bims-auttor Biomed News
on Autophagy and mTOR
Issue of 2025–08–17
forty-two papers selected by
Viktor Korolchuk, Newcastle University
  1. Mitochondrial damage triggers the concerted degradation of negative regulators of neuronal autophagy.
  2. mTORC1-selective inhibitors rescue cellular phenotypes in TSC iPSC-derived neurons.
  3. Retrograde axonal transport of autophagic vesicles and dynein-dynactin protein interaction are attenuated during aging in the rat optic nerve in vivo.
  4. The Loss of Complex I in Renal Oncocytoma Is Associated with Defective Mitophagy Due to Lysosomal Dysfunction.
  5. Plant-specific mitochondrial fission machinery connects mitochondrial dynamics and mitophagosome formation for piecemeal mitophagy.
  6. Transcriptional dynamics uncover the role of BNIP3 in mitophagy during muscle remodeling in Drosophila.
  7. Recent advances of the mechanistic target of rapamycin (mTOR) inhibitors for drug discovery.
  8. FoxO3 Activation Alleviates Doxorubicin-Induced Cardiomyopathy by Enhancing Autophagic Flux and Suppressing mTOR/ROS Signalling.
  9. Lysosomal TPC2 channel as a new target of chlorpromazine and clomipramine to induce protective autophagy in L-BMAA-induced neurodegeneration.
  10. Bridging autophagy and endolysosomal dysfunction: Role of bridging integrator 1 in Alzheimer's disease.
  11. Metabolic Regulation of Cardiovascular Aging.
  12. Regulation of transcriptome plasticity by mTOR signaling pathway.
  13. mTOR Signaling in Macrophages: All Depends on the Context.
  14. RICTOR regulates an interspecies crosstalk that influences longevity through a novel methionine cycle-mitophagy axis.
  15. BLOC1S1 variants cause lysosomal and autophagic defects resulting in a hypomyelinating leukodystrophy with epileptic encephalopathy.
  16. Biological Modulation of Autophagy by Nanoplastics: A Current Overview.
  17. Most autophagic cell death studies lack evidence of causality.
  18. Mst1 inhibition attenuates obesity cardiomyopathy via reversing FUNDC1-related mitophagy.
  19. Energy deprivation in youth and old age.
  20. Inhibition of calcium-sensing receptor by its antagonist protects dopaminergic neurons from MPTP/MPP+-induced neurotoxicity via regulating mitochondrial function, autophagy, and apoptosis in vivo and in vitro.
  21. Defective Ribosome Recycling: A Bridge Between Translation Fidelity, Organelle Dysfunction, and Diseases: Exploring How Flawed Ribosome Recycling Factors Impact Ribosome Metabolism and Organelle Homeostasis, Leading to Human Diseases.
  22. Exploring the Therapeutic Potential of Natural Compounds Targeting Macro-Autophagy in OP Management: A Comprehensive Review.
  23. Neural stem cell-specific deficiency of (pro)renin receptor causes brain malformation and perinatal lethality in mice.
  24. LncRNA GTF3C1 promotes diabetic corneal wound healing by regulating GABARAP and PTEN to augment autophagy.
  25. Glaucoma-associated Optineurin mutations increase transcellular degradation of mitochondria in a vertebrate optic nerve.
  26. Autophagy and Reactive Oxygen Species in Megakaryopoiesis and Platelet Production.
  27. Discovery of a novel mitophagy inducer attenuating postoperative cognitive dysfunction through structure-based virtual screening and biological validation.
  28. The role of lysine acetylation in metabolic sensing and proteostasis.
  29. Alpha-synuclein inclusions reduced by PIKfyve inhibition in Parkinson's disease cell models.
  30. The interplay between physical exercise and autophagy signaling in brain health, neurodegenerative diseases and aging.
  31. A growing problem: the many unsolved mysteries of cell growth.
  32. ER-phagy and proteostasis defects prime pancreatic epithelial state changes in KRAS-mediated oncogenesis.
  33. Dysregulation of GTPase-activating protein-binding protein1 in the pathogenesis of metabolic dysfunction-associated steatotic liver disease.
  34. Genetic depletion of early autophagy protein ATG13 impairs mitochondrial energy metabolism, augments oxidative stress, induces the polarization of macrophages to M1 inflammatory mode, and compromises myelin integrity in skeletal muscle.
  35. PARP7 inhibition stabilizes STAT1/STAT2 and relieves experimental autoimmune encephalomyelitis in mice.
  36. Gene therapy for lysosomal storage diseases.
  37. Endogenous and exogenous viral reactivation as a driver of epigenetic drift and mitophagy failure in aging.
  38. Mechanisms of cellular fitness and cell competition: Towards an integrated view.
  39. USP30 inhibition augments mitophagy to prevent T cell exhaustion.
  40. Skin Epidermal Progenitor Maintenance by the SRCAP-H2A.Z axis Downstream to ERK and mTOR Signaling.
  41. TOR signalling mediates the collective movement of Border cells in Drosophila oogenesis.
  42. Polysialylation of Glioblastoma Cells Is Regulated by Autophagy Under Nutrient Deprivation.
  1. Nat Commun. 2025 Aug 09. 16(1): 7367
    Mitochondrial damage triggers the concerted degradation of negative regulators of neuronal autophagy.
    Bishal Basak, Erika L F Holzbaur.
      Mutations that disrupt the clearance of damaged mitochondria via mitophagy are causative for neurological disorders including Parkinson's. Here, we identify a Mitophagic Stress Response (MitoSR) activated by mitochondrial damage in neurons and operating in parallel to canonical Pink1/Parkin-dependent mitophagy. Increasing levels of mitochondrial stress trigger a graded response that induces the concerted degradation of negative regulators of autophagy including Myotubularin-related phosphatase (MTMR)5, MTMR2 and Rubicon via the ubiquitin-proteasome pathway and selective proteolysis. MTMR5/MTMR2 inhibit autophagosome biogenesis; consistent with this, mitochondrial engulfment by autophagosomes is enhanced upon MTMR2 depletion. Rubicon inhibits lysosomal function, blocking later steps of neuronal autophagy; Rubicon depletion relieves this inhibition. Targeted depletion of both MTMR2 and Rubicon is sufficient to enhance mitophagy, promoting autophagosome biogenesis and facilitating mitophagosome-lysosome fusion. Together, these findings suggest that therapeutic activation of MitoSR to induce the selective degradation of negative regulators of autophagy may enhance mitochondrial quality control in stressed neurons.
    DOI:  https://doi.org/10.1038/s41467-025-62379-5
  2. Front Neurosci. 2025 ;19 1595880
    mTORC1-selective inhibitors rescue cellular phenotypes in TSC iPSC-derived neurons.
    Elizabeth D Buttermore, Gayathri Rajaram Srinivasan, Hellen Jumo, Amanda C Swanson, Benjamin O'Kelly, Nina R Makhortova, Mustafa Sahin, Stelios T Tzannis.
      The mechanistic target of rapamycin (mTOR) pathway plays an important role in regulating multiple cellular processes, including cell growth, autophagy, proliferation, protein synthesis, and lipid synthesis, among others. Given the central role of this pathway in multiple cellular processes, it is not surprising that mTOR pathway dysregulation is a key mechanism underlying several neurological disorders, including Tuberous Sclerosis Complex (TSC). TSC patients typically present with pathogenic variants in the TSC1 or TSC2 genes, which encode proteins forming a complex that plays an important role in modulating mTOR activity. We previously reported cellular and functional deficits in induced pluripotent stem cell (iPSC)-derived neurons from TSC patients. These deficits were reversed by inhibiting mTOR activity using rapamycin treatment, revealing the role of mTOR signaling in the regulation of cell morphology and hyperexcitability phenotypes in TSC patient-derived neurons. However, chronic rapamycin treatment inhibits both mTORC1 and mTORC2 activity and its clinical use is associated with significant side effects. With the development of novel mTORC1-selective compounds, we aimed to assess whether selective inhibition of mTORC1 likewise reversed the cellular and functional deficits found in TSC patient-derived neurons. Our results indicate that the novel, selective mTORC1 inhibitors nearly fully reversed the cellular and functional deficits of TSC2 -/ - iPSC-derived neurons in a fashion and magnitude similar to rapamycin, as they all reversed and near-normalized their neuronal hyperexcitability and abnormal morphology as compared to the DMSO-treated cells. These data suggest that mTORC1-specific compounds could provide clinical therapeutic benefit similar to rapamycin without the same side effects.
    Keywords:  TSC2; hyperexcitability; iPSC-derived neurons; mTOR; mTORC1; mTORC2; soma size
    DOI:  https://doi.org/10.3389/fnins.2025.1595880
  3. Neural Regen Res. 2025 Aug 13.
    Retrograde axonal transport of autophagic vesicles and dynein-dynactin protein interaction are attenuated during aging in the rat optic nerve in vivo.
    Xiaoyue Luo, Jiong Zhang, Johan Tolö, Sebastian Kügler, Uwe Michel, Mathias Bähr, Jan Christoph Koch.
      Aging is characterized by a decreased autophagic activity contributing to the intracellular deposition of damaged organelles and macromolecules. Autophagy is particularly challenging in neurons since autophagic vesicles are formed at the axonal tip and must be transported to the soma where final degradation occurs. Here, we examined if axonal transport of autophagic vesicles is altered during aging. We employed two-photon microscopy for in vivo imaging in the optic nerve of young and aged rats. In old animals (> 18 months old), retrograde autophagic vesicle transport was significantly reduced with regard to motility and velocity. While activation of autophagy was decreased, expression of key proteins of the autophagy-lysosomal pathway including p62 and procathepsin D and the number of autophagolysosomes was increased. Maturation of autophagic vesicles was shifted to more distal regions of the axon and axonal lysosomal clearing was impaired. In a pull-down assay, the protein binding between dynein and dynactin was decreased by half, which could explain the retrograde axonal transport effects. Taken together, retrograde axonal autophagic vesicle transport in vivo is diminished during aging accompanied by decreased autophagy activation, alterations of the lysosomal pathway, and a reduced dynein-dynactin binding.
