eLife: latest articles by subject

Photo-downregulation of SIRT4 mitigates aging in mice by enhancing H3K9ac via fatty acid metabolism

yangyingchun@xiyi.edu.cn (Fangqing Deng) — Thu, 08 Oct 2026 00:00:00 +0000

As organisms age, mitochondrial metabolic activity declines, and disrupted gene expression regulation mediated by histone acetylation induces the emergence of senescent physiological phenotypes in tissues. In this study, we found that periodic exposure to red light significantly increased histone H3 Lys9 acetylation (H3K9ac) levels in the tissues and organs of aged mice. Following red light exposure, silent information regulation factor 4 (SIRT4) protein levels in keratinocytes were notably reduced, whereas glycolysis, fatty acid metabolism, and the tricarboxylic acid (TCA) cycle were significantly activated in keratinocytes. The reduction in mitochondrial SIRT4 levels enhances the acetylation of mitochondrial metabolic proteins, particularly malonyl-CoA decarboxylase, a potent inhibitor of the key rate-limiting enzyme carnitine palmitoyltransferase 1A (CPT1A) in fatty acid oxidation. This process promotes mitochondrial fatty acid oxidation and the TCA cycle. Additionally, the decrease in SIRT4 activates SIRT1 through feedback mechanisms, thereby alleviating its inhibition on PPAR-α in senescent keratinocytes and comprehensively activating the expression of genes related to lipid metabolism. This lipid metabolism activation ultimately facilitates the accumulation of acetyl-CoA within keratinocytes, increases H3K9ac levels, and reshapes the expression patterns of senescence-related genes. Eventually, cellular aging is effectively mitigated by the synergistic regulation of metabolism, inflammation, and gene expression.

Early recruitment of membrane-bound DNaseX to phagocytic cups in macrophages

xuefeng.wang@uc.edu (Arghajit Pyne) — Thu, 08 Oct 2026 00:00:00 +0000

Macrophages engulf and degrade pathogens and cellular debris through phagocytosis. The degradation process was generally believed to occur only after phagosome internalization and maturation. Here, we report an early DNase activity at the nascent phagocytic cup (PC) prior to its closure. Using a fluorescent DNase sensor, we revealed rapid and ubiquitous DNase activity upon PC formation across various macrophage types. We further identified the responsible enzyme as the membrane-bound DNaseX, which is constitutively recruited to the PC during PC formation. F-actin polymerization was found to correlate with DNase activity in the PC, likely by promoting physical engagement of DNaseX with solid DNA materials. Functionally, we show that macrophages degrade extracellular DNA (eDNA) within bacterial biofilms through direct physical contact, clearing the eDNA structures without internalization. These findings reveal a previously unrecognized DNA degradation mechanism operating at the macrophage membrane, suitable for degrading bulky eDNA materials which cannot be directly internalized by macrophages.

A high-throughput assay for the measurement of Ca²⁺ oscillations and insulin release from uniformly sized mouse β-cell (MIN6) spheroids

thomas.voets@kuleuven.be (Patricia Davidson) — Mon, 05 Oct 2026 00:00:00 +0000

Diabetes mellitus is a rapidly growing global health challenge, necessitating the development of more effective anti-diabetic therapies, including drugs that improve insulin release from pancreatic β-cells. Traditional high-throughput screening methods typically rely on 2D β-cell cultures, but such cultures do not mimic the 3D organization and cell-to-cell communication of β-cells in pancreatic islets of Langerhans. Existing 3D β-cell culture models are hindered by high costs, technical complexity, and limited compatibility with high-throughput screening platforms. In this work, we developed an approach for generating 19 homogeneously shaped pancreatic β-cell spheroids in each well of a 96-well plate, using micropatterned polyethylene glycol (PEG)-based hydrogels and murine mouse insulinoma 6 (MIN6) insulinoma cells. The uniform shape and positioning of the individual spheroids enabled the simultaneous, real-time imaging of Ca²⁺ signals in up to 1824 independent spheroids in response to glucose and various test compounds. Using this approach, we show that increasing glucose causes concentration-dependent Ca²⁺ oscillations in individual spheroids, that these Ca²⁺ oscillations are sensitive to modulators of ATP-sensitive K⁺ channels, and that the frequency of Ca²⁺ oscillations correlates with insulin secretion. Finally, we demonstrate that the neurosteroid pregnenolone sulfate, an agonist of the cation channel TRPM3, increases the frequency of glucose-induced Ca²⁺ oscillations and enhances insulin release; the TRPM3 antagonist isosakuranetin inhibited these responses. In conclusion, we established a cost-effective and scalable 3D β-cell platform for high-throughput screening of insulin release-modifying compounds, with potential applications in drug development and personalized medicine for the management of diabetes mellitus.

