The FEBS journal最新文献

{"title":"Nutrient-specific combinatorial secretion of GLP-1 and neurotransmitters in the enteroendocrine L-cell line GLUTag.","authors":"Yo Ito, Kazuki Harada, Yuri Osuga-Yoshiike, Masami Yokota Hirai, Tetsuya Kitaguchi, Takashi Tsuboi","doi":"10.1111/febs.70753","DOIUrl":"https://doi.org/10.1111/febs.70753","url":null,"abstract":"<p><p>Enteroendocrine L cells function as chemosensors in the intestine, secreting glucagon-like peptide-1 (GLP-1) to signal nutrient ingestion to the brain. Since GLP-1 secretion is induced by a variety of nutrients, including sugars, amino acids, and fatty acids, GLP-1 receptor-expressing neurons are also activated regardless of the nutrient identity, making it unclear how the brain discriminates between different nutrients. By examining vesicle dynamics and extracellular signals associated with GLP-1, glutamate, and ATP in GLUTag cells using total internal reflection fluorescence (TIRF) microscopy, a technique that selectively visualizes fluorescent molecules near the plasma membrane, we demonstrated that distinct nutrients evoke specific secretory patterns. D-glucose induced the co-secretion of GLP-1, glutamate, and ATP, whereas L-glutamine induced the secretion of GLP-1 and glutamate but not ATP. Butyrate and sucralose, which are also GLP-1 secretagogues, did not induce the secretion of glutamate or ATP. While Ca²⁺ acts as the trigger for exocytosis, additional regulatory mechanisms are required to generate these distinct secretory patterns. We therefore investigated the cAMP and cGMP pathways and found that neither their activation nor inhibition detectably affected glutamate and ATP secretion, suggesting the involvement of other nutrient-specific signaling pathways. Collectively, our findings suggest that L cells distinguish and encode nutrient identity as combinatorial secretion patterns of GLP-1 and neurotransmitters.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149187273","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Toward understanding the catalytic mechanism for two classes of bacterial phospholipid N-methyltransferases","authors":"Irina Shevyreva,&nbsp;Lena Sophie Fritsch,&nbsp;Leander Mika Koch,&nbsp;Anton Effing,&nbsp;Meriyem Aktas,&nbsp;Franz Narberhaus","doi":"10.1111/febs.70571","DOIUrl":"10.1111/febs.70571","url":null,"abstract":"<p>Phosphatidylcholine (PC), the predominant phospholipid in eukaryotic membranes, also plays a crucial role in certain bacterial species, often mediating interactions with eukaryotic hosts. In bacteria, a major pathway for PC biosynthesis involves the three-step methylation of phosphatidylethanolamine, catalyzed by phospholipid <i>N</i>-methyltransferases (Pmts). While the binding site for the methyl donor <i>S</i>-adenosyl-<i><span>l</span></i>-methionine is well characterized in Pmt enzymes, the detailed mechanism of methyl group transfer remains poorly understood. In this study, we combined computational and biochemical approaches to identify the amino acid residues critical for the catalytic activity of two distinct Pmt classes: the <i>Rhodobacter</i> (<i>R</i>)-type enzyme from <i>Rubellimicrobium thermophilum</i> (<i>Rt</i>PmtA) and the <i>Sinorhizobium</i> (<i>S</i>)-type enzyme from <i>Agrobacterium tumefaciens</i> (<i>At</i>PmtA). Despite low sequence identity, both enzyme types share similar reaction mechanisms, with tyrosine residues playing key roles in methyl group transfer. In <i>Rt</i>PmtA, two highly conserved tyrosines located within the substrate-binding pocket on the N-terminal αA-helix are critical for enzymatic function. In contrast, <i>At</i>PmtA depends on a single tyrosine buried in the protein core for catalysis. These findings reveal distinct active site architectures and suggest that <i>R</i>-type and <i>S</i>-type enzymes have evolved class-specific structural strategies for tyrosine activation. This divergence highlights the evolutionary flexibility of Pmt enzymes, despite their shared catalytic function.