    Keywords:  aging; autophagic vesicles; autophagy; autophagy-lysosomal pathway; axonal transport; dynein; optic nerve; p150Glued; retrograde transport; two-photon microscopy
    DOI:  https://doi.org/10.4103/NRR.NRR-D-24-01326
  4. Int J Mol Sci. 2025 Aug 07. pii: 7654. [Epub ahead of print]26(15):
    The Loss of Complex I in Renal Oncocytoma Is Associated with Defective Mitophagy Due to Lysosomal Dysfunction.
    Lin Lin, Neal Patel, Lucia Fernandez-Del-Rio, Cristiane Benica, Blake Wilde, Eirini Christodoulou, Shinji Ohtake, Anhyo Jeong, Aboubacar Kaba, Nedas Matulionis, Randy Caliliw, Xiaowu Gai, Heather Christofk, David Shackelford, Brian Shuch.
      Renal oncocytoma (RO) is a benign renal neoplasm characterized by dense accumulation of dysfunctional mitochondria possibly resulting from increased mitochondrial biogenesis and decreased mitophagy; however, the mechanisms controlling these mitochondrial changes are unclear. ROs harbor recurrent inactivating mutations in mitochondrial genes encoding the Electron Transport Chain (ETC) Complex I, and we hypothesize that Complex I loss in ROs directly impairs mitophagy. Our analysis of ROs and normal kidney (NK) tissues shows that a significant portion (8 out of 17) of ROs have mtDNA Complex I loss-of-function mutations with high variant allele frequency (>50%). ROs indeed exhibit reduced Complex I expression and activity. Analysis of the various steps of mitophagy pathway demonstrates that AMPK activation in ROs leads to induction of mitochondrial biogenesis, autophagy, and formation of autophagosomes. However, the subsequent steps involving lysosome biogenesis and function are defective, resulting in an overall inhibition of mitophagy. Inhibiting Complex I in a normal kidney cell line recapitulated the observed lysosomal and mitophagy defects. Our data suggest Complex I loss in RO results in defective mitophagy due to lysosomal loss and dysfunction.
    Keywords:  autophagy/mitophagy; complex I; lysosome; metabolism; mitochondrial dysfunction; renal oncocytoma
    DOI:  https://doi.org/10.3390/ijms26157654
  5. Proc Natl Acad Sci U S A. 2025 Aug 19. 122(33): e2504921122
    Plant-specific mitochondrial fission machinery connects mitochondrial dynamics and mitophagosome formation for piecemeal mitophagy.
    Juncai Ma, Chaorui Li, Kaike Ren, Kaiyan Zhang, Lanlan Feng, Kai Ching Law, Ka Kit Chung, Yizhou Bing, Caiji Gao, Byung-Ho Kang, Xiaohong Zhuang.
      As the energy center of the cell, mitochondria display enormous metabolic plasticity to meet the cellular demand for plant growth and development, which is tightly linked to their structural and dynamic plasticity. Mitochondrial number and morphology are coordinated through the actions of the mitochondrial division and fusion. Meanwhile, damaged mitochondrial contents are removed to avoid excess toxicity to the plant cells. Mitophagy, a selective degradation pathway of mitochondria through a double-membrane sac named autophagosome (also known as mitophagosome), plays a crucial role in maintaining mitochondrial homeostasis. Typically, wholesale mitophagy requires the elongation of a cup-shaped phagophore along the entire mitochondrion, which finally seals and closes as a mitophagosome. How plant mitophagosome formation and mitochondria sequestration are coordinated remains incompletely understood. In this work, we report an unappreciated role of the plant-specific mitochondrial fission regulator ELM1, together with the dynamin-related protein family DRP3 and the autophagic regulator SH3P2, to coordinate mitochondria segregation for piecemeal mitophagy under heat stress conditions. Dysfunction in mitochondrial fission activity impairs heat-induced mitophagy, leading to an accumulation of interconnected megamitochondria which are partially sequestered by the ATG8-positive phagophore. Furthermore, we show that the ELM1-mediated piecemeal mitophagy also engages the plant archetypal selective autophagic receptor NBR1. Using 3D tomography analysis, we illustrate the morphological features and spatial relationship of the megamitochondria and phagophore intermediates in connection with the mitochondrial fission sites. Collectively, our study provides an updated model of mitophagosome formation for piecemeal mitophagy mediated by the plant-unique mitochondrial fission machinery.
    Keywords:  ELM1; SH3P2; mitochondrial fission; mitophagosome; mitophagy
    DOI:  https://doi.org/10.1073/pnas.2504921122
  6. Elife. 2025 Aug 13. pii: RP105834. [Epub ahead of print]14
    Transcriptional dynamics uncover the role of BNIP3 in mitophagy during muscle remodeling in Drosophila.
    Hiroki Taoka, Tadayoshi Murakawa, Kohei Kawaguchi, Michiko Koizumi, Tatsuya Kaminishi, Yuriko Sakamaki, Kaori Tanaka, Akihito Harada, Keiichi Inoue, Tomotake Kanki, Yasuyuki Ohkawa, Naonobu Fujita.
      Differentiated muscle cells contain myofibrils and well-organized organelles, enabling powerful contractions. Muscle cell reorganization occurs in response to various physiological stimuli; however, the mechanisms behind this remodeling remain enigmatic due to the lack of a genetically trackable system. Previously, we reported that a subset of larval muscle cells is remodeled into adult abdominal muscle through an autophagy-dependent mechanism in Drosophila. To unveil the underlying mechanisms of this remodeling, we performed a comparative time-course RNA-seq analysis of isolated muscle cells with or without autophagy. It revealed both transcriptional dynamics independent of autophagy and highlighted the significance of BNIP3-mediated mitophagy in muscle remodeling. Mechanistically, we found that BNIP3 recruits autophagic machinery to mitochondria through its LC3-interacting motif and minimal essential region, which interact with Atg8a and Atg18a, respectively. Loss of BNIP3 leads to a substantial accumulation of larval mitochondria, ultimately impairing muscle remodeling. In summary, this study demonstrates that BNIP3-dependent mitophagy is critical for orchestrating the dynamic process of muscle remodeling.
    Keywords:  BNIP3; D. melanogaster; Drosophila; autophagy; cell biology; developmental biology; metamorphosis; mitochondria; muscle
    DOI:  https://doi.org/10.7554/eLife.105834
  7. Eur J Med Chem. 2025 Aug 06. pii: S0223-5234(25)00811-6. [Epub ahead of print]298 118046
    Recent advances of the mechanistic target of rapamycin (mTOR) inhibitors for drug discovery.
    Sha Ni, Hui Qu, Da Liu, Lin Yuan, Mengqi Li, Wancheng Zhao.
      The mechanistic target of rapamycin (mTOR), a serine/threonine kinase, serves as a central regulator of cellular growth, proliferation, metabolism, and survival through its two distinct multiprotein complexes, mTORC1 and mTORC2. Aberrant activation of the mTOR signaling pathway is frequently implicated in a wide range of human cancers and is closely associated with tumor progression, therapeutic resistance, and poor clinical outcomes. Accordingly, pharmacological inhibition of mTOR has emerged as a compelling strategy in the development of anticancer therapeutics. To date, several mTOR inhibitors have received regulatory approval or are currently undergoing clinical evaluation. This review provides an up-to-date development of small-molecule mTOR inhibitors from 2019 to the present. Emphasis is placed on their structural classification, mechanisms of action, and medicinal chemistry optimization strategies. We believe that this review, together with previous summaries from other research groups, will offer valuable insights to support the rational design and development of next-generation mTOR inhibitors with improved pharmacokinetic properties and enhanced target selectivity.
    Keywords:  Cancer therapy; Mechanistic target of rapamycin (mTOR); Structural optimization; Targeted drug discovery; mTOR inhibitors
    DOI:  https://doi.org/10.1016/j.ejmech.2025.118046
  8. J Cell Mol Med. 2025 Aug;29(15): e70775
    FoxO3 Activation Alleviates Doxorubicin-Induced Cardiomyopathy by Enhancing Autophagic Flux and Suppressing mTOR/ROS Signalling.
    Zao-Shang Chang, Le Wang, Ju-Xiang Zhou, Mei-Xiu-Li Li, Meng-Yun Yang, Bin Luo, Jia-Jun Liu, Xiao-Ye Sun, Jing-Bo Xia.
      Doxorubicin (DOX) is an effective chemotherapy drug, but its use is limited by cardiotoxicity, known as DOX-induced cardiomyopathy. The transcription factor FoxO3, which regulates autophagy and oxidative stress, has unclear mechanisms in this condition. We found that DOX-induced cardiomyopathy involved cardiac atrophy, cardiac dysfunction, fibrosis and mitochondrial damage. DOX reduced H9c2 cardiomyocyte viability and glutathione levels (GSH), increased reactive oxygen species (ROS), malondialdehyde (MDA) and lactate dehydrogenase (LDH) and inhibited superoxide dismutase 2 (SOD2) and catalase (CAT) expression. DOX also suppressed FoxO3 activation and increased the autophagy protein LC3 II/I ratio. Overexpressing FoxO3 enhanced LC3B, Beclin 1 and autophagic flux, while reducing p62 and suppressing mTOR activation in heart. Brefeldin A1 (BafA1), an autophagy inhibitor and rapamycin (Rapa), an autophagy activator, were administered to H9c2 cardiomyocytes to elucidate the regulatory mechanism of FoxO3. Mechanically, our data revealed that FoxO3 overexpression enhanced autophagy and suppressed ROS production and mTOR activation in both in vitro and in vivo models of DOX exposure. Collectively, targeting FoxO3 to enhance protective autophagy may offer a therapeutic strategy against DOX-induced cardiomyopathy.
    Keywords:   FoxO3 ; autophagy; cardiomyopathy; doxorubicin; reactive oxygen species
    DOI:  https://doi.org/10.1111/jcmm.70775
  9. Biochem Pharmacol. 2025 Aug 10. pii: S0006-2952(25)00484-8. [Epub ahead of print]242(Pt 2): 117219
    Lysosomal TPC2 channel as a new target of chlorpromazine and clomipramine to induce protective autophagy in L-BMAA-induced neurodegeneration.