Zinc is a key regulator of the sperm-specific K⁺ channel (Slo3) function

kawai.takafumi.ra@ehime-u.ac.jp (Haruhiko Miyata) — Wed, 30 Sep 2026 00:00:00 +0000

The voltage- and pH-gated Slo3 potassium channel is exclusively expressed in mammalian spermatozoa. Its sensitivity to both voltage and alkalization plays a crucial role in sperm fertility, which is tightly coupled to the capacitation process. Here, we show that sperm-enriched divalent cation Zn²⁺ undergoes dynamic alteration in spermatozoa during capacitation. We also found that intracellular Zn²⁺ regulates alkalinization-induced hyperpolarization in mouse spermatozoa, which is mediated by the Slo3 channel. Further examination of zinc regulation in mouse Slo3 (mSlo3) revealed that, in the Xenopus oocyte expression system, intracellular zinc directly inhibits mouse Slo3 currents in a dose-dependent manner at micromolar concentrations, with exceptionally slow dissociation. By combining MD simulations and electrophysiology, we also identified amino acid residues contributing to the Zn²⁺ slow dissociation from Slo3 channels. Our studies uncover the importance of intracellular zinc dynamics and its regulatory role in ion channels during sperm capacitation.

Tau hyperphosphorylation impairs cooperative binding to microtubules and perturbs organelle trafficking in neurons

daniel.beaudet@mcgill.ca (Adam G Hendricks) — Mon, 28 Sep 2026 00:00:00 +0000

Tau, a neuronal microtubule-associated protein (MAP), organizes the axonal cytoskeleton, and regulates intracellular transport. Tau hyperphosphorylation is linked to neurodegeneration in tauopathies, including Alzheimer’s disease. Tau binds microtubules cooperatively to form cohesive envelopes, which are thought to control access to the microtubule lattice and regulate the activity of motor proteins and other MAPs. However, how disease-related perturbations affect tau dynamics and its function as a selective barrier to intracellular transport remains unclear. Using tau phospho-variants in vitro and in live neurons, we show that tau hyperphosphorylation disrupts cooperative microtubule binding and dysregulates lysosome transport. Hyperphosphorylated tau does not form envelopes, distributes more uniformly along the axon, and dissociates faster from microtubules. Tau weakly inhibits KIF5C motility, but strongly inhibits KIF1A. Hyperphosphorylation reduces KIF5C inhibition but increases KIF1A inhibition by decreasing processivity and accelerating detachment. Consistent with these effects, hyperphosphorylated tau alters lysosome transport in neurons. While phospho-resistant tau inhibits processive lysosome motility, hyperphosphorylated tau weakens tau-mediated regulation of lysosome transport, mimicking tau knockout neurons that exhibit enhanced processivity. Altogether, these findings show that hyperphosphorylation disrupts tau envelopes and impairs lysosome trafficking, likely contributing to early defects in degradative pathways that drive neurodegeneration.

Wound-induced syncytia outpace mononucleate neighbors during Drosophila wound repair

shane.hutson@vanderbilt.edu (Andrea Page-McCaw) — Tue, 22 Sep 2026 00:00:00 +0000

In response to injury, cells proliferate, migrate, and invade to replace missing cells and close wounds. However, the role of other wound-induced cell behaviors is not understood, including the formation of syncytia (multinucleated cells). Here, we use in vivo live imaging to analyze wound-induced syncytia in mitotically competent Drosophila pupae. We find that almost half the epithelial cells near a wound fuse to form large syncytia. When the autophagy gene Atg1 is knocked down, fewer syncytia form, and wounds close more slowly. Further, a computational model of tissue fluidity indicates that cell fusion speeds wound closure time by about one-third. Syncytia use several routes to speed wound repair: they outpace diploid cells at the wound margin to lead the initial resealing of the wound; they reduce the need for intercalation as the tissue reshapes during closure; and they pool resources of their component cells to concentrate them toward the wound margin. In addition to wound healing, these properties of syncytia are likely to contribute to their roles in development and pathology.