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":"293 20","pages":"6253-6271"},"PeriodicalIF":4.2,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/febs.70571","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147825194","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":"Effects of GLP-1 agonists on the gut microbiota in type 2 diabetes mellitus: a systematic review","authors":"Ranicleide Santos Dantas,&nbsp;Lucas Vinícius Souza Santos,&nbsp;André Gustavo Carvalho de Oliveira,&nbsp;Marina dos Santos Barreto,&nbsp;Deise Maria Rego Rodrigues Silva,&nbsp;Pedro Henrique Macedo Moura,&nbsp;Eloia Emanuelly Dias Silva,&nbsp;Ronaldy Santana Santos,&nbsp;Lucas Alves da Mota Santana,&nbsp;Rajiv Gandhi Gopalsamy,&nbsp;Adriana Gibara Guimarães,&nbsp;Lysandro Pinto Borges","doi":"10.1111/febs.70656","DOIUrl":"10.1111/febs.70656","url":null,"abstract":"<p>Diabetes mellitus (DM) is a metabolic disease characterised by chronic hyperglycemia. The Glucagon-Like Peptide-1 Receptor Agonists (GLP-1 RAs) used in type 2 diabetes mellitus (T2DM) have been highlighted for their potential benefits to the gut microbiota in the context of this pathology. Therefore, it is important to investigate the relationship between microbiota and GLP-1 RAs used in T2DM. This review aimed at evaluating the effects of GLP-1 agonists on gut microbiota in T2DM individuals. The protocol was previously registered in PROSPERO, and the search was conducted in PubMed, Scopus, Web of Science, and Embase databases in March 2025. Two reviewers have read the titles and abstracts and selected the included articles based on established criteria. The initial search identified 5532 publications, of which 17 studies were included: 12 preclinical and 5 clinical. Most were conducted in China between 2016 and 2025. GLP-1 agonists have been shown to modulate the gut microbiota, characterised by an increase in Bacteroidetes, <i>Akkermansia muciniphila</i>, and <i>Lactobacillus</i>. These changes are accompanied by an improvement of intestinal villi, increase in occludin expression, as well as an improvement in colonic inflammation. We identified a higher abundance of bacterial species associated with intestinal balance (eubiosis), accompanied by reduced inflammation and insulin resistance. Conversely, there was a lower abundance of bacteria related to dysbiosis, such as <i>Firmicutes</i> and <i>Proteobacteria</i>, which can be unfavourable when in excess. GLP-1 agonists influence the intestinal microbiota, improving metabolic parameters and anti-inflammatory effects. However, further clinical studies are needed to corroborate the findings of this review.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":"293 20","pages":"5971-5995"},"PeriodicalIF":4.2,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/febs.70656","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148803957","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":"Unraveling in vitro phase separation and aggregation properties of the structured region of FMRP and the impact of Fragile X syndrome-linked mutations","authors":"Flavia Catalano,&nbsp;Alessandra Bigi,&nbsp;Francesca Troilo,&nbsp;Federica Gabriele,&nbsp;Gianluca Pistoia,&nbsp;Italia A. Asteriti,&nbsp;Francesco Angelucci,&nbsp;Giorgio Giardina,&nbsp;Fabrizio Chiti,&nbsp;Carlo Travaglini-Allocatelli,&nbsp;Adele Di Matteo","doi":"10.1111/febs.70564","DOIUrl":"10.1111/febs.70564","url":null,"abstract":"<p>Fragile X messenger ribonucleoprotein 1 (FMRP) is a multidomain RNA-binding protein highly expressed in neurons. It comprises a structured N-terminal region (NTR) containing five RNA/protein interaction domains and a large intrinsically disordered C-terminal region. A limited number of fragile X syndrome (FXS)-associated point mutations have been identified in the NTR, leading to the expression of mutated protein variants. Here, we show that the destabilizing effects of these mutations on the NTR region are less severe than those previously observed in the isolated domains, suggesting the presence of inter-domain interactions that stabilize the overall NTR architecture. Moreover, we demonstrate that the NTR structured region has an intrinsic propensity to undergo liquid–liquid phase separation (LLPS) and amyloid fibril formation <i>in vitro</i>, depending on protein concentration, and we characterize how three FXS-associated mutations (R138Q, G266E, and I304N) affect these processes. We show that the mutations either destabilize the entire NTR (G266E/I304N), markedly affect the kinetics of LLPS and suppress the droplet liquid nature (R138Q/G266E), or promote solid or gel-like non-amyloid aggregation (G266E), thus providing mechanistic insights into how they may alter protein function, contributing to the pathogenic mechanism. These findings suggest that the interplay between protein stability, LLPS, and fibrillization is finely regulated and may be critical for understanding FMRP function and its dysfunction in disease.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":"293 20","pages":"6155-6175"},"PeriodicalIF":4.2,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/febs.70564","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147825183","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":"Long-read sequencing-based atlas of tissue-specific expression of DNM1L transcript variants","authors":"Feng Yan,&nbsp;Jafar S. Jabbari,&nbsp;Naomi X. L. Ling,&nbsp;Anne M. Kong,&nbsp;Jia Q. Truong,&nbsp;Marnie L. Maddock,&nbsp;Ayeshah A. Rosdah,&nbsp;Christopher G. Langendorf,&nbsp;Lifang Zhang,&nbsp;Jarmon G. Lees,&nbsp;Sebastian Bass-Stringer,&nbsp;Danise Ann Onda,&nbsp;Alice Pébay,&nbsp;Mirella Dottori,&nbsp;Kim Loh,&nbsp;Jessica K. Holien,&nbsp;Sean Lal,&nbsp;Nadia M. Davidson,&nbsp;Jonathan S. Oakhill,&nbsp;Shiang Y. Lim","doi":"10.1111/febs.70568","DOIUrl":"10.1111/febs.70568","url":null,"abstract":"<p>Dynamin-related protein 1 (Drp1), encoded by <i>DNM1L</i>, is essential for mitochondrial fission, but its functional roles remain unclear due to isoform-specific effects from alternative splicing. Short-read RNA sequencing fails to resolve full-length isoforms involving distant exons, limiting our understanding. Here, we applied targeted long-read sequencing to profile full-length <i>DNM1L</i> transcripts in human left ventricle and induced pluripotent stem cell-derived cardiomyocytes, recovering all annotated isoforms with conserved expression patterns and isoforms 1–4 being the most abundant. Functional assays revealed that isoform abundance does not predict enzymatic activity. Extending this to six different mouse tissues, we identified distinct, tissue-enriched expression profiles. Functional rescue in Drp1-knockout mouse embryonic fibroblasts showed isoform-dependent differences in mitochondrial fission. Isoforms lacking the A-insert robustly rescued mitochondrial fission, with maximal activity observed for variants also lacking the B-insert (e.g. isoform b), consistent with a modulatory role of exon 3 in Drp1 activity. Our cross-species atlas integrates long-read transcriptomics with functional validation, revealing how isoform diversity underpins tissue-specific mitochondrial dynamics and physiological roles of Drp1.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":"293 20","pages":"6208-6229"},"PeriodicalIF":4.2,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/febs.70568","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147793742","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":"Genetic dissection reveals distinct contributions of the eS31 N-terminal domain to translational accuracy in Saccharomyces cerevisiae","authors":"Qingxuan Gao,&nbsp;Hiroshi Otsuka,&nbsp;Kei Endo,&nbsp;Koichi Ito","doi":"10.1111/febs.70510","DOIUrl":"10.1111/febs.70510","url":null,"abstract":"<p>The eukaryote-specific N-terminal domain of ribosomal protein eS31 is a flexible extension near the decoding center, but its role in translational control has been obscured by pleiotropic defects associated with complete domain deletion. To resolve this ambiguity, we dissected its function at amino acid resolution in <i>Saccharomyces cerevisiae</i> using a genetic screen for ribosome stalling at CGA codon repeats. By functionally separating the N-terminal ubiquitin moiety from the ribosomal domain, our screen bypassed artifacts and identified a critical cluster of basic residues (K79–K82) within this region. Charge-reversing point mutations in this cluster alleviate stalling not by impairing ribosome-associated quality control, but by reducing decoding fidelity, as supported by paromomycin sensitivity and genetic suppression by the loss of the eEF2 diphthamide modification. Crucially, the mutant lacking the entire domain operates through a fundamentally distinct mechanism, exhibiting a severe defect in termination fidelity and a paradoxical requirement for wild-type eS31 that suggests a global structural perturbation. Our findings thus resolve the function of the N-terminal domain of eS31 into two distinct modes: a residue-specific, electrostatic role in fine-tuning elongation fidelity, and a broader structural role for the entire domain in maintaining ribosome integrity for accurate termination.