogenic phenotype in adipocytes, another striking example whereby autophagy controls cell behavior.
    Keywords:  Adipocyte; FASN; autophagosome; lipogenesis; lipophagy; p62
    DOI:  https://doi.org/10.1080/15548627.2023.2246357
  23. Antioxidants (Basel). 2023 Aug 20. pii: 1644. [Epub ahead of print]12(8):
    Regulation of Mitochondrial Respiration by Hydrogen Sulfide.
    Dandan Huang, Guangqin Jing, Shuhua Zhu.
      Hydrogen sulfide (H2S), the third gasotransmitter, has positive roles in animals and plants. Mitochondria are the source and the target of H2S and the regulatory hub in metabolism, stress, and disease. Mitochondrial bioenergetics is a vital process that produces ATP and provides energy to support the physiological and biochemical processes. H2S regulates mitochondrial bioenergetic functions and mitochondrial oxidative phosphorylation. The article summarizes the recent knowledge of the chemical and biological characteristics, the mitochondrial biosynthesis of H2S, and the regulatory effects of H2S on the tricarboxylic acid cycle and the mitochondrial respiratory chain complexes. The roles of H2S on the tricarboxylic acid cycle and mitochondrial respiratory complexes in mammals have been widely studied. The biological function of H2S is now a hot topic in plants. Mitochondria are also vital organelles regulating plant processes. The regulation of H2S in plant mitochondrial functions is gaining more and more attention. This paper mainly summarizes the current knowledge on the regulatory effects of H2S on the tricarboxylic acid cycle (TCA) and the mitochondrial respiratory chain. A study of the roles of H2S in mitochondrial respiration in plants to elucidate the botanical function of H2S in plants would be highly desirable.
    Keywords:  hydrogen sulfide; mitochondria; mitochondrial respiratory complex; oxidative phosphorylation; tricarboxylic acid cycle
    DOI:  https://doi.org/10.3390/antiox12081644
  24. Biomolecules. 2023 Jul 31. pii: 1202. [Epub ahead of print]13(8):
    Fatty Acid-Activated Proton Transport by Bisaryl Anion Transporters Depolarises Mitochondria and Reduces the Viability of MDA-MB-231 Breast Cancer Cells.
    Edward York, Daniel A McNaughton, Meryem-Nur Duman, Philip A Gale, Tristan Rawling.
      In respiring mitochondria, the proton gradient across the inner mitochondrial membrane is used to drive ATP production. Mitochondrial uncouplers, which are typically weak acid protonophores, can disrupt this process to induce mitochondrial dysfunction and apoptosis in cancer cells. We have shown that bisaryl urea-based anion transporters can also mediate mitochondrial uncoupling through a novel fatty acid-activated proton transport mechanism, where the bisaryl urea promotes the transbilayer movement of deprotonated fatty acids and proton transport. In this paper, we investigated the impact of replacing the urea group with squaramide, amide and diurea anion binding motifs. Bisaryl squaramides were found to depolarise mitochondria and reduce MDA-MB-231 breast cancer cell viability to similar extents as their urea counterpart. Bisaryl amides and diureas were less active and required higher concentrations to produce these effects. For all scaffolds, the substitution of the bisaryl rings with lipophilic electron-withdrawing groups was required for activity. An investigation of the proton transport mechanism in vesicles showed that active compounds participate in fatty acid-activated proton transport, except for a squaramide analogue, which was sufficiently acidic to act as a classical protonophore and transport protons in the absence of free fatty acids.
    Keywords:  anion transporter; anticancer; membrane; mitochondria; proton transport; uncouplers
    DOI:  https://doi.org/10.3390/biom13081202
  25. Cells. 2023 Aug 18. pii: 2093. [Epub ahead of print]12(16):
    Activated Lymphocyte-Derived DNA Drives Glucose Metabolic Adaptation for Inducing Macrophage Inflammatory Response in Systemic Lupus Erythematosus.
    Hanqing Zhao, Zhenke Wen, Sidong Xiong.
      Activated lymphocyte-derived DNA (ALD-DNA) has been reported to drive the polarization of macrophages toward M2b, producing inflammatory cytokines and inducing inflammation, correspondingly playing an essential role in the development of systemic lupus erythematosus (SLE). Recently, accumulating evidence has pinpointed metabolic adaptation as the crucial cell-intrinsic determinant for inflammatory response, in which glucose metabolism is the key event. However, whether and how glucose metabolism was involved in ALD-DNA-induced macrophage inflammatory response and SLE development remains unclear. Herein, we performed glucose metabolomic analyses of ALD-DNA-stimulated macrophages and uncovered increased glycolysis and diminished pentose phosphate pathway (PPP), as well as enhanced glycogenesis. In ALD-DNA-stimulated macrophages, increased glycolysis resulted in higher lactate production, whereas diminished PPP efficiently led to lower levels of nicotinamide adenine dinucleotide phosphate (NADPH) with higher levels of reactive oxygen species (ROS). While blockade of lactate generation exerted no significant effect on macrophage inflammation in response to ALD-DNA, scavenging ROS fundamentally inhibited the inflammatory response of ALD-DNA-stimulated macrophages. Further, cyclic adenosine monophosphate (cAMP), a master for regulating glycogen metabolism, was downregulated by ALD-DNA in macrophages, which subsequently imbalanced glycogen metabolism toward glycogenesis but not glycogenolysis. Administration of cAMP effectively restored glycogenolysis and enhanced PPP, which correspondingly reduced ROS levels and inhibited the inflammatory response of ALD-DNA-stimulated macrophages. Finally, blocking glucose metabolism using 2-deoxy-D-glucose (2-DG) efficiently restricted macrophage inflammatory response and alleviated ALD-DNA-induced lupus disease. Together, our findings demonstrate that ALD-DNA drives the adaptation of glucose metabolism for inducing macrophage inflammatory response in SLE, which might further our understanding of disease pathogenesis and provide clues for interventive explorations.