Defective neuronal differentiation in Lowe syndrome is associated with mitochondrial dysfunction and impaired cilia-related Sonic Hedgehog signaling

yangsun@stanford.edu (Benjamin Lawson) — Fri, 18 Sep 2026 00:00:00 +0000

Human brain development requires tight coordination of metabolic and signaling pathways. Lowe syndrome (LS) is a recessive X-linked disorder characterized by proximal tubular renal disease, congenital cataracts, glaucoma, and neurodevelopmental delays. While LS results from mutations in the OCRL gene, which encodes an inositol polyphosphate 5-phosphatase, the cellular mechanisms driving neuronal dysfunction remain poorly understood. In this study, using patient-derived iPSC neurons, an Ocrl knockout mouse model, and an independent zebrafish OCRL-deficient model, we identified mitochondrial dysfunction as a conserved phenotype of OCRL loss across species. Collectively, our findings showed that OCRL deficiency leads to reduced mitochondrial activity, decreased mtDNA levels, reduced mitochondrial content (TOM20), and increased oxidative stress. We further showed that OCRL-deficient neural cells exhibited an altered balance of neuronal versus astrocytic differentiation, rather than a defect in neurogenesis. Additionally, we observed impaired Sonic Hedgehog (Shh) signaling and ciliary homeostasis. Thus, our findings support a model in which OCRL deficiency is associated with mitochondrial dysfunction, increased oxidative stress, altered neural lineage balance, and reduced Hedgehog pathway activity, providing a framework for understanding these interconnected phenotypes.

The power of theory in the life sciences

jacob.fine@mail.utoronto.ca (Adam MR Groh) — Fri, 18 Sep 2026 00:00:00 +0000

The rapid growth of high-throughput biology and genomics over the past two decades has helped catalogue many different aspects of gene function in diverse cell types and conditions. More recently, advances in artificial intelligence and deep learning have shown tremendous promise in making accurate predictions of functional genomics measurements. These advances make it tempting to equate experimental cataloguing and accurate prediction with the growth of our theoretical understanding of biological processes – an equivalence we believe is ultimately misleading.

Intracellular growth of Chlamydia trachomatis leads to global histone hypermethylation by impairing demethylation

asubtil@pasteur.fr (Adrian Gabriel Torres) — Mon, 14 Sep 2026 00:00:00 +0000

Chlamydia trachomatis, an intracellular bacterium, highjacks metabolites from the host cell for its own proliferation. We provide evidence of global hypermethylation of the host proteome, including histones, during the late stages of infection. Single cell analyses revealed co-occurrence of several methylated residues on histones, while infection did not alter S-adenosyl methionine levels. Histone hypermethylation correlated positively with bacterial load and was prevented by antibiotic treatment. Mapping of trimethylation of histone 3 at residues K4 and K9 revealed a broad distribution throughout chromatin. Nuclear fractions of infected cells exhibited a fourfold decrease of demethylase activity against H3K4me3 and a twofold increase in succinate concentration, a competitive inhibitor for the demethylase co-factor a-ketoglutarate. Supplementation of the culture medium with dimethyl-ketoglutarate (DMKG) or with iron, a second co-factor of histone lysine demethylases, reduced histone hypermethylation. DMKG supplementation modified the transcription of about one third of the infection-responsive genes, indicating that histone hypermethylation contributes to modulating the transcriptional response of the host to infection. Finally, chemical inhibition of histone demethylases in a mouse model of infection showed a moderate benefit regarding the outcome of infection. Overall, our data show that the metabolic pressure exerted by a pathogen with an intracellular lifestyle drives epigenetic changes in infected cells.

Sarcomere dynamic instability and stochastic heterogeneity drive robust cardiomyocyte contraction

w.zimmermann@med.uni-goettingen.de (Christoph F Schmidt) — Mon, 14 Sep 2026 00:00:00 +0000

Cardiac contraction is driven by the collective action of cardiomyocytes (CMs) that contain parallel bundles of myofibrils consisting of linear chains of sarcomeres, the basic force-generating units. The dynamics of individual sarcomeres within intact CMs remain incompletely understood. While most models assume uniform, synchronized contractions, recent studies hint at unexpected heterogeneity, whose origins and significance are not yet clear. By combining the culture of fluorescent sarcomere-reporter human induced pluripotent stem cell-derived CMs on micropatterned soft gels of different stiffness (5–85 kPa) with AI-based tracking of sarcomere motion, we found that increasingly stiff substrates inhibited overall CM contraction, but, surprisingly, did not diminish individual sarcomere dynamics. Instead, sarcomeres competed in a tug-of-war, causing increasing heterogeneity, including rapid length oscillations and overextensions (popping). Statistical analysis showed that the heterogeneous dynamics were not caused by static structural differences but were largely stochastic. Stochastic heterogeneity is thus an intrinsic property of cardiac sarcomeres and likely mediates the adaptation of CM contractility to mechanical constraints. A mesoscopic model of coupled sarcomeres shows that these phenomena can be explained by a non-monotonic force–velocity relationship and stochastic fluctuations, where dynamic instability at a critical yielding force creates heterogeneity. Stochastic heterogeneity compensates for structural disorder by randomizing yield events beat-to-beat, preventing damage to specific sarcomeres. Our findings recast cardiac sarcomeres as active, dynamically unstable, and stochastic units engaged in a stochastic tug-of-war, where transient, velocity-dependent forces dominate. We propose that pathological disorder in cardiomyopathy drives a transition from protective stochastic fluctuations to more deterministic, persistently overloaded sarcomeres.

