Acta Physiologica最新文献

{"title":"Unlocking mitochondrial drug targets: The importance of mitochondrial transport proteins","authors":"Charlotte A. Hoogstraten,&nbsp;Tom J. J. Schirris,&nbsp;Frans G. M. Russel","doi":"10.1111/apha.14150","DOIUrl":"10.1111/apha.14150","url":null,"abstract":"<p>A disturbed mitochondrial function contributes to the pathology of many common diseases. These organelles are therefore important therapeutic targets. On the contrary, many adverse effects of drugs can be explained by a mitochondrial off-target effect, in particular, due to an interaction with carrier proteins in the inner membrane. Yet this class of transport proteins remains underappreciated and understudied. The aim of this review is to provide a deeper understanding of the role of mitochondrial carriers in health and disease and their significance as drug targets. We present literature-based evidence that mitochondrial carrier proteins are associated with prevalent diseases and emphasize their potential as drug (off-)target sites by summarizing known mitochondrial drug–transporter interactions. Studying these carriers will enhance our knowledge of mitochondrial drug on- and off-targets and provide opportunities to further improve the efficacy and safety of drugs.</p>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"240 6","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.14150","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140652303","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A potent and selective activator of large-conductance Ca2+-activated K+ channels induces preservation of mitochondrial function after hypoxia and reoxygenation by handling of calcium and transmembrane potential","authors":"Itanna Isis Araujo de Souza,&nbsp;Thais da Silva Barenco,&nbsp;Maria Eduarda Maciel Fernandes Pavarino,&nbsp;Marcos Tadeu Couto,&nbsp;Gabriel Oliveira de Resende,&nbsp;Dahienne Ferreira de Oliveira,&nbsp;Cristiano Gonsalves Ponte,&nbsp;José Hamilton Matheus Nascimento,&nbsp;Leonardo Maciel","doi":"10.1111/apha.14151","DOIUrl":"10.1111/apha.14151","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aims</h3>\u0000 \u0000 <p>Ischaemic heart disease remains a significant cause of mortality globally. A pharmacological agent that protects cardiac mitochondria against oxygen deprivation injuries is welcome in therapy against acute myocardial infarction. Here, we evaluate the effect of large-conductance Ca²⁺-activated K⁺ channels (BKCa) activator, Compound Z, in isolated mitochondria under hypoxia and reoxygenation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Mitochondria from mice hearts were obtained by differential centrifugation. The isolated mitochondria were incubated with a BKCa channel activator, Compound Z, and subjected to normoxia or hypoxia/reoxygenation. Mitochondrial function was evaluated by measurement of O₂ consumption in the complexes I, II, and IV in the respiratory states 1, 2, 3, and by maximal uncoupled O₂ uptake, ATP production, ROS production, transmembrane potential, and calcium retention capacity.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Incubation of isolated mitochondria with Compound Z under normoxia conditions reduced the mitochondrial functions and induced the production of a significant amount of ROS. However, under hypoxia/reoxygenation, the Compound Z prevented a profound reduction in mitochondrial functions, including reducing ROS production over the hypoxia/reoxygenation group. Furthermore, hypoxia/reoxygenation induced a large mitochondria depolarization, which Compound Z incubation prevented, but, even so, Compound Z created a small depolarization. The mitochondrial calcium uptake was prevented by the BKCa activator, extruding the mitochondrial calcium present before Compound Z incubation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>The Compound Z acts as a mitochondrial BKCa channel activator and can protect mitochondria function against hypoxia/reoxygenation injury, by handling mitochondrial calcium and transmembrane potential.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"240 6","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140810621","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"New guidelines to uncover the physiology of extracellular vesicles","authors":"Didde R. Hansen,&nbsp;Per Svenningsen","doi":"10.1111/apha.14153","DOIUrl":"10.1111/apha.14153","url":null,"abstract":"&lt;p&gt;Extracellular vesicles (EVs)—nanosized membrane-enclosed particles containing cellular RNA, lipids, and proteins—are secreted from cells into body fluids such as urine and plasma. The EVs provide exciting opportunities to understand human and animal physiology in that they can be used as liquid biopsies to gain mechanistic insight into complex conditions, such as hypertension.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; Moreover, EVs may serve as vehicles for intercellular communication, potentially adding new layers to the understanding of physiology. However, challenges to purify, characterize, and determine, for example, the intercellular transfer of EVs, have remained a hurdle to realizing the potential of EVs. To address these challenges, the International Society of Extracellular Vesicles (ISEV) has published the “Minimal Information for Studies of Extracellular Vesicles” (MISEV) as a guideline for best practices in EV research. An updated version—MISEV2023&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt;—has been published and contains essential information on the advantages and limitations of current methods to study EV biology. This article will highlight new additions to the MISEV2023 critical for determining the physiological role of EVs.