bims-auttor 2026-10-25 papers

bims-auttor

Biomed News

on Autophagy and mTOR

Issue of 2026–10–25
thirty papers selected by
Viktor Korolchuk, Newcastle University

PRKN dephosphorylation by PTEN-L couples mitophagy inhibition to GSDME pyroptosis suppression.
Rapalink-1 reveals an mTOR- and p53-regulated transcriptional program in Neuro-2a cells.
Stathmin 1 regulates mitophagy and non-proliferative cellular function in hematopoietic stem and progenitor cells.
Autophagy, endolysosomes and extracellular space in autoimmune and innate immune defects.
Apelin-13 prevents GATA4-mediated neuronal senescence by restoring autophagy through mTORC1 inhibition.
The Lysosomal Clock: Are We Only as Old as Our Lysosomes?
Lck regulates T cell activation through phosphorylation of p62.
SSH1 knockdown increases autophagosome formation through ATG9A recruitment and promotes tau protein degradation.
ClC-7 links PIKfyve inhibition to Rab-dependent LRRK2 activity at lysosomes.
Swollen lysosomes grab Rabs for a CASM-free route to LRRK2 activation.
The Long Splice Variant of Ribosomal Protein S24 Protects Cells from Stress and Is Induced by AMPK-ULK1-Regulated Autophagy Independent of mTORC1.
A Cilia-Centered Nicotinamide Adenine Dinucleotide (NAD+) Signaling Network Regulates Hypothalamic Lysosomal Homeostasis and Metabolic Aging.
cAMP signaling promotes acute lysosome biogenesis through TFEB nuclear import-export dynamics.
Receptor-Specific ER-Phagy in Neurodegenerative Diseases: Molecular Mechanisms and Emerging Therapeutic Opportunities.
HAP40 functions as a proteostasis regulator by controlling huntingtin interactions and its release into the extracellular space.
Rethinking autophagy during odontogenesis through autophagic flux.
Lysosomal protein transmembrane 5 protects against myocardial ischemia-reperfusion injury by promoting mitophagy via the NEDD4-LC3 axis.
A critical mechanistic synthesis of PINK1-mediated mitophagy signaling and its therapeutic targeting in Parkinson's disease neurodegeneration.
Bruce suppresses autophagy-regulated caspase activity and wing tissue growth in Drosophila.
Pharmacological Activation of Autophagy Ameliorates Neuromuscular-Associated Defects and Extends Lifespan in a Caenorhabditis elegans Model of Spinal Muscular Atrophy.
Simultaneous and Real-Time Imaging of Mitochondrial and Lysosomal ATP with Inducible Excessive Mitophagy for Antitumor Therapy via a Multifunctional Fluorescent Probe.
A USP28-TM9SF3-Golgiphagy axis maintains glycosylation homeostasis and promotes breast cancer progression.
Dysregulated PIKfyve-dependent inhibition of ClC-7 causes ammonium-dependent endolysosomal vacuolization and autophagic flux impairment: Rescue by glutaminase inhibition.
Development of DCL1191 as a Potent, Selective and Orally Bioavailable Inhibitor for Autophagy-Associated Transcription Factor EB (TFEB).
Translational control of microglial metabolism, inflammatory responses, and survival by the eIF4E-binding proteins.
Mitophagy coordinates organelle crosstalk in health and diseases.
Machine learning image analysis predicts Parkinson disease genotype and mitochondrial lysosomal abnormalities in iPS neurons.
Chaperone-mediated autophagy curbs senescence.
GPI lipid remodeling regulates lipophagy in response to glucose deprivation.
Hsc70-Mediated Targeting Chimeras for Targeted Protein Degradation via Chaperone-Mediated Autophagy.

Autophagy. 2026 Oct 20.

PRKN dephosphorylation by PTEN-L couples mitophagy inhibition to GSDME pyroptosis suppression.

Chenghao Yan, Xu Liu, Xinyu Gong, Xiaofang Wu, Haodong Xu, Liming Wang.

  Mitochondrial damage is a potent trigger of inflammatory cell death; however, how damaged mitochondria transduce stress signals to initiate cell death execution, and how this process is finely regulated, remain incompletely understood. We recently identified that the PINK1-PRKN axis, activated upon mitochondrial depolarization, not only initiates mitophagy but also drives pyroptosis via the ubiquitination and degradation of MCL1, which in turn promotes BAX and BAK1 activation, leading to CASP3 activation and GSDME cleavage. PTEN-L functions as a negative regulator of this pathway by directly dephosphorylating PRKN, which concurrently suppresses both mitophagy and pyroptosis, thereby coupling organelle quality control to inflammatory cell death.

Keywords:  GSDME-dependent pyroptosis; PINK1-PRKN axis; PTEN-L dephosphorylation; mitochondrial damage; mitophagy

DOI:  https://doi.org/10.1080/15548627.2026.2751925
Biol Open. 2026 Oct 15. pii: bio062902. [Epub ahead of print]15(10):

Rapalink-1 reveals an mTOR- and p53-regulated transcriptional program in Neuro-2a cells.

Joel Karikari Nyarkoh, Matthew Wolan, Eric Barrett, Aidan M Sokolov, Rachel A Lyman, Trudy F C Mackay, David M Feliciano.

  The mammalian target of rapamycin (mTOR) is the catalytic subunit of two exclusive complexes referred to as mTORC1 and mTORC2. The mTORCs phosphorylate different substrates and control different cellular processes. Inhibitors of mTORC1 include rapamycin analogs (rapalogs) that are useful in many clinical settings. However, they have failed in cancer trials potentially due to resistance mechanisms and incomplete inhibition of mTORC1 phosphorylation of select substrates. The rapamycin sensitivity of mTORC1 substrates is likely encoded by the substrate's primary amino acid sequence determinants and the ability of substrates to fit into the catalytic region of the kinase super-complex. Thus, some mTORC1 substrates are unaffected by rapalogs. Second-generation ATP-binding pocket inhibitors are mTOR catalytic inhibitors that bind in an ATP-competitive manner. Torin1 is an exemplary second-generation mTOR inhibitor with superior inhibition of mTORC1 substrates, including 4EBP. However, these inhibitors fail to demonstrate selectivity between mTORC1 and mTORC2. Third-generation bisteric mTORC1 inhibitors are exemplified by Rapalink-1, which links a rapamycin moiety to the ATP-competitive inhibitor MLN-0128. Here, we report that Rapalink-1 inhibits three mTORC1 substrates, including 4EBP and Ulk1, which are rapamycin insensitive. To provide additional mechanistic insight into the Rapalink-1 mechanism of action, RNA sequencing of Neuro-2a cells treated with Rapalink-1 was performed. Rapalink-1 caused transcriptomic changes indicative of reductions in the mTOR pathway and brain development. Many transcripts contained a p53 binding site, and consistent with this finding, we also observed reduced levels of p53. These results confirm and expand upon the Rapalink-1 mechanism of action.

Keywords:  Cancer; Rapalink-1; mTOR; mTORC1

DOI:  https://doi.org/10.1242/bio.062902
iScience. 2026 Nov 20. 29(11): 117458

Stathmin 1 regulates mitophagy and non-proliferative cellular function in hematopoietic stem and progenitor cells.

