EMBO Journal最新文献_第4页

The TrkC-PTPσ complex governs synapse maturation and anxiogenic avoidance via synaptic protein phosphorylation. TrkC-PTPσ复合体通过突触蛋白磷酸化调节突触成熟和焦虑性回避。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2024-11-01 Epub Date: 2024-09-27 DOI: 10.1038/s44318-024-00252-9

Husam Khaled, Zahra Ghasemi, Mai Inagaki, Kyle Patel, Yusuke Naito, Benjamin Feller, Nayoung Yi, Farin B Bourojeni, Alfred Kihoon Lee, Nicolas Chofflet, Artur Kania, Hidetaka Kosako, Masanori Tachikawa, Steven Connor, Hideto Takahashi

{"title":"The TrkC-PTPσ complex governs synapse maturation and anxiogenic avoidance via synaptic protein phosphorylation.","authors":"Husam Khaled, Zahra Ghasemi, Mai Inagaki, Kyle Patel, Yusuke Naito, Benjamin Feller, Nayoung Yi, Farin B Bourojeni, Alfred Kihoon Lee, Nicolas Chofflet, Artur Kania, Hidetaka Kosako, Masanori Tachikawa, Steven Connor, Hideto Takahashi","doi":"10.1038/s44318-024-00252-9","DOIUrl":"10.1038/s44318-024-00252-9","url":null,"abstract":"The precise organization of pre- and postsynaptic terminals is crucial for normal synaptic function in the brain. In addition to its canonical role as a neurotrophin-3 receptor tyrosine kinase, postsynaptic TrkC promotes excitatory synapse organization through interaction with presynaptic receptor-type tyrosine phosphatase PTPσ. To isolate the synaptic organizer function of TrkC from its role as a neurotrophin-3 receptor, we generated mice carrying TrkC point mutations that selectively abolish PTPσ binding. The excitatory synapses in mutant mice had abnormal synaptic vesicle clustering and postsynaptic density elongation, more silent synapses, and fewer active synapses, which additionally exhibited enhanced basal transmission with impaired release probability. Alongside these phenotypes, we observed aberrant synaptic protein phosphorylation, but no differences in the neurotrophin signaling pathway. Consistent with reports linking these aberrantly phosphorylated proteins to neuropsychiatric disorders, mutant TrkC knock-in mice displayed impaired social responses and increased avoidance behavior. Thus, through its regulation of synaptic protein phosphorylation, the TrkC-PTPσ complex is crucial for the maturation, but not formation, of excitatory synapses in vivo.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"5690-5717"},"PeriodicalIF":9.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11574141/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142331678","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Unlocking metabolic insights with mouse genetic diversity. 用小鼠基因多样性揭示新陈代谢的奥秘

IF 9.4 1区生物学

EMBO Journal Pub Date : 2024-11-01 Epub Date: 2024-09-16 DOI: 10.1038/s44318-024-00221-2

Stewart W C Masson, Harry B Cutler, David E James

引用次数: 0

Chromatin protein complexes involved in gene repression in lamina-associated domains. 参与板层相关结构域基因抑制的染色质蛋白复合物

IF 9.4 1区生物学

EMBO Journal Pub Date : 2024-11-01 Epub Date: 2024-09-25 DOI: 10.1038/s44318-024-00214-1

Stefano G Manzo, Abdelghani Mazouzi, Christ Leemans, Tom van Schaik, Nadia Neyazi, Marjon S van Ruiten, Benjamin D Rowland, Thijn R Brummelkamp, Bas van Steensel