&lt;/p&gt;&lt;p&gt;The current MISEV2023 guidelines stand on the shoulders of the two previous versions: MISEV2014 and MISEV2018. The MISEV2023 document was updated by expert task forces within the specific sections and through online feedback from over 1000 ISEV members. This community effort has resulted in a rich source of detailed and comprehensive information on EVs and important sample-specific recommendations and caveats for collecting, preprocessing, and characterizing EVs isolated from biofluids and tissue samples. MISEV2023 also contains updated nomenclature and characterization sections to integrate the greater complexity and diversity of EVs and nonvesicular extracellular particles, such as exomeres, uncovered by recent EV research. Importantly, MISEV2023 values transparency highly and should be considered a guide to rigorous and reproducible EV science.&lt;/p&gt;&lt;p&gt;A significant challenge for studying EV biology in living organisms is the low EV concentration in body fluids. For example, the EV concentration in human blood—one of the most studied body fluids—is seven orders of magnitude lower than albumin and approximately one-tenth of the fasting insulin level (Figure 1). In contrast to hormones and plasma proteins, often secreted from a small number of cells,&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; EVs in body fluids are derived from various cell types, and ~90% of the circulating plasma EVs are derived from blood cells.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; The low abundance challenges not only cell type-specific EV cargo analyses but also the determination of how they are taken up by other cells and their biodistribution, for example, whether plasma EVs are filtered into the urine.&lt;/p&gt;&lt;p&gt;The EV biodistribution has been primarily assessed by bolus injection of EVs isolat","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"240 6","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.14153","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140654699","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unique features of β-cell metabolism are lost in type 2 diabetes","authors":"Felipe Muñoz,&nbsp;Malin Fex,&nbsp;Thomas Moritz,&nbsp;Hindrik Mulder,&nbsp;Luis Rodrigo Cataldo","doi":"10.1111/apha.14148","DOIUrl":"10.1111/apha.14148","url":null,"abstract":"<p>Pancreatic β cells play an essential role in the control of systemic glucose homeostasis as they sense blood glucose levels and respond by secreting insulin. Upon stimulating glucose uptake in insulin-sensitive tissues post-prandially, this anabolic hormone restores blood glucose levels to pre-prandial levels. Maintaining physiological glucose levels thus relies on proper β-cell function. To fulfill this highly specialized nutrient sensor role, β cells have evolved a unique genetic program that shapes its distinct cellular metabolism. In this review, the unique genetic and metabolic features of β cells will be outlined, including their alterations in type 2 diabetes (T2D). β cells selectively express a set of genes in a cell type-specific manner; for instance, the glucose activating hexokinase IV enzyme or Glucokinase (<i>GCK</i>), whereas other genes are selectively “disallowed”, including lactate dehydrogenase A (<i>LDHA</i>) and monocarboxylate transporter 1 (<i>MCT1</i>). This selective gene program equips β cells with a unique metabolic apparatus to ensure that nutrient metabolism is coupled to appropriate insulin secretion, thereby avoiding hyperglycemia, as well as life-threatening hypoglycemia. Unlike most cell types, β cells exhibit specialized bioenergetic features, including supply-driven rather than demand-driven metabolism and a high basal mitochondrial proton leak respiration. The understanding of these unique genetically programmed metabolic features and their alterations that lead to β-cell dysfunction is crucial for a comprehensive understanding of T2D pathophysiology and the development of innovative therapeutic approaches for T2D patients.</p>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"240 6","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.14148","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140662093","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Extracellular acidification increases uterine contraction in pregnant mouse by increasing intracellular calcium","authors":"Asmaa M. Almohanna,&nbsp;Karen Noble,&nbsp;Susan Wray","doi":"10.1111/apha.14147","DOIUrl":"10.1111/apha.14147","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aims</h3>\u0000 \u0000 <p>As uterine extracellular pH decreases during the ischemic conditions of labor, but its effects on myometrial contraction are largely unknown, there is a need to elucidate its physiological effects and mechanisms of action. Furthermore, it is not known if any of the effects of extracellular acidification are affected by pregnancy, thus we also determined how gestation affects the response to acidification.