Luana Chiquetto, Meg Schuetz, Qian Dong, Mia Warmka, Liana Valin, Ashley Jones, Patrick Hunt, Copper Petermeier, Jie Wang, Nate Roundy, Zev J Greenberg, Wei Yang, Christine R Zhang, Grant A Challen, Cliff J Luke, Robert A J Signer, Wandy L Beatty, Stephen Sykes, Weikai Li, David J Kast, Laura G Schuettpelz.

  Stathmin 1 is a cytoplasmic phosphoprotein that regulates microtubule dynamics. Stathmin 1 expression is a feature of proliferating cells, and it is overexpressed in many cancers, including leukemias. In contrast to its roles in proliferating cells, considerably less is known of stathmin 1 in quiescent cells. Importantly, stathmin 1 is highly expressed in hematopoietic stem and progenitor cells (HSPCs), and herein we found that stathmin 1 loss is associated with altered microtubule architecture and markedly impaired HSPC function. Transcriptomic studies suggested metabolic differences in Stmn1 -/- HSPCs, and further mechanistic studies revealed defective mitochondrial structure and function. Microtubules facilitate autophagosome formation and mitophagy, and indeed we found that this critical mitochondrial quality control process is impaired in Stmn1 -/- HSPCs. Finally, stimulation of autophagy improved Stmn1 -/- HSPC colony-forming ability. Together, these data identify a non-proliferative role for stathmin 1 in the regulation of HSPC mitochondrial quality control and cellular function.

Keywords:  autophagy; hematopoietic stem cells; metabolism; microtubules; mitophagy; stathmin

DOI:  https://doi.org/10.1016/j.isci.2026.117458
Front Immunol. 2026 ;17 1947320

Autophagy, endolysosomes and extracellular space in autoimmune and innate immune defects.

Juliane Schuler, Lea Tollmann, Robert Walter Körner, Birk Möller, Emil Schober, Charlotte Schöner, Maaike Kusters, Ming Lim, Tim Niehues, Heinz Jungbluth, Hormos S Dafsari.

  Autophagy is increasingly recognized as a central immunological process whose roles extend far beyond intracellular recycling. By coordinating lysosomal degradation, organelle quality control, selective antimicrobial clearance, and inflammatory signal termination, autophagy acts as a decisive checkpoint at the crossroads between protective innate immunity and pathological immune persistence. Xenophagy, the selective autophagic elimination of intracellular pathogens, is a particularly important process at the interface between host defense, endosomal trafficking and immune resolution. Distinct monogenic disorders affecting EPG5-dependent autophagosome-lysosome fusion, LYST-dependent lysosomal and granule organization, or RAB27A-dependent lytic-granule exocytosis illustrate how different lesions in intracellular trafficking can impair microbial handling and contribute to immune dysregulation. Functioning autophagy also boosts cellular resilience through the removal of intracellular debris via exocytosis. In parallel, neutrophil extracellular traps (NETs) have emerged as potent antimicrobial structures that also aid cellular resilience but have a dual role in immunity: while NET formation can restrict pathogen dissemination, excessive or insufficiently cleared NETs expose chromatin, histones, proteases and modified autoantigens that can drive autoimmunity, thromboinflammation and tissue damage. In this review, we discuss the intricate links between xenophagy, its intracellular endolysosomal hubs, and its extracellular targets and traps as an integrated cell-biological and immunopathological network. We highlight how autophagy initiation and verified degradative flux, mitochondrial quality control, reactive oxygen species, peptidylarginine deiminase 4 (PAD4)-dependent chromatin decondensation, and endolysosomal trafficking may intersect with neutrophil effector functions in a stimulus- and model-dependent manner. Particular emphasis is placed on endosomal checkpoint proteins such as TOM1, which link ubiquitinated cargo sorting, IL-1R1/NF-κB signal termination, autophagosome maturation, and lysosomal degradation. We propose that defective endosomal and autophagic resolution mechanisms blur the boundary between efficient antimicrobial defense and chronic inflammatory auto-amplification. This concept is highly relevant for a wide range of autoimmune conditions, including systemic lupus erythematosus, rheumatoid arthritis, ANCA-associated vasculitis, autoinflammatory syndromes, immunodeficiency, and neuroinflammatory disease. Finally, we discuss therapeutic strategies aimed at restoring immune resolution, including modulation of autophagy, enhancement of NET clearance, targeting of PAD4 and inflammasome pathways as well as correction of endolysosomal trafficking defects. Understanding these intricately linked networks may open new avenues for mechanism-based treatment of autoimmune and innate immune disorders.

Keywords:  autoimmunity; autophagy; endosomes; innate immunity; neutrophil extracellular traps

DOI:  https://doi.org/10.3389/fimmu.2026.1947320
Cell Death Dis. 2026 Jul 27. pii: 900. [Epub ahead of print]17(1):

Apelin-13 prevents GATA4-mediated neuronal senescence by restoring autophagy through mTORC1 inhibition.

Su Jong Han, Ji Hyeon Cho, Jae Ryong Lim, Jee Hyeon Yoon, Ji Yong Park, Han Seung Chang, Su Yeol Kim, Ha Jin Kim, Seung Gyu Lee, Se Jin Mun, Jong Hwa Yun, Chang Woo Chae, Young Hyun Jung, Ho Jae Han.

Neuronal senescence, triggered by oxidative stress and inflammatory responses, is a significant risk factor for brain aging, ultimately leading to cognitive decline. Apelin-13, an exercise-induced myokine, exhibits potential neuroprotective effects by the APJ system, but its protective effects against neuronal senescence and the underlying mechanisms are unknown. This study aimed to elucidate how apelin-13 prevents D-galactose-induced neuronal senescence in SH-SY5Ys, human induced pluripotent stem cell-derived neuronal differentiated cells (iPSC-NDs), and an aging mouse model. The administration of ML233, an apelin receptor APJ agonist, attenuated brain aging and cognitive impairment in D-galactose-induced aging mice. In vitro findings showed that apelin-13 failed to scavenge the excessively generated D-galactose-induced reactive oxygen species (ROS) but prevented aging through APJ-Gαq-mediated signaling in SH-SY5Y cells. Apelin-13 activated protein kinase C (PKC) and calmodulin-dependent protein kinase II (CaMKII) to phosphorylate AMPK, which led to the inhibition of mammalian target of rapamycin complex 1 (mTORC1). Inhibition of mTORC1 promoted the nuclear translocation of transcription factor EB (TFEB), restoring lysosomal function and autophagic flux impaired by D-galactose. Furthermore, D-galactose treatment increased the expression of GATA binding protein 4 (GATA4), a transcription factor that contributes to paracrine senescence by increasing the expression of pro-inflammatory cytokines. Neuronal autophagy restored by apelin-13 promoted GATA4 clearance, ultimately preventing pro-inflammatory cytokine-induced paracrine senescence under D-galactose conditions. Collectively, these results demonstrate that apelin-13 prevents neuronal senescence by inhibiting the mTORC1-GATA4 axis through the restoration of autophagy. Our study highlights apelin-13 as a promising therapeutic candidate for age-related cognitive decline by targeting the oxidative stress-inflammation-neuronal senescence axis through the modulation of autophagy.

DOI: https://doi.org/10.1038/s41419-026-09121-1
Traffic. 2026 Dec;27(4): e70056

The Lysosomal Clock: Are We Only as Old as Our Lysosomes?

Alexis Diaz Vegas, Thierry Galli.