    Valentina Tedeschi, Raffaella Ciancio, Giorgia Magliocca, Emilia Esposito, Silvia Piccirillo, Valentina Rubino, Alessandra Preziuso, Tatiana Spadoni, Noemi Di Muraglia, Giuseppina Ruggiero, Anna Pannaccione, Agnese Secondo.
      Several neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) are characterized by toxic aggregates accumulation due to autophagy blockade, prompting researchers to identify new autophagy-activating drugs. Here we tested, in an in vitro ALS/PDC model, the neuroprotective effects of the antipsychotic Chlorpromazine (CPZ) and the antidepressant Clomipramine (CMI), chosen by drug repurposing approach for their ability to stimulate TPC2 lysosomal channel. Patch-clamp electrophysiology on enlarged lysosomes in NSC-34 motor neurons showed that CPZ and CMI induced large inwardly-rectifying currents, that were inhibited by TPC2 synthetic blocker trans-Ned-19. The same currents were evoked by TPC2 endogenous agonist NAADP and its mimetic agent TPC2-A1-N, and inhibited by trans-Ned-19 and siRNAs against TPC2 (siTPC2). CPZ and CMI elicited a significant [Ca2+]i increase that rapidly induced nuclear translocation of TFEB (transcription factor EB), the master regulator of autophagy. Accordingly, TPC2 stimulation by both the drugs boosted autophagy, as revealed by the activation of autophagy initiators ULK and AMPK α and modification of LC3-II/p62(SQSTM1) ratio. Furthermore, by normalizing autophagy markers, CPZ and CMI counteracted the detrimental effects induced by L-BMAA, a neurotoxin mimicking ALS/PDC. Notably, siTPC2 partially reverted CMI- and CPZ-induced neuroprotection as well as that produced by NAADP. At mitochondrial level, these drugs prevented ATP reduction and ROS overproduction in motor neurons exposed to L-BMAA for 24 h. For a longer L-BMAA exposure, CPZ and CMI counteracted LDH, cytochrome C and SMAC/DIABLO release, thus preventing cell demise. These findings suggest that TPC2 activation by drug repurposing could provide novel therapeutic options for ALS via autophagy regulation.
    Keywords:  ALS/PDC; Autophagy; Chlorpromazine; Clomipramine; Drug repurposing; Lysosomal Ca(2+) homeostasis; TPC2 channel
    DOI:  https://doi.org/10.1016/j.bcp.2025.117219
  10. Neural Regen Res. 2025 Aug 13.
    Bridging autophagy and endolysosomal dysfunction: Role of bridging integrator 1 in Alzheimer's disease.
    Julia Duckhorn, Doo Kyung Kim, Yu-Wen Alvin Huang.
      Alzheimer's disease is a devastating neurodegenerative disorder affecting millions worldwide, with current treatments offering only limited benefits. Central to emerging research is the role of autophagy and endolysosomal pathways, which are essential for clearing misfolded proteins and damaged organelles. Bridging integrator 1 (BIN1), traditionally recognized for its role in membrane remodeling and endocytosis, has recently emerged as a top genetic risk factor for Alzheimer's disease, linking cellular clearance mechanisms to the development of toxic amyloid-beta plaques and tau tangles. In this review, we provide an accessible overview of how disruptions in autophagy and endolysosomal trafficking contribute to the neurodegeneration process in Alzheimer's disease, positioning BIN1 as a central mediator within this complex network. Recent advances have shown that alterations in BIN1 expression and isoform distribution are associated with increased tau pathology and changes in amyloid-beta processing. Moreover, BIN1 appears to also influence synaptic transmission, neuroinflammation, and overall cellular homeostasis. The integration of recent findings not only deepens our understanding of Alzheimer's disease pathology but also opens new avenues for the development of targeted treatments. This timely perspective underscores the potential of modulating BIN1 activity to enhance cellular clearance mechanisms and offers hope for more effective interventions for Alzheimer's disease.
    Keywords:  Alzheimer's disease; amyloid-beta; autophagy; bridging integrator 1; cellular clearance; endolysosomal network; genetic risk factors; membrane dynamics; neurodegeneration; neuroinflammation; synaptic transmission; tau
    DOI:  https://doi.org/10.4103/NRR.NRR-D-25-00243
  11. Curr Cardiol Rep. 2025 Aug 15. 27(1): 128
    Metabolic Regulation of Cardiovascular Aging.
    Michael Gao, Toren Finkel.
       PURPOSE OF REVIEW: Metabolic changes can play a critical role in the structural and functional decline of the aging cardiovascular system. In this review, we examine how key metabolic pathways and regulatory mechanisms influence cardiovascular aging, highlighting recent studies into metabolic flexibility, mitochondrial function, nutrient sensing, and energy utilization in the aging heart. Potential metabolic-based interventions to mitigate cardiac aging are also discussed.
    RECENT FINDINGS: Various metabolic changes have been observed in the aging heart. Impaired metabolic flexibility, as seen by reduced fatty acid oxidation with an increased reliance on glucose, is observed. Mitochondrial dysfunction and increased oxidative stress in aged cardiomyocytes may lead to energy deficits, contributing to myocardial fibrosis and diastolic dysfunction. Accelerated cardiovascular aging is also connected to the dysregulation of nutrient-sensing pathways- such as AMP-activated protein kinase (AMPK), sirtuins, and the mechanistic target of rapamycin (mTOR). Enhancing the age-dependent decline in autophagy and mitophagy, which clears damaged organelles, appears to preserve cardiac function in aging. Recent studies have shown that interventions such as caloric restriction, exercise, and metformin can favorably remodel cardiac metabolism and delay age-related cardiac deterioration. Metabolic changes, including energy substrate shifts, mitochondrial oxidative stress, and impaired nutrient signaling, play a direct role in cardiovascular aging. Targeting these metabolic factors and pathways holds promise for alleviating age-associated cardiac dysfunction. Recent studies focusing on lifestyle or pharmacologic means of metabolic modulation provide and outline for the promotion of healthy cardiovascular aging, thereby reducing the burden of cardiovascular disease in the growing aging population.
    Keywords:  Autophagy; Cardiovascular aging; Metabolic flexibility; Metabolism; Mitochondrial dysfunction; Nutrient sensing
    DOI:  https://doi.org/10.1007/s11886-025-02279-8
  12. Exp Mol Med. 2025 Aug 14.
    Regulation of transcriptome plasticity by mTOR signaling pathway.
    Jeongsik Yong, Hyunjoo Kim, Euyeon Lee, Yoonju Jung.
      The mechanistic target of rapamycin (mTOR) pathway, long recognized for its critical roles in cellular metabolism and growth, is increasingly appreciated for its regulatory impact on the transcriptome. Recent insights into mTOR's regulation of alternative splicing and polyadenylation reveal a sophisticated mechanism by which mTOR influences RNA processing to affect the proteome's diversity and functionality. Here, in this Review, we delve into the multifaceted roles of mTOR in modulating transcriptome plasticity, highlighting its influence beyond traditional functions such as protein synthesis and cell growth. By examining the latest findings, we explore how mTOR-mediated transcriptome plasticity plays a pivotal role in cellular adaptation and pathogenesis. Studies indicate that mTOR modulation of RNA processing pathways enables cells to respond dynamically to environmental and metabolic cues, thereby altering protein function and cellular behavior in a context-dependent manner. This capability is crucial for both normal physiological responses and the development of disease. The Review also discusses the implications of these findings for understanding complex biological systems and diseases, particularly cancer, where mTOR's regulation of transcript diversity could drive tumor heterogeneity and treatment resistance. As research continues to uncover the extensive influence of mTOR on RNA processing, it becomes clear that a comprehensive understanding of these mechanisms is essential for the development of targeted therapies and the prediction of their outcomes in clinical settings.
    DOI:  https://doi.org/10.1038/s12276-025-01508-y
  13. Int J Mol Sci. 2025 Aug 06. pii: 7598. [Epub ahead of print]26(15):
    mTOR Signaling in Macrophages: All Depends on the Context.
    Angelika Fedor, Krzysztof Bryniarski, Katarzyna Nazimek.
      Macrophages are undoubtedly one of the most widely studied cells of the immune system, among other reasons, because they are involved in a wide variety of biological processes. Deregulation of their activity is observed in a number of different disorders, including autoimmune diseases. At the same time, mammalian target of rapamycin (mTOR) is attracting increasing research attention because the pathways dependent on this kinase are activated by a variety of signals, including cytokines and proinflammatory mediators, mediate essential processes for cell survival and metabolism, and can be regulated epigenetically via microRNAs. Therefore, our narrative review aimed to summarize and discuss recent advances in the knowledge of the activation of mTOR signaling in macrophages, with a special focus on autoimmune disorders and the possibility of mTOR control by microRNAs. The summarized research observations allowed us to conclude that the effects of activity and/or inhibition of individual mTOR complexes in macrophages are largely context dependent, and therefore, these broad immunological contexts and other specific conditions should always be taken into account when attempting to modulate these pathways for therapeutic purposes.
    Keywords:  autoimmunity; immune regulation; immune tolerance; mTORC1; mTORC2; macrophages; mammalian target of rapamycin; mechanistic target of rapamycin; miRNAs; miRs
    DOI:  https://doi.org/10.3390/ijms26157598
  14. bioRxiv. 2025 Jul 14. pii: 2025.07.11.664440. [Epub ahead of print]
    RICTOR regulates an interspecies crosstalk that influences longevity through a novel methionine cycle-mitophagy axis.
    Simran Motwani, Somya Bhandari, Shivani Chitkara, Rajat Ujjainiya, Shantanu Sengupta, Arnab Mukhopadhyay.