    Keywords:  ALD-DNA; SLE; cAMP; glucose metabolism; macrophage inflammatory response
    DOI:  https://doi.org/10.3390/cells12162093
  26. J Cell Mol Med. 2023 Aug 21.
    OPA1, a molecular regulator of dilated cardiomyopathy.
    Jiaqi Chen, Jianan Shao, Yaoyao Wang, Kangxiang Wu, Mingyuan Huang.
      Dilated cardiomyopathy (DCM) is a disease with no specific treatment, poor prognosis and high mortality. During DCM development, there is apoptosis, mitochondrial dynamics imbalance and changes in cristae structure. Optic atrophy 1 (OPA1) appears at high frequency in these three aspects. DCM LMNA (LaminA/C) gene mutation can activate TP53, and the study of P53 shows that P53 affects OPA1 through Bak/Bax and OMA1(a metalloprotease). OPA1 can be considered the missing link between DCMp53 and DCM apoptosis, mitochondrial dynamics imbalance and changes in cristae structure. OPA1 regulates apoptosis by regulating the release of cytochrome c from the mitochondrial matrix through CJs (crisp linkages, located in the inner mitochondrial membrane) and unbalances mitochondrial fusion and fission by affecting mitochondrial inner membrane (IM) fusion. OPA1 is also associated with the formation and maintenance of mitochondrial cristae. OPA1 is not the root cause of DCM, but it is an essential mediator in P53 mediating the occurrence and development of DCM, so OPA1 also becomes a molecular regulator of DCM. This review discusses the implication of OPA1 for DCM from three aspects: apoptosis, mitochondrial dynamics and ridge structure.
    Keywords:  OPA1; P53; apoptosis; cristae; dilated cardiomyopathy; fusion
    DOI:  https://doi.org/10.1111/jcmm.17918
  27. Int J Mol Sci. 2023 Aug 12. pii: 12720. [Epub ahead of print]24(16):
    Circulating Sphingolipids and Glucose Homeostasis: An Update.
    Sarah Ali-Berrada, Jeanne Guitton, Sophie Tan-Chen, Anna Gyulkhandanyan, Eric Hajduch, Hervé Le Stunff.
      Sphingolipids are a family of lipid molecules produced through different pathways in mammals. Sphingolipids are structural components of membranes, but in response to obesity, they are implicated in the regulation of various cellular processes, including inflammation, apoptosis, cell proliferation, autophagy, and insulin resistance which favors dysregulation of glucose metabolism. Of all sphingolipids, two species, ceramides and sphingosine-1-phosphate (S1P), are also found abundantly secreted into the bloodstream and associated with lipoproteins or extracellular vesicles. Plasma concentrations of these sphingolipids can be altered upon metabolic disorders and could serve as predictive biomarkers of these diseases. Recent important advances suggest that circulating sphingolipids not only serve as biomarkers but could also serve as mediators in the dysregulation of glucose homeostasis. In this review, advances of molecular mechanisms involved in the regulation of ceramides and S1P association to lipoproteins or extracellular vesicles and how they could alter glucose metabolism are discussed.
    Keywords:  biomarkers; ceramides; extracellular vesicles; lipoproteins; sphingosine-1-phosphate
    DOI:  https://doi.org/10.3390/ijms241612720
  28. Front Cell Neurosci. 2023 ;17 1228968
    Ferroptosis and mitochondrial dysfunction in acute central nervous system injury.
    Wenxue Dong, Fanghe Gong, Yu Zhao, Hongmin Bai, Ruixin Yang.
      Acute central nervous system injuries (ACNSI), encompassing traumatic brain injury (TBI), non-traumatic brain injury like stroke and encephalomeningitis, as well as spinal cord injuries, are linked to significant rates of disability and mortality globally. Nevertheless, effective and feasible treatment plans are still to be formulated. There are primary and secondary injuries occurred after ACNSI. Most ACNSIs exhibit comparable secondary injuries, which offer numerous potential therapeutic targets for enhancing clinical outcomes. Ferroptosis, a newly discovered form of cell death, is characterized as a lipid peroxidation process that is dependent on iron and oxidative conditions, which is also indispensable to mitochondria. Ferroptosis play a vital role in many neuropathological pathways, and ACNSIs may induce mitochondrial dysfunction, thereby indicating the essentiality of the mitochondrial connection to ferroptosis in ACNSIs. Nevertheless, there remains a lack of clarity regarding the involvement of mitochondria in the occurrence of ferroptosis as a secondary injuries of ACNSIs. In recent studies, anti-ferroptosis agents such as the ferroptosis inhibitor Ferrostain-1 and iron chelation therapy have shown potential in ameliorating the deleterious effects of ferroptosis in cases of traumatic ACNSI. The importance of this evidence is extremely significant in relation to the research and control of ACNSIs. Therefore, our review aims to provide researchers focusing on enhancing the therapeutic outcomes of ACNSIs with valuable insights by summarizing the physiopathological mechanisms of ACNSIs and exploring the correlation between ferroptosis, mitochondrial dysfunction, and ACNSIs.