{"title":"Chromatin protein complexes involved in gene repression in lamina-associated domains.","authors":"Stefano G Manzo, Abdelghani Mazouzi, Christ Leemans, Tom van Schaik, Nadia Neyazi, Marjon S van Ruiten, Benjamin D Rowland, Thijn R Brummelkamp, Bas van Steensel","doi":"10.1038/s44318-024-00214-1","DOIUrl":"10.1038/s44318-024-00214-1","url":null,"abstract":"Lamina-associated domains (LADs) are large chromatin regions that are associated with the nuclear lamina (NL) and form a repressive environment for transcription. The molecular players that mediate gene repression in LADs are currently unknown. Here, we performed FACS-based whole-genome genetic screens in human cells using LAD-integrated fluorescent reporters to identify such regulators. Surprisingly, the screen identified very few NL proteins, but revealed roles for dozens of known chromatin regulators. Among these are the negative elongation factor (NELF) complex and interacting factors involved in RNA polymerase pausing, suggesting that regulation of transcription elongation is a mechanism to repress transcription in LADs. Furthermore, the chromatin remodeler complex BAF and the activation complex Mediator can work both as activators and repressors in LADs, depending on the local context and possibly by rewiring heterochromatin. Our data indicate that the fundamental regulators of transcription and chromatin remodeling, rather than interaction with NL proteins, play a major role in transcription regulation within LADs.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"5260-5287"},"PeriodicalIF":9.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11535540/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142331674","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

RNA fine-tunes estrogen receptor-alpha binding on low-affinity DNA motifs for transcriptional regulation. RNA 可微调雌激素受体-α 与低亲和性 DNA 基团的结合，从而实现转录调控。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2024-11-01 Epub Date: 2024-09-16 DOI: 10.1038/s44318-024-00225-y

Deepanshu Soota, Bharath Saravanan, Rajat Mann, Tripti Kharbanda, Dimple Notani

{"title":"RNA fine-tunes estrogen receptor-alpha binding on low-affinity DNA motifs for transcriptional regulation.","authors":"Deepanshu Soota, Bharath Saravanan, Rajat Mann, Tripti Kharbanda, Dimple Notani","doi":"10.1038/s44318-024-00225-y","DOIUrl":"10.1038/s44318-024-00225-y","url":null,"abstract":"Transcription factors (TFs) regulate gene expression by binding with varying strengths to DNA via their DNA-binding domain. Additionally, some TFs also interact with RNA, which modulates transcription factor binding to chromatin. However, whether RNA-mediated TF binding results in differential transcriptional outcomes remains unknown. In this study, we demonstrate that estrogen receptor α (ERα), a ligand-activated TF, interacts with RNA in a ligand-dependent manner. Defects in RNA binding lead to genome-wide loss of ERα recruitment, particularly at weaker ERα-motifs. Furthermore, ERα mobility in the nucleus increases in the absence of its RNA-binding capacity. Unexpectedly, this increased mobility coincides with robust polymerase loading and transcription of ERα-regulated genes that harbor low-strength motifs. However, highly stable binding of ERα on chromatin negatively impacts ligand-dependent transcription. Collectively, our results suggest that RNA interactions spatially confine ERα on low-affinity sites to fine-tune gene transcription.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"5186-5210"},"PeriodicalIF":9.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11535219/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142300039","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Real-time assessment of mitochondrial DNA heteroplasmy dynamics at the single-cell level. 在单细胞水平上实时评估线粒体 DNA 异构动态。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2024-11-01 Epub Date: 2024-08-05 DOI: 10.1038/s44318-024-00183-5

Rodaria Roussou, Dirk Metzler, Francesco Padovani, Felix Thoma, Rebecca Schwarz, Boris Shraiman, Kurt M Schmoller, Christof Osman

{"title":"Real-time assessment of mitochondrial DNA heteroplasmy dynamics at the single-cell level.","authors":"Rodaria Roussou, Dirk Metzler, Francesco Padovani, Felix Thoma, Rebecca Schwarz, Boris Shraiman, Kurt M Schmoller, Christof Osman","doi":"10.1038/s44318-024-00183-5","DOIUrl":"10.1038/s44318-024-00183-5","url":null,"abstract":"Mitochondrial DNA (mtDNA) is present in multiple copies within cells and is required for mitochondrial ATP generation. Even within individual cells, mtDNA copies can differ in their sequence, a state known as heteroplasmy. The principles underlying dynamic changes in the degree of heteroplasmy remain incompletely understood, due to the inability to monitor this phenomenon in real time. Here, we employ mtDNA-based fluorescent markers, microfluidics, and automated cell tracking, to follow mtDNA variants in live heteroplasmic yeast populations at the single-cell level. This approach, in combination with direct mtDNA tracking and data-driven mathematical modeling reveals asymmetric partitioning of mtDNA copies during cell division, as well as limited mitochondrial fusion and fission frequencies, as critical driving forces for mtDNA variant segregation. Given that our approach also facilitates assessment of segregation between intact and mutant mtDNA, we anticipate that it will be instrumental in elucidating the mechanisms underlying the purifying selection of mtDNA.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"5340-5359"},"PeriodicalIF":9.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11574196/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141894804","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Combining systems and synthetic biology for in vivo enzymology. 将系统生物学与合成生物学相结合，用于体内酶学研究。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2024-11-01 Epub Date: 2024-09-25 DOI: 10.1038/s44318-024-00251-w

