Function (Oxford, England)最新文献

{"title":"Pre-and Postfusion Tuning of Regulated Exocytosis by Cell Metabolites.","authors":"Robert Zorec, Alexei Verkhratsky","doi":"10.1093/function/zqac062","DOIUrl":"https://doi.org/10.1093/function/zqac062","url":null,"abstract":"1Laboratory of Cell Engineering, Celica Biomedical, 1000 Ljubljana, Slovenia, 2Laboratory of Neuroendocrinology – Molecular Cell Physiology, Institute of Pathophysiology, University of Ljubljana, Medical Faculty, 1000 Ljubljana, Slovenia, 3Faculty of Biology, Medicine and Health, The University of Manchester, Manchester M13 9PT, UK and 4Achucarro Center for Neuroscience, IKERBASQUE, Basque Foundation for Science, 48011 Bilbao, Spain ∗Address correspondence to R.Z. (e-mail: robert.zorec@mf.uni.lj.si)","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":"4 1","pages":"zqac062"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/b8/d5/zqac062.PMC9789503.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10680268","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Calcium Transients at ER Subdomains Initiate Autophagosome Formation: A Single Spark Can Start a Prairie Fire.","authors":"Shuang Peng","doi":"10.1093/function/zqad004","DOIUrl":"https://doi.org/10.1093/function/zqad004","url":null,"abstract":"Autophagy is an evolutionarily conserved and tightly regulated lysosome-mediated intracellular bulk degradation pathway by which intracellular macromolecules are sequestered in autophagosomes and delivered to lysosomes for degradation and recycling. Identification of autophagy-related (ATG) genes in yeast has promoted the understanding of the molecular mechanism of autophagosome formation. 1 The proteins encoded by these genes play a crucial role at different steps of autophagosome formation. For example, Atg17/Atg13/Atg1 complexes form condensates and localize on the vacuole membrane, thereby recruiting downstream autophagy proteins to promote the formation of the isolation membrane on the vacuole. 2 Autophagosome biogenesis involves nucleation, expansion, and closure of the isolation membrane. Calcium (Ca 2 + ) is well known as an essential second messenger in eukaryotic cells. 3 Ca 2 + levels are distinct in different sub-cellular compartments and are built up by Ca 2 + channels and pumps located in the plasma membrane and organelles. Due to the resulting highly localized gradients, cytoplasmic Ca 2 + signals display spatiotemporal heterogeneity in the form of sparks,","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":"4 2","pages":"zqad004"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9936261/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9363206","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Capillary-Mitochondrial Oxygen Transport in Muscle: Paradigm Shifts.","authors":"David C Poole,&nbsp;Timothy I Musch","doi":"10.1093/function/zqad013","DOIUrl":"https://doi.org/10.1093/function/zqad013","url":null,"abstract":"<p><p>When exercising humans increase their oxygen uptake (V̇O₂) 20-fold above rest the numbers are staggering: Each minute the O₂ transport system - lungs, cardiovascular, active muscles - transports and utilizes 161 sextillion (10 ²¹) O₂ molecules. Leg extension exercise increases the quadriceps muscles' blood flow 100-times; transporting 17 sextillion O₂ molecules per kilogram per minute from microcirculation (capillaries) to mitochondria powering their cellular energetics. Within these muscles, the capillary network constitutes a prodigious blood-tissue interface essential to exchange O₂ and carbon dioxide requisite for muscle function. In disease, microcirculatory dysfunction underlies the pathophysiology of heart failure, diabetes, hypertension, pulmonary disease, sepsis, stroke and senile dementia. Effective therapeutic countermeasure design demands knowledge of microvascular/capillary function in health to recognize and combat pathological dysfunction. Dated concepts of skeletal muscle capillary (from the Latin <i>capillus</i> meaning 'hair') function prevail despite rigorous data-supported contemporary models; hindering progress in the field for future and current students, researchers and clinicians. Following closely the 100th anniversary of August Krogh's 1920 Nobel Prize for capillary function this Evidence Review presents an anatomical and physiological development of this dynamic field: Constructing a scientifically defensible platform for our current understanding of microcirculatory physiological function in supporting blood-mitochondrial O₂ transport. New developments include: 1. Putative roles of red blood cell aquaporin and rhesus channels in determining tissue O₂ diffusion. 