Lysosomes are a major organelle involved in intracellular degradation, membrane traffic and metabolic signaling, but how their biochemical composition changes during normal aging remains poorly defined. Puszynska and colleagues now combine lysosome purification with metabolomics and lipidomics across tissues, species and ages to reveal a conserved signature of lysosomal aging characterized by accumulation of glycerophosphodiesters (GPDs) and cystine and remodeling of bis(monoacylglycero)phosphate (BMP). Strikingly, these changes are largely obscured in whole-tissue analyses and resemble metabolic abnormalities associated with lysosomal storage disorders, including CLN3 disease and cystinosis. The signature develops progressively with age, can predict chronological age, and is attenuated by caloric restriction in peripheral tissues but not in the brain. Within the brain, age-dependent metabolite accumulation is particularly prominent in microglia and is also detected in neurons, linking lysosomal aging to cell populations central to neurodegenerative disease. These findings define an organelle-level metabolic clock, suggesting that one might be only as young as one's lysosomes. Establishing whether GPDs, cystine and BMP remodeling merely mark lysosomal age or actively contribute to declining lysosomal degradation and membrane traffic may uncover a metabolic connection between physiological aging, lysosomal storage disorders and vulnerability to late-onset neurodegeneration.

DOI: https://doi.org/10.1111/tra.70056
EMBO Rep. 2026 Oct 23.

Lck regulates T cell activation through phosphorylation of p62.

Zhihui Xiao, Yun-Yi Li, Zhi-Long Chen, Wenhui Ye, Li Wang, Chen-Si Zhao, Yingqiu Li.

Autophagy is crucial for T cell activation, yet how T cell receptor (TCR) signaling regulates autophagy is largely unknown. The autophagy receptor p62 was first identified as a lymphocyte-specific protein tyrosine kinase (Lck) SH2 domain ligand. However, the functional significance of the Lck-p62 association in T cells remains unclear. Here, we demonstrate that Lck inhibits TCR-induced autophagy via phosphorylating p62, thereby promoting T cell activation. Upon TCR stimulation, Lck transiently phosphorylates p62 at tyrosine 433 (Y433), peaking at 5 min and declining by 15 min. The p62-Y433F mutant displays enhanced TCR-induced association with LC3 and ULK1 complex components, thereby promoting autophagy. Consequently, this mutant suppresses TCR-induced NF-κB activation and IL-2 production by strengthening its interaction with Bcl10 and accelerating the autophagic clearance of Bcl10. Together, we demonstrate that the transient phosphorylation of p62 by Lck facilitates p62 transition between adapting Bcl10-NF-κB signaling and promoting Bcl10 autophagic degradation, revealing a temporal cooperation between TCR signaling and autophagy that occurs during the early phase of TCR stimulation.

DOI: https://doi.org/10.1038/s44319-026-00902-5
Autophagy. 2026 Oct 23.

SSH1 knockdown increases autophagosome formation through ATG9A recruitment and promotes tau protein degradation.

Morgan C Stephens, Richard I Han, Alma M Perez, Hilary Chester, Maria de Haro, Arsh Ali, Amy Hammett, Ruhee Dere, Ismael Al-Ramahi, Juan Botas.

  Pathological accumulation of MAPT/tau protein is a defining feature of Alzheimer disease (AD) and related tauopathies, highlighting the need to identify druggable regulators of MAPT/tau clearance. Using Drosophila behavioral assays focused on cytoskeletal remodeling pathways dysregulated in AD, we identified genes whose genetic modulation mitigates MAPT/tau-induced behavioral deficits. These modifiers were validated by histopathology and mechanistically examined in human tauopathy cell models to determine their impact on autophagy-dependent MAPT/tau degradation. Autophagic flux, ATG9A trafficking, and autophagosome biogenesis were further analyzed. Across models, reduction of the phosphatase SSH1 consistently lowered steady-state MAPT/tau levels by enhancing autophagic flux through a mechanism distinct from its canonical regulation of CFL1. Mechanistically, SSH1 functions as a negative regulator of early autophagosome formation: SSH1 depletion promotes ATG9A mobilization to the endoplasmic reticulum-phagophore assembly site (ER-PAS), thereby accelerating autophagic vesicle biogenesis. Importantly, the MAPT/tau-lowering effect of Dmssh attenuation was abolished in flies haploinsufficient for DmAtg9, demonstrating that SSH1-mediated MAPT/tau clearance requires ATG9 function. Consistent with a direct regulatory interaction, in vitro phosphatase assays revealed that recombinant SSH1 decreases ATG9A phosphorylation in the presence of actin, identifying an SSH1-ATG9A regulatory axis controlling autophagosome initiation. These findings position SSH1 as a nodal inhibitor of autophagy initiation whose inhibition enhances MAPT/tau proteolysis. Notably, SSH1 haploinsufficiency also reduces SNCA/α-synuclein accumulation in vivo, indicating broader relevance to neurodegenerative proteopathies. By integrating in vivo functional screening with mechanistic studies in human cells, this work identifies SSH1 as a druggable phosphatase that constrains autophagy at the level of ATG9A-dependent vesicle formation.

Keywords:  Autophagosome biogenesis; MAPT/tau aggregation; autophagy; flux; lysosomal degradation; phosphatase; proteopathy

DOI:  https://doi.org/10.1080/15548627.2026.2752745
J Cell Biol. 2026 Nov 02. pii: e202511137. [Epub ahead of print]225(11):

ClC-7 links PIKfyve inhibition to Rab-dependent LRRK2 activity at lysosomes.

Devin Clegg, Amanda Bentley-DeSousa, Agnes Roczniak-Ferguson, Shawn M Ferguson.

Increased activity of leucine-rich repeat kinase 2 (LRRK2) confers Parkinson's disease risk. LRRK2 dynamically localizes to lysosomal membranes in response to various stresses, yet the mechanisms by which distinct lysosomal perturbations are communicated to LRRK2 remain unclear. Here, we show that inhibition of the lysosomal lipid kinase PIKfyve promotes LRRK2 recruitment and signaling through a pathway that requires the lysosomal chloride/proton antiporter ClC-7. ClC-7 in turn controls the accumulation of multiple Rab GTPases on lysosomes. LRRK2 signaling under these conditions requires its established Rab-binding surfaces, with Rab12 contributing significantly to this response. This pathway operates independently of CASM. In contrast, lysosomal stresses that induce CASM require both Rab-binding sites on LRRK2 and GABARAP for robust LRRK2 signaling. These findings identify ClC-7-dependent lysosomal remodeling and Rab accumulation as key features linking PIKfyve inhibition to LRRK2 signaling and reveal that distinct lysosomal stresses engage different combinations of Rab and GABARAP inputs to activate LRRK2.

DOI: https://doi.org/10.1083/jcb.202511137
J Cell Biol. 2026 Nov 02. pii: e202610007. [Epub ahead of print]225(11):

Swollen lysosomes grab Rabs for a CASM-free route to LRRK2 activation.

Suzanne R Pfeffer.

Multiple lysosomal stresses activate Parkinson's-linked LRRK2 kinase, and these involve the so-called "CASM" pathway to help recruit LRRK2 to lysosome surfaces. Clegg et al. (https://doi.org/10.1083/jcb.202511137) show that LRRK2, activated upon lysosome swelling caused by PIKfyve inhibition, instead relies solely on Rab GTPase binding for lysosome localization and activation.