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Nonpregnant, mid-, and term-pregnant myometrial strips were obtained from humanely killed mice. Contractions were recorded under spontaneous, depolarized, and oxytocin-stimulated conditions. The extracellular pH of the perfusate was changed from 7.4 to 6.9 or 7.9 in HEPES-buffered physiological saline. Intracellular pH was measured using SNARF, and intracellular calcium was measured using Indo-1. Statistical differences were tested using the appropriate <i>t</i>-test.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Extracellular acidification significantly increased the frequency and amplitude of spontaneous contractions in pregnant, but not nonpregnant, myometrium, whereas alkalinization decreased contractions. Intracellular acidification, via Na-butyrate, transiently increased force in pregnant tissue. Intracellular pH was gradually acidified when extracellular pH was acidified, but extracellular acidification increased contractility before any significant change in intracellular pH. If myometrial force was driven by oxytocin or high-K depolarization, then extracellular pH did not further increase force. Intracellular calcium changes mirrored those of force in the spontaneously contracting pregnant myometrium, and if calcium entry was prevented by nifedipine, extracellular acidification could not induce a rise in force.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Extracellular acidification increases excitability, calcium entry, and thus force in pregnant mouse myometrium, and this may contribute to increasing contractions during labor when ischemic conditions and acidemia occur.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"240 6","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140676097","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Smoking cessation only partially reverses cardiac metabolic and structural remodeling in mice","authors":"Jekaterina Aid,&nbsp;Ajime Tom Tanjeko,&nbsp;Jef Serré,&nbsp;Moritz Eggelbusch,&nbsp;Wendy Noort,&nbsp;Gerard M. J. de Wit,&nbsp;Michel van Weeghel,&nbsp;Marju Puurand,&nbsp;Kersti Tepp,&nbsp;Ghislaine Gayan-Ramirez,&nbsp;Hans Degens,&nbsp;Tuuli Käämbre,&nbsp;Rob C. I. Wüst","doi":"10.1111/apha.14145","DOIUrl":"10.1111/apha.14145","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aims</h3>\u0000 \u0000 <p>Active cigarette smoking is a major risk factor for chronic obstructive pulmonary disease that remains elevated after cessation. Skeletal muscle dysfunction has been well documented after smoking, but little is known about cardiac adaptations to cigarette smoking. The underlying cellular and molecular cardiac adaptations, independent of confounding lifestyle factors, and time course of reversibility by smoking cessation remain unclear. We hypothesized that smoking negatively affects cardiac metabolism and induces local inflammation in mice, which do not readily reverse upon 2-week smoking cessation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Mice were exposed to air or cigarette smoke for 14 weeks with or without 1- or 2-week smoke cessation. We measured cardiac mitochondrial respiration by high-resolution respirometry, cardiac mitochondrial density, abundance of mitochondrial supercomplexes by electrophoresis, and capillarization, fibrosis, and macrophage infiltration by immunohistology, and performed cardiac metabolome and lipidome analysis by mass spectrometry.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Mitochondrial protein, supercomplex content, and respiration (all <i>p</i> &lt; 0.03) were lower after smoking, which were largely reversed within 2-week smoking cessation. Metabolome and lipidome analyses revealed alterations in mitochondrial metabolism, a shift from fatty acid to glucose metabolism, which did not revert to control upon smoking cessation. Capillary density was not different after smoking but increased after smoking cessation (<i>p</i> = 0.02). Macrophage infiltration and fibrosis (<i>p</i> &lt; 0.04) were higher after smoking but did not revert to control upon smoking cessation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>While cigarette-impaired smoking-induced cardiac mitochondrial function was reversed by smoking cessation, the remaining fibrosis and macrophage infiltration may contribute to the increased risk of cardiovascular events after smoking cessation.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"240 7","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.14145","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140676893","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Skeletal muscle mitochondria: A potential target for postmenopausal hormone replacement therapy","authors":"Takashi Yokota","doi":"10.1111/apha.14149","DOIUrl":"10.1111/apha.14149","url":null,"abstract":"&lt;p&gt;In this issue of &lt;i&gt;Acta Physiologica&lt;/i&gt;, Kleis-Olsen et al.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; investigated the association of postmenopausal hormone replacement therapy (HRT) with skeletal muscle mitochondrial function measured using biopsy samples from human vastus lateralis muscle. They reported that postmenopausal women who received a combination of estradiol and progestin had higher mitochondrial respiratory capacity in the skeletal muscle compared with non-treated postmenopausal women. Since estrogen deficiency due to menopause is associated with skeletal muscle dysfunction characterized by muscle weakness and muscle loss,&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; it is clinically relevant to examine whether HRT may prevent menopause-related impairment of skeletal muscle energy metabolism.