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The 23rd FEBS YSF was held from 26th to 29th June 2024 in Pavia, Italy. Over 100 PhD students and early postdoctoral researchers from around 30 different countries came together at the inspiring rooms of the University of Pavia for a four‐day event. This year's topic was ‘Biochemistry for bridging the gap’, meaning the opportunity to have a comprehensive perspective on all biochemistry applications. Four renowned keynote speakers presented their latest research, accompanied by four career‐focused speakers, as well as additional sessions on academic career opportunities, including fellowships, women in science, and laboratory sustainability. Additionally, 10 selected YSF participants gave short talks to a large audience, while the remaining attendees shared their research findings through flash talks and two dedicated poster sessions. Scientific exchange and networking were encouraged during the poster sessions, breaks, and the social events. The meeting was a prelude before attending the 48th FEBS congress, celebrated in Milan. The success of the series will be continued during the 24th YSF edition: ‘Inspired by nature, driven by science’, which will take place from 2nd to 5th July 2025 in Sapanca, Türkiye.

Cyclin M (CNNM1-4) proteins maintain cellular and body magnesium (Mg2+) homeostasis. Using various biochemical approaches, we have identified members of the CNNM family as direct interacting partners of ADP-ribosylation factor-like GTPase 15 (ARL15), a small GTP-binding protein. ARL15 interacts with CNNMs at their carboxyl-terminal conserved cystathionine-β-synthase (CBS) domains. In silico modeling of the interaction between CNNM2 and ARL15 supports that the small GTPase specifically binds the CBS1 and CNBH domains. Immunocytochemical experiments demonstrate that CNNM2 and ARL15 co-localize in the kidney, with both proteins showing subcellular localization in the endoplasmic reticulum, Golgi apparatus and the plasma membrane. Most importantly, we found that ARL15 is required for forming complex N-glycosylation of CNNMs. Overexpression of ARL15 promotes complex N-glycosylation of CNNM3. Mg2+ uptake experiments with a stable isotope demonstrate that there is a significant increase of 25Mg2+ uptake upon knockdown of ARL15 in multiple kidney cancer cell lines. Altogether, our results establish ARL15 as a novel negative regulator of Mg2+ transport by promoting the complex N-glycosylation of CNNMs.

Despite the importance of electron transfer between redox proteins in photosynthesis and respiration, the inter-protein electron transfer rate between redox partner proteins has never been measured as a function of their separation in aqueous solution. Here, we use electrochemical tunneling spectroscopy to show that the current between two protein partners decays along more than 10 nm in the solution. Molecular dynamics simulations reveal a reduced ionic density and extended electric field in the volume confined between the proteins. The distance-decay factor and the calculated local barrier for electron transfer are regulated by the electrochemical potential applied to the proteins. Redox partners could use electrochemically gated, long distance electron transfer through the solution in order to conciliate high specificity with weak binding, thus keeping high turnover rates in the crowded environment of cells. Electron transport chains rely on interactions between redox proteins, but the distance-dependence of the electron transfer rate through the solution is unknown. Here, the authors show that the current between two redox protein partners occurs at long distances and is electrochemically gated.

Skeletal muscle is more resilient to ischemia-reperfusion injury than other organs. Tissue specific post-translational modifications of cytochrome c (Cyt c ) are involved in ischemia-reperfusion injury by regulating mitochondrial respiration and apoptosis. Here, we describe an acetylation site of Cyt c , lysine 39 (K39), which was mapped in ischemic porcine skeletal muscle and removed by sirtuin5 in vitro. Using purified protein and cellular double knockout models, we show that K39 acetylation and acetylmimetic K39Q replacement increases cytochrome c oxidase (COX) activity and ROS scavenging while inhibiting apoptosis via decreased binding to Apaf-1, caspase cleavage and activity, and cardiolipin peroxidase activity. These results are discussed with X-ray crystallography structures of K39 acetylated (1.50 Å) and acetylmimetic K39Q Cyt c (1.36 Å) and NMR dynamics. We propose that K39 acetylation is an adaptive response that controls electron transport chain flux, allowing skeletal muscle to meet heightened energy demand while simultaneously providing the tissue with robust resilience to ischemia-reperfusion injury. The authors report that acetylation of cytochrome c on K39 acts as a molecular switch in ischemic skeletal muscle, but not other tissues, to increase respiration and prevent apoptosis. This gives skeletal muscle robust resilience to ischemia and ischemia-reperfusion injury.

It has been recently shown that electron transfer between mitochondrial cytochrome c and the cytochrome c 1 subunit of the cytochrome bc 1 can proceed at long-distance through the aqueous solution. Cytochrome c is thought to adjust its activity by changing the affinity for its partners via Tyr48 phosphorylation, but it is unknown how it impacts the nanoscopic environment, interaction forces, and long-range electron transfer. Here, we constrain the orientation and separation between cytochrome c 1 and cytochrome c or the phosphomimetic Y48 p CMF cytochrome c , and deploy an array of single-molecule, bulk, and computational methods to investigate the molecular mechanism of electron transfer regulation by cytochrome c phosphorylation. We demonstrate that phosphorylation impairs long-range electron transfer, shortens the long-distance charge conduit between the partners, strengthens their interaction, and departs it from equilibrium. These results unveil a nanoscopic view of the interaction between redox protein partners in electron transport chains and its mechanisms of regulation. Electron transfer between mitochondrial cytochrome c and subunit of cytochrome bc 1 can proceed at long distance. Here the authors investigate further the mechanism and show phosphorylation regulation of the interactions between the protein partners in the electron transport chain.

While most organelles are surrounded by membranes, cells also contain membraneless organelles, which remain separated in the cell by avoiding the mixture of their components with the surroundings. Actually, liquid–liquid phase separation provides a simple but smart mechanism for the cell to control the spatial localization and processing of molecules, without relying on membrane boundaries. This Special ‘In the Limelight’ section, entitled ‘Membraneless organelles’, consists of three review articles, each focused on a particular aspect. The first article deals with assembly of coacervates as mediated by polyproline II helices, as well as with condensate stability. The second article addresses the formation of protein–nucleic acid coacervates by prion‐like proteins and their link to human diseases. Finally, the last article focuses on mitochondrial cytochrome c translocation into the nucleus after DNA damage, with the subsequent inhibition of nucleosome assembly/disassembly activity of histone chaperones and its impact on chromatin dynamics and nuclear condensates. This Special ‘In the Limelight’ section consists of three review articles on aspects related to membraneless organelles. The first article deals with coacervate assembly as mediated by polyproline II helices, the second addresses the formation of protein–nucleic acid coacervates by prion‐like proteins, and the last article focuses on mitochondrial cytochrome c translocation into the nucleus after DNA damage.

The aim of this study was to address the lack of protocols for nuclear magnetic resonance (NMR)‐based metabolomics in the agri‐food sector by providing a reproducible workflow for the preparation and analysis of water‐soluble metabolite fractions. These fractions, rich in primary metabolites such as sugars, amino acids, and organic acids, are key to assessing agri‐food products' composition, quality, as well as to monitor their manufacturing and development processes. The protocol differentiates solid and liquid matrices, optimizing extraction procedures accordingly. Representative agri‐food products—strawberry leaves (solid) and wine (liquid)—were analyzed to demonstrate the method's versatility and applicability. Key steps include tailored sample preparation, optimization of NMR acquisition, and spectral quality control, ensuring high data quality and reproducibility. The proposed workflow enhances reproducibility across agri‐food metabolomics studies and facilitates integration into broader food quality, traceability, and safety frameworks.

This work was supported by the Spanish Association Against Cancer (PROYE18061FERN to M.F.F.), the Asturias Government (PCTI) co-funding 2018-2023/FEDER (IDI/2018/146 and IDI/2021/000077 to M.F.F.), the Health Institute Carlos III (Plan Nacional de I+D+I) co-funding FEDER (PI18/01527 and PI21/01067 to M.F.F and A.F.F.), CIBERER Acciones Cooperativas y Complementarias Intramurales (ACCI20-35 to M.F.F.), the Fundación General CSIC (0348_CIE_6_E to M.F.F.), the ISCIII (COV00624 to J.R.T. and M.F.F.), ISPA and the Asociación Galbán (2021-052-INTRAMUR GALBAN-GOURR to R.G.U.), ISPA-Jannsen (2021-048-INTRAMURAL NOV-TEVAR to J.R.T.), CSIC (202020E092 to M.F.F), and the European Commission NextGenerationEU, through CSIC’s Global Health Platform (PTI Salud Global) and the Spanish Ministry of Science and Innovation through the Recovery, Transformation and Resilience Plan (SGL2021-03-39 and SGL2021-03-040).

Hu antigen R (HuR) is a 36-kDa ubiquitous member of the ELAV/Hu family of RNA-binding proteins (RBPs), which plays an important role as a post-transcriptional regulator of specific RNAs under physiological and pathological conditions, including cancer. Herein, we review HuR protein structure, function, and its regulation, as well as its implications in the pathogenesis, progression, and treatment of hepatobiliary cancers. In particular, we focus on hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), tumors where the increased cytoplasmic localization of HuR and activity are proposed, as valuable diagnostic and prognostic markers. An overview of the main regulatory axes involving HuR, which are associated with cell proliferation, invasion, metastasis, apoptosis, and autophagy in HCC, is provided. These include the transcriptional, post-transcriptional, and post-translational modulators of HuR function, in addition to HuR target transcripts. Finally, whereas studies addressing the relevance of targeting HuR in CCA are limited, in the past few years, HuR has emerged as a potential therapeutic target in HCC. In fact, the therapeutic efficacy of some pharmacological inhibitors of HuR has been evaluated, in early experimental models of HCC. We, further, discuss the major findings and future perspectives of therapeutic approaches that specifically block HuR interactions, either with post-translational modifiers or cognate transcripts in hepatobiliary cancers.

Chromatin homeostasis mediates essential processes in eukaryotes, where histone chaperones have emerged as major regulatory factors during DNA replication, repair, and transcription. The dynamic nature of these processes, however, has severely impeded their characterization at the molecular level. Here, fluorescence optical tweezers are applied to follow histone chaperone dynamics in real time. The molecular action of SET/template‐activating factor‐Iβ and nucleophosmin 1—representing the two most common histone chaperone folds—are examined using both nucleosomes and isolated histones. It is shown that these chaperones present binding specificity for fully dismantled nucleosomes and are able to recognize and disrupt non‐native histone‐DNA interactions. Furthermore, the histone eviction process and its modulation by cytochrome c are scrutinized. This approach shows that despite the different structures of these chaperones, they present conserved modes of action mediating nucleosome remodeling. This study focuses on the molecular action of two histone chaperones: SET/template‐activating factor‐Iβ and nucleophosmin 1. It is shown how these chaperones have specificity for fully dismantled nucleosomes, characterized the histone eviction (removal) process, and its modulation by cytochrome c. Overall, it is shown that these chaperones exhibit conserved modes of action mediating nucleosome remodeling despite their structural differences.