bims-auttor Biomed News
on Autophagy and mTOR
Issue of 2026–06–28
sixty-two papers selected by
Viktor Korolchuk, Newcastle University
  1. Small bites for big problems: stepwise aggregate degradation by autophagy.
  2. Stage- and compartment-specific remodeling of autophagy and selective mitophagy in glaucoma: from aqueous outflow dysfunction to retinal ganglion cell neurodegeneration.
  3. Efficient pharmacological modulation of autophagy in isolated muscle fibers: impact on excitation-contraction coupling.
  4. Mitophagy mitigates tau acetylation via the ULK1-NAD+/SIRT1 axis in Alzheimer's disease.
  5. BCAS-3 is required for the progression of autophagosome formation to degrade paternal mitochondria in Caenorhabditis elegans.
  6. Lipid transfer protein ORP3 mediates lysosomal repair via LC3B and ubiquitin-TAK1-p38 signaling.
  7. mTOR Substrate Phosphorylation in Growth Control: An Update.
  8. Regulatory mechanisms of post-translational modifications on autophagic flux in neurons following ischemic stroke.
  9. Robust and sensitive ELISA detection of total and activated PRKN.
  10. PIKfyve influences inter-organelle contacts with lysosomes to modulate the endoplasmic reticulum.
  11. The irisin-PINK1/Parkin axis plays an essential role in mediating microglial mitophagy: A crucial mechanism for exercise-induced neuroprotection against Parkinson's disease.
  12. The Dual Roles of Autophagy in Important Picornaviruses Infecting Livestock and Poultry.
  13. RRAGD p.(Ser76Leu) Variant Causes Dysregulated Expression of Muscle Development and Cytoskeleton Genes in Cardiomyocytes.
  14. Cell Death by Holocrine Secretion: The Final Step of Epithelial Differentiation in Sebaceous Glands.
  15. YIF1A activates mTORC1 signaling to promote cellular senescence.
  16. mTORC2-Nav1.2 signaling drives early hyperexcitability in Alzheimer's disease mouse model.
  17. PINK1 loss in astrocytes triggers inflammatory dysfunction and neuronal death.
  18. mRAVE governs lysosomal catabolism through basal and mTORC1-regulated V-ATPase assembly.
  19. Physical exercise as a precision strategy for targeted PINK1 recruitment- a mechanistic review.
  20. Lysosomal ion homeostasis drives delayed hair cell death after aminoglycoside uptake.
  21. Omipalisib reduces hyperphosphorylated tau protein by modulating mTOR-autophagy pathway.
  22. Diacylglycerol kinase ζ in B lymphocytes supports CD40-mediated immune synapse formation, mTORC1 signaling, and plasma cell fate.
  23. Comparative Genomics Reveals Recurrent Loss of Autophagy-Related 9B (ATG9B) in Amniotes.
  24. Sensing centrosome amplification: the interface between centriole duplication and autophagy.
  25. Deciphering the Neuroautophagic Interactome: Molecular Circuits Linking Selective Autophagy to Neuropathological Cascades in Neurological Disorders.
  26. Structural Mechanism and Cellular Restriction of Tau Seeding from Endolysosomes.
  27. Diverse Forms of Autophagy and Their Roles in Liver Disease and Aging: A Comprehensive Review.
  28. TORC1 inactivation induces a noncanonical, separase-independent cohesin degradation.
  29. Ketone-Dependent Restoration of Autophagy and Mitochondrial Quality Control Through VPS35 in a Drosophila Model of C99-Induced Neurodegeneration.
  30. The Role of ATG8 in Promoting Lipid Accumulation in the Oleaginous Fungus Mucor circinelloides During Nitrogen Limitation.
  31. Regulation of Innate Immune Signaling by Autophagy.
  32. Molecular diversity of mitochondrial autophagy receptors: context-dependent effects in human health and disease.
  33. miRNA family miR-29 inhibits PINK1-PRKN signaling via ATG9A.
  34. Biallelic ATG9B Variants Define a Novel Autophagy-Related Neurodevelopmental Disorder with Cerebellar Ataxia.
  35. Reversible suppression of autophagy in a mouse model reveals neuronal resilience.
  36. CRISPR screen identifies autophagy inhibition (GNS561) as a PARP inhibitor (AZD5305) combination strategy in small cell lung cancer.
  37. Aminochrome-Induced Disruption of Autophagosome-Lysosome Fusion: Implications for Protein Aggregation in Parkinson's Disease.
  38. Cordycepin attenuates diabetic nephropathy by dual-pathway activation of TFEB to restore autophagy and ameliorate podocyte injury.