    Keywords:  acute central nervous system injury; ferroptosis; mitochondrial homeostasis; spinal cord injury; traumatic brain injury
    DOI:  https://doi.org/10.3389/fncel.2023.1228968
  29. Metabolites. 2023 Aug 18. pii: 954. [Epub ahead of print]13(8):
    Metabolic Profile of Alzheimer's Disease: Is 10-Hydroxy-2-decenoic Acid a Pertinent Metabolic Adjuster?
    Yuan Gong, Hongjie Luo, Zeju Li, Yijun Feng, Zhen Liu, Jie Chang.
      Alzheimer's disease (AD) represents a significant public health concern in modern society. Metabolic syndrome (MetS), which includes diabetes mellitus (DM) and obesity, represents a modifiable risk factor for AD. MetS and AD are interconnected through various mechanisms, such as mitochondrial dysfunction, oxidative stress, insulin resistance (IR), vascular impairment, inflammation, and endoplasmic reticulum (ER) stress. Therefore, it is necessary to seek a multi-targeted and safer approach to intervention. Thus, 10-hydroxy-2-decenoic acid (10-HDA), a unique hydroxy fatty acid in royal jelly, has shown promising anti-neuroinflammatory, blood-brain barrier (BBB)-preserving, and neurogenesis-promoting properties. In this paper, we provide a summary of the relationship between MetS and AD, together with an introduction to 10-HDA as a potential intervention nutrient. In addition, molecular docking is performed to explore the metabolic tuning properties of 10-HDA with associated macromolecules such as GLP-1R, PPARs, GSK-3, and TREM2. In conclusion, there is a close relationship between AD and MetS, and 10-HDA shows potential as a beneficial nutritional intervention for both AD and MetS.
    Keywords:  10-HDA; Alzheimer’s disease; diabetes mellitus; molecular docking; obesity
    DOI:  https://doi.org/10.3390/metabo13080954
  30. Biochem Cell Biol. 2023 Aug 21.
    NDUFA4 promotes the progression of head and neck paraganglioma by inhibiting ferroptosis.
    Zhigang Wang, Erxing Tao, Yiming Chen, Qi Wang, Min Liu, Liang Wei, Siyi Xu, Wei Chen, Chunlong Zhong.
      NDUFA4 is a component of respiratory chain-oxidative phosphorylation pathway. NDUFA4 is highly expressed in tumor tissues, but little is known about the function of NDUFA4 in head and neck paraganglioma (HNPGL). We examined NDUFA4 expression in tissues from 10 HNPGL patients and 6 controls using qRT-PCR and Western blotting. NDUFA4 knockdown PGL-626 cells were established by using lentivirus infection and puromycin screening. Cell viability, ATP production, lipid reactive oxygen species, and mitochondrial membrane potential assays were performed to investigate the ferroptotic effects in NDUFA4 deficiency HNPGL cancer cells. Xenograft mouse model was created to detect the synergetic antitumor action between NDUFA4 deficiency and Metformin. NDUFA4 was upregulated in tumor tissues of HNPGL patients. NDUFA4 knockdown impaired the assembly of mitochondrial respiratory chain complexes and decreased the production of ATP and reduced cancer cell viability. Mechanistically, NDUFA4 knockdown increased cell ferroptosis, which further promoted Metformin-induced ferroptosis in PGL-626 cells. Therefore, NDUFA4 deficiency enhanced Metformin-mediated inhibition of the HNPGL progression in mice. In conclusion, NDUFA4 promotes the progression of HNPGL, and NDUFA4 knockdown enhances Metformin-mediated inhibition of the HNPGL progression in a mouse model.
    Keywords:  HNPGL; NDUFA4; ferroptosis; mitochondria; mouse
    DOI:  https://doi.org/10.1139/bcb-2023-0018
  31. Biochim Biophys Acta Mol Cell Res. 2023 Aug 17. pii: S0167-4889(23)00141-6. [Epub ahead of print] 119568
    Exogenous H2S alleviates senescence of glomerular mesangial cells through up-regulating mitophagy by activation of AMPK-ULK1-PINK1-parkin pathway in mice.
    E Yaqi, Yan Lin, Guoliang Yan, Jiahe Yang, Lijie Jiao, Ren Wu, Qiuyi Yan, Yinuo Chen, Yongxiang Chen, Xinwu Yan, Hongzhu Li.