&lt;/p&gt;&lt;p&gt;Menopause is defined by the permanent cessation of menstruation occurred at an average age around 50 years. It is natural course of reproductive aging for women and the transition into menopause is characterized by a significant reduction in circulating estrogen levels. Menopause may accelerate age-related functional decline with both physiological and psychological symptoms and adversely affect cardiovascular and musculoskeletal health. Because women live longer than men, women are more likely to experience negative changes in skeletal muscle, leading to reduced quality of life with increased morbidity and mortality.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;HRT is a pharmacological therapy that contains ovarian hormones (estrogen with or without progesterone), prescribed to manage menopausal symptoms. Although estrogen alone is enough to treat menopausal symptoms, it may increase the risk of cancer of the uterus (endometrial cancer), and therefore, progesterone is usually added to estrogen to reduce the risk of endometrial cancer back to normal. HRT has multiple health benefits, including reduced risk of cardiovascular diseases and all-cause mortality as well as relief of menopausal symptoms.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; Estrogen is considered to be a key regulator of whole-body energy homeostasis.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; Compared with other organs, skeletal muscle exhibits higher metabolic flexibility in response to hormone stimulation as well as exercise and environmental factors.&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; However, the effect of HRT on skeletal muscle mitochondria in postmenopausal women remains fully unclear.&lt;/p&gt;&lt;p&gt;Previous studies have shown the effects of estrogen on skeletal muscle mitochondria in ovariectomized rodents (animal models of menopause),&lt;span&gt;&lt;sup&gt;6, 7&lt;/sup&gt;&lt;/span&gt; but Kleis-Olsen et al. for the first time demonstrated the association of postmenopausal HRT with increased mitochondrial respiratory capacity in the skeletal muscle in human.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; Middle-aged postmenopausal women who had received a combination of estradiol and progestin for 3.6 years on average were participated in their cross-sectional study. Compared with matched non-treated postmen","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"240 6","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.14149","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140613721","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The homeostatic effects of the RE-1 silencing transcription factor on cortical networks are altered under ictogenic conditions in the mouse","authors":"Carmela Vitale,&nbsp;Giulia Natali,&nbsp;Maria Sabina Cerullo,&nbsp;Thomas Floss,&nbsp;Caterina Michetti,&nbsp;Giorgio Grasselli,&nbsp;Fabio Benfenati","doi":"10.1111/apha.14146","DOIUrl":"10.1111/apha.14146","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>The Repressor Element-1 Silencing Transcription Factor (REST) is an epigenetic master regulator playing a crucial role in the nervous system. In early developmental stages, REST downregulation promotes neuronal differentiation and the acquisition of the neuronal phenotype. In addition, postnatal fluctuations in REST expression contribute to shaping neuronal networks and maintaining network homeostasis. Here we investigate the role of the early postnatal deletion of neuronal REST in the assembly and strength of excitatory and inhibitory synaptic connections.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We investigated excitatory and inhibitory synaptic transmission by patch-clamp recordings in acute neocortical slices in a conditional knockout mouse model (<i>Rest</i>^GTi) in which <i>Rest</i> was deleted by delivering PHP.eB adeno-associated viruses encoding CRE recombinase under the control of the human synapsin I promoter in the lateral ventricles of P0-P1 pups.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We show that, under physiological conditions, <i>Rest</i> deletion increased the intrinsic excitability of principal cortical neurons in the primary visual cortex and the density and strength of excitatory synaptic connections impinging on them, without affecting inhibitory transmission. Conversely, in the presence of a pathological excitation/inhibition imbalance induced by pentylenetetrazol, <i>Rest</i> deletion prevented the increase in synaptic excitation and decreased seizure severity.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>The data indicate that REST exerts distinct effects on the excitability of cortical circuits depending on whether it acts under physiological conditions or in the presence of pathologic network hyperexcitability. In the former case, REST preserves a correct excitatory/inhibitory balance in cortical circuits, while in the latter REST loses its homeostatic activity and may become pro-epileptogenic.