Sara Castaño-Cerezo, Alexandre Chamas, Hanna Kulyk, Christian Treitz, Floriant Bellvert, Andreas Tholey, Virginie Galéote, Carole Camarasa, Stéphanie Heux, Luis F Garcia-Alles, Pierre Millard, Gilles Truan

{"title":"Combining systems and synthetic biology for in vivo enzymology.","authors":"Sara Castaño-Cerezo, Alexandre Chamas, Hanna Kulyk, Christian Treitz, Floriant Bellvert, Andreas Tholey, Virginie Galéote, Carole Camarasa, Stéphanie Heux, Luis F Garcia-Alles, Pierre Millard, Gilles Truan","doi":"10.1038/s44318-024-00251-w","DOIUrl":"10.1038/s44318-024-00251-w","url":null,"abstract":"Enzymatic parameters are classically determined in vitro, under conditions that are far from those encountered in cells, casting doubt on their physiological relevance. We developed a generic approach combining tools from synthetic and systems biology to measure enzymatic parameters in vivo. In the context of a synthetic carotenoid pathway in Saccharomyces cerevisiae, we focused on a phytoene synthase and three phytoene desaturases, which are difficult to study in vitro. We designed, built, and analyzed a collection of yeast strains mimicking substantial variations in substrate concentration by strategically manipulating the expression of geranyl-geranyl pyrophosphate (GGPP) synthase. We successfully determined in vivo Michaelis-Menten parameters (KM, Vmax, and kcat) for GGPP-converting phytoene synthase from absolute metabolomics, fluxomics and proteomics data, highlighting differences between in vivo and in vitro parameters. Leveraging the versatility of the same set of strains, we then extracted enzymatic parameters for two of the three phytoene desaturases. Our approach demonstrates the feasibility of assessing enzymatic parameters directly in vivo, providing a novel perspective on the kinetic characteristics of enzymes in real cellular conditions.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"5169-5185"},"PeriodicalIF":9.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11535393/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142331675","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Non-cell-autonomous regulation of germline proteostasis by insulin/IGF-1 signaling-induced dietary peptide uptake via PEPT-1. 胰岛素/IGF-1 信号通过 PEPT-1 诱导的膳食肽吸收对生殖细胞蛋白稳态的非细胞自主调节

IF 9.4 1区生物学

EMBO Journal Pub Date : 2024-11-01 Epub Date: 2024-09-16 DOI: 10.1038/s44318-024-00234-x

Tahir Muhammad, Stacey L Edwards, Allison C Morphis, Mary V Johnson, Vitor De Oliveira, Tomasz Chamera, Siyan Liu, Ngoc Gia Tuong Nguyen, Jian Li