      Hydrogen sulfide (H2S) is the third gas signaling molecule that has been shown to be involved in the regulating vital activities in the body, including inhibition of aging. However, it is unknown whether H2S alleviates aging in the kidney and glomerular mesangial cells (GMCs) by modulating their mitophagy. Here, results of experiments in vivo and in vitro showed that compared with control group, the renal function of mice and GMCs viability were decreased in D-gal (D-galactose) group, while the activity of SA-β-gal and p21 expression were increased, Cyclin D1 and Klotho expressions were decreased; H2S content and CSE expression were lower; ROS and MDA contents and mitochondrial permeability transition pore (mPTP) opening were rised; ATP production and mitochondrial membrane potential (Δψm) were reduced; Apoptotic rate, the expression of cleaved caspase-9 and -3, Cyt c, p62 and Drp1 were enhanced and the expression of Bcl-2, Mfn2, Beclin-1, LC3 II/I, PINK1 and parkin were decreased. In addition, phospho-AMPK/AMPK and phospho-ULK1/ULK1 were also decreased significantly. Compared with the D-gal group, the changes of above indexes were reversed in the D-gal + NaHS (Sodium hydrosulfide, an exogenous H2S donor) group. The reverse effects of NaHS were similar to that of AICAR (an AMPK agonist) and kinetin (a PINK1 agonist), respectively. Taken together, these results suggest that exogenous H2S increases mitophagy and inhibits apoptosis as well as oxidative stress through up-regulation of AMPK-ULK1-PINK1-parkin pathway, which delays kidney senescence in mice.
    Keywords:  Glomerular mesangial cells; Hydrogen sulfide; Kidney; Mitophagy; Senescence
    DOI:  https://doi.org/10.1016/j.bbamcr.2023.119568
  32. Cardiovasc Drugs Ther. 2023 Aug 23.
    PDHA1 Alleviates Myocardial Ischemia-Reperfusion Injury by Improving Myocardial Insulin Resistance During Cardiopulmonary Bypass Surgery in Rats.
    Kai-Yuan Chen, Zhou Liu, Jing Yi, Yong-Peng Hui, Ying-Nan Song, Jun-Hou Lu, Hong-Jin Chen, Si-Yuan Yang, Xuan-Yi Hu, Deng-Shen Zhang, Gui-You Liang.
      OBJECTIVE: Cardiopulmonary bypass (CPB) is a requisite technique for thoracotomy in advanced cardiovascular surgery. However, the consequent myocardial ischemia-reperfusion injury (MIRI) is the primary culprit behind cardiac dysfunction and fatal consequences post-operation. Prior research has posited that myocardial insulin resistance (IR) plays a vital role in exacerbating the progression of MIRI. Nonetheless, the exact mechanisms underlying this phenomenon remain obscure.METHODS: We constructed pyruvate dehydrogenase E1 α subunit (PDHA1) interference and overexpression rats and used ascending aorta occlusion in an in vivo model of CPB-MIRI. We devised an in vivo model of CPB-MIRI by constructing rat models with both pyruvate dehydrogenase E1α subunit (PDHA1) interference and overexpression through ascending aorta occlusion. We analyzed myocardial glucose metabolism and the degree of myocardial injury using functional monitoring, biochemical assays, and histological analysis.
    RESULTS: We discovered a clear downregulation of glucose transporter 4 (GLUT4) protein content expression in the CPB I/R model. In particular, cardiac-specific PDHA1 interference resulted in exacerbated cardiac dysfunction, significantly increased myocardial infarction area, more pronounced myocardial edema, and markedly increased cardiomyocyte apoptosis. Notably, the opposite effect was observed with PDHA1 overexpression, leading to a mitigated cardiac dysfunction and decreased incidence of myocardial infarction post-global ischemia. Mechanistically, PDHA1 plays a crucial role in regulating the protein content expression of GLUT4 on cardiomyocytes, thereby controlling the uptake and utilization of myocardial glucose, influencing the development of myocardial insulin resistance, and ultimately modulating MIRI.
    CONCLUSION: Overall, our study sheds new light on the pivotal role of PDHA1 in glucose metabolism and the development of myocardial insulin resistance. Our findings hold promising therapeutic potential for addressing the deleterious effects of MIRI in patients.
    Keywords:  Cardiopulmonary bypass; GLUT4; Myocardial insulin resistance; Myocardial ischemia-reperfusion injury; PDHA1
    DOI:  https://doi.org/10.1007/s10557-023-07501-9
  33. Am J Physiol Cell Physiol. 2023 Aug 21.
    Hexosamine Biosynthetic Pathway and O-GlcNAc cycling of Glucose Metabolism in Brain Function and Disease.
    Dong Yeol Kim, Jiwon Park, Inn-Oc Han.
      Impaired brain glucose metabolism is considered a hallmark of brain dysfunction and neurodegeneration. Disruption of the hexosamine biosynthetic pathway (HBP) and subsequent O-linked N-acetylglucosamine (O-GlcNAc) cycling has been identified as an emerging link between altered glucose metabolism and defects in the brain. Myriads of cytosolic and nuclear proteins in the nervous system are modified at serine or threonine residues with a single N-acetylglucosamine (O-GlcNAc) molecule by O-GlcNAc transferase (OGT), which can be removed by β-N-acetylglucosaminidase (O-GlcNAcase, OGA). Homeostatic regulation of O-GlcNAc cycling is important for maintenance of normal brain activity. While significant evidence linking dysregulated HBP metabolism and aberrant O-GlcNAc cycling to induction or progression of neuronal diseases has been obtained, the issue of whether altered O-GlcNAcylation is causal in brain pathogenesis remains uncertain. Elucidation of the specific functions and regulatory mechanisms of individual O-GlcNAcylated neuronal proteins in both normal and diseased states may facilitate the identification of novel therapeutic targets for various neuronal disorders. The information presented in this review highlights the importance of HBP/O-GlcNAcylation in the neuronal system and summarizes the roles and potential mechanisms of O-GlcNAcylated neuronal proteins in maintaining normal brain function and initiation and progression of neurological diseases.