Correction: Irisin directly stimulates osteoclastogenesis and bone resorption in vitro and in vivo

Thu, 10 Sep 2026 00:00:00 +0000

Nim1-related kinases regulate septin organization and cytokinesis by modulating Hof1 at the cell division site

spalani@iisc.ac.in (Anubhav Dhar) — Wed, 09 Sep 2026 00:00:00 +0000

The septin scaffold recruits and organizes actomyosin ring (AMR) components; thus, ensuring faithful cytokinesis. The septin-associated kinases – Elm1, Gin4, Hsl1, and Kcc4 are thought to stabilize and regulate the septin architecture at the bud neck, but the underlying mechanisms remain largely unknown. Here, we present a comprehensive, quantitative analysis of these four septin-associated kinases and reveal major roles for Elm1 and Gin4 in septin stability and architectural transitions during the cell cycle. We find that Elm1 and Gin4 play a previously overlooked role in AMR organization and constriction during cytokinesis. We report that the Gin4 kinase interacts directly with the AMR component and F-BAR protein Hof1 via its C-terminal membrane-binding kinase associated-1 (KA1) domain, and is likely involved in the proper organization and anchoring of Hof1 at the bud neck, representing an unappreciated mode of regulation during cytokinesis. We further show that Gin4 controls septin organization and AMR constriction in a kinase-independent manner, similar to Elm1. Using an extensive GFP-GBP-based tethering assay in elm1Δ and gin4Δ cells, we identify an important role for Hsl1 in maintaining septin organization and cell shape in coordination with Elm1, Gin4, and Kcc4, independent of its role in the morphogenetic checkpoint. Furthermore, our data indicate that Hsl1 acts downstream of Elm1, with its membrane-binding KA1 domain being critical for its function. Together, these findings reveal new insights into the modes by which the kinases Gin4 and Elm1 regulate cytokinesis, highlight a redundant role for Hsl1 in controlling septin organization and cytokinesis, and uncover the inherent redundancy and adaptability of the septin kinase network in Saccharomyces cerevisiae.

Cellular modifiers of TDP-43 phase transition and cytoplasmic aggregation

yihongye@gmail.com (Jizhong Zou) — Tue, 08 Sep 2026 00:00:00 +0000

RNA-binding protein TAR DNA-binding protein 43 (TDP-43) can form liquid-like nuclear assemblies whose phase behavior is thought to influence its aggregation propensity and neurotoxic activity. The mechanisms that govern the liquid-to-solid phase transition of TDP-43 remain poorly defined. Here, we combined chemical and genome-wide genetic screens to identify cellular factors that modulate the phase behavior of an RNA-binding-defective TDP-43 mutant. Our screens uncovered multiple cellular processes, including RNA splicing, protein translation, proteostasis imbalance, and nuclear export as TDP-43 phase regulators. We also developed a semi-permeabilized cell system that partially recapitulates the TDP-43 phase transition in vitro, and showed that nuclear export inhibition reshapes the nuclear environment to favor RNA-dependent liquid-liquid phase separation (LLPS) of TDP-43, which mitigates its aggregation. Nuclear export inhibition in a brain organoid model bearing an ALS-associated mutation reduces pathogenic phospho-TDP-43 accumulation. These findings identify multiple modulators of TDP-43 phase transitions in a sensitized model system and establish a framework for further dissecting the link between nuclear transport and TDP-43 phase dynamics.

Slap restricts oncogenic Src-family kinase signaling to maintain colonic epithelial homeostasis

audrey.sirvent@crbm.cnrs.fr (Audrey Sirvent) — Tue, 08 Sep 2026 00:00:00 +0000

Src-family kinases (SFKs) regulate proliferation in colonic epithelial cells (CECs), but the mechanisms that restrain their activity remain poorly defined. We identify Src-like adaptor protein (SLAP), a negative regulator of receptor tyrosine kinase signaling, as a key suppressor of SFK activity in the colon. Constitutive and inducible epithelial-specific Slap deletion using a villin-CreERT2 model increases CEC proliferation and accelerates tumorigenesis in the azoxymethane/dextran sodium sulfate model. Slap deficiency also enhances SFK-dependent expansion of normal and tumor-derived colonic organoids. Mechanistically, we identify the receptor tyrosine kinase EPHB2 as a critical upstream activator of SFKs and a direct target of SLAP-mediated regulation. Loss of Slap increased EphB2 protein abundance and tyrosine phosphorylation, and enhanced its association with active SRC. Pharmacological inhibition of EPHB2 suppressed SRC activation and reversed the hyperproliferative phenotype induced by Slap deficiency. Together, these findings uncover a non-genetic mechanism driving SFK activation during colonic transformation and establish SLAP as a tumor suppressor that constrains oncogenic EPHB2–SFK signaling in the colonic epithelium.

BetaII-spectrin gaps and patches emerge from the patterned assembly of the actin/spectrin membrane skeleton in human motor neuron axons

thomas.durcan@mcgill.ca (Agustín Anastasía) — Tue, 08 Sep 2026 00:00:00 +0000

The actin/spectrin membrane-associated periodic skeleton (MPS) is a cytoskeletal structure that supports axonal integrity and function. Lower spinal motor neurons (MNs) are characterized by exceptionally long axons and are particularly susceptible to degeneration in a wide range of hereditary neuromuscular disorders, including amyotrophic lateral sclerosis. Using confocal and super-resolution imaging, we characterized the spatial distribution of βII-spectrin and the assembly pattern of the MPS in human MN axons derived from induced pluripotent stem cells. We discovered a striking gap-and-patch pattern in the medial axon, where sharply demarcated βII-spectrin gaps alternate with patches containing a well-organized MPS. The pattern is acutely induced by the kinase inhibitor staurosporine and pharmacological inhibition of actin polymerization prevents patch formation, indicating a requirement for actin nucleation in MPS assembly. Our data supports a model in which spectrin incorporation into nascent MPS patches depletes neighboring regions, producing long-range gaps-and-patches patterns.

Centrosome migration and apical membrane formation during epithelial polarization in MDCK cysts

kenghui@gate.sinica.edu.tw (Keng-Hui Lin) — Tue, 08 Sep 2026 00:00:00 +0000

Polarization is crucial for the proper functioning of epithelial cells. Early hallmarks include the trafficking and enrichment of polarity molecules to form the apical membrane (AM) or cell–cell junctions, and the apical positioning of the centrosome. However, the dependencies among polarity molecules, AM formation, and centrosome positioning remain poorly understood. When cultured in Matrigel, de novo polarization of a single epithelial cell is often coupled with cytokinesis. During mitotic exit, centrosomes move to the future AM site, raising questions about their role in polarization. We perturbed centrosomes and polarity regulators in Matrigel-cultured cells and manipulated polarity direction using suspension culture to examine the relationships among polarization features. Surprisingly, centrosomal microtubules may not be necessary for centrosome positioning or AM formation, but their absence reduces the efficiency of AM formation. The polarity regulator Par3, rather than AM component trafficking, influences centrosome positioning. In suspension culture, centrosomes migrate in the direction opposite to AM formation. Taken together, our findings define the hierarchical relationships among several polarization features and show that centrosome-based polarity is not universal in epithelial cells, providing new insights into the mechanisms of epithelial polarization.

The insulin/IGF axis is critically important for controlling gene transcription in the podocyte

Richard.Coward@bristol.ac.uk (Aaron R Jeffries) — Fri, 04 Sep 2026 00:00:00 +0000

Podocyte integrity depends critically on signalling through the insulin receptor and IGF1 receptor, and this study defines their combined importance using dual-receptor knockdown in mice and cultured podocytes. Podocyte-specific reduction of both receptors in transgenic mice caused kidney disease characterised by albuminuria and glomerulosclerosis, with premature death occurring in some animals between 4 and 24 weeks. Receptor-deficient cultured podocytes exhibited >50% cell loss within 7 days. Integrated proteomic and transcriptomic analyses revealed marked depletion of spliceosome-associated proteins and widespread intron retention with premature termination codons, indicating profound disruption of RNA processing. Phospho-proteomic profiling further showed that insulin/IGF1 stimulation induces dynamic post-translational modifications across spliceosomal components and regulatory kinases. Together, these findings uncover a previously unrecognised role for podocyte insulin/IGF1 signalling in maintaining spliceosomal integrity and transcriptional fidelity, establishing this hormonal axis as a key extrinsic regulator of podocyte gene expression.

Polo-like kinase phosphorylation of the orphan kinesin KIN-G negatively regulates centrin arm biogenesis in Trypanosoma brucei