      Adaptive modulation of physiological traits in response to environmental variability, particularly dietary fluctuations, is essential for organismal fitness. Such adaptability is governed by complex gene-diet interactions, yet the molecular circuits integrating microbe-derived metabolites with host metabolic and stress response pathways remain less explored. Here, we identify the conserved mechanistic target of rapamycin complex 2 (mTORC2) component, RICTOR, as a critical regulator of dietary plasticity in Caenorhabditis elegans , specifically in response to bacterially derived vitamin B12 (B12). Loss of rict-1 , the C. elegans ortholog of RICTOR, confers enhanced osmotic stress tolerance and longevity on B12-rich bacterial diets. These phenotypic adaptations require two B12-dependent enzymes: methionine synthase (METR-1), functioning in the folate-methionine cycle (Met-C), and methylmalonyl-CoA mutase (MMCM-1), a mitochondrial enzyme essential for propionate catabolism. The latter catalyzes the formation of succinyl-CoA, subsequently converted to succinate via the tricarboxylic acid (TCA) cycle. Elevated succinate levels were found to induce mitochondrial fragmentation, thereby activating mitophagy, an autophagic process indispensable for the increased stress resilience and longevity observed in the rict-1 mutants. Crucially, this Met-C-mitophagy axis is modulated by microbial inputs, with B12 and methionine acting as proximal dietary signals. Our findings delineate a mechanistic framework through which RICTOR restrains host sensitivity to microbial-derived metabolites, thus maintaining mitochondrial homeostasis and regulating lifespan. This work reveals a pivotal role for RICTOR in insulating host physiology from environmental nutrient-driven perturbations by modulating organellar quality control pathways.
    DOI:  https://doi.org/10.1101/2025.07.11.664440
  15. medRxiv. 2025 Jul 17. pii: 2025.07.17.25331211. [Epub ahead of print]
    BLOC1S1 variants cause lysosomal and autophagic defects resulting in a hypomyelinating leukodystrophy with epileptic encephalopathy.
    Raffaella De Pace, Carlos A Dominguez Gonzalez, Chad Williamson, Guy Helman, Leslie E Sanderson, Brianna Disanza, Nicole Hsiao-Sanchez, Amy Pizzino, Kayla Muirhead, Joshua L Bonkowsky, Ryan J Taft, Nouriya A Sannaa, Patricia Dias, Ana Sofia Quintas, Mehmet Burak Multu, Hasan Bas, Hasan Ozturk, Majid Mojarrad, Masoome Alerasool, Shahriar Sheikhani, Hayder Kadhim Jabbar, Awatif Hameed Issa, Henry Houlden, Emir Zonic, Tahsin Stefan Barakat, Kornelia Tripolski, Antonio Romito, Eden Teferedegn, Arastoo Vossough, Matthew T Whitehead, Elizabeth Bhoj, Rebecca C Ahrens-Nicklas, Cas Simons, Ernst Wolvetang, Tjakko J van Ham, Aida M Bertoli-Avella, Reza Maroofian, Juan S Bonifacino, Adeline Vanderver.
      BLOC1S1 encodes a subunit shared by the BLOC-1 and BORC hetero-octameric complexes that regulate various endolysosomal processes. Here, we report the identification of seven distinct variants in BLOC1S1 in eleven individuals from seven independent families presenting with early psychomotor delay, hypotonia, spasticity, epileptic encephalopathy, optic atrophy, and leuko-axonopathy with hypomyelination. A subset of the affected individuals also have features of hypopigmentation and ocular albinism that are similar, although milder, than those of individuals with BLOC-1-related Hermansky-Pudlak syndrome. Functional analyses show that BLOC1S1 knockout (KO) impairs the anterograde transport of lysosomes and autophagy in both non-neuronal cells and iPSC-derived neurons. Rescue experiments reveal that most BLOC1S1 variants exhibit reduced expression, decreased assembly with other BORC/BLOC-1 subunits, and/or impaired restoration of lysosome transport and autophagy in BLOC1S1-KO cells. Additionally, we show that KO of BLOC1S1 reduces pigmentation in a melanocytic cell line, and that five of the BLOC1S1 variants partially or fully restore pigmentation. These findings provide genetic, clinical, and functional evidence that loss-of-function (LoF) of BLOC1S1 leads to more pronounced deficits in BORC than BLOC-1 function. We conclude that the biallelic BLOC1S1 variants characterized here primarily result in a neurological disorder with prominent leukodystrophy, similar to the recently reported condition caused by variants in the BORCS8 subunit of BORC. Together, these findings establish BORCopathies as a distinct disease entity.
    DOI:  https://doi.org/10.1101/2025.07.17.25331211
  16. Int J Mol Sci. 2025 Jul 22. pii: 7035. [Epub ahead of print]26(15):
    Biological Modulation of Autophagy by Nanoplastics: A Current Overview.
    Francesco Fanghella, Mirko Pesce, Sara Franceschelli, Valeria Panella, Osama Elsallabi, Tiziano Lupi, Benedetta Rizza, Maria Giulia Di Battista, Annalisa Bruno, Patrizia Ballerini, Antonia Patruno, Lorenza Speranza.
      Nanoplastics (NPs), an emerging class of environmental pollutants, are increasingly recognized for their potential to interfere with critical cellular processes. Autophagy, a conserved degradative pathway essential for maintaining cellular homeostasis and adaptation to stress, has recently become a focal point of nanotoxicology research. This review synthesizes current evidence on the interactions between NPs and autophagic pathways across diverse biological systems. Findings indicate that NPs can trigger autophagy as an early cellular response; however, prolonged exposure may lead to autophagic dysfunction, contributing to impaired cell viability and disrupted signaling. Particular attention is given to the physiochemical properties of NPs such as size, surface charge, and polymer type, which influence cellular uptake and intracellular trafficking. We also highlight key mechanistic pathways, including oxidative stress and mTOR modulation. Notably, most available studies focus almost exclusively on polystyrene (PS)-based NPs, with limited data on other types of polymers, and several reports lack comprehensive assessment of autophagic flux or downstream effects. In conclusion, a better understanding of NP-autophagy crosstalk-particularly beyond PS-is crucial to evaluate the real toxic potential of NPs and guide future research in human health and nanotechnology.
    Keywords:  autophagy; cardiovascular system; gastrointestinal system; mTOR; mitophagy; nanoplastics; nervous system; reproductive system; respiratory system
    DOI:  https://doi.org/10.3390/ijms26157035
  17. FEBS Open Bio. 2025 Aug 11.
    Most autophagic cell death studies lack evidence of causality.
    Ali Burak Özkaya, Yasmin Ghaseminejad.
      Autophagy plays a critical role in maintaining cellular homeostasis and is implicated in various physiological and pathological processes, including cancer, neurodegeneration, and metabolic disorders. Although typically associated with cell survival, autophagy has also been proposed to contribute to cell death, referred to as autophagic cell death (ACD). However, the identification of ACD remains contentious due to inconsistencies in experimental methodologies and terminological misuse. In this study, we systematically evaluated 104 research articles published in 2022 that claimed to demonstrate ACD. Articles were assessed based on established criteria, including evidence for autophagy, evidence for cell death, exclusion of apoptosis, and experimental designs demonstrating causality. Our findings reveal that only 12.5% of the articles fulfilled all ACD criteria, while 37.5% provided only correlation-level evidence. Additionally, 54.81% failed to demonstrate autophagy flux, 32.7% relied on viability loss rather than direct evidence of cell death, and 45.0% of studies utilizing autophagy inhibition failed to demonstrate actual inhibition of autophagy. Inconsistent terminology was also prevalent, with "autophagy-mediated cell death" often misclassified as ACD and ACD frequently misused to describe autophagy co-occurring with cell death. These issues highlight a lack of rigor in current practices, with correlation-level evidence, inappropriate experimental designs, and terminological misuse undermining study robustness. To address these challenges, we developed a systematic workflow providing experimental and analytical guidance for classifying evidence for different modes of autophagy. Our analysis underscores the need for greater rigor, standardized approaches, and precise terminology to advance understanding of the interplay between autophagy and cell death.
    Keywords:  apoptosis; autophagic cell death; autophagy; autophagy‐associated cell death; autophagy‐mediated cell death; cell viability
    DOI:  https://doi.org/10.1002/2211-5463.70101
  18. Cell Signal. 2025 Aug 07. pii: S0898-6568(25)00473-5. [Epub ahead of print] 112058
    Mst1 inhibition attenuates obesity cardiomyopathy via reversing FUNDC1-related mitophagy.
    Ding Yan, Zhu Linli, Zhang Mengyu, Li Xia, Liu Hailan, Zhang Chunquan.
      Mitophagy dysfunction is an important pathological manifestation of obesity cardiomyopathy, a disease characterized by myocardial hypertrophy and diastolic dysfunction. Mammalian Ste20-like kinase 1 (Mst1) regulates mitophagy and is involved in diabetic cardiomyopathy. However, the relationship between Mst1 and mitophagy in obesity cardiomyopathy remains unexplored. This study aimed to determine whether Mst1 contributes to obesity cardiomyopathy by modulating FUN14 domain-containing 1 (FUNDC1)-mediated mitophagy. We found that Mst1 expression was significantly upregulated in obesity cardiomyopathy. Mst1 knockdown ameliorated ventricular remodeling, diastolic dysfunction, and subclinical systolic impairment in high-fat diet (HFD)-induced obese mice. At the molecular level, palmitic acid treatment induced mitochondrial damage, manifested by increased reactive oxygen species production, reduced mitochondrial membrane potential, and ATP depletion. Mechanistically, Mst1 activation suppressed FUNDC1 expression, inhibiting mitophagy. Conversely, Mst1 deficiency restored FUNDC1 expression, reactivating protective mitophagy, maintaining mitochondrial homeostasis, and alleviating cardiomyopathy. Finally, we established that Mst1 regulates FUNDC1 through the peroxisome proliferator-activated receptor gamma coactivator 1-alpha/nuclear respiratory factor 1 (PGC-1α/NRF1) pathway. Inhibition of the PGC-1α/NRF1 pathway reversed the Mst1 knockout-induced FUNDC1 upregulation. Collectively, our findings demonstrate that Mst1 drives obesity cardiomyopathy by suppressing FUNDC1-dependent mitophagy.
    Keywords:  Mst1; Myocardial injury; Obesity; Speckle tracking
    DOI:  https://doi.org/10.1016/j.cellsig.2025.112058
  19. J Cell Sci. 2025 Aug 15. pii: jcs264018. [Epub ahead of print]138(16):
    Energy deprivation in youth and old age.