2. Recent discoveries regarding intramyocyte O₂ transport. 3. Developing a comprehensive capillary functional model for muscle O₂ delivery-to-V̇O₂ matching. 4. Use of kinetics analysis to discriminate control mechanisms from collateral or pathological phenomena.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":"4 3","pages":"zqad013"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10165549/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9479237","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Molecular Circadian Clock of Phox2b-expressing Cells Drives Daily Variation of the Hypoxic but Not Hypercapnic Ventilatory Response in Mice.","authors":"Aaron A Jones,&nbsp;Gabriella M Marino,&nbsp;Allison R Spears,&nbsp;Deanna M Arble","doi":"10.1093/function/zqad023","DOIUrl":"https://doi.org/10.1093/function/zqad023","url":null,"abstract":"<p><p>While the suprachiasmatic nucleus (SCN) controls 24-h rhythms in breathing, including minute ventilation (V_E), the mechanisms by which the SCN drives these daily changes are not well understood. Moreover, the extent to which the circadian clock regulates hypercapnic and hypoxic ventilatory chemoreflexes is unknown. We hypothesized that the SCN regulates daily breathing and chemoreflex rhythms by synchronizing the molecular circadian clock of cells. We used whole-body plethysmography to assess ventilatory function in transgenic BMAL1 knockout (KO) mice to determine the role of the molecular clock in regulating daily rhythms in ventilation and chemoreflex. Unlike their wild-type littermates, BMAL1 KO mice exhibited a blunted daily rhythm in V_E and failed to demonstrate daily variation in the hypoxic ventilatory response (HVR) or hypercapnic ventilatory response (HCVR). To determine if the observed phenotype was mediated by the molecular clock of key respiratory cells, we then assessed ventilatory rhythms in BMAL1^fl/fl; Phox2b^Cre/+ mice, which lack BMAL1 in all Phox2b-expressing chemoreceptor cells (hereafter called BKOP). BKOP mice lacked daily variation in HVR, similar to BMAL1 KO mice. However, unlike BMAL1 KO mice, BKOP mice exhibited circadian variations in V_E and HCVR comparable to controls. These data indicate that the SCN regulates daily rhythms in V_E, HVR, and HCVR, in part, through the synchronization of the molecular clock. Moreover, the molecular clock of Phox2b-expressing cells is specifically necessary for daily variation in the hypoxic chemoreflex. These findings suggest that disruption of circadian biology may undermine respiratory homeostasis, which, in turn, may have clinical implications for respiratory disease.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":"4 4","pages":"zqad023"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/d7/c6/zqad023.PMC10278984.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9713062","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Challenging Dogma about Myonuclei Behavior in Skeletal Muscle Cells.","authors":"Espen E Spangenburg","doi":"10.1093/function/zqac068","DOIUrl":"https://doi.org/10.1093/function/zqac068","url":null,"abstract":"As I think about my time in graduate school or as a postdoc, I remember reading countless papers with some version of the following phrase “skeletal muscle is postmitotic. . .” or “DNA synthesis does not occur after fusion. . .” Collectively these statements are something I always accepted as proven and something I would venture to say that most individuals, who study skeletal muscle would consider dogma. Thus, reading the work of Borowik et al.1 in this issue of Function, caused me to stop and really focus on the data because the ideas challenged these very same concepts. Perhaps, this illustrates the dangers of the word “dogma” in science. As previously suggested by others, it may be better to think that the concept of postmitotic myonuclei was never dogma but instead a paradigm of understanding based on a wealth of published evidence.2 The paradigm of postmitotic myonuclei was established across multiple labs using a variety of scientific approaches, which provided confidence to the field that paradigm was valid due to the high degree of rigor3–6. The work in this issue of Function by Borowik et al.,1 demonstrates increases in DNA synthesis in myonuclei, which would suggest myonuclear replication