DOI: https://doi.org/10.1083/jcb.202610007
Biochemistry. 2026 Sep 15. 65(18): 2916-2927

The Long Splice Variant of Ribosomal Protein S24 Protects Cells from Stress and Is Induced by AMPK-ULK1-Regulated Autophagy Independent of mTORC1.

Runqi Qian, Jenna Goodbrand, Shannon N Adams, Erin Trella, James Uniacke.

All living organisms have developed complex mechanisms to detect and react to environmental changes to maintain internal balance and support survival. One strategy that cells employ to respond to stress is to refocus the translation machinery to express select stress response proteins, this includes the emerging field of specialized ribosomes. We have previously shown that a long splice variant of ribosomal protein S24 (RPS24L) is induced by several fold in hypoxic monolayers and spheroids in several human cell lines in an autophagy-dependent manner. Here, we show that an allosteric activator of AMPK is sufficient to induce RPS24L and autophagy in normoxia in an ULK1-dependent, but mTORC1-independent manner. Overexpression of RPS24L protected cells from serum starvation and hypoxia, while RPS24 short isoform overexpression during stress impaired autophagy and the ability for cells to survive relative to controls. We show that SRSF1 interacts with RPS24 mRNA and its autophagy-dependent decrease shifts splicing toward the RPS24L variant. This study provides new insights into the signaling and mechanisms that regulate a ribosomal protein splice isoform that protects cells from stress and that has been previously linked to cancer progression.

DOI: https://doi.org/10.1021/acs.biochem.6c00572
Aging Cell. 2026 Nov;25(11): e70745

A Cilia-Centered Nicotinamide Adenine Dinucleotide (NAD+) Signaling Network Regulates Hypothalamic Lysosomal Homeostasis and Metabolic Aging.

Se Eun Park, Eun Roh, Jae Woo Park, Seong Jun Kim, So Yeon Jeong, Chae Beom Park, Hyo Sun Lim, Ji Soo Kim, Mun Gyeom Kim, Myeong Ju Kim, Young In Cho, Wontae Jeong, Gil Myoung Kang, Sang-Yeob Kim, Se Hee Min, Min-Seon Kim.

  Nicotinamide adenine dinucleotide (NAD+) is an essential metabolite that regulates diverse cellular metabolic processes. Primary cilia, hair-like organelles on the cell surface, function as critical signaling hubs. Here, we demonstrate that cellular NAD+ levels are key regulators of both primary cilia growth and lysosomal function in hypothalamic neurons. NAD+ depletion induces ciliary shortening and diminishes lysosomal activity in a cilia-dependent manner. Mechanistically, the lysosomal repair complex protein CHMP4B translocates from periciliary satellites to lysosomes during lysosomal stress, a process impaired by ciliary dysgenesis. Disrupted lysosomal recruitment of CHMP4B leads to abnormal lysosomal Ca2+ signaling and lysosomal dysfunction. Aged mice with hypothalamic NAD+ deficiency exhibit shortened cilia and lysosomal stress phenotypes, both of which are restored by calorie restriction (CR). Moreover, CR improves aging-associated metabolic dysfunction, at least in part, through hypothalamic cilia-dependent mechanisms. These findings identify a primary cilium-mediated-NAD+ signaling axis that maintains lysosomal homeostasis in hypothalamic neurons, the disruption of which drives metabolic aging.

Keywords:  CHMP4B; NAD+; TRPML1; aging; calorie restriction; hypothalamic neurons; lysosomal homeostasis; primary cilia

DOI:  https://doi.org/10.1111/acel.70745
J Cell Sci. 2026 Oct 20. pii: jcs.264721. [Epub ahead of print]

cAMP signaling promotes acute lysosome biogenesis through TFEB nuclear import-export dynamics.

Saumya Bhatt, Mohammad Ali Abbas Zaidi, Hadley R Taggart, Nicholas Woods, Yiyang Wu, Subramanian P Ramanathan, Cody N Rozeveld, Micah B Schott.

  Cyclic adenosine monophosphate (cAMP) signaling is a major stimulus for lipid and glucose catabolism, yet catabolic processes like these can also coordinate with lysosome-dependent degradation. However, the impact of cAMP signaling on lysosomal dynamics remains unclear. Transcription factor EB (TFEB), a master regulator of lysosomal biogenesis, is regulated by stimulus-dependent nuclear-cytoplasmic shuttling through a variety of phosphorylation events. Here, we find that elevating intracellular cAMP with forskolin and IBMX induces rapid nuclear import of TFEB-GFP within 30 minutes and coincides with a transient upregulation of TFEB target lysosome genes. By 8 hours, TFEB returns to the cytoplasm, accompanied by transcriptional downregulation. Inhibition of cAMP-dependent protein kinase A (PKA) using H89 did not block nuclear import but unexpectedly caused sustained nuclear accumulation, indicating that PKA promotes TFEB nuclear export. Consistent with this, phosphoproteomic profiling revealed increased phosphorylation of a PKA-consensus motif (RRxS) during the export phase. These findings suggest that cAMP-PKA signaling plays a novel role in temporally "tuning" lysosomal gene expression by regulating TFEB nuclear-cytoplasmic shuttling.

Keywords:  Lysosome; Nuclear Export; Nuclear import; Protein Kinase A; Transcription Factor EB; cAMP

DOI:  https://doi.org/10.1242/jcs.264721
Ageing Res Rev. 2026 Oct 22. pii: S1568-1637(26)00418-6. [Epub ahead of print] 103426

Receptor-Specific ER-Phagy in Neurodegenerative Diseases: Molecular Mechanisms and Emerging Therapeutic Opportunities.

Suramya Malhotra, Rajat Sandhir.

  Neurodegenerative diseases (NDs) constitute a major global health burden driven by rising life expectancy and the lack of disease-modifying therapies. Central to these progressive pathologies is the accumulation and aggregation of conformationally altered proteins, categorizing them as 'proteinopathies'. These aberrant aggregates disrupt cellular homeostasis and trigger chronic stress responses that drive progressive neuronal dysfunction and loss. The endoplasmic reticulum (ER) is a dynamic organelle defined by remarkable structural diversity and functional plasticity, that preserves cellular homeostasis by orchestrating protein folding and quality control, lipid biosynthesis, calcium sequestration and metabolic detoxification. However, sustained ER stress and functional dysregulation are increasingly implicated in neurodegenerative cascades. In this context, ER-selective autophagy (ER-phagy) has emerged as an indispensable quality-control pathway. Mediated by dedicated ER-phagy receptors that target distinct subdomains for lysosomal clearance, this pathway preserves organellar integrity and mitigates proteotoxic burden in post-mitotic neurons. Nonetheless, the full mechanistic landscape of ER-phagy remains poorly defined, with receptor-specific functions, regulatory signalling networks and CNS expression profiles only beginning to be resolved. This review synthesizes current insights into ER-phagy in neurodegeneration, dissects receptor-specific mechanisms, and highlights emerging pharmacological interventions. Ultimately, the therapeutic potential of modulating receptor-specific ER-phagy as an untapped strategy to resolve ER stress, re-establish neuronal proteostasis and to combat neurodegenerative conditions is highlighted.

Keywords:  Autophagy; ER-phagy; Endoplasmic Reticulum; Misfolded protein; Neurodegenerative diseases; Proteinopathy

DOI:  https://doi.org/10.1016/j.arr.2026.103426
Proc Natl Acad Sci U S A. 2026 Oct 27. 123(43): e2611301123

HAP40 functions as a proteostasis regulator by controlling huntingtin interactions and its release into the extracellular space.