    Keywords:  Hexosamine biosynthetic pathway; Neurodegeneration; O-GlcNAcylation
    DOI:  https://doi.org/10.1152/ajpcell.00191.2023
  34. Mini Rev Med Chem. 2023 Aug 23.
    Current Insight on the Role of Glucokinase and Glucokinase Regulatory Protein in Diabetes.
    Ajita Paliwal, Vartika Paliwal, Smita Jain, Sarvesh Paliwal, Swapnil Sharma.
      The glucokinase regulator (GCKR) gene encodes an inhibitor of the glucokinase enzyme (GCK), found only in hepatocytes and responsible for glucose metabolism. A common GCKR coding variation has been linked to various metabolic traits in genome-wide association studies. Rare GCKR polymorphisms influence GKRP activity, expression, and localization. Despite not being the cause, these variations are linked to hypertriglyceridemia. Because of their crystal structures, we now better understand the molecular interactions between GKRP and the GCK. Finally, small molecules that specifically bind to GKRP and decrease blood sugar levels in diabetic models have been identified. GCKR allelic spectrum changes affect lipid and glucose homeostasis. GKRP dysfunction has been linked to a variety of molecular causes, according to functional analysis. Numerous studies have shown that GKRP dysfunction is not the only cause of hypertriglyceridemia, implying that type 2 diabetes could be treated by activating liver-specific GCK via small molecule GKRP inhibition. The review emphasizes current discoveries concerning the characteristic roles of glucokinase and GKRP in hepatic glucose metabolism and diabetes. This information has influenced the growth of directed molecular therapies for diabetes, which has improved our understanding of lipid and glucose physiology.
    Keywords:  Glucokinase; diabetes therapy.; glucokinase regulator; glucokinase regulatory protein; glucose homeostasis
    DOI:  https://doi.org/10.2174/1389557523666230823151927
  35. Nat Metab. 2023 Aug;5(8): 1275-1289
    The pentose phosphate pathway in health and disease.
    Tara TeSlaa, Markus Ralser, Jing Fan, Joshua D Rabinowitz.
      The pentose phosphate pathway (PPP) is a glucose-oxidizing pathway that runs in parallel to upper glycolysis to produce ribose 5-phosphate and nicotinamide adenine dinucleotide phosphate (NADPH). Ribose 5-phosphate is used for nucleotide synthesis, while NADPH is involved in redox homoeostasis as well as in promoting biosynthetic processes, such as the synthesis of tetrahydrofolate, deoxyribonucleotides, proline, fatty acids and cholesterol. Through NADPH, the PPP plays a critical role in suppressing oxidative stress, including in certain cancers, in which PPP inhibition may be therapeutically useful. Conversely, PPP-derived NADPH also supports purposeful cellular generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) for signalling and pathogen killing. Genetic deficiencies in the PPP occur relatively commonly in the committed pathway enzyme glucose-6-phosphate dehydrogenase (G6PD). G6PD deficiency typically manifests as haemolytic anaemia due to red cell oxidative damage but, in severe cases, also results in infections due to lack of leucocyte oxidative burst, highlighting the dual redox roles of the pathway in free radical production and detoxification. This Review discusses the PPP in mammals, covering its roles in biochemistry, physiology and disease.
    DOI:  https://doi.org/10.1038/s42255-023-00863-2
  36. J Appl Physiol (1985). 2023 Aug 24.
    High-intensity aerobic, but not resistance or combined, exercise training improves both cardiometabolic health and skeletal muscle mitochondrial dynamics.
    Gregory N Ruegsegger, Mark W Pataky, Suvyaktha Simha, Matthew M Robinson, Katherine A Klaus, K Sreekumaran Nair.