is occurring. Within the manuscript, the authors provide a synopsis describing a sequence of publications that led them to test if DNA synthesis may be occurring in myonuclei. Specifically, the authors had published papers describing increases in DNA synthesis in skeletal muscle across a variety of models (ie, exercise in humans or mechanical stimulation of muscle in mice). Although not proven, the authors assumed that satellite cell expansion explained the DNA synthesis measures. Thus, in this current study, the authors used a genetic mouse model where satellite cells were ablated, and they hypothesized that no increases in DNA synthesis should be detected. Surprisingly, the data indicated an increase in DNA synthesis even when the satellite cells were ablated, which the authors interpreted to mean that the increase was due to proliferation of nonmuscle cells. Before proceeding to nonmuscle cells, the authors sought to rule out myonuclei as the source of DNA synthesis. To accomplish this, the authors developed a mouse model where a skeletal muscle-specific Tet-On mouse (HSA-rtTA) was crossed with a tetracycline-response element histone 2B-green fluorescent protein mouse (TRE-H2B-GFP). Using this mouse, allowed the investigators the ability to sort the GFP+ myonuclei and sort the GFP− nuclei (from nonmuscle cells) into two distinct fractions. The authors confirmed the ability to separate two fractions using multiple different approaches. Upon confirmation that isolation of myonuclei was possible, they then delivered deuterium oxide (D2O) to the animals, which will only incorporate into DNA using de novo pathways ruling out any signal accumulation due to DNA repair. After the D2O exposure, the investigators were able to isolate the different fractions ","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":"4 1","pages":"zqac068"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9834966/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9251318","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Renal Dysfunction due to Tenofovir-Diphosphate Inhibition of Mitochondrial Complex V (ATP Synthase).","authors":"Nicolas Sluis-Cremer","doi":"10.1093/function/zqad010","DOIUrl":"https://doi.org/10.1093/function/zqad010","url":null,"abstract":"Prescription drugs are a common cause of kidney injury. Druginduced nephrotoxicity, however, is a complex process, and likely involves a combination of factors, including (i) drug characteristics (eg, solubility, structure, and charge); (ii) drug dose and duration of therapy; (iii) inherent drug toxicity; (iv) renal metabolism and excretion of the drug; and (v) patient characteristics that enhance their risk for kidney injury. The mechanisms of drug-induced nephrotoxicity and prevention strategies have been reviewed extensively elsewhere.1,2 Tenofovir disoproxil fumarate (TDF) is a nucleoside reverse transcriptase inhibitor used to treat HIV and HBV infections. TDF therapy, however, has been associated with renal impairment, characterized by a decline in glomerular filtration rate and proximal tubular dysfunction.3 TDF is a prodrug that is rapidly metabolized to the active component tenofovir in plasma. In cells, tenofvoir is metabolized to its active diphosphate form by adenylate monophosphate kinase (tenofovir monophosphate) and 5′-nucleoside diphosphate (tenofovir diphosphate).4 Renal injury is likely related to intracellular tenofovir accumulation in proximal tubule cells. A molecular mechanism of TDF-induced renal toxicity, however, is lacking, but it is thought to be via mitochondrial depletion and structural change, including size and shape changes, and leakage of mitochondrial proteins into the cytosol, with resultant DNA damage, which may even induce apoptosis of the cell. In a recent study, Pearson et al. developed an innovative approach to screen for disease-related functional defects in RPTEC/TERT1 cells, a well-differentiated human-derived cell line that replicates many of the major characteristics of proximal tubular kidney cells in vivo.5 The RPTEC/TERT1 cells were exposed to TDF, and high-throughput imaging was used to generate quantitative readouts of solute transport and mitochondrial morphology, which facilitated development of treatment protocols that reproduced well-described features in patients. By using multiparametric metabolic profiling, including metabolomic screening, oxygen consumption measurements, and RNA-sequencing, the authors determined a molecular