Eduardo Silva Ramos, Annett Boeddrich, Christian Haenig, Philipp Trepte, Orchid Ammar, Christopher Secker, Oliver Popp, Andranik Ivanov, Stephanie Beetz, Leonard Roth, Roxane M Papawassiliou, Luisanna C Hernandez Jeppesen, Theo Wallenfang, Brandon Keith, Rachel J Harding, Franziska Schindler, Tomas Koudelka, Nadine Scharek, Martina Zenkner, Nancy Neuendorf, Sabrina Golusik, Philipp Mertins, Ilaria Piazza, Sigrid Schnoegl, Erich E Wanker.

  Huntingtin-associated protein 40 (HAP40) forms a stable protein complex with huntingtin (HTT). Its cellular function and how HAP40 loss influences mutant HTT (mHTT) abundance and pathobiology are currently unclear. Here, using diverse cellular models and omics methods, we demonstrate that HAP40 is an obligate interaction partner of HTT and through its binding controls HTT interactions and the abundance of HTT-associated proteins, indicating that it functions as a HTT interaction regulatory unit. Also, loss of HAP40 in mHTT-expressing striatal cells impairs autophagic protein degradation and triggers transcriptional activation of the CLEAR network, demonstrating that it functions as a proteostasis regulator that acts on quality control pathways. Finally, mHTT-expressing cells lacking HAP40 showed increased secretion of a ~205 kDa mHTT fragment through an endoplasmic reticulum (ER)/Golgi-associated route, indicating that striatal cells reduce intracellular mHTT-induced proteotoxicity through activation of secretory pathways. Together, these results establish HAP40 as a critical proteostasis regulator that through controlling HTT interactions maintains cellular homeostasis.

Keywords:  HAP40; Huntington’s disease; autophagy; mutant HTT; proteostasis

DOI:  https://doi.org/10.1073/pnas.2611301123
Autophagy Rep. 2026 ;5(1): 2748072

Rethinking autophagy during odontogenesis through autophagic flux.

Bruno Calsa, Patrícia Aline Boer.

  Tooth development requires precise coordination of proliferation, differentiation, and tissue remodeling. Although macroautophagy/autophagy has been implicated in odontogenesis, its dynamic regulation during embryonic tooth development remains poorly understood because previous studies relied primarily on static markers. In our recent study, we analyzed autophagic flux in mouse tooth germs using a tandem fluorescent reporter of microtubule associated protein 1 light chain 3 (LC3) combined with lysosomal associated membrane protein 1 (LAMP1) immunostaining and found that gestational protein restriction altered the autophagic vesicle profile in a stage- and compartment-specific manner. The most pronounced alterations occurred at the bud stage and coincided with reduced cell proliferation and increased apoptosis. These findings suggest that early odontogenesis is a particularly vulnerable window in which efficient and properly timed autophagic flux may be required for morphogenesis. Because tandem reporters cannot distinguish canonical autophagy from non-degradative LC3-dependent pathways, we also discuss this limitation and raise new questions about the role of autophagy in epithelial-mesenchymal interactions.

Keywords:  CASM; LC3; developmental origins of health and disease; endolysosomal maturation; epithelial–mesenchymal interactions; gestational protein restriction; tandem reporter; tooth development

DOI:  https://doi.org/10.1080/27694127.2026.2748072
Clin Transl Med. 2026 Oct;pii: e70876. [Epub ahead of print]16(10):

Lysosomal protein transmembrane 5 protects against myocardial ischemia-reperfusion injury by promoting mitophagy via the NEDD4-LC3 axis.

Yadan Zhang, Qingqing Wu, Yang Xiao, Ying Liu, Qi Yao, Jiabin Yu, Shasha Wang, Si Chen, Xiaofeng Zeng, Qizhu Tang.

   BACKGROUND: Mitophagy is essential for mitochondrial quality control during myocardial ischemia-reperfusion (I/R) injury. Lysosomal protein transmembrane 5 (LAPTM5) has been implicated in cardiovascular disease and autophagy, but its role in cardiac mitophagy remains unclear.
METHODS: LAPTM5 knockout mice and cardiomyocyte-targeted AAV9-cTnT-LAPTM5 were used to determine the role of LAPTM5 in myocardial I/R injury. Cardiomyocyte hypoxia/reoxygenation models, mt-Keima imaging, mitochondrial fractionation, LC3-mitochondrial colocalization, co-immunoprecipitation, molecular docking, site-directed mutagenesis, NEDD4 gain- and loss-of-function, and p62 ubiquitination assays were used to investigate the underlying mechanism. Depending on data distribution and group number, appropriate parametric or non-parametric statistics were applied together with correction for multiple testing.
RESULTS: LAPTM5 expression progressively decreased following I/R or H/R stress. LAPTM5 deficiency aggravated myocardial injury, cardiac dysfunction, and mitochondrial structural and functional damage, whereas LAPTM5 overexpression attenuated these abnormalities. LAPTM5 promoted mitophagy by enhancing LC3 recruitment to mitochondria. Mechanistically, LAPTM5 recruited NEDD4 to mitochondria through its PY3 motif and facilitated NEDD4-LC3 complex formation. NEDD4 depletion abolished LAPTM5-mediated mitophagy and cytoprotection, whereas re-expression of NEDD4-WT, but not the E3-inactive NEDD4-CS mutant, restored these effects. NEDD4-WT also increased p62 ubiquitination. AAV9-mediated LAPTM5 re-expression reduced infarct size, improved cardiac function, and preserved mitochondrial integrity in LAPTM5-deficient hearts.
CONCLUSIONS: LAPTM5 protects against myocardial I/R injury by promoting mitophagy through the NEDD4-LC3 axis. PY3-dependent recruitment of NEDD4 and its E3 ubiquitin ligase activity facilitate LC3-associated mitochondrial clearance, accompanied by enhanced p62 ubiquitination, thereby preserving mitochondrial homeostasis during reperfusion.

Keywords:  LAPTM5; cardioprotection; heart; ischemia/reperfusion; mitophagy

DOI:  https://doi.org/10.1002/ctm2.70876
Exp Neurol. 2026 Oct 18. pii: S0014-4886(26)00446-2. [Epub ahead of print]408 116078

A critical mechanistic synthesis of PINK1-mediated mitophagy signaling and its therapeutic targeting in Parkinson's disease neurodegeneration.

Abida Khan, Talha Jawaid, Zia Ur Rehman, Mohammed Kanan Alshammari, Md Afroz Bakht, Faiyaz Shakeel, Mohammed Zawiah, Mohd Imran.