      This study investigated how different exercise training modalities influence skeletal muscle mitochondrial dynamics. Healthy (average B.M.I.: 25.8 kg/m2), sedentary younger and older participants underwent 12 weeks of supervised high-intensity aerobic interval training (HIIT) (n = 13), resistance training (RT) (n = 14), or combined training (CT) (n = 11). Mitochondrial structure was assessed using transmission electron microscopy (TEM). Regulators of mitochondrial fission and fusion, cardiorespiratory fitness (VO2peak), insulin sensitivity via a hyperinsulinemic-euglycemic clamp, and muscle mitochondrial respiration were assessed. TEM showed increased mitochondrial volume, number, and perimeter following HIIT (p < 0.01), increased mitochondrial number following CT (p < 0.05), and no change in mitochondrial abundance after RT. Increased mitochondrial volume associated with increased mitochondrial respiration and insulin sensitivity following HIIT (p < 0.05). Increased mitochondrial perimeter associated with increased mitochondrial respiration, insulin sensitivity, and VO2peak following HIIT (p < 0.05). No such relationships were observed following CT or RT. OPA1, a regulator of fusion, was increased following HIIT (p < 0.05), while FIS1, a regulator of fission, was decreased following HIIT and CT (p < 0.05). HIIT also increased the ratio of OPA1/FIS1 (p < 0.01), indicative of the balance between fission and fusion, which positively correlated with improvements in respiration, insulin sensitivity, and VO2peak (p <0.05). In conclusion, HIIT induces a larger, more fused mitochondrial tubular network. Changes indicative of increased fusion following HIIT associate with improvements in mitochondrial respiration, insulin sensitivity, and VO2peak supporting the idea that enhanced mitochondrial fusion accompanies notable health benefits of HIIT.
    Keywords:  HIIT; aerobic exercise; fission; fusion; mitochondria
    DOI:  https://doi.org/10.1152/japplphysiol.00405.2023
  37. Antioxidants (Basel). 2023 Aug 21. pii: 1648. [Epub ahead of print]12(8):
    The Unfolded Protein Response: A Double-Edged Sword for Brain Health.
    Magdalena Gebert, Jakub Sławski, Leszek Kalinowski, James F Collawn, Rafal Bartoszewski.
      Efficient brain function requires as much as 20% of the total oxygen intake to support normal neuronal cell function. This level of oxygen usage, however, leads to the generation of free radicals, and thus can lead to oxidative stress and potentially to age-related cognitive decay and even neurodegenerative diseases. The regulation of this system requires a complex monitoring network to maintain proper oxygen homeostasis. Furthermore, the high content of mitochondria in the brain has elevated glucose demands, and thus requires a normal redox balance. Maintaining this is mediated by adaptive stress response pathways that permit cells to survive oxidative stress and to minimize cellular damage. These stress pathways rely on the proper function of the endoplasmic reticulum (ER) and the activation of the unfolded protein response (UPR), a cellular pathway responsible for normal ER function and cell survival. Interestingly, the UPR has two opposing signaling pathways, one that promotes cell survival and one that induces apoptosis. In this narrative review, we discuss the opposing roles of the UPR signaling pathways and how a better understanding of these stress pathways could potentially allow for the development of effective strategies to prevent age-related cognitive decay as well as treat neurodegenerative diseases.
    Keywords:  brain; calcium; endoplasmic reticulum stress; mitochondria unfolded protein response; neurodegeneration; nitrosative stress; oxidative stress; oxygen homeostasis; proteostasis
    DOI:  https://doi.org/10.3390/antiox12081648
  38. Signal Transduct Target Ther. 2023 Aug 23. 8(1): 311
    Mitochondrial heterogeneity in diseases.
    Long Chen, Mengnan Zhou, Hao Li, Delin Liu, Peng Liao, Yao Zong, Changqing Zhang, Weiguo Zou, Junjie Gao.
      As key organelles involved in cellular metabolism, mitochondria frequently undergo adaptive changes in morphology, components and functions in response to various environmental stresses and cellular demands. Previous studies of mitochondria research have gradually evolved, from focusing on morphological change analysis to systematic multiomics, thereby revealing the mitochondrial variation between cells or within the mitochondrial population within a single cell. The phenomenon of mitochondrial variation features is defined as mitochondrial heterogeneity. Moreover, mitochondrial heterogeneity has been reported to influence a variety of physiological processes, including tissue homeostasis, tissue repair, immunoregulation, and tumor progression. Here, we comprehensively review the mitochondrial heterogeneity in different tissues under pathological states, involving variant features of mitochondrial DNA, RNA, protein and lipid components. Then, the mechanisms that contribute to mitochondrial heterogeneity are also summarized, such as the mutation of the mitochondrial genome and the import of mitochondrial proteins that result in the heterogeneity of mitochondrial DNA and protein components. Additionally, multiple perspectives are investigated to better comprehend the mysteries of mitochondrial heterogeneity between cells. Finally, we summarize the prospective mitochondrial heterogeneity-targeting therapies in terms of alleviating mitochondrial oxidative damage, reducing mitochondrial carbon stress and enhancing mitochondrial biogenesis to relieve various pathological conditions. The possibility of recent technological advances in targeted mitochondrial gene editing is also discussed.
    DOI:  https://doi.org/10.1038/s41392-023-01546-w
  39. Cancers (Basel). 2023 Aug 11. pii: 4058. [Epub ahead of print]15(16):
    Mitochondrial Metabolism: A New Dimension of Personalized Oncology.
    Babak Behnam, Farzad Taghizadeh-Hesary.