    Michael Stern.
      In youth, energy deprivation primarily results from fasting. Because inconsistent nutrient availability is common for most organisms, natural selection has provided mechanisms that detect nutrient-deprived states, followed by adaptive responses that increase the likelihood of survival until nutrients are restored. Organisms respond to fasting first by oxidizing the cellular cytoplasm, then by activating redox-sensitive kinases - namely the c-Jun N-terminal kinases (henceforth collectively termed JNK) and AMP-activated protein kinase (AMPK) - and Foxo transcription factors (henceforth referred to collectively as Foxo). Together, JNK, AMPK and Foxo induce autophagy. This fasting response is beneficial because autophagy supplies substrates for metabolism that replace missing nutrients and enhances removal of damaged organelles such as mitochondria, which increases lifespan and enhances survival through the fast. Although this response is adaptive in the context of acute nutrient deprivation, it can have harmful consequences when activated chronically. Here, I propose that cells from old organisms are constitutively energy deprived because of lifetime accumulation of dysfunctional mitochondria. As a result, these cells reactivate the fasting response seen in youth. Hence, old organisms constitutively oxidize the cellular cytoplasm and activate JNK, AMPK, Foxo and, finally, autophagy. However, because energy deprivation in old age is driven by mitochondrial insufficiency rather than nutrient deprivation, this response fails to restore ATP production and becomes chronic and deleterious. I suggest that many age-related pathologies, such as oxidative stress, neurodegeneration and sarcopenia, result from aberrant activation of the fasting response.
    Keywords:  Aging; Autophagy; Nutrient deprivation; Oxidative Stress; Signal transduction
    DOI:  https://doi.org/10.1242/jcs.264018
  20. Neurosci Lett. 2025 Aug 09. pii: S0304-3940(25)00239-3. [Epub ahead of print]865 138351
    Inhibition of calcium-sensing receptor by its antagonist protects dopaminergic neurons from MPTP/MPP+-induced neurotoxicity via regulating mitochondrial function, autophagy, and apoptosis in vivo and in vitro.
    Huiping Qi, Dongfang Shen, Huan Wang, Wenxu Sang, Chenggong Jiang.
      Parkinson's disease (PD)‌ is characterized by progressive degeneration of dopaminergic neurons. The role of calcium-sensing receptor (CaSR) in the pathogenesis of PD remains poorly understood. We employed the CaSR antagonist NPS-2143 in bothin vivoandin vitroexperiments to investigate the therapeutic potential of CaSR modulation. Our findings revealed that MPTP/MPP+ exposure significantly upregulated CaSR expression. Functionally, CaSR overexpression exacerbated intracellular Ca2+ dyshomeostasis under MPTP/MPP+ toxicity. Inhibition of CaSR with NPS-2143 demonstrated marked neuroprotection, evidenced by improved motor function and preservation of dopaminergic neurons in MPTP-treated mice, alongside reduced cellular apoptosis in MPP+-injured MN9D cells. Mechanistically, NPS-2143 enhanced autophagy in MPP+-exposed cells while reversing 3-MA-induced autophagy suppression. Furthermore, NPS-2143 mitigated mitochondrial dysfunction, as shown by reduced reactive oxygen species accumulation, restored mitochondrial membrane potential, and normalized ATP production in MPP+-treated cells. These results collectively demonstrate that CaSR antagonism protects dopaminergic neurons through coordinated regulation of mitochondrial homeostasis, autophagic flux, and apoptotic pathways. Our study highlights CaSR as a promising therapeutic target for PD prevention and identifies NPS-2143 as a potential neuroprotective agent targeting CaSR.
    Keywords:  Antagonist; Autophagy; Calcium-sensing receptor; Dopaminergic neurons; Mitochondrial function; Parkinson’s disease
    DOI:  https://doi.org/10.1016/j.neulet.2025.138351
  21. Bioessays. 2025 Aug 11. e70054
    Defective Ribosome Recycling: A Bridge Between Translation Fidelity, Organelle Dysfunction, and Diseases: Exploring How Flawed Ribosome Recycling Factors Impact Ribosome Metabolism and Organelle Homeostasis, Leading to Human Diseases.
    Foozhan Tahmasebinia, Zhihao Wu.
      Ribosome recycling is a fundamental biological process crucial for cellular health. Defective recycling disrupts ribosome biogenesis and organelle function, particularly in mitochondria, contributing to ribosomopathies, neurodegenerative diseases, and cancer. While not directly linked to human diseases via known genetic mutations, emerging evidence suggests a critical interplay between ribosome recycling and organelle quality control. Impaired ribosome recycling leads to aberrant ribosome production, compromised translational quality control, protein misfolding, and subsequent organelle dysfunction and cellular stress. These cascading defects underscore the critical need for effective ribosome reutilization, especially under stress, as disruptions can cause translational arrest and heightened stress signaling, perturbing cellular homeostasis. Our analyses establish an indirect but significant link between ribosome recycling and human disease, offering new perspectives on how translational fidelity and organelle maintenance converge to support cellular well-being.
    Keywords:  40S subunit recycling; CAT‐tailing; cancer; mitochondria; neurodegenerative diseases; ribosome recycling; ribosome‐associated quality control (RQC)
    DOI:  https://doi.org/10.1002/bies.70054
  22. J Cell Biochem. 2025 Aug;126(8): e70055
    Exploring the Therapeutic Potential of Natural Compounds Targeting Macro-Autophagy in OP Management: A Comprehensive Review.
    Nima Montazeri-Najafabady, Pooneh Mokaram, Sanaz Dastghaib.
      Osteoporosis (OP) is a major health problem among the elderly. It involves a loss of bone mass and deterioration of the structure of bone. Age, genetic factors, and hormonal changes are all contributing causes that increase the tendency to skeletal imbalance between osteoblast and osteoclast activity. Prolonged use and side effects are the problems with current medication therapies. As a result, nonpharmacological interventions especially those using natural products are attracting more attention due to their distinct structures, less toxicity, and side effects. Autophagy plays a role in maintaining cellular balance and is engaged in both normal and abnormal physiological processes. The development of OP is also characterized by the disruption of autophagy in osteoblasts and osteoclasts. This comprehensive review examines natural products that regulate autophagy and their consequent impacts on bone cells. These compounds may prove useful in strengthening osteoblastic differentiation, stimulating bone formation and inhibiting osteoclastic resorption. Uncovering the complex relationship between autophagy and OP may open up new avenues of treatment. Also, it can teach us how to design personalized medical interventions for those patients at greatest risk. The autophagy pathway is a recently discovered target for natural products in the prevention and treatment of OP. However, more research is needed to explore the action mechanisms, good clinical effects and possible adverse reactions of these compounds so as to find novel and safer treatment for the common bone disease OP.
    Keywords:  OP; autophagy; bone loss; natural products; osteoblast
    DOI:  https://doi.org/10.1002/jcb.70055
  23. J Biochem. 2025 Aug 15. pii: mvaf047. [Epub ahead of print]
    Neural stem cell-specific deficiency of (pro)renin receptor causes brain malformation and perinatal lethality in mice.
    Misuzu Hashimoto, Misaki Hibi, Koya Matsukubo, Hitoshi Kimura, Kuma Hiraoka, Swapna Paramanya Biswas, Chiharu Suzuki-Nakagawa, Yasuhiko Kizuka, Jun-Dal Kim, Akiyoshi Fukamizu, Atsuhiro Ichihara, Tsutomu Nakagawa.
      (Pro)renin receptor [(P)RR], encoded by Atp6ap2, is a transmembrane protein found in many organs. It functions in lysosomes as part of the vacuolar-ATPase complex, facilitating autophagy and degradation. Mutations in ATP6AP2 are linked to neurological conditions, including X-linked parkinsonism with spasticity. However, our understanding of the role of (P)RR in whole brain development remains incomplete. Here, we generated mice with neural stem cell (NSC)-specific (P)RR deficiency (CKO). CKO mice exhibited significant brain atrophy during mid-gestation, leading to perinatal lethality. Fetal CKO brains showed lateral ventricular enlargement with malformation of neocortex and ganglionic eminence (GE) from mid-gestation. CKO brains showed massive apoptosis in multiple regions along with microglial activation at E15. On the contrary, CKO NSCs showed normal self-renewal ability, suggesting that (P)RR is critical for survival of differentiated cells. In line with this, the mechanistic study using RNA-seq of primary NSCs revealed downregulation of genes related to neurodevelopment and myelination. We also found p62 and LC3-II protein accumulation, hallmarks of deregulated autophagic pathways, in CKO fetal brains and NSCs. These findings demonstrate that (P)RR is crucial for guiding NSC differentiation and ensuring the coordinated construction of brain architecture during development.
    Keywords:  (pro)renin receptor; RNA-seq; autophagy; brain development; neural stem cell
    DOI:  https://doi.org/10.1093/jb/mvaf047
  24. Eye Vis (Lond). 2025 Aug 11. 12(1): 33
    LncRNA GTF3C1 promotes diabetic corneal wound healing by regulating GABARAP and PTEN to augment autophagy.
    Danling Liao, Wenqu Chen, Yuyang Deng, Shijia Wei, Li Wang, Jianzhang Hu.
       BACKGROUND: Diabetic keratopathy (DK) is a common ocular complication of diabetes, with its progression closely linked to autophagy regulation. This study aims to explore the role of long non-coding RNAs (lncRNAs) in modulating autophagy during diabetic pathogenesis, focusing on lncRNA general transcription factor IIIC subunit 1 (GTF3C1) and its potential as a therapeutic target for diabetic corneal neuropathy (DCN).
    METHODS: High-throughput sequencing identified dysregulated lncRNAs in the trigeminal ganglia of diabetic mice. Functional validation included mechanistic studies on lncRNA GTF3C1, miR-542-3p, and autophagy-related targets. Autophagy activity, corneal nerve density, and epithelial healing were quantified using quantitative real-time polymerase chain reaction (qRT-PCR), immunofluorescence, and histology in diabetic models.