  Parkinson's disease (PD) is a progressive neurodegenerative disorder that is associated with loss of dopaminergic neurons, mitochondrial dysfunction and disruption of cellular homeostasis. PTEN-induced kinase 1 (PINK1) plays a crucial role in mitochondrial quality control by regulating mitophagy, mitochondrial dynamics, and calcium signaling to maintain neuronal bioenergetic homeostasis. This review critically evaluates the molecular pathways underlying PINK1-mediated mitochondrial integrity and the mechanisms by which loss-of-function mutations contribute to the pathogenesis of PD. Familial early-onset PD is strongly associated with pathogenic PINK1 mutations identified through genetic studies. Therapeutic approaches targeting the PINK1 pathway are examined, including adeno-associated virus (AAV)-based gene delivery, direct small-molecule PINK1 activation (MTK458), and indirect modulation of mitophagy and mitochondrial homeostasis by compounds such as curcumin, resveratrol, cannabidiol, gastrodin, and quercetin. Moreover, the complementary restoration of mitochondrial homeostasis through the modulation of downstream targets, such as transcription factor EB (TFEB) activation and BCL2-interacting protein 3-like (BNIP3L/NIX)-mediated mitophagy, is discussed as an indirect therapeutic strategy. Another important finding is that PD is a biologically and clinically heterogeneous disease that requires biomarker-directed and genotype-stratified therapeutic development. Finally, major translational issues are critically evaluated, including challenges related to blood-brain barrier penetration, target specificity, and long-term safety of mitochondrial modulators.

Keywords:  Mitochondrial dysfunction; Mitophagy; Oxidative stress; PINK1/Parkin; Parkinson's disease

DOI:  https://doi.org/10.1016/j.expneurol.2026.116078
Elife. 2026 Oct 19. pii: RP109876. [Epub ahead of print]15

Bruce suppresses autophagy-regulated caspase activity and wing tissue growth in Drosophila.

Natsuki Shinoda, Yutaro Hama, Nozomi Hanawa, Masayuki Miura.

  Caspases are cysteine-aspartic proteases that mediate both lethal and non-lethal cellular outcomes, including the promotion of tissue growth. However, the mechanisms underlying the differential regulation of these activities remain unclear. We have previously shown that among the two Drosophila executioner caspases, Dcp-1 and Drice, Dcp-1 promotes tissue growth in a non-lethal manner, independent of canonical apoptotic signaling. Herein, we demonstrated that overexpressed Dcp-1, but not Drice, was activated without canonical apoptosome components. TurboID-based proximity labeling revealed distinct proximal proteomes, among which Sirtuin 1, an Atg8a deacetylase, which promotes autophagy, was specifically required for Dcp-1 activation. Autophagy-related genes, including Bcl-2 family members Debcl and Buffy, are required for Dcp-1 activation. Structure-based prediction using AlphaFold3 further identified Bruce, an autophagy-regulated inhibitor of apoptosis, as a Dcp-1-specific regulator acting outside the apoptosome-mediated pathway. Physiologically, Bruce suppresses wing tissue growth. These findings indicate that non-lethal Dcp-1 activity is governed by the autophagy-Bruce axis, enabling distinct non-lethal functions independent of cell death.

Keywords:  AlphaFold3; D. melanogaster; TurboID; apoptosis; autophagy; caspase; cell biology; developmental biology; tissue growth

DOI:  https://doi.org/10.7554/eLife.109876
ACS Chem Neurosci. 2026 Sep 16. 17(18): 3272-3282

Pharmacological Activation of Autophagy Ameliorates Neuromuscular-Associated Defects and Extends Lifespan in a Caenorhabditis elegans Model of Spinal Muscular Atrophy.

Saman Rashid, Coral Crespo Gómez, Maria Dimitriadi.

  Spinal muscular atrophy (SMA) is a severe neuromuscular disorder caused by homozygous deletions or mutations in the SMN1 gene, resulting in reduced levels of the ubiquitously expressed survival motor neuron protein and progressive degeneration of lower motor neurons. Although autophagy dysregulation has been implicated in SMA pathology, the therapeutic benefit of modulating this pathway remains controversial. Here, we screened autophagy modulators in a previously characterized Caenorhabditis elegans SMA model. We identified that pharmacological activation of autophagy, but not inhibition, significantly improved neuromuscular function, as indicated by two independent functional readouts: pharyngeal pumping and locomotor activity assays. These beneficial effects were validated in an independent severe C. elegans SMA mutant allele and were observed in metabolically active and inactive food conditions. Furthermore, autophagy activators significantly extended lifespan of SMA nematodes without affecting controls. Notably, rapamycin and resveratrol increased endogenous SMN-1 protein levels, and improved neuromuscular function was dependent on an intact autophagy pathway. Collectively, our findings support enhancing autophagic activity as a combinatorial treatment strategy for SMA patients.

Keywords:   C. elegans ; Spinal muscular atrophy; autophagy; drug screen; neurodegeneration; neuromuscular function

DOI:  https://doi.org/10.1021/acschemneuro.6c00569
Anal Chem. 2026 Sep 29. 98(38): 28495-28510

Simultaneous and Real-Time Imaging of Mitochondrial and Lysosomal ATP with Inducible Excessive Mitophagy for Antitumor Therapy via a Multifunctional Fluorescent Probe.

Zhou Wu, Bin Yang, Jun Wang, Ruihong Yao, Zhihao Lu, Yong Li, Yanli Li, Yuemao Dou, Jiajia Zeng, Zhirong Geng, Zhilin Wang.

Mitophagy is essential for mitochondrial quality control and cellular homeostasis, while its aberrant hyperactivation has emerged as a promising strategy to selectively eliminate cancer cells. This process depends on the adenosine triphosphate (ATP) interplay between mitochondria and lysosomes, yet probes that simultaneously enable dual-organelle ATP imaging and mitophagy regulation are still lacking. Herein, we report MLA, a powerful fluorescent probe that integrates spectrally resolved ATP imaging in both organelles with inducible excessive mitophagy. Bearing pH-adapted fluorophores and a glutathione (GSH)-cleavable disulfide, MLA operates in two modes: at low doses, it serves as a biocompatible reporter to map ATP fluctuations under various perturbations; at high doses, it depletes mitochondrial GSH, thereby triggering a reactive oxygen species (ROS) burst that induces excessive mitophagy and cancer cell death. Mechanistically, it was discovered that this process consumes the transmembrane glycoprotein Mucin 1 (MUC1) whose degradation blocks autophagic flux, and thus leads to lethal accumulation of undegraded autophagosomes, markedly suppressing proliferation. In vivo, MLA enables specific imaging of intratumoral ATP and exhibits tumor-inhibitory capacity. Co-administration with the ATP synthase inhibitor oligomycin A (Omy A) further amplifies the tumor-suppressive effect, validating a simultaneous and drastic ATP/GSH dual-depletion strategy as a feasible combination therapy. MLA represents the first fluorescent probe to synergize dual-organelle ATP imaging with mitophagy regulation, offering a powerful tool for fundamental research and a new paradigm for the design of versatile fluorescent probes.

DOI: https://doi.org/10.1021/acs.analchem.6c04402
EMBO J. 2026 Oct 19.

A USP28-TM9SF3-Golgiphagy axis maintains glycosylation homeostasis and promotes breast cancer progression.

Jiaxin Xu, Yang Cai, Yuting Zhang, Jiejie Yang, Yixian Cui.