fingerprint of TDF toxicity. They found that TDF results in a dose-dependent decrease in mitochondrial ATP synthase, or complex V (EC 3.6.3.14) activity and expression, whereas other mitochondrial functions and pathways were well preserved. Tenofovir disphosphate was found to directly inhibit complex V. Downregulation of complex V expression was also observed in human biopsies. Complex V synthesizes ATP from ADP in the mitochondrial matrix using the energy provided by the proton electrochemical gradient, and mutations in complex V give rise to severe mitochondrial disease phenotypes, ranging from neuropathy, ataxia, and retinitis pigmentosa to maternally inherited Leigh syndrome.6 Of note, in a rat model of TDF nephrotoxicity, the activities of the electron chain compl","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":"4 3","pages":"zqad010"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10165542/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9479236","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Endogenous Amyloid-formed Ca²⁺-permeable Channels in Aged 3xTg AD Mice.","authors":"Shuangtao Li,&nbsp;Xiaoyu Ji,&nbsp;Ming Gao,&nbsp;Bing Huang,&nbsp;Shuang Peng,&nbsp;Jie Wu","doi":"10.1093/function/zqad025","DOIUrl":"https://doi.org/10.1093/function/zqad025","url":null,"abstract":"<p><p>Alzheimer's disease (AD), the leading cause of dementia, is characterized by the accumulation of beta-amyloid peptides (Aβ). However, whether Aβ itself is a key toxic agent in AD pathogenesis and the precise mechanism of Aβ-elicited neurotoxicity are still debated. Emerging evidence demonstrates that the Aβ channel/pore hypothesis could explain Aβ toxicity, because Aβ oligomers are able to disrupt membranes and cause edge-conductivity pores that may disrupt cell Ca²⁺ homeostasis and drive neurotoxicity in AD. However, all available data to support this hypothesis have been collected from \"in vitro\" experiments using high concentrations of exogenous Aβ. It is still unknown whether Aβ channels can be formed by endogenous Aβ in AD animal models. Here, we report an unexpected finding of the spontaneous Ca²⁺ oscillations in aged 3xTg AD mice but not in age-matched wild-type mice. These spontaneous Ca²⁺ oscillations are sensitive to extracellular Ca²⁺, ZnCl₂, and the Aβ channel blocker Anle138b, suggesting that these spontaneous Ca²⁺ oscillations in aged 3xTg AD mice are mediated by endogenous Aβ-formed channels.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":"4 4","pages":"zqad025"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10278988/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10337522","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ion Channels and Transporters in Immunity-Where do We Stand?","authors":"Birgit Hoeger,&nbsp;Susanna Zierler","doi":"10.1093/function/zqac070","DOIUrl":"https://doi.org/10.1093/function/zqac070","url":null,"abstract":"Ions are indispensable for cellular integrity. They constitute organellar identity and homeostasis within the physical barrier of biomembranes, support electrical potential across membranes, provide nutritional support, and serve as signaling entities that are able to adapt to varying challenges within milliseconds. Ion channels are the molecular mediators that shuttle ions between the different cellular compartments, often rather unspecific for certain cations or anions, often in a surprisingly selective manner. Their critical role in every cell type is undoubted. Immune cells are specialized cell types with unique molecular properties. They need to be able to rapidly adapt to various kinds of sudden environmental changes, and, to defend the body from dangerous intruders, consequently respond by massive cellular rearrangements in terms of activation, differentiation, or function. These require pronounced molecular rearrangements, among which ions and ion channels take a central part. Within the last two decades, a number of excellent studies have shed light on the role of distinct ion channels and transporters in immunity. Foremost, the identification of the molecular components ORAI and STIM that mediate store-operated calcium signals in activating lymphocytic and innate immune cells has significantly pushed the field toward studying ion movements and their regulation as the basis for understanding immunity.1–3 With the identification of detrimental mutations in ORAIand STIM-encoding genes causing human immunodeficiencies due to lack of appropriate calcium entry machineries,4 the stage was set for a comprehensive investigation of ion channels in health and disease. Since then, we have gained considerable insight into certain ion channel families and mechanisms. Much attention has been attributed to understanding ion homeostasis and ion signaling in T-cell immunity. Very recently, the attention has moved to VGCCs (voltage-gated Ca2+ channel subunits) being relevant in calcium signaling and triggering downstream effector functions in T cells, without functioning as ion channels themselves.5 To date, a growing number of ion-conducting channels and transporters have been identified to modulate T-, B-, NK, and dendritic cell function, monocytes, macrophages, and neutrophils, as well as mast cell homeostasis (Figure 1).3 This is impressive, but we are still far away from understanding the complex relationships of ion conductance and cellular responses, notwithstanding their contribution to (human) diseases. So where do we go from here? In our opinion, there are a few critical questions that will guide our immediate and longterm attention, and require joint efforts to be deciphered. First, it is still partly unclear which ion channels and family members are functionally expressed in diverse immune cell subsets, which proteins they colocalize or interact with, and under which preconditions they are active. We will surely untangle yet unrecognized ion c","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":"4 1","pages":"zqac070"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/93/e3/zqac070.PMC9846422.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9133762","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"\"Study the Past if You Would Define the Future.\"-Confucius.","authors":"Anant B Parekh,&nbsp;Lord Bhikhu C Parekh","doi":"10.1093/function/zqac073","DOIUrl":"https://doi.org/10.1093/function/zqac073","url":null,"abstract":"","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":"4 1","pages":"zqac073"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9850269/pdf/zqac073.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9133763","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integration of High-Throughput Imaging and Multiparametric Metabolic Profiling Reveals a Mitochondrial Mechanism of Tenofovir Toxicity.","authors":"Adam Pearson,&nbsp;Dominik Haenni,&nbsp;Jamal Bouitbir,&nbsp;Matthew Hunt,&nbsp;Brendan A I Payne,&nbsp;Ashwin Sachdeva,&nbsp;Rachel K Y Hung,&nbsp;Frank A Post,&nbsp;John Connolly,&nbsp;Stellor Nlandu-Khodo,&nbsp;Nevena Jankovic,&nbsp;Milica Bugarski,&nbsp;Andrew M Hall","doi":"10.1093/function/zqac065","DOIUrl":"https://doi.org/10.1093/function/zqac065","url":null,"abstract":"<p><p>Nephrotoxicity is a major cause of kidney disease and failure in drug development, but understanding of cellular mechanisms is limited, highlighting the need for better experimental models and methodological approaches. Most nephrotoxins damage the proximal tubule (PT), causing functional impairment of solute reabsorption and systemic metabolic complications. The antiviral drug tenofovir disoproxil fumarate (TDF) is an archetypal nephrotoxin, inducing mitochondrial abnormalities and urinary solute wasting, for reasons that were previously unclear. Here, we developed an automated, high-throughput imaging pipeline to screen the effects of TDF on solute transport and mitochondrial morphology in human-derived RPTEC/TERT1 cells, and leveraged this to generate realistic models of functional toxicity. By applying multiparametric metabolic profiling-including oxygen consumption measurements, metabolomics, and transcriptomics-we elucidated a highly robust molecular fingerprint of TDF exposure. Crucially, we identified that the active metabolite inhibits complex V (ATP synthase), and that TDF treatment causes rapid, dose-dependent loss of complex V activity and expression. Moreover, we found evidence of complex V suppression in kidney biopsies from humans with TDF toxicity. Thus, we demonstrate an effective and convenient experimental approach to screen for disease relevant functional defects in kidney cells in vitro, and reveal a new paradigm for understanding the pathogenesis of a substantial cause of nephrotoxicity.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":"4 1","pages":"zqac065"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9840465/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9444607","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}