{"title":"Non-cell-autonomous regulation of germline proteostasis by insulin/IGF-1 signaling-induced dietary peptide uptake via PEPT-1.","authors":"Tahir Muhammad, Stacey L Edwards, Allison C Morphis, Mary V Johnson, Vitor De Oliveira, Tomasz Chamera, Siyan Liu, Ngoc Gia Tuong Nguyen, Jian Li","doi":"10.1038/s44318-024-00234-x","DOIUrl":"10.1038/s44318-024-00234-x","url":null,"abstract":"Gametogenesis involves active protein synthesis and is proposed to rely on proteostasis. Our previous work in C. elegans indicates that germline development requires coordinated activities of insulin/IGF-1 signaling (IIS) and HSF-1, the central regulator of the heat shock response. However, the downstream mechanisms were not identified. Here, we show that depletion of HSF-1 from germ cells impairs chaperone gene expression, causing protein degradation and aggregation and, consequently, reduced fecundity and gamete quality. Conversely, reduced IIS confers germ cell resilience to HSF-1 depletion-induced protein folding defects and various proteotoxic stresses. Surprisingly, this effect was not mediated by an enhanced stress response, which underlies longevity in low IIS conditions, but by reduced ribosome biogenesis and translation rate. We found that IIS activates the expression of intestinal peptide transporter PEPT-1 by alleviating its repression by FOXO/DAF-16, allowing dietary proteins to be efficiently incorporated into an amino acid pool that fuels germline protein synthesis. Our data suggest this non-cell-autonomous pathway is critical for proteostasis regulation during gametogenesis.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"4892-4921"},"PeriodicalIF":9.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11535032/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142300037","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Cancer cell-intrinsic biosynthesis of itaconate promotes tumor immunogenicity. 癌细胞内在的伊他康酸生物合成促进了肿瘤免疫原性。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2024-11-01 Epub Date: 2024-09-30 DOI: 10.1038/s44318-024-00217-y

Zining Wang, Lei Cui, Yanxun Lin, Bitao Huo, Hongxia Zhang, Chunyuan Xie, Huanling Zhang, Yongxiang Liu, Huan Jin, Hui Guo, Mengyun Li, Xiaojuan Wang, Penghui Zhou, Peng Huang, Jinyun Liu, Xiaojun Xia

{"title":"Cancer cell-intrinsic biosynthesis of itaconate promotes tumor immunogenicity.","authors":"Zining Wang, Lei Cui, Yanxun Lin, Bitao Huo, Hongxia Zhang, Chunyuan Xie, Huanling Zhang, Yongxiang Liu, Huan Jin, Hui Guo, Mengyun Li, Xiaojuan Wang, Penghui Zhou, Peng Huang, Jinyun Liu, Xiaojun Xia","doi":"10.1038/s44318-024-00217-y","DOIUrl":"10.1038/s44318-024-00217-y","url":null,"abstract":"The Krebs cycle byproduct itaconate has recently emerged as an important metabolite regulating macrophage immune functions, but its role in tumor cells remains unknown. Here, we show that increased tumor-intrinsic cis-aconitate decarboxylase (ACOD1 or CAD, encoded by immune-responsive gene 1, Irg1) expression and itaconate production promote tumor immunogenicity and anti-tumor immune responses. Furthermore, we identify thimerosal, a vaccine preservative, as a specific inducer of IRG1 expression in tumor cells but not in macrophages, thereby enhancing tumor immunogenicity. Mechanistically, thimerosal induces itaconate production through a ROS-RIPK3-IRF1 signaling axis in tumor cells. Further, increased IRG1/itaconate upregulates antigen presentation-related gene expression via promoting TFEB nuclear translocation. Intratumoral injection of thimerosal induced itaconate production, activated the tumor immune microenvironment, and inhibited tumor growth in a T cell-dependent manner. Importantly, IRG1 deficiency markedly impaired tumor response to thimerosal treatment. Furthermore, itaconate induction by thimerosal potentiates the anti-tumor efficacy of adoptive T-cell therapy and anti-PD1 therapy in a mouse lymphoma model. Hence, our findings identify a new role for tumor intrinsic IRG1/itaconate in promoting tumor immunogenicity and provide a translational means to increase immunotherapy efficacy.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"5530-5547"},"PeriodicalIF":9.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11574104/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142331671","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A human progeria-associated BAF-1 mutation modulates gene expression and accelerates aging in C. elegans. 人类早衰症相关的 BAF-1 基因突变会调节基因表达并加速优雅小鼠的衰老。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2024-11-01 Epub Date: 2024-10-04 DOI: 10.1038/s44318-024-00261-8

Raquel Romero-Bueno, Adrián Fragoso-Luna, Cristina Ayuso, Nina Mellmann, Alan Kavsek, Christian G Riedel, Jordan D Ward, Peter Askjaer