      Energy is needed by cancer cells to stay alive and communicate with their surroundings. The primary organelles for cellular metabolism and energy synthesis are mitochondria. Researchers recently proved that cancer cells can steal immune cells' mitochondria using nanoscale tubes. This finding demonstrates the dependence of cancer cells on normal cells for their living and function. It also denotes the importance of mitochondria in cancer cells' biology. Emerging evidence has demonstrated how mitochondria are essential for cancer cells to survive in the harsh tumor microenvironments, evade the immune system, obtain more aggressive features, and resist treatments. For instance, functional mitochondria can improve cancer resistance against radiotherapy by scavenging the released reactive oxygen species. Therefore, targeting mitochondria can potentially enhance oncological outcomes, according to this notion. The tumors' responses to anticancer treatments vary, ranging from a complete response to even cancer progression during treatment. Therefore, personalized cancer treatment is of crucial importance. So far, personalized cancer treatment has been based on genomic analysis. Evidence shows that tumors with high mitochondrial content are more resistant to treatment. This paper illustrates how mitochondrial metabolism can participate in cancer resistance to chemotherapy, immunotherapy, and radiotherapy. Pretreatment evaluation of mitochondrial metabolism can provide additional information to genomic analysis and can help to improve personalized oncological treatments. This article outlines the importance of mitochondrial metabolism in cancer biology and personalized treatments.
    Keywords:  T cell; cancer stem cell; mitochondria; personalized oncology
    DOI:  https://doi.org/10.3390/cancers15164058
  40. Autophagy. 2023 Aug 23. 1-2
    Autophagy is regulated by endoplasmic reticulum calcium homeostasis and sphingolipid metabolism.
    Shiyan Liu, Mutian Chen, Yichang Wang, Huihui Li, Shiqian Qi, Jia Geng, Kefeng Lu.
      Calcium is involved in a variety of cellular processes. As the crucial components of cell membranes, sphingolipids also play important roles as signaling molecules. Intracellular calcium homeostasis, autophagy initiation and sphingolipid synthesis are associated with the endoplasmic reticulum (ER). Recently, through genetic screening and lipidomics analysis in Saccharomyces cerevisiae, we found that the ER calcium channel Csg2 converts sphingolipid metabolism into macroautophagy/autophagy regulation by controlling ER calcium homeostasis. The results showed that Csg2 acts as a calcium channel to mediate ER calcium efflux into the cytoplasm, and deletion of CSG2 causes a distinct increase of ER calcium concentration, thereby disrupting the stability of the sphingolipid synthase Aur1, leading to the accumulation of the bioactive sphingolipid phytosphingosine (PHS), which specifically and completely blocks autophagy. In summary, our work links calcium homeostasis, sphingolipid metabolism, and autophagy initiation via the ER calcium channel Csg2.
    Keywords:  Autophagosome; Csg2; ER; calcium; sphingolipid; starvation
    DOI:  https://doi.org/10.1080/15548627.2023.2249761
  41. Biology (Basel). 2023 Aug 03. pii: 1081. [Epub ahead of print]12(8):
    Metabolic Reprogramming toward Aerobic Glycolysis and the Gut Microbiota Involved in the Brain Amyloid Pathology.
    Toshiyuki Murai, Satoru Matsuda.
      Alzheimer's disease (AD) is characterized by the formation of senile plaques consisting of fibrillated amyloid-β (Aβ), dystrophic neurites, and the neurofibrillary tangles of tau. The oligomers/fibrillar Aβ damages the neurons or initiates an intracellular signaling cascade for neuronal cell death leading to Aβ toxicity. The Aβ is a 4 kDa molecular weight peptide originating from the C-terminal region of the amyloid precursor protein via proteolytic cleavage. Apart from the typical AD hallmarks, certain deficits in metabolic alterations have been identified. This study describes the emerging features of AD from the aspect of metabolic reprogramming in the main pathway of carbohydrate metabolism in the human brain. Particularly, the neurons in patients with AD favor glycolysis despite a normal mitochondrial function indicating a Warburg-like effect. In addition, certain dietary patterns are well known for their properties in preventing AD. Among those, a ketogenic diet may substantially improve the symptoms of AD. An effective therapeutic method for the treatment, mitigation, and prevention of AD has not yet been established. Therefore, the researchers pursue the development and establishment of novel therapies effective in suppressing AD symptoms and the elucidation of their underlying protective mechanisms against neurodegeneration aiming for AD therapy in the near future.
    Keywords:  Alzheimer’s disease; Warburg effect; aerobic glycolysis; amyloid-β; glucose metabolism; ketogenic diet
    DOI:  https://doi.org/10.3390/biology12081081
  42. bioRxiv. 2023 Aug 16. pii: 2023.08.07.552354. [Epub ahead of print]
    The actin binding protein profilin 1 is critical for mitochondria function.
    Tracy-Ann Read, Bruno A Cisterna, Kristen Skruber, Samah Ahmadieh, Halli L Lindamood, Josefine A Vitriol, Yang Shi, Austin E Y T Lefebvre, Joseph B Black, Mitchell T Butler, James A Bear, Alena Cherezova, Daria V Ilatovskaya, Neil L Weintraub, Eric A Vitriol.
      Profilin 1 (PFN1) is an actin binding protein that is vital for the polymerization of monomeric actin into filaments. Here we screened knockout cells for novel functions of PFN1 and discovered that mitophagy, a type of selective autophagy that removes defective or damaged mitochondria from the cell, was significantly upregulated in the absence of PFN1. Despite successful autophagosome formation and fusion with the lysosome, and activation of additional mitochondrial quality control pathways, PFN1 knockout cells still accumulate damaged, dysfunctional mitochondria. Subsequent imaging and functional assays showed that loss of PFN1 significantly affects mitochondria morphology, dynamics, and respiration. Further experiments revealed that PFN1 is located to the mitochondria matrix and is likely regulating mitochondria function from within rather than through polymerizing actin at the mitochondria surface. Finally, PFN1 mutants associated with amyotrophic lateral sclerosis (ALS) fail to rescue PFN1 knockout mitochondrial phenotypes and form aggregates within mitochondria, further perturbing them. Together, these results suggest a novel function for PFN1 in regulating mitochondria and identify a potential pathogenic mechanism of ALS-linked PFN1 variants.
    DOI:  https://doi.org/10.1101/2023.08.07.552354
  43. Cell Death Dis. 2023 Aug 25. 14(8): 560
    The m6A modification-mediated OGDHL exerts a tumor suppressor role in ccRCC by downregulating FASN to inhibit lipid synthesis and ERK signaling.
    Jian Shi, Daojia Miao, Qingyang Lv, Keshan Wang, Qi Wang, Huageng Liang, Hongmei Yang, Zhiyong Xiong, Xiaoping Zhang.
      Metabolic reprogramming is a hallmark of cancer, and the impact of lipid metabolism as a crucial aspect of metabolic reprogramming on clear cell renal cell carcinoma (ccRCC) progression has been established. However, the regulatory mechanisms underlying the relationship between metabolic abnormalities and ccRCC progression remain unclear. Therefore, this study aimed to identify key regulatory factors of metabolic reprogramming in ccRCC and provide potential therapeutic targets for ccRCC patients. Potential metabolic regulatory factors in ccRCC were screened using bioinformatics analysis. Public databases and patient samples were used to investigate the aberrant expression of Oxoglutarate dehydrogenase-like (OGDHL) in ccRCC. The function of OGDHL in ccRCC growth and metastasis was evaluated through in vitro and in vivo functional experiments. Mechanistic insights were obtained through luciferase reporter assays, chromatin immunoprecipitation, RNA methylation immunoprecipitation, and mutagenesis studies. OGDHL mRNA and protein levels were significantly downregulated in ccRCC tissues. Upregulation of OGDHL expression effectively inhibited ccRCC growth and metastasis both in vitro and in vivo. Furthermore, FTO-mediated OGDHL m6A demethylation suppressed its expression in ccRCC. Mechanistically, low levels of OGDHL promoted TFAP2A expression by inhibiting ubiquitination levels, which then bound to the FASN promoter region and transcriptionally activated FASN expression, thereby promoting lipid accumulation and ERK pathway activation. Our findings demonstrate the impact of OGDHL on ccRCC progression and highlight the role of the FTO/OGDHL/TFAP2A/FASN axis in regulating ccRCC lipid metabolism and progression, providing new targets for ccRCC therapy.
    DOI:  https://doi.org/10.1038/s41419-023-06090-7
  44. Pharmacol Res. 2023 Aug 22. pii: S1043-6618(23)00248-7. [Epub ahead of print] 106892
    Amino acids contribute to adaptive thermogenesis. New insights into the mechanisms of action of recent drugs for metabolic disorders are emerging.
    Chiara Ruocco, Alexis Malavazos, Maurizio Ragni, Michele O Carruba, Alessandra Valerio, Gianluca Iacobellis, Enzo Nisoli.
      Adaptive thermogenesis is the heat production by muscle contractions (shivering thermogenesis) or brown adipose tissue (BAT) and beige fat (non-shivering thermogenesis) in response to external stimuli, including cold exposure. BAT and beige fat communicate with peripheral organs and the brain through a variegate secretory and absorption processes - controlling adipokines, microRNAs, extracellular vesicles, and metabolites - and have received much attention as potential therapeutic targets for managing obesity-related disorders. The sympathetic nervous system and norepinephrine-releasing adipose tissue macrophages (ATM) activate uncoupling protein 1 (UCP1), expressed explicitly in brown and beige adipocytes, dissolving the electrochemical gradient and uncoupling tricarboxylic acid cycle and the electron transport chain from ATP production. Mounting evidence has attracted attention to the multiple effects of dietary and endogenously synthesised amino acids in BAT thermogenesis and metabolic phenotype in animals and humans. However, the mechanisms implicated in these processes have yet to be conclusively characterized. In the present review article, we aim to define the principal investigation areas in this context, including intestinal microbiota constitution, adipose autophagy modulation, and secretome and metabolic fluxes control, which lead to increased brown/beige thermogenesis. Finally, also based on our recent epicardial adipose tissue results, we summarise the evidence supporting the notion that the new dual and triple agonists of glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and glucagon (GCG) receptor - with never before seen weight loss and insulin-sensitizing efficacy - promote thermogenic-like amino acid profiles in BAT with robust heat production and likely trigger sympathetic activation and adaptive thermogenesis by controlling amino acid metabolism and ATM expansion in BAT and beige fat.
    Keywords:  Adaptive thermogenesis; Adipose autophagy; Branched-chain amino acids; Brown adipose tissue; Dual agonists; Obesity; Secretome; Uncoupling protein 1
    DOI:  https://doi.org/10.1016/j.phrs.2023.106892
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