Selective autophagy of the Golgi apparatus (Golgiphagy) is essential for Golgi quality control, yet its regulation and physiological functions remain poorly understood. Here, we identify the deubiquitinase USP28 as an upstream regulator of the Golgiphagy receptor TM9SF3. USP28 removes degradative K48-linked ubiquitin chains from TM9SF3, preventing its proteasomal degradation and sustaining Golgiphagy under nutrient and Golgi stresses. CRM1-dependent nuclear export enables the stress-induced translocation of USP28 to the Golgi, where it stabilizes TM9SF3, promoting Golgi fragmentation and autophagic clearance. Loss of USP28 or TM9SF3 impairs Golgiphagy, disrupts glycosylation fidelity, and inhibits breast cancer cell proliferation. Proteomic and functional analyses identify the glycosyltransferase MGAT5 as a selective TM9SF3-dependent Golgiphagy cargo, revealing how this pathway maintains glycosylation homeostasis. In syngeneic tumor models, USP28 knockout or pharmacological inhibition reduces TM9SF3 abundance, compromises Golgiphagy, perturbs glycosylation, and markedly suppresses tumor growth-effects restored by wild-type but not LC3-binding-deficient TM9SF3. Together, these findings reveal a USP28-TM9SF3-Golgiphagy axis that couples ubiquitin signaling to Golgi glycosylation control and represents a therapeutically targetable pathway for breast cancer.

DOI: https://doi.org/10.1038/s44318-026-00947-1
Biochim Biophys Acta Mol Cell Res. 2026 Oct 22. pii: S0167-4889(26)00138-2. [Epub ahead of print] 120239

Dysregulated PIKfyve-dependent inhibition of ClC-7 causes ammonium-dependent endolysosomal vacuolization and autophagic flux impairment: Rescue by glutaminase inhibition.

Junsuke Uwada, Hitomi Nakazawa, Takashi Yazawa, Ikunobu Muramatsu, Takayoshi Masuoka.

  ClC-7 is a lysosomal 2Cl-/1H+ antiporter essential for normal lysosomal function. PIKfyve-generated PI(3,5)P2 negatively regulates ClC-7 activity, and gain-of-function mutations (e.g., Y715C) that abolish this regulation cause severe genetic disorders. At the cellular level, these variants induce extensive endolysosomal vacuolization accompanied by impaired autophagic flux; however, the precise molecular mechanism driving vacuole enlargement remained elusive. Here, we report that prominent vacuole formation in cells expressing ClC-7 gain-of-function variants is closely associated with a marked intracellular ammonium accumulation. Furthermore, vacuole enlargement was attenuated by an ammonium scavenger and accelerated by exogenous glutamine or ammonium chloride, while pharmacological glutaminase inhibition suppressed both vacuole size and ammonium accumulation. Pharmacological inhibition of PIKfyve likewise induced vacuolization and ammonium accumulation, both of which were suppressed by ClC-7 knockout. Using a newly modified lipid-probe, we found that unlike PIKfyve inhibition, PI(3,5)P2 is maintained on ClC-7 gain-of-function vacuoles. The formation of vacuoles induced by the overexpression of SNX10, which downregulates PI(3,5)P2 synthesis, or by expression of a gain-of-function ClC-6 mutant was also accompanied by a marked accumulation of cellular ammonium. Additionally, cells overexpressing ClC-3 or ClC-5 exhibited vacuolization associated with cellular ammonium accumulation under the control of the accessory protein TMEM9. The impairment of autophagic flux triggered by either ClC-7 gain-of-function expression or PIKfyve inhibition was restored by glutaminase inhibition. Collectively, these findings demonstrate that glutamine-derived ammonium drives endolysosomal vacuolization and autophagic dysfunction downstream of the PIKfyve-ClC-7 axis, identifying glutaminase inhibition as a potential therapeutic strategy for associated genetic disorders.

Keywords:  Ammonia; Autophagy; ClC-7; Endosome; Lysosome; PI(3,5)P(2); PIKfyve

DOI:  https://doi.org/10.1016/j.bbamcr.2026.120239
J Med Chem. 2026 Oct 22. 69(20): 24197-24218

Development of DCL1191 as a Potent, Selective and Orally Bioavailable Inhibitor for Autophagy-Associated Transcription Factor EB (TFEB).

Changle Du, Yaping Rong, Zilu Wang, Tongtong Wang, Yuqi Lin, Yuhan Luo, Yuhan Su, Pengfei Fang, Biao Yu, Zhen Wang, Jing Wang, Ke Ding.

  Transcription factor EB (TFEB) is a promising target for autophagy regulation and cancer therapy, yet it has long been regarded as an undruggable protein. Starting from eltrombopag, an FDA-approved agent that exhibits both thrombopoietin receptor (Tpo-R) agonistic activity and TFEB inhibitory potency, we performed systematic structure-activity relationship optimization and identified DCL1191 as a potent, selective, and orally bioavailable TFEB inhibitor. DCL1191 binds TFEB with a Kd of 80.5 nM and disrupts the TFEB-DNA interaction with an IC50 of 60.5 nM. Computational modeling combined with site-directed mutagenesis elucidated its precise binding mode. DCL1191 exhibits diminished activity toward Tpo-R and MITF. Mechanistically, DCL1191 effectively represses the transcription of TFEB target genes and blocks intracellular autophagic flux. In autophagy-hyperactivated U87 glioblastoma cells, DCL1191 substantially sensitizes tumor cells to temozolomide chemotherapy. Pharmacokinetic evaluation in rats further demonstrated that DCL1191 possesses an i.v. half-life of 16.33 h and satisfactory oral bioavailability of 18.77%.

Keywords:  DCL1191; autophagy; inhibitor; structure−activity relationship; transcription factor EB

DOI:  https://doi.org/10.1021/acs.jmedchem.6c01755
Proc Natl Acad Sci U S A. 2026 Oct 27. 123(43): e2610766123

Translational control of microglial metabolism, inflammatory responses, and survival by the eIF4E-binding proteins.

Sara Bermudez, Jung-Hyun Choi, Niaz Mahmood, Jacob W Vogel, Hashem Almousa, Ziying Huang, Sung-Hoon Kim, Vivian Yuchan Zhu, Linqiao Zhou, Diana Casas-Antillon, Moein Yaqubi, Danielle Cozachenco, Jo Anne Stratton, Oskar Hansson, Luke Healy, Argel Aguilar-Valles, Nahum Sonenberg.

  In Alzheimer's disease (AD), activation of the mechanistic target of rapamycin (mTOR) pathway promotes microglial neuroprotective functions by engaging multiple cell receptors. However, the relevant downstream effectors are not fully understood. mTOR complex 1 (mTORC1) promotes mRNA translation by phosphorylating and inactivating eukaryotic translation initiation factor 4E-binding protein 1 and 2 (4E-BP1/2), which are expressed in microglia. 4E-BP1 levels in cerebrospinal fluid (CSF) are elevated in AD and correlate with markers of microglial reactivity and disease progression. Using linear regression analysis, we found that elevated CSF 4E-BP1 levels strengthen the association between soluble TREM2 levels and neurodegeneration in amyloid-positive individuals. To investigate the underlying mechanism, we performed in vitro experiments demonstrating that amyloid-β inactivated 4E-BP1 in murine microglia. The mTOR-mediated inactivation is highly dependent on Spleen Tyrosine Kinase (SYK) signaling and repeated exposure to amyloid-β impaired this process, whereas prolonged exposure increased 4E-BP1 levels in microglia. Deletion of 4E-BP1/2 resulted in increased mitochondrial mass and oxidative phosphorylation, reduced pro-inflammatory signaling, and protected microglia from amyloid-induced apoptosis. Thus, impaired 4E-BP1 inactivation-due to reduced mTOR signaling or excess 4E-BP1-disrupts immune resolution, leading to metabolic exhaustion and microglial cell death. We identify the SYK-mTORC1-4E-BP1 signaling axis as a key regulator of microglial mitochondrial biogenesis and immune resolution in AD.