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":"293 20","pages":"6076-6099"},"PeriodicalIF":4.2,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/febs.70510","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147505950","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":"Bip1 regulates AMPK signaling in response to endoplasmic reticulum stress","authors":"Mengdan Zhu,&nbsp;Chuanhai Fu","doi":"10.1111/febs.70496","DOIUrl":"10.1111/febs.70496","url":null,"abstract":"<p>The accumulation of misfolded and unfolded proteins within the endoplasmic reticulum (ER) lumen induces ER stress, which in turn triggers various consequences, such as the unfolded protein response (UPR). AMP-activated protein kinase (AMPK) is also a cellular stress sensor. However, the interplay between AMPK and ER stress remains poorly understood. In this study, we report that in the fission yeast <i>Schizosaccharomyces pombe</i>, the deletion of <i>erd2</i>, a central component for the retrieval of ER-resident proteins, leads to the accumulation of the canonical ER luminal chaperone Bip1 in the cytosol. Moreover, we demonstrate that <i>erd2</i> deletion increases the levels of the AMPK upstream kinase Ssp1 in a Bip1-dependent manner, thereby promoting AMPK phosphorylation. Intriguingly, although these phenotypes are not dependent on UPR, they can also be caused by ER stress. We further identify multiple E3 ubiquitin ligases that are responsible for the regulation of Ssp1 stability, and Bip1 physically interacts with and stabilises Ssp1 by inhibiting ubiquitination of Ssp1. Additionally, we elucidate that AMPK activation, mediated by the stabilised Ssp1, is required to sustain cell viability, particularly in cells lacking Erd2. Collectively, our findings demonstrate the important role of Erd2 in the maintenance of cellular homeostasis and establish a link between ER stress and AMPK signalling.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":"293 20","pages":"6051-6075"},"PeriodicalIF":4.2,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147476849","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CDK14 is a critical regulator of haematopoietic stem and progenitor cell maintenance and post-transplantation proliferation","authors":"Ya-fei Li,&nbsp;Tian-jing Li,&nbsp;Yin Huang,&nbsp;Ke Bai,&nbsp;Rong-rong Gao,&nbsp;Jia-xin Yang,&nbsp;Lan-yue Ma,&nbsp;Yan-mei Yu,&nbsp;Jinjin Ma,&nbsp;Qi Chen,&nbsp;Yang Liu","doi":"10.1111/febs.70562","DOIUrl":"10.1111/febs.70562","url":null,"abstract":"<p>Cyclin-dependent kinase (CDK) 14 is involved in Wnt signalling, tissue repair, and tumourigenesis, but its function in haematopoiesis remains unexplored. Here, we found that CDK14 was necessary to maintain physiological haematopoiesis under steady-state and haematopoietic reconstitution after transplantation using genetic and pharmacological interventions. By utilising <i>Cdk14</i> knockout and haematopoietic-deletion (<i>Cdk14</i>^∆HC) mouse models, in combination with the selective CDK14 inhibitor FMF-04-159-2, we showed that ablation of CDK14 resulted in diminished haematopoietic stem and progenitor cells (HSPCs), and disrupted the proportion of mature haematopoietic cells. Single-cell RNA sequencing analysis of bone marrow from <i>Cdk14</i>^∆HC mice revealed impaired cell cycle progression, perturbed HSPC proportion, and altered niche-HSPC interactions. Furthermore, genetic and pharmacological ablation of CDK14 markedly decreased HSPC proliferation after transplantation in vivo and reduced colony formation in vitro. These findings identify CDK14 as a critical regulator of haematopoietic homeostasis and highlight its essential role in supporting HSPC function under stress conditions.