    RESULTS: lncRNA GTF3C1 was significantly downregulated in diabetic trigeminal ganglion (TG). It functioned as a molecular sponge for miR-542-3p, alleviating its repression on GABA type A receptor-associated protein (GABARAP) and phosphatase and tensin homolog (PTEN), thereby enhancing autophagy activity. This process promoted corneal nerve fiber regeneration and epithelial wound healing in diabetic mice.
    CONCLUSIONS: Our findings highlight lncRNA GTF3C1 as a critical regulator of autophagy in diabetic corneal nerves, offering a potential diagnostic and therapeutic target for DCN. This study provides molecular insights into the pathogenesis of DCN and lays the groundwork for future clinical strategies.
    Keywords:  Autophagy; Diabetic corneal neuropathy; GABARAP; LncRNA GTF3C1; Nerve regeneration; PTEN
    DOI:  https://doi.org/10.1186/s40662-025-00448-y
  25. Elife. 2025 Aug 12. pii: e103844. [Epub ahead of print]14
    Glaucoma-associated Optineurin mutations increase transcellular degradation of mitochondria in a vertebrate optic nerve.
    Yaeram Jeong, Chung-Ha O Davis, Aaron Muscarella, Hector H Navarro, Viraj Deshpande, Lucy G Moore, Keun-Young Kim, Mark H Ellisman, Nicholas Marsh-Armstrong.
      We previously described a process whereby mitochondria shed by retinal ganglion cell (RGC) axons are transferred to and degraded by surrounding astrocytes in the optic nerve head of mice. Since the mitophagy receptor Optineurin (OPTN) is one of few large-effect glaucoma genes and axonal damage occurs at the optic nerve head in glaucoma, here we explored whether OPTN mutations perturb the transcellular degradation of mitochondria. Live-imaging of Xenopus laevis optic nerves revealed that diverse human mutant but not wildtype OPTN increase stationary mitochondria and mitophagy machinery and their colocalization within, and in the case of the glaucoma-associated OPTN mutations also outside of, RGC axons. These extra-axonal mitochondria are degraded by astrocytes. Our studies demonstrate that expression of OPTN carrying a glaucoma-associated mutation results in increased transcellular degradation of axonal mitochondria.
    Keywords:  neuroscience; xenopus
    DOI:  https://doi.org/10.7554/eLife.103844
  26. DNA Cell Biol. 2025 Jul 25.
    Autophagy and Reactive Oxygen Species in Megakaryopoiesis and Platelet Production.
    Abbas Khosravi, Abtin Ghasempour, Mostafa Paridar, Pargol Mashati, Mina Darvishi, Mehraneh Karimzadeh, Rashin Mohseni, Amir Ali Hamidieh.
      Megakaryocytes (MKs), which are differentiated from megakaryocytic-erythrocytic progenitors, generate platelets (PLTs) by expanding and branching their cellular fragments under the influence of cytokines and intercellular mechanisms such as autophagy and release of reactive oxygen species (ROS) in the bone marrow. Autophagy is a self-destructive process that plays a significant role in cell growth and energy maintenance of the cells. In contrast, ROS are toxic products of cellular metabolism that are harmful to human stem cells but have a crucial role in determining lineage commitment at the common myeloid progenitor stage and deriving further maturation progression toward MKs and PLTs production, with an interconnected relationship in the onset and deriving of autophagy. This review summarizes and discusses what has been discovered about the current state of knowledge regarding autophagy effects on MK differentiation, ROS effects on megakaryopoiesis (MKp), and the relationship between these molecules and autophagy initiation. Furthermore, in vitro applications of controlling these external factors on MKp are reviewed according to pertinent studies. Utilizing these regulatory mechanisms supports an improved design of in vitro MKp for introducing artificial PLT sources and might be beneficial in creating novel treatments of PLT-related coagulation disorders.
    Keywords:  ROS; autophagy; megakaryocytes; megakaryopoiesis; platelets
    DOI:  https://doi.org/10.1177/10445498251361641
  27. Free Radic Biol Med. 2025 Aug 11. pii: S0891-5849(25)00885-8. [Epub ahead of print]
    Discovery of a novel mitophagy inducer attenuating postoperative cognitive dysfunction through structure-based virtual screening and biological validation.
    Lina Zhang, Yujin Wu, Jiaying Li, Chenglong Li, Shuai Liu, Sihua Qi.
      Postoperative cognitive dysfunction (POCD), a prevalent complication following surgery and anesthesia, currently lacks effective therapeutics. Given the crucial regulatory role of the PTEN-induced kinase 1 (PINK1)/Parkin-mediated mitophagy in maintaining mitochondrial homeostasis and suppressing neuroinflammatory responses, we aimed to identify novel mitophagy inducers as potential therapeutic interventions for POCD. Employing structure-based virtual screening of a small-molecule library of compounds, we identified tamarixetin as a potent and selective PINK1 activator. Comprehensive molecular dynamics simulations and cellular thermal shift assays validated its stable binding interaction with PINK1. Treatment with tamarixetin significantly enhanced mitophagic activity in the hippocampal region of surgically treated mice, concurrently reducing cytosolic mitochondrial DNA accumulation and reactive oxygen species levels, attenuating neuroinflammatory responses, and improving cognitive function in behavioral tests. Mechanistically, tamarixetin treatment promoted PINK1 stabilization and strengthened PINK1-Translocase Of Outer Mitochondrial Membrane 40 interactions, while facilitating Parkin recruitment to mitochondria and enhancing mitofusin 2 ubiquitination, ultimately promoting mitophagic flux in both lipopolysaccharide-stimulated HT22 neuronal and BV2 microglial cell lines. Our study identifies tamarixetin as a novel pharmacological activator of PINK1-dependent mitophagy and elucidates its therapeutic potential in POCD by counteracting mitochondrial dysfunction and neuroinflammation. These findings provide a promising foundation for developing mitophagy-targeted therapies for POCD.
    Keywords:  PTEN-induced kinase 1; Parkin; Postoperative cognitive dysfunction; mitophagy; tamarixetin
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.08.016
  28. Pharmacol Ther. 2025 Aug 07. pii: S0163-7258(25)00120-2. [Epub ahead of print] 108908
    The role of lysine acetylation in metabolic sensing and proteostasis.
    Aziz Eftekhari, Sabir Usman, Takhar Kasumov.
      Post-translational acetylation of lysine residues is a dynamic and reversible modification that plays a pivotal role in regulating protein structure, function, and interactions. This modification is mediated by central metabolite acetyl-CoA and is tightly controlled by the opposing actions of lysine acetyltransferases (KATs) and lysine deacetylases (KDACs), including the NAD+-dependent sirtuins. As a nutrient-sensing post-translational modification (PTM), acetylation is essential for maintaining cellular homeostasis, particularly by modulating proteostasis and metabolic flexibility-the ability of cells to rewire metabolic pathways in response to fluctuating energy demands and nutrient availability. Dysregulation of acetylation has been implicated in the pathogenesis of metabolic disorders, neurodegenerative diseases, and cancer. Emerging evidence suggests that targeting acetylation-regulating enzymes with small-molecule inhibitors or activators hold promise for elucidating the role of acetylation in metabolic sensing and protein homeostasis, also known as proteostasis. This review examines the regulation of acetylation across various metabolic states, its impact on metabolic adaptability, and its intricate interplay with proteostasis mechanisms. Additionally, it highlights the role of site-specific acetylation dynamics and sirtuin biology shaping metabolic regulation, providing key insights into the mechanisms underlying metabolic disorders and their progression. Understanding the regulatory mechanisms governing acetylation-dependent metabolic sensing could facilitate the development of precision therapeutics to restore metabolic homeostasis.
    Keywords:  Acetylation; Autophagy; Deacetylation; Metabolic flexibility; Proteastasis; Sirtuins
    DOI:  https://doi.org/10.1016/j.pharmthera.2025.108908
  29. Neurobiol Dis. 2025 Aug 12. pii: S0969-9961(25)00269-4. [Epub ahead of print] 107053
    Alpha-synuclein inclusions reduced by PIKfyve inhibition in Parkinson's disease cell models.
    Sara Lucas-Del-Pozo, Giuseppe Uras, Federico Fierli, Veronica Lentini, Sofia Koletsi, Carlos Lazaro-Hernandez, Kai-Yin Chau, Derralynn A Hughes, Anthony H V Schapira.
       OBJECTIVE: Parkinson's disease (PD) pathophysiology is associated with a progressive loss of dopaminergic neurons in the substantia nigra and accumulation of insoluble inclusions of misfolded alpha-synuclein. In this study, we used a neuroblastoma-derived cell model overexpressing a pro-aggregation form of alpha-synuclein and human-derived induced-pluripotent stem cells (iPSCs) to investigate the efficacy of PIKfyve-mediated lysosomal biogenesis to reduce alpha-synuclein inclusions.
    METHODS: We used high-content imaging and enzymatic assays to follow the progression of lysosomal biogenesis, lysosomal catabolism and alpha-synuclein accumulation. The cell models used recapitulated important elements of the biochemical phenotype observed in PD dopaminergic neurons, including alpha-synuclein inclusions and impaired glucocerebrosidase.
    RESULTS: PIKfyve inhibition by YM201636 resulted in a lysosomal-dependant reduction of alpha-synuclein inclusions as early as 24 h post-treatment. YM201636 induced an increase in nuclear translocation of TFEB, and an increase in lysosomal markers LAMP1 and HEXA. PIKfyve-inhibition was also tested in neuronal-differentiated neuroblastoma-derived cells and iPSCs-derived dopaminergic neurons. In these cells, YM201636 substantially reduced alpha-synuclein inclusions and increased TFEB nuclear localisation.
    CONCLUSION: These findings suggest that PIKfyve signalling pathways could represent a therapeutic target to reduce alpha-synuclein in PD.
    Keywords:  Alpha-synuclein; PIKfyve; Parkinson's disease; TFEB
    DOI:  https://doi.org/10.1016/j.nbd.2025.107053
  30. Front Aging Neurosci. 2025 ;17 1579208
    The interplay between physical exercise and autophagy signaling in brain health, neurodegenerative diseases and aging.
    Bo Gao, Li Wang, Jian Gong, Zehua Zhu, Qi Liu, Han Yuan, Haitao Wang.