Ziyin.Li@uth.tmc.edu (Huiqing Hu) — Fri, 04 Sep 2026 00:00:00 +0000

The unicellular parasite Trypanosoma brucei assembles a motile flagellum that is required for locomotion, cell division plane placement, and cell-cell communication. Inheritance of the flagellum during the cell cycle relies on the faithful duplication/segregation of multiple flagellum-associated cytoskeletal structures, including a centrin-marked, bar-shaped structure termed centrin arm, which also determines the site for Golgi assembly. Biogenesis of the centrin arm requires the Polo-like kinase homolog TbPLK and the orphan kinesin KIN-G, but the mechanistic role of TbPLK in centrin arm biogenesis remains elusive. Here, we report that TbPLK phosphorylates KIN-G, disrupts its microtubule-binding activity, and negatively regulates its function. TbPLK phosphorylates KIN-G in vitro at multiple residues, two of which are in vivo TbPLK phosphosites, including the Thr301 residue within one of the microtubule-binding motifs of the kinesin motor domain. Phosphorylation of Thr301 by TbPLK inhibits the microtubule-binding activity of KIN-G in vitro, and expression of a Thr301 phospho-mimic mutant in T. brucei disrupts centrin arm integrity, Golgi duplication, flagellum attachment zone elongation, flagellum positioning, and cell division plane placement. In wild-type T. brucei cells, Thr301 phosphorylation occurs on a small portion of the KIN-G population, suggesting that KIN-G undergoes phosphorylation/dephosphorylation cycles to regulate its activity. Together, these findings uncover a negative role of TbPLK-mediated phosphorylation of KIN-G in regulating centrin arm biogenesis in trypanosomes.

A biochemical mechanism for Stu2/XMAP215-family microtubule polymerases

Luke.Rice@UTSouthwestern.edu (Binnu Gangadharan) — Thu, 03 Sep 2026 00:00:00 +0000

Defining quantitative biochemical mechanisms of microtubule dynamics and regulation is a current challenge. Stu2/XMAP215-family polymerases use tubulin-binding TOG domains to catalyze microtubule growth, but how polymerase activity results from the number and tubulin-binding properties of TOGs is not understood. We tested whether an enzyme-like biochemical model for the unrelated actin polymerase Ena/VASP could be applied to quantitatively relate Stu2 microtubule polymerase activity to the number of its TOGs, and the rate constants governing their interactions with tubulin. Stu2 activity displayed enzyme-like characteristics consistent with the biochemical model: Stu2 stimulated microtubule growth rates with hyperbolic dependence on tubulin concentration, and the amount of Stu2 on the microtubule end did not vary with tubulin concentration (microtubule growth rate). Complementary measurements of TOG:tubulin binding revealed high affinity (10 nM) and slow dissociation (0.03 s^–1). The polymerase and binding measurements can be unified within the biochemical model: Stu2 operates with high efficiency, acting as a tubulin-shuttling antenna on the microtubule end that is primarily limited by the rate of tubulin:TOG association. Our work thus provides a quantitative biochemical mechanism for TOG-based polymerases. That unrelated microtubule and actin polymerases use the same enzyme-like mechanism provides an example of convergent evolution in the cytoskeleton.

Cardiolipin deficiency disrupts electron transport chain and drives steatohepatitis

kfunai@utah.edu (Alek D Peterlin) — Wed, 02 Sep 2026 00:00:00 +0000

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a progressive disorder marked by lipid accumulation, leading to metabolic dysfunction-associated steatohepatitis (MASH). A key feature of the transition to MASH involves oxidative stress resulting from defects in mitochondrial oxidative phosphorylation (OXPHOS). Here, we show that pathological alterations in the lipid composition of the inner mitochondrial membrane (IMM) directly instigate electron transfer inefficiency to promote oxidative stress. Specifically, mitochondrial cardiolipin (CL) was downregulated with MASLD/MASH in humans and in mice. Hepatocyte-specific CL synthase knockout (CLS-LKO) led to spontaneous and robust MASH with extensive steatotic and fibrotic phenotype. Loss of CL paradoxically increased mitochondrial respiratory capacity but also promoted electron leak primarily at sites III_QO and II_F of the electron transport chain (ETC), reduced the formation of I + III₂ + IV respiratory supercomplex, and disrupted the propensity of coenzyme Q to become reduced. Thus, low mitochondrial CL disrupts the ETC to promote oxidative stress and contributes to the pathogenesis of MASH.

SETD6-mediated methylation of PPARγ establishes a transcriptional feedback circuit promoting lipid accumulation in liver-derived cells

ledan@post.bgu.ac.il (Anand Chopra) — Fri, 28 Aug 2026 00:00:00 +0000

Peroxisome proliferator-activated receptor gamma (PPARγ) is a key transcriptional regulator of genes mediating adipogenesis (fat-cell differentiation), and lipid storage in several cell types like hepatocytes. As such, its regulation is crucial for cell and organismal physiology. Indeed, PPARγ’s activity is regulated by multiple mechanisms, including post-transcriptional modifications, which, when dys-coordinated, may contribute to the pathogenesis of various states, including obesity, insulin resistance, and fatty liver disease. Here, we demonstrate that SETD6 binds to and methylates PPARγ at lysine 170 (K170) both in vitro and in liver-derived cells. This methylation event, in turn, is required for PPARγ-mediated activation of SETD6 transcription via promoter binding, forming a positive feedback regulatory loop. RNA-sequencing revealed that both SETD6 and PPARγ methylation at K170 are required for full induction of lipid metabolism genes’ expression, manifesting functionally in lipid droplet biogenesis in liver-derived cells. Together, our findings uncover a novel role for lysine methylation of PPARγ in the regulation of lipid synthesis and lipid droplet biogenesis, thereby identifying putative new therapeutic targets for lipid overproduction diseases, including metabolic dysfunction-associated fatty liver disease and obesity.