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":"293 20","pages":"6137-6154"},"PeriodicalIF":4.2,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147825146","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Surface charge alterations in urinary extracellular vesicles mirror diabetic kidney disease pathophysiology.","authors":"Melanie Tepuš, Maria Pia Savoca, Mabrouka Maamra, Conor J Meehan, Dimitrios S Goumenos, Timothy Johnson, Elisabetta A M Verderio","doi":"10.1111/febs.70764","DOIUrl":"https://doi.org/10.1111/febs.70764","url":null,"abstract":"<p><p>Urinary extracellular vesicles (uEVs) are an attractive source of biomarkers as their cargo of proteins, nucleic acids and lipids reflects cell pathophysiology. The physical properties of uEVs such as their electrical nature measured by the zeta potential (charge at the interface of vesicle and liquid) are seldom explored although their understanding may lead to translational applications of EVs in clinical settings. In diabetes and diabetic kidney disease (DKD), post-translational modifications resulting from loss of glycocalyx (diabetes) and gain of extracellular matrix components (tissue fibrosis) could potentially affect the electrical charge of pathologically relevant EVs. DKD cohorts obtained by adhering to industry-standard reproducible criteria were stratified into stable and progressive disease based on estimated glomerular filtration rate (eGFR) loss and compared to nonkidney disease diabetic and healthy controls. Surface charge analysis revealed a significant difference in the zeta potential of large uEVs between the diabetic and healthy cohorts, as well as between the diabetic and DKD-progressive cohorts. These differences are mechanistically consistent with pathological alterations observed in heparan sulfate (HS) content. Accordingly, uEVs from DKD patients exhibited higher HS levels than those from diabetic individuals, as assessed by SP-IRIS/ExoView using HS-binding capture. Comparative proteomic analysis further demonstrated an increased abundance of the sulfated glycosaminoglycan lumican in DKD uEVs relative to diabetes, consistent with its reported upregulation in early fibrotic stages of DKD. Notably, our findings indicate for the first time that the zeta potential of large uEVs may be predictive of the progression of diabetes into DKD.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149186786","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Selective autophagy pathways in ageing and neurodegeneration: Emerging roles for mitophagy and nucleophagy.","authors":"Maria Markaki, Nektarios Tavernarakis","doi":"10.1111/febs.70738","DOIUrl":"https://doi.org/10.1111/febs.70738","url":null,"abstract":"<p><p>Ageing is characterized by the progressive accumulation of molecular and cellular damage, driven by both genetic and nongenetic factors and ultimately leading to functional decline and an increased risk of disease. Convergent evidence indicates that many of the mechanisms influencing ageing are intimately related to the ability of the organism to cope with intrinsic and extrinsic stress. Key determinants of this capacity are the molecular pathways that coordinate stress responses throughout life. Among these, general and cargo-specific autophagy have emerged as integral components of cellular and systemic adaptation to stress. Here, we focus on mitophagy, a selective form of autophagy targeting mitochondria, and nucleophagy, the selective autophagic recycling of nuclear material. These processes help safeguard the integrity of two organelles that are central to long-term cellular survival and function. Such homeostatic mechanisms are vital in long-lived neurons, where they mediate damage removal during ageing to protect against neurodegeneration. We further discuss how perturbations in these autophagic pathways may contribute to ageing and neurodegenerative disorders. Finally, we outline key open questions and future challenges in the field, including the largely unexplored possibility of functional connections between mitophagy and nucleophagy, which we identify as an important direction for future research.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149186383","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}