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"240 6","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.14146","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140568269","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Amyloid precursor protein induces reactive astrogliosis","authors":"Gretsen Velezmoro Jauregui,&nbsp;Dragana Vukić,&nbsp;Isaac G. Onyango,&nbsp;Carlos Arias,&nbsp;Jan S. Novotný,&nbsp;Kateřina Texlová,&nbsp;Shanshan Wang,&nbsp;Kristina Locker Kovačovicova,&nbsp;Natalie Polakova,&nbsp;Jana Zelinkova,&nbsp;Maria Čarna,&nbsp;Valentina Lacovich,&nbsp;Brian P. Head,&nbsp;Daniel Havas,&nbsp;Martin Mistrik,&nbsp;Robert Zorec,&nbsp;Alexei Verkhratsky,&nbsp;Liam Keegan,&nbsp;Mary A. O'Connell,&nbsp;Robert Rissman,&nbsp;Gorazd B. Stokin","doi":"10.1111/apha.14142","DOIUrl":"10.1111/apha.14142","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>Astrocytes respond to stressors by acquiring a reactive state characterized by changes in their morphology and function. Molecules underlying reactive astrogliosis, however, remain largely unknown. Given that several studies observed increase in the Amyloid Precursor Protein (APP) in reactive astrocytes, we here test whether APP plays a role in reactive astrogliosis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We investigated whether APP instigates reactive astroglios by examining in vitro and in vivo the morphology and function of naive and APP-deficient astrocytes in response to APP and well-established stressors.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Overexpression of APP in cultured astrocytes led to remodeling of the intermediate filament network, enhancement of cytokine production, and activation of cellular programs centered around the interferon (IFN) pathway, all signs of reactive astrogliosis. Conversely, APP deletion abrogated remodeling of the intermediate filament network and blunted expression of IFN-stimulated gene products in response to lipopolysaccharide. Following traumatic brain injury (TBI), mouse reactive astrocytes also exhibited an association between APP and IFN, while APP deletion curbed the increase in glial fibrillary acidic protein observed canonically in astrocytes in response to TBI.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>The APP thus represents a candidate molecular inducer and regulator of reactive astrogliosis. This finding has implications for understanding pathophysiology of neurodegenerative and other diseases of the nervous system characterized by reactive astrogliosis and opens potential new therapeutic avenues targeting APP and its pathways to modulate reactive astrogliosis.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"240 6","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.14142","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140568021","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The 2-oxoglutarate/malate carrier extends the family of mitochondrial carriers capable of fatty acid and 2,4-dinitrophenol-activated proton transport","authors":"Kristina Žuna,&nbsp;Tatyana Tyschuk,&nbsp;Taraneh Beikbaghban,&nbsp;Felix Sternberg,&nbsp;Jürgen Kreiter,&nbsp;Elena E. Pohl","doi":"10.1111/apha.14143","DOIUrl":"10.1111/apha.14143","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aims</h3>\u0000 \u0000 <p>Metabolic reprogramming in cancer cells has been linked to mitochondrial dysfunction. The mitochondrial 2-oxoglutarate/malate carrier (OGC) has been suggested as a potential target for preventing cancer progression. Although OGC is involved in the malate/aspartate shuttle, its exact role in cancer metabolism remains unclear. We aimed to investigate whether OGC may contribute to the alteration of mitochondrial inner membrane potential by transporting protons.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The expression of OGC in mouse tissues and cancer cells was investigated by PCR and Western blot analysis. The proton transport function of recombinant murine OGC was evaluated by measuring the membrane conductance (<i>G</i>_m) of planar lipid bilayers. OGC-mediated substrate transport was measured in proteoliposomes using ¹⁴C-malate.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>OGC increases proton <i>G</i>_m only in the presence of natural (long-chain fatty acids, FA) or chemical (2,4-dinitrophenol) protonophores. The increase in OGC activity directly correlates with the increase in the number of unsaturated bonds of the FA. OGC substrates and inhibitors compete with FA for the same protein binding site. Arginine 90 was identified as a critical amino acid for the binding of FA, ATP, 2-oxoglutarate, and malate, which is a first step towards understanding the OGC-mediated proton transport mechanism.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>OGC extends the family of mitochondrial transporters with dual function: (i) metabolite transport and (ii) proton transport facilitated in the presence of protonophores. Elucidating the contribution of OGC to uncoupling may be essential for the design of targeted drugs for the treatment of cancer and other metabolic diseases.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"240 6","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.14143","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140568281","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}