{"title":"A human progeria-associated BAF-1 mutation modulates gene expression and accelerates aging in C. elegans.","authors":"Raquel Romero-Bueno, Adrián Fragoso-Luna, Cristina Ayuso, Nina Mellmann, Alan Kavsek, Christian G Riedel, Jordan D Ward, Peter Askjaer","doi":"10.1038/s44318-024-00261-8","DOIUrl":"10.1038/s44318-024-00261-8","url":null,"abstract":"Alterations in the nuclear envelope are linked to a variety of rare diseases termed laminopathies. A single amino acid substitution at position 12 (A12T) of the human nuclear envelope protein BAF (Barrier to Autointegration Factor) causes Néstor-Guillermo Progeria Syndrome (NGPS). This premature ageing condition leads to growth retardation and severe skeletal defects, but the underlying mechanisms are unknown. Here, we have generated a novel in vivo model for NGPS by modifying the baf-1 locus in C. elegans to mimic the human NGPS mutation. These baf-1(G12T) mutant worms displayed multiple phenotypes related to fertility, lifespan, and stress resistance. Importantly, nuclear morphology deteriorated faster during aging in baf-1(G12T) compared to wild-type animals, recapitulating an important hallmark of cells from progeria patients. Although localization of BAF-1(G12T) was similar to wild-type BAF-1, lamin accumulation at the nuclear envelope was reduced in mutant worms. Tissue-specific chromatin binding and transcriptome analyses showed reduced BAF-1 association in most genes deregulated by the baf-1(G12T) mutation, suggesting that altered BAF chromatin association induces NGPS phenotypes via altered gene expression.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"5718-5746"},"PeriodicalIF":9.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11574047/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142376273","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

IF1 is a cold-regulated switch of ATP synthase hydrolytic activity to support thermogenesis in brown fat. IF1 是 ATP 合成酶水解活性的冷调节开关，支持棕色脂肪的热生成。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2024-11-01 Epub Date: 2024-09-16 DOI: 10.1038/s44318-024-00215-0

Henver S Brunetta, Anna S Jung, Fernando Valdivieso-Rivera, Stepheny C de Campos Zani, Joel Guerra, Vanessa O Furino, Annelise Francisco, Marcelo Berçot, Pedro M Moraes-Vieira, Susanne Keipert, Martin Jastroch, Laurent O Martinez, Carlos H Sponton, Roger F Castilho, Marcelo A Mori, Alexander Bartelt

{"title":"IF1 is a cold-regulated switch of ATP synthase hydrolytic activity to support thermogenesis in brown fat.","authors":"Henver S Brunetta, Anna S Jung, Fernando Valdivieso-Rivera, Stepheny C de Campos Zani, Joel Guerra, Vanessa O Furino, Annelise Francisco, Marcelo Berçot, Pedro M Moraes-Vieira, Susanne Keipert, Martin Jastroch, Laurent O Martinez, Carlos H Sponton, Roger F Castilho, Marcelo A Mori, Alexander Bartelt","doi":"10.1038/s44318-024-00215-0","DOIUrl":"10.1038/s44318-024-00215-0","url":null,"abstract":"While mechanisms controlling uncoupling protein-1 (UCP1) in thermogenic adipocytes play a pivotal role in non-shivering thermogenesis, it remains unclear whether F1Fo-ATP synthase function is also regulated in brown adipose tissue (BAT). Here, we show that inhibitory factor 1 (IF1, encoded by Atp5if1), an inhibitor of ATP synthase hydrolytic activity, is a critical negative regulator of brown adipocyte energy metabolism. In vivo, IF1 levels are diminished in BAT of cold-adapted mice compared to controls. Additionally, the capacity of ATP synthase to generate mitochondrial membrane potential (MMP) through ATP hydrolysis (the so-called \"reverse mode\" of ATP synthase) is increased in brown fat. In cultured brown adipocytes, IF1 overexpression results in an inability of mitochondria to sustain the MMP upon adrenergic stimulation, leading to a quiescent-like phenotype in brown adipocytes. In mice, adeno-associated virus-mediated IF1 overexpression in BAT suppresses adrenergic-stimulated thermogenesis and decreases mitochondrial respiration in BAT. Taken together, our work identifies downregulation of IF1 upon cold as a critical event for the facilitation of the reverse mode of ATP synthase as well as to enable energetic adaptation of BAT to effectively support non-shivering thermogenesis.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"4870-4891"},"PeriodicalIF":9.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11535227/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142300035","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0