      Brain health is increasingly recognized as a critical component of overall wellbeing, particularly concerning neurodegenerative diseases, which are characterized by the progressive degeneration of the nervous system. Conditions such as Alzheimer's disease (AD) and Parkinson's disease, together with less common disorders, resembling Amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD), significantly impact cognitive and physical health, affecting over 50 million individuals worldwide. This review explores the multifaceted relationship between brain health and neurodegeneration, emphasizing the roles of biological, environmental, and lifestyle factors. Notably, physical activity has been identified as a potent intervention that enhances neuroplasticity and metabolic resilience while mitigating the effects of neurodegeneration. Research indicates that exercise activates autophagy, which is crucial for clearing neurotoxic aggregates like amyloid-beta and α-synuclein, thereby promoting neuronal health. Additionally, exercise stimulates the production of neurotrophic factors such as BDNF and GDNF, which are essential for neuronal survival and function. Despite the promising findings regarding exercise as a preventive and therapeutic strategy for neurodegenerative diseases, further investigation into the underlying mechanisms is necessary to optimize these interventions. This review aims to elucidate the complex interactions between exercise, autophagy, and brain health to provide insights into effective strategies for combating neurodegeneration.
    Keywords:  autophagy; brain; exercise; health; neurodegenerative diseases
    DOI:  https://doi.org/10.3389/fnagi.2025.1579208
  31. Mol Biol Cell. 2025 Aug 13. mbcE21070359
    A growing problem: the many unsolved mysteries of cell growth.
    Douglas R Kellogg.
      Growth is the essential vital process that drives life forward and always occurs within cells. Cell growth fuels the cell divisions that drive proliferation of single-celled organisms and growth of multi-cellular organisms. Mechanisms that control the extent and location of growth within cells generate the extraordinary diversity of cell sizes and shapes seen across the tree of life and within the human body, and nearly all cancers show profound defects in control of cell growth that lead to severe aberrations in cell size and shape. Yet we know little about how cell growth occurs or how it is controlled. For decades we have known how basic building blocks such as amino acids and lipids are built, but an enormous gap has always remained in our understanding of how these building blocks are used to build out cells of highly diverse sizes and shapes under varying environmental conditions and in diverse developmental contexts. Given the fundamental importance of growth in biology and cancer, our minimal understanding of cell growth is a growing problem. Here, a few of the intriguing and important questions about cell growth are considered.
    DOI:  https://doi.org/10.1091/mbc.E21-07-0359
  32. Dev Cell. 2025 Aug 13. pii: S1534-5807(25)00473-3. [Epub ahead of print]
    ER-phagy and proteostasis defects prime pancreatic epithelial state changes in KRAS-mediated oncogenesis.
    Carla Salomó Coll, Marisa Di Monaco, Jocelyn Holkham, Matthew Smith, Morwenna Muir, Philippe Gautier, Hywel Dunn-Davies, Xiaozhong Zheng, Roopesh Krishnankutty, Alain J Kemp, Katie Winnington-Ingram, Alex von Kriegsheim, Jennifer P Morton, Natalia Jimenez-Moreno, Damian Mole, Simon Wilkinson.
      Pre-malignant transformation of pancreatic acinar cells by oncogenic Kras is dependent upon stochastic emergence of metaplastic cell states. Here, we reveal that an early, transcriptionally mediated effect of Kras is sporadic failure of proteostatic endoplasmic reticulum (ER)-phagy. Genetically altered mice deficient in ER-phagy demonstrate that this event cooperates with Kras to drive acinar-ductal metaplasia (ADM) and subsequent cancer. Mechanistically, proteomics and high-resolution imaging uncover pathologic aggregation of a subset of ER proteins, including the injury marker REG3B, resulting from failure to physically interact with the ER-phagy receptor CCPG1. Spatial transcriptomics demonstrate that the appearance of sporadic intracellular aggregates upon Kras activation marks rare acinar cells existing in an injured, ADM-primed state. Importantly, engineered mutants of REG3B establish that aggregate formation is sufficient to directly engender this epithelial cell state. Pancreatic cancer can thus arise from stochastic pathologic protein aggregates that are influenced by, and cooperate with, an oncogene.
    Keywords:  ADM; CANCER; CCPG1; ER-phagy; KRAS; autophagy; inflammation; metaplasia; pancreas; proteostasis
    DOI:  https://doi.org/10.1016/j.devcel.2025.07.016
  33. Nat Commun. 2025 Aug 14. 16(1): 7570
    Dysregulation of GTPase-activating protein-binding protein1 in the pathogenesis of metabolic dysfunction-associated steatotic liver disease.
    Qinqin Ouyang, Jiaqi Su, Yixuan Li, Haiping Liao, Haiying Guo, Yanan Sun, Xiaoyu Wang, Juan Chen, Josephine Thinwa, Wen-Xing Ding, Herbert Tilg, Fazheng Ren, Hao Zhang, Rong Liu.
      Metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) are two common liver disorders characterized by abnormal lipid accumulation. Our study found reduced levels of GTPase-activating protein-binding protein1 (G3BP1) in patients with MASLD and MASH, suggesting its involvement in these liver disorders. Hepatocyte-specific G3BP1 knockout (G3BP1 HKO) male mice had more severe MASLD and MASH than their corresponding controls. Intriguingly, the G3BP1 HKO MASLD model male mice exhibit dysregulated autophagy, and biochemical analyses demonstrated that G3BP1 promotes autophagosome-lysosome fusion through direct interactions with the SNARE proteins STX17 and VAMP8. We also show that hepatic knockout of G3BP1 promotes de novo lipogenesis, and ultimately found that G3BP1 is required for the nuclear translocation of the well-known liver-lipid-regulating transcription factor TFE3. Taken together, our results suggest that G3BP1 should be investigated as a potential target for developing medical interventions to treat MASLD and MASH.
    DOI:  https://doi.org/10.1038/s41467-025-63022-z
  34. Res Sq. 2025 Aug 06. pii: rs.3.rs-7189456. [Epub ahead of print]
    Genetic depletion of early autophagy protein ATG13 impairs mitochondrial energy metabolism, augments oxidative stress, induces the polarization of macrophages to M1 inflammatory mode, and compromises myelin integrity in skeletal muscle.
    Mubaraq A Toriola, Emma Timlin, Sarojini Bulbule, Amy Reyes, Omolola Mary Adedeji, C Gunnar Gottschalk, Animesh Barua, Leggy A Arnold, Avik Roy.
      M1 macrophage activation is crucial in chronic inflammatory diseases, yet its molecular mechanism is unclear. Our study shows that hemizygous deletion of early autophagy gene atg13 (Tg +/- ATG13) disrupts cellular autophagy, hinders mitochondrial oxidative metabolism, increases reactive oxygen species (ROS) in splenic macrophages, leading to its M1 polarization. Reduced macroautophagy markers WDFY3 and LC3, flow-cytometric analysis of M1/M2 markers (CD40, CD86, CD115, CD163, and CD206), deficit of oxygen metabolism evaluated by ROS-sensor dye DCFDA, and seahorse oxygen consumption studie s rev ealed that atg13 gene ablation impairs mitochondrial function triggering M1 polarization. Additionally, redox imbalance may impair Sirtuin-1 activity via nitrosylation, increasing the level of acetylated p65 in macrophages contributing to the inflammatory response in M1Mφ. Additionally, the ablation of the atg13 gene resulted in the increased infiltration of M1Mφ in muscle vasculature, deterioration of myelin integrity in nerve bundles, and a reduction in muscle strength following treadmill exercise. These findings underscore the significance of ATG13 in post-exertional malaise (PEM).
    DOI:  https://doi.org/10.21203/rs.3.rs-7189456/v1
  35. Cell Rep. 2025 Aug 12. pii: S2211-1247(25)00901-5. [Epub ahead of print]44(8): 116130
    PARP7 inhibition stabilizes STAT1/STAT2 and relieves experimental autoimmune encephalomyelitis in mice.
    Jiashu Xu, Tao Yu, Zongwei Yue, Xuan Lu, Yandong Zhang, Lei Wang, Samaneh Shabani Åhrling, Michael R Smith, Yan Chun Li, Jason Matthews, Hening Lin.
      The regulation of type I interferon signaling is crucial for precisely tuning the innate immune response to combat pathogen invasions, fight cancer, and prevent autoimmune diseases. PARP7, a mono-ADP-ribosyltransferase also called TiPARP (tetrachlorodibenzo-p-dioxin [TCDD]-inducible PARP), is reported to inhibit the production of type I interferons. Here, we find that PARP7 suppresses type I interferon signaling instead of interferon production. PARP7 ADP-ribosylates and promotes the ubiquitination of signal transducer and activator of transcription 1 (STAT1) and STAT2, which recruits p62 to promote the degradation of STAT1 and STAT2 through autophagy. By reducing STAT1 and STAT2 levels, PARP7 decreases type I interferon signaling. We further show that the inhibition of PARP7 promotes type I interferon signaling and relieves experimental autoimmune encephalomyelitis (EAE) symptoms in mice. Our findings revealed a molecular mechanism via which PARP7 suppresses type I interferon signaling, offering insights into the immune-modulatory function of PARP7 and suggesting PARP7 inhibition as a potential treatment strategy for multiple sclerosis.
    Keywords:  ADP-ribosylation; CP: Molecular biology; CP: Neuroscience; EAE; PARP7; STAT1; STAT2; TiPARP; autophagy; multiple sclerosis; type I interferon signaling; ubiquitination
    DOI:  https://doi.org/10.1016/j.celrep.2025.116130
  36. Brain Dev. 2025 Aug 08. pii: S0387-7604(25)00081-6. [Epub ahead of print]47(5): 104399
    Gene therapy for lysosomal storage diseases.
    Hiroshi Kobayashi.
      Lysosomal storage diseases (LSDs) are metabolic disorders caused by the dysfunction of enzymes and other substances localized in lysosomes, known as intracellular organelles. There are many types of LSDs, with a wide range of clinical manifestations. LSDs are highly amenable to gene therapy due to various reasons, including the fact that they are essentially monogenic diseases and existence of cross-correction mechanisms. The only gene therapy product currently approved for lysosomal diseases is one for metachromatic leukodystrophy, but several have progressed to phase III clinical trials such as the products for Mucopolysaccharidosis or Fabry disease. However, serious adverse events have been reported even with gene therapy methods that have been considered safe. Therefore, research on the safety of gene therapy is becoming increasingly important.
    Keywords:  Cross-correction; Enzyme replacement therapy; Ex vivo gene therapy; Hematopoietic stem cell transplantation; In vivo gene therapy; Lysosomal storage diseases
    DOI:  https://doi.org/10.1016/j.braindev.2025.104399
  37. Biogerontology. 2025 Aug 12. 26(5): 159
    Endogenous and exogenous viral reactivation as a driver of epigenetic drift and mitophagy failure in aging.
    Evgeniia Bakaleinikova.
      Aging is increasingly understood as a multifactorial process involving mitochondrial dysfunction, epigenetic drift, and chronic inflammation. While many age-related pathologies have been linked to impaired mitophagy and transcriptional deregulation, the upstream mechanisms driving these phenomena remain elusive. Here, a unifying hypothesis is proposed: that the progressive reactivation of human endogenous retroviruses (HERVs), combined with latent viral infections acquired during life, imposes an escalating burden on the epigenetic regulatory system. This "virome pressure" demands continuous silencing via DNA methylation, histone deacetylation, and NAD⁺-dependent pathways. With age, these silencing mechanisms deteriorate, leading to HERV reactivation, disruption of key mitochondrial quality control genes, and activation of innate immune responses. This is likened to a molecular peat bog, a simmering threat buried beneath the surface, where silencing mechanisms struggle to contain viral elements until pressure builds and erupts as the organism ages. This model integrates virology, epigenetics, and mitochondrial biology to offer novel insights into the aging process and suggests new targets for therapeutic intervention research.
    Keywords:  Aging; Epigenetic drift; Human endogenous retroviruses (HERVs); Mitochondrial dysfunction; Viral reactivation
    DOI:  https://doi.org/10.1007/s10522-025-10286-z
  38. Curr Opin Cell Biol. 2025 Aug 09. pii: S0955-0674(25)00109-7. [Epub ahead of print]96 102571
    Mechanisms of cellular fitness and cell competition: Towards an integrated view.
    Jules Lavalou, Karyna Kulakova, Yogaspoorthi J Subramaniam, Eugenia Piddini.
      Cell competition is a fundamental mechanism of tissue quality control that enables the selective elimination of less fit, mis-specified, diseased or aged cells. By shaping tissue composition, it plays a critical role in development, organismal health and a wide range of physiological and pathological contexts, including cancer. As its biological significance continues to grow, elucidating the molecular mechanisms underlying cell competition is essential for advancing our understanding of tissue biology, disease progression and future therapeutic strategies. In this review, we highlight recently identified, evolutionarily conserved pathways that govern cell competition through metabolites and systemic signals, proteostasis and mechanical exchange. By integrating findings across species and pathways, we reveal how these distinct mechanisms may intersect and coordinate to determine competitive outcomes, providing a conceptual framework to inform and guide future research.
    DOI:  https://doi.org/10.1016/j.ceb.2025.102571
  39. Sci Adv. 2025 Aug 15. 11(33): eadv6902
    USP30 inhibition augments mitophagy to prevent T cell exhaustion.
    Ruohan Zhang, Fengxia Gao, Jianying Li, Jiacheng Jin, Kangxuan Chen, Samhita Chaudhuri, Zhiwei Liao, Tong Xiao, Yang Xu, Haitao Wen, Kai He, Zihai Li, Gang Xin, Nuo Sun.
      The exhaustion of tumor-infiltrating CD8+ T cells poses a substantial challenge in cancer immunotherapy, with mitochondrial health essential for sustaining T cell functionality. Mitophagy, a critical process for mitochondrial quality control, is severely impaired in exhausted CD8+ T cells, yet the underlying mechanisms remain unclear. We identified ubiquitin-specific protease 30 (USP30), a mitochondrial deubiquitinase that inhibits mitophagy, as a key factor up-regulated in exhausted CD8+ T cells. Notably, prolonged antigen stimulation triggers the T cell receptor and nuclear factor of activated T cell 1 signaling, which drives the transcriptional up-regulation of USP30. Excitingly, our interventions targeting USP30 through genetic deletion or pharmacological inhibition effectively restored mitophagy, improved mitochondrial fitness, and rejuvenated CD8+ T cell effector functions. These interventions reinvigorated antitumor responses and markedly suppressed tumor growth. Our findings establish USP30 as a critical regulator of mitophagy and a promising therapeutic target for reversing T cell exhaustion and enhancing the efficacy of cancer immunotherapy.
    DOI:  https://doi.org/10.1126/sciadv.adv6902
  40. J Invest Dermatol. 2025 Aug 12. pii: S0022-202X(25)02333-4. [Epub ahead of print]
    Skin Epidermal Progenitor Maintenance by the SRCAP-H2A.Z axis Downstream to ERK and mTOR Signaling.
    Stephenie H Droll, Celia Xue, Elena Dewar, Nicholas Chamberlain, Benny J Zhang, Max C Levine, Xiaomin Bao.
      Epidermal progenitor function is crucial for supporting continuous skin epidermal renewal. How progenitors assimilate inputs from their niche to sustain their function is incompletely defined. In this study, we examine the role of the histone H2A variant, H2A.Z, and the ATP-dependent chromatin remodeling complexes which regulate its occupancy. We show that H2A.Z expression and chromatin occupancy are significantly diminished during keratinocyte differentiation. Although two chromatin remodelers are known to deposit H2A.Z, we find that SRCAP is essential for H2A.Z deposition in epidermal progenitors while EP400 is dispensable. Both H2A.Z isoforms, H2AZ1 and H2AZ2, are essential for progenitor proliferation as knockdown of either isoform induces DNA damage and deforms nuclear morphology. Although H2A.Z is greatly reduced in differentiation, we find that the residual H2A.Z and SRCAP continue to maintain the nuclear integrity of differentiating keratinocytes. Since growth-factor induced signaling pathways play pivotal regulatory roles in progenitor maintenance and differentiation, we performed a targeted inhibitor screen to determine if these pathways might influence H2A.Z. Inhibition of ERK or mTOR signaling significantly reduces H2A.Z chromatin occupancy and leads to deformed nuclear morphology. This study provides an example of how signaling inputs are linked to chromatin remodeling, supporting epidermal progenitor maintenance.
    DOI:  https://doi.org/10.1016/j.jid.2025.07.022
  41. Development. 2025 Aug 11. pii: dev.204612. [Epub ahead of print]
    TOR signalling mediates the collective movement of Border cells in Drosophila oogenesis.
    Sudipta Halder, Adhisree Sharma, Sayan Acharjee, Neha Biju, Mincy Kunjumon, Rohan Jayant Khadilkar, Mohit Prasad.
      Collective cell migration is seen in various biological processes spanning embryonic development, organogenesis, wound healing and, unfortunately, cancer metastasis. Here, we have examined the role of the evolutionary conserved Target of Rapamycin signalling (TOR) in mediating collective cell movement employing the model of migrating BCs in Drosophila oogenesis. Though TOR signalling is classically linked to cell growth, cell proliferation and metabolism, here we demonstrate TOR Complex1 (TORC1) regulates efficient group cell movement of BCs. Employing live cell imaging, genetics, and tissue immunohistochemistry, we demonstrate TOR functions through transcription factor Reptor to modulate the Death-associated inhibitor of apoptosis 1 (DIAP1) in mediating efficient movement of BCs. Coincidentally, Rapamycin-treated myeloblast Kasumi-1 cells exhibit lower levels of transcript for DIAP-1 homolog, Baculoviral IAP repeat-containing 2 (BIRC2), similar to what is observed in flies.
    Keywords:   Drosophila oogenesis; BC migration; BIRC2; Collective cell movement; DIAP1; REPTOR; TOR signalling
    DOI:  https://doi.org/10.1242/dev.204612
  42. Int J Mol Sci. 2025 Aug 06. pii: 7625. [Epub ahead of print]26(15):
    Polysialylation of Glioblastoma Cells Is Regulated by Autophagy Under Nutrient Deprivation.
    Sofia Scibetta, Giuseppe Pepe, Marco Iuliano, Alessia Iaiza, Elisabetta Palazzo, Marika Quadri, Thomas J Boltje, Francesco Fazi, Vincenzo Petrozza, Sabrina Di Bartolomeo, Alba Di Pardo, Antonella Calogero, Giorgio Mangino, Vittorio Maglione, Paolo Rosa.
      Glioblastoma (GBM) is a highly aggressive brain tumor marked by invasive growth and therapy resistance. Tumor cells adapt to hostile conditions, such as hypoxia and nutrient deprivation, by activating survival mechanisms including autophagy and metabolic reprogramming. Among GBM-associated changes, hypersialylation, particularly, the aberrant expression of polysialic acid (PSA), has been linked to increased plasticity, motility, and immune evasion. PSA, a long α2,8-linked sialic acid polymer typically attached to the NCAM, is abundant in the embryonic brain and re-expressed in cancers, correlating with poor prognosis. Here, we investigated how PSA expression was regulated in GBM cells under nutrient-limiting conditions. Serum starvation induced a marked increase in PSA-NCAM, driven by upregulation of the polysialyltransferase ST8SiaIV and an autophagy-dependent recycling of sialic acids from degraded glycoproteins. Inhibition of autophagy or sialidases impaired PSA induction, and PSA regulation appeared dependent on p53 function. Immunohistochemical analysis of GBM tissues revealed co-localization of PSA and LC3, particularly around necrotic regions. In conclusion, we identified a novel mechanism by which GBM cells sustain PSA-NCAM expression via autophagy-mediated sialic acid recycling under nutrient stress. This pathway may enhance cell migration, immune escape, and stem-like properties, offering a potential therapeutic target in GBM.
    Keywords:  autophagy; glioblastoma; nutrient deprivation; polysialic acid; tumor microenvironment
    DOI:  https://doi.org/10.3390/ijms26157625
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