Keywords:  Alzheimer’s disease; inflammation; mTOR; microglia

DOI:  https://doi.org/10.1073/pnas.2610766123
Signal Transduct Target Ther. 2026 Oct 20. pii: 458. [Epub ahead of print]11(1):

Mitophagy coordinates organelle crosstalk in health and diseases.

Mengyao Wu, Pengyi He, Yajun Lian, Tuo Zhang, Yiqi Wu, Lu Wang, Daolin Tang, Yongming Yao, Renqi Yao.

Eukaryotic cells contain various membrane- and non-membrane-bound organelles, whose spatial and functional organization underpins intracellular homeostasis. Organelle coordination is governed by complex signaling and metabolic networks, often facilitated by direct physical contacts and molecular exchange. Mitochondria, as central hubs of bioenergetic and metabolic activity, are essential to functional coordination among cellular organelles. They engage in diverse cellular processes, encompassing ATP production, biosynthesis of key metabolites, calcium ion buffering, redox balance, and cellular turnover. To preserve their integrity and functionality, dysfunctional mitochondria undergo selective elimination via mitophagy, a specialized form of macroautophagy. Mitophagy plays dual roles in maintaining mitochondrial fidelity and actively shapes interorganelle communication. Through bidirectional signaling, mitophagy influences the activity of multiple organelles, including the endoplasmic reticulum, nucleus, lysosomes, peroxisomes, and lipid droplets. This interorganelle crosstalk is essential for adapting to metabolic stress, maintaining redox balance, and coordinating cell fate decisions. In this review, we explore the intricate signaling networks connecting mitophagy with various organelles and discuss how these interactions influence organ function and overall cellular health. We also highlight emerging small-molecule modulators of mitophagy, providing insight into potential therapeutic strategies aimed at restoring or enhancing organelle communication in pathological conditions.

DOI: https://doi.org/10.1038/s41392-026-02812-3
NPJ Parkinsons Dis. 2026 Aug 01. pii: 255. [Epub ahead of print]12(1):

Machine learning image analysis predicts Parkinson disease genotype and mitochondrial lysosomal abnormalities in iPS neurons.

Yan Li, Maximilian Powell, Jessica Chedid, Ratneswary Sutharsan, Adahir Labrador-Garrido, Dad Abu-Bonsrah, Chiara Pavan, Tyra Fraser, Dmitry Ovchinnikov, Melanie Zhong, Ryan Davis, Dario Strbenac, Jennifer A Johnston, Lachlan H Thompson, Deniz Kirik, Clare L Parish, Glenda M Halliday, Carolyn M Sue, Nicolas Dzamko, Gautam Wali.

Mitochondrial and lysosomal dysfunction are central features of Parkinson's disease (PD) across major genetic forms including PRKN, SNCA, and LRRK2. We applied cell morphomics, a machine-learning-based framework combining high-content imaging with quantitative feature extraction, to analyse mitochondrial and lysosomal morphology at single-cell resolution in iPS cell-derived cortical neurons from PD patients and healthy controls (13 lines total). Supervised machine-learning models distinguished PD neurons from controls with high accuracy (AUC = 0.87) and reliably separated individual genotypes. Feature importance and attribution analysis revealed genotype-specific organelle biases in the relative contribution of mitochondrial and lysosomal features, with mitochondrial features dominating classification in PRKN neurons, balanced mitochondrial and lysosomal contributions in SNCA neurons, and a greater lysosomal contribution in LRRK2 neurons. Multi-class models retained strong performance, and findings were reproduced across two independent laboratories using different dyes and imaging conditions. These results demonstrate that morphomics provides a robust and scalable framework to quantify genotype-specific organelle abnormalities in PD neurons and supports its application for cellular stratification and biomarker discovery.

DOI: https://doi.org/10.1038/s41531-026-01458-w
Nat Aging. 2026 Oct 19.

Chaperone-mediated autophagy curbs senescence.

Shweta S Dipali, Matthew J Yousefzadeh.

DOI: https://doi.org/10.1038/s43587-026-01264-2
J Cell Sci. 2026 Oct 22. pii: jcs.264932. [Epub ahead of print]

GPI lipid remodeling regulates lipophagy in response to glucose deprivation.

Kuya Matsunaga, Kazuki Hanaoka, Yujia Yang, Hinako Nishii, Antonio Cordones-Romero, Sergio Lopez-Martin, Manuel Muñiz, Kouichi Funato.

  Lipophagy is an important microautophagic process that degrades lipid droplets (LDs) to mobilize stored lipids as an energy source during nutrient starvation. However, the molecular mechanisms regulating lipophagy in response to nutrient starvation remain poorly understood. We found that budding yeast mutants defective in glycosylphosphatidylinositol (GPI) lipid remodeling exhibited aberrant accumulation of lipid droplets (LDs), neutral lipids, and a reduced degradation of Faa4-GFP, a lipophagy reporter under glucose starvation. Furthermore, we demonstrated that glycosylphosphatidylinositol-anchored proteins (GPI-APs) localize to vacuoles in response to glucose depletion, and that a mutant defective in endocytosis has defects in lipophagy. These results imply that GPI lipid remodeling is required for lipophagy upon glucose starvation, and we propose that endocytosis functions to supply the lipid portion of GPI-APs, remodeled to C26 diacylglycerol, to the vacuolar membrane for lipophagy.

Keywords:   Saccharomyces cerevisiae ; Endocytosis; GPI lipid remodeling; Lipid Droplet; Lipophagy; Liquid-ordered (Lo) domain

DOI:  https://doi.org/10.1242/jcs.264932
J Med Chem. 2026 Oct 08. 69(19): 21937-21954

Hsc70-Mediated Targeting Chimeras for Targeted Protein Degradation via Chaperone-Mediated Autophagy.

Chao Chen, Ying Zheng, Xiuyu Tao, Liya Yang, Chaoyue Wang, Xiaoqian Liu, Ruixi Zhao, Haokang Ding, Peng Sun, Haotian Liu, Shiqi Liu, Chenyuan Jiang, Min Huang, Bing Zhou.

  Despite the remarkable success of proteolysis-targeting chimeras (PROTACs), challenges such as limited applicability to certain cytosolic proteins, potential resistance risks, and off-target effects remain. Novel degradation strategies harnessing the autophagy/lysosome pathway may broaden the scope of protein targets and address resistance, providing a promising complement to PROTACs. Herein, the bifunctional small-molecule Hsc70-Mediated Targeting Chimeras, termed Hsc70TACs, was designed by conjugating a small molecule targeting Hsc70 with the ligands of the protein of interest (POI). We demonstrate the scope of Hsc70TACs through the degradation of therapeutically relevant proteins such as BRD4, MDM2 and even cell-membrane protein PD-L1 across diverse cellular contexts. More importantly, compound B-2, a novel BRD4 Hsc70TAC, shows favorable pharmacokinetic properties and robust in vivo BRD4 degradation, thus further highlighting the potential value of Hsc70TAC. Overall, Hsc70TAC demonstrates a new avenue to target and degrade disease-associated proteins, providing a valuable addition to current protein degradation technologies.

Keywords:  Bifunctional small molecule; Chaperone-mediated autophagy; Hsc70 targeting chimera; Lysosomal degradation; Targeted protein degradation

DOI:  https://doi.org/10.1021/acs.jmedchem.6c01010