  39. GPR107 promotes autophagy secretion in psoriatic keratinocytes by inhibiting BECN1 K48-linked ubiquitination.
  40. RNASET2 degrades mRNAs that protect against lipotoxicity.
  41. Myofibroblast- specific autophagy drives cyst growth in autosomal dominant polycystic kidney disease.
  42. STING Modulating ER-Phagy in the Prelimbic Cortex Neurons Contributed to Neuropathic Pain and Emotional Comorbidity.
  43. IRE1 regulates the proteostasis of TDP-43/TARDBP in ALS/FTD through ribosome-associated quality control.
  44. Mitochondrial quality control in health and disease: Updates 2026.
  45. Spermidine in Alzheimer's Disease: Evidence from Animal Models and Human Studies.
  46. Research Progress and Prospects of Flavonoids in the Treatment of Diseases by Regulating Autophagy: A Narrative Review.
  47. VMA21 deficiency leads to autophagic dysregulation and altered vesicle trafficking in X-linked myopathy with excessive autophagy.
  48. RBM15 promotes hyperglycemia-induced retinal endothelial cell injury by regulating FOXO3 stability via m6A modification.
  49. Organelle-directed metabolic glycan labeling.
  50. Characterization of the lysosomal arginine transporter SLC7A14.
  51. Mitochondrial degradation of metallothionein enables local zinc mobilization during zinc limitation.
  52. RBM12 Maintains Glioma Stem Cells by Activating Amino Acid-Dependent mTORC1 Signaling via SLC7A5 mRNA Stabilization.
  53. Karyoptosis mediates cell death and neurodegeneration upon proteotoxic stress.
  54. Dietary cholesterol activates a Ral-dependent pathway driving LDLR turnover.
  55. EGR1 mediates neuronal damage via suppressing HIF1A-induced mitophagy following traumatic brain injury.
  56. Emodin induces defensive autophagy against white spot syndrome virus infection via targeting the hemocyanin-mediated endoplasmic reticulum-mitochondrial crosstalk in shrimp.
  57. The p97 adaptor p47/NSFL1C is necessary for stress granule dissolution after heat stress.
  58. Hypoxia-induced MIC19 myristoylation promotes PRKN-dependent VDAC2 ubiquitination and activates mitophagy in non-small cell lung cancer.
  59. The ALS- and FTD-associated proteins annexin A11 and CHMP2B act sequentially in plasma membrane repair.
  60. AOC1 regulates labor initiation through spermidine-induced autophagy of placental trophoblast cells via EIF5A hypusination.
  61. TMEM184A-mediated autophagy in MHC-I degradation promotes tumor immune evasion.
  62. Metabolism, autophagy, and cell death: The triangular axis in tumor survival and therapeutic resistance.
  1. Biochem Soc Trans. 2026 Jun 24. 54(6): 803-814
    Small bites for big problems: stepwise aggregate degradation by autophagy.
    Mark S Hipp, Mario Mauthe.
      Protein aggregates are a pathological hallmark of diverse disorders, including many neurodegenerative diseases, but also cardiometabolic disease and cancer. While the ubiquitin-proteasome system efficiently removes many soluble misfolded proteins, large or persistent assemblies often require the autophagy-lysosome pathway for their degradation. In the present mini-review, we summarize our knowledge of aggrephagy, the selective clearance of protein aggregates by autophagy, and discuss two recent manuscripts that argue that some aggregates must be primed for autophagosomal degradation, through chaperone-mediated remodeling. Aggrephagy substrates are defined by aggregate architecture, biophysical state, surface accessibility, and the physical constraints of membrane capture. These features help to explain why recruitment of selective autophagy receptors is necessary yet insufficient for clearance. Receptor clustering is required to concentrate early autophagy factors to establish initiation hubs, but successful degradation often requires upstream generation of smaller 'aggrephagy-competent' cargo units, which contain autophagy receptor clusters that successfully initiate autophagosome formation. Recent work supports a model in which larger aggregates are cleared through stepwise degradation enabled by prior remodeling steps that involve p97/VCP-driven disintegration or a chaperone module (DNAJB6-HSP70-HSP110) cooperating with the proteasomal 19S regulatory particle.
    Keywords:  autophagy; cellular protein quality control; molecular chaperones; piecemeal; selective autophagy receptors
    DOI:  https://doi.org/10.1042/BST20250460
  2. Front Cell Dev Biol. 2026 ;14 1842496
    Stage- and compartment-specific remodeling of autophagy and selective mitophagy in glaucoma: from aqueous outflow dysfunction to retinal ganglion cell neurodegeneration.
    Pai Zhou, Ying Deng, Yasha Zhou, Jing Lu, Qinghua Peng, Yijing Yang.
       Background: Glaucoma is a leading cause of irreversible blindness and is increasingly understood as a chronic neurodegenerative disorder rather than a disease explained solely by elevated intraocular pressure (IOP). Although IOP lowering remains the cornerstone of treatment, many patients continue to progress despite apparently adequate pressure control, indicating that additional mechanisms shape retinal ganglion cell (RGC) vulnerability and disease course. Among these, autophagy and mitophagy have emerged as central regulators of cellular stress adaptation in both anterior and posterior ocular tissues.