Zasp52’s differentially expressed intrinsically disordered region confers thin filament stability at the Z-disc

frieder.schoeck@mcgill.ca (Frieder Schöck) — Thu, 27 Aug 2026 00:00:00 +0000

The Drosophila scaffolding protein Zasp52 is required to maintain structure at the muscle Z-disc, which experiences strong forces during contraction. It is alternatively spliced into many isoforms, some of which contain a long intrinsically disordered region (IDR). We show that this region is primarily expressed in the indirect flight muscle (IFM) and is required for maintaining the integrity of the Z-disc. Deleting the IDR-encoding exon 15e results in flightlessness and structural IFM defects, including sarcomere bending at the Z-disc and an inability to de-contract. These defects are indicative of a lack of proper thin filament anchoring to the Z-disc. This is further supported by a genetic interaction between exon 15e and actin. Fluorescence recovery after photobleaching of an isoform lacking exon 15e shows that the IDR is required for maintaining Zasp52 at the Z-disc and thereby stabilizing Z-discs. Lastly, we can rescue these phenotypes by restricting IFM use. Together, these results suggest that Zasp52’s IDR confers thin filament stability at the Z-disc of IFM.

Disruption of sphingolipid metabolism promotes tau seeding through endolysosomal membrane rigidification and rupture

carmen.nussbaum@med.uni-muenchen.de (Carl Alexander Sandhof) — Thu, 27 Aug 2026 00:00:00 +0000

Endolysosomal dysfunction is a hallmark of Alzheimer’s disease and related tauopathies, yet underlying mechanisms remain poorly understood. This study investigates the role of sphingolipid metabolism in maintaining endolysosomal membrane integrity and its impact on tau aggregation and toxicity in Caenorhabditis elegans and human cell culture models. Fluorescence recovery after photobleaching and C-Laurdan dye imaging revealed that silencing sphingolipid metabolism genes reduced endolysosomal vesicle membrane fluidity, increasing their rupture. The accumulation of aggregated tau in endolysosomal vesicles further aggravated endomembrane rigidification and damage, and promoted seeded tau aggregation, potentially by facilitating the escape of tau seeds from the endolysosomal system. Supplementation with unsaturated fatty acids improved membrane fluidity, suppressing endolysosomal rupture and seeded tau aggregation in cell models, and alleviating tau-associated neurotoxicity in C. elegans. Together, this study provides mechanistic insight into how perturbation of sphingolipid metabolism promotes endolysosomal membrane damage and contributes to the escape of aggregated tau from this compartment, suggesting that restoration of membrane fluidity may represent a strategy to limit tau propagation and toxicity.

MOTS-c is a mitochondrial-encoded interferon-linked host defense peptide

berenice.benayoun@usc.edu (Bérénice A Benayoun) — Tue, 18 Aug 2026 00:00:00 +0000

The mitochondrial DNA (mtDNA) can trigger immune responses and directly entrap pathogens, but it is not known to encode active immune factors. The immune system is traditionally thought to be exclusively nuclear-encoded. Here, we report the identification of a host defense peptide (HDP) encoded in the human mitochondrial genome that presumably derives from the primordial proto-mitochondrial bacteria. We demonstrate that MOTS-c (mitochondrial open reading frame from the 12 S rRNA type-c) is a mitochondrial-encoded amphipathic and cationic peptide with direct antibacterial and immunomodulatory functions, consistent with the peptide chemistry and functions of known HDPs. MOTS-c targeted Escherichia coli and methicillin-resistant Staphylococcus aureus (MRSA), in part, by targeting their membranes using its hydrophobic and cationic domains. In a mouse model of acute peritonitis, MOTS-c fully neutralized MRSA infectivity. In human monocytes, interferon gamma (IFNγ), lipopolysaccharides (LPS), and differentiation signals each induced the expression of endogenous MOTS-c. Notably, exogenous MOTS-c, applied during primary mouse monocyte differentiation, reprogrammed the cells into macrophages with distinct transcriptomic signatures related to antigen presentation and IFN signaling. MOTS-c-programmed macrophages exhibited enhanced bacterial clearance and shifted metabolism. Our findings support MOTS-c as a first-in-class mitochondrial-encoded HDP and indicate that our immune system is not only encoded by the nuclear genome but also by the co-evolved mitochondrial genome.

How to give cells an identity crisis

hollien@biology.utah.edu (Julie Hollien) — Thu, 13 Aug 2026 00:00:00 +0000

The transcription factor CHOP helps cells switch from an emergency stress response to a chronic one, where cells survive but lose some of the functions that define their identity.

Aging-associated increase of GATA4 levels in articular cartilage is linked to impaired regenerative capacity of chondrocytes and osteoarthritis

hal46@pitt.edu (Alyssa Aguglia) — Wed, 12 Aug 2026 00:00:00 +0000

Although the causal association between aging and osteoarthritis (OA) has been documented, our understanding of the underlying mechanism remains incomplete. To define the regulatory molecules governing chondrocyte aging, we performed transcriptomic analysis of young and old human chondrocytes from healthy donors. The data predicted that GATA-binding protein 4 (GATA4) may play a key role in mediating the difference between young and old chondrocytes. Results from immunostaining and western blot showed significantly higher GATA4 levels in old human or mouse chondrocytes when compared to young cells. Moreover, overexpressing GATA4 in young chondrocytes remarkably reduced their cartilage-forming capacity in vitro and induced the upregulation of proinflammatory cytokines. Conversely, suppressing GATA4 expression in old chondrocytes, through either siRNA or a small-molecule inhibitor NSC140905, increased the production of aggrecan and collagen type II, and also decreased levels of matrix-degrading enzymes. In OA mice induced by surgical destabilization of the medial meniscus, intra-articular injection of lentiviral vectors carrying mouse Gata4 resulted in a higher OA severity, synovial inflammation, and pain level when compared to control vectors. Mechanistically, we found that overexpressing GATA4 significantly increased the phosphorylation of SMAD1/5. Our work demonstrates that the aging-associated increase of GATA4 in chondrocytes plays a vital role in OA progression, which may also serve as a target to reduce OA in the older population.

A tool to pulse-label yeast nuclear pore complexes in imaging and biochemical experiments

l.m.veenhoff@rug.nl (Annemiek C Veldsink) — Mon, 10 Aug 2026 00:00:00 +0000

Nuclear pore complexes (NPCs) are key gateways to the nucleus and major organizers of genome architecture. Despite their importance, it is still not fully understood how NPCs are formed and degraded. Tools to track specific NPCs over time or under stress could unlock critical insights into these questions. Here, we demonstrate that a brief pulse of expression of a previously developed nanobody against baker’s yeast nucleoporin Nup84 (Nordeen et al., 2020) enables a robust, rapid, and straightforward method for pulse-labeling NPCs in both imaging and affinity purification experiments. This approach offers an alternative to permanent, yet less rapid, genetic fluorophore- or tag-switching techniques, and provides a powerful tool for studying NPC inheritance and turnover through both microscopy and biochemical methods.

Analysis of cancer mutations introduced into the Drosophila melanogaster Notch negative regulatory region uncovers a diversity of regulatory outcomes

martin.baron@manchester.ac.uk (Hideyuki Shimizu) — Tue, 04 Aug 2026 00:00:00 +0000

Activating mutations of Notch are drivers of the blood cell cancer, T-ALL, and some solid tumours. The negative regulatory region (NRR) of the extracellular domain (ECD) and the PEST region of the intracellular domain (ICD) are mutation hot spots which can act synergistically in T-ALL. The NRR, comprised of a heterodimerisation domain (HD) and three Lin12/Notch repeats (LNR A-C), masks the S2 cleavage site, normally only exposed following ligand binding and cleaved as the first step that ultimately leads to ICD release. Drosophila mutants have played a key role in analysing Notch structure/function, but there have been few mutational studies of the NRR. Here, we expressed, in S2 cells, over 20 cancer mutations located in the HD, LNR and LNR/HD interface, introduced into Drosophila Notch. Mutations in the HD domain core did not activate, likely due to absence in Drosophila of an S1 cleavage within the HD required for mammalian Notch activity. In contrast, mutations in the LNR/HD interface behaved similarly to T-ALL, activating constitutively with no further ligand induction and were synergistic with PEST deletion. Mutations of surface-exposed residues of LNR-C also activated constitutively but remained inducible both by ligand and by an intracellular endocytic regulator, Deltex, and were not synergistic with PEST deletions. These mutations caused elevated Notch levels and decreased turnover, suggesting a novel regulatory mechanism. Our results, therefore, uncover a variety of outcomes arising from perturbations of the NRR and will facilitate the establishment of Drosophila cancer models and the development of mutant-specific approaches to effective therapies.