    Main Body: This review argues that glaucoma can be more coherently interpreted through a stage- and compartment-specific framework of autophagy and selective mitophagy. In the conventional outflow pathway, autophagy contributes to mechanoadaptation, proteostasis, and extracellular matrix homeostasis, whereas chronic oxidative and biomechanical stress may impair lysosomal function and autophagic flux, thereby promoting outflow dysfunction and ocular hypertension. In the posterior segment, RGCs and their axons are highly dependent on autophagy for proteostasis and mitochondrial quality control because of their polarized morphology and substantial metabolic demand. Experimental work suggests that autophagy may be protective during early or acute stress but become insufficient, stalled, or maladaptive during chronic injury. Recent human stem cell and animal studies further implicate optineurin-linked autophagic-lysosomal dysfunction, AMPK-mTORC1 imbalance, and reduced PINK1/Parkin-associated mitophagy as mechanistic nodes linking mitochondrial stress to RGC degeneration. These observations support a model in which glaucoma progression reflects not simply more or less autophagy, but failure to maintain effective quality control across distinct ocular compartments and disease stages.
    Conclusion: A compartment-aware and time-resolved view of autophagy and mitophagy offers a more nuanced framework for glaucoma pathogenesis and therapy. Future progress will likely depend less on indiscriminate pathway modulation than on restoring selective, flux-competent quality control, particularly mitochondrial turnover, in the appropriate tissue and at the appropriate stage of disease.
    Keywords:  autophagy; glaucoma; mitophagy; neurodegeneration; retinal ganglion cell; trabecular meshwork
    DOI:  https://doi.org/10.3389/fcell.2026.1842496
  3. Autophagy. 2026 Jun 25. 1-16
    Efficient pharmacological modulation of autophagy in isolated muscle fibers: impact on excitation-contraction coupling.
    Julie Gaillard, Céline Malleval, Camille Dauvois, Lina Gueloua, Jonathan Schreiber, Carole Kretz-Remy, Yann-Gaël Gangloff, Bruno Allard, Christine Berthier, Vincent Jacquemond.
      Macroautophagy/autophagy is a key regulator of muscle mass and of muscle adaptation to stress and defective autophagy is a feature of many muscle disorders. Still, how changes in autophagic flux influence the integrity and function of differentiated muscle fibers remains under-documented. Specifically, links between autophagy and mechanisms involved in Ca2+ homeostasis and excitation-contraction coupling are largely unexplored. We developed an assay to monitor autophagy modulation in mouse muscle fibers maintained in culture. Exposure to 3-methyladenine, an inhibitor of autophagy initiation, reduced the density of autophagic vesicles. Conversely, hydroxychloroquine, a blocker of autolysosome formation, as well as two MTOR inhibitors that activate autophagy, rapamycin and torin-1, enhanced the vesicle density. The density of lysosomal vesicles was increased by MTOR inhibitors and by hydroxychloroquine, but insensitive to 3-methyladenine. Measurements of Ca2+ signals associated with contractile activation revealed that voltage-activated sarcoplasmic reticulum Ca2+ release was unaffected by torin-1 but was depressed in 3-methyladenine- and in hydroxychloroquine-exposed fibers, suggesting that restraining autophagic flux is detrimental to excitation contraction coupling. The density of the inner plasma membrane network that carries the electrical excitation was depressed by 3-methyladenine and hydroxychloroquine, likely contributing to the function defect. Results establish that autophagic flux is preserved and can be manipulated in cultured muscle fibers, and revealed the power of the approach to tackle the cellular and subcellular consequences of autophagy modulation. They also uncover the possibility that autophagy is a determinant of maintenance and/or function of excitation-contraction coupling, with a potential role in several muscle disease situations.Abbreviations: 3-MA: 3-methyladenine; EC: excitation-contraction; HCQ: hydroxychloroquine; MTM1: myotubularin 1; RYR1: ryanodine receptor 1.
    Keywords:  3-methyladenine; rapamycin; ryanodine receptor; sarcoplasmic reticulum Ca2+ release; skeletal muscle; torin-1
    DOI:  https://doi.org/10.1080/15548627.2026.2693256
  4. Autophagy. 2026 Jun 21. 1-3
    Mitophagy mitigates tau acetylation via the ULK1-NAD+/SIRT1 axis in Alzheimer's disease.
    Jun-Ping Pan, Jianying Zhang, Ping-Jie Wang, Guobing Chen, Evandro Fei Fang.
      Autophagy preserves neuronal integrity by clearing damaged proteins and other subcellular components, yet it declines with age and exacerbates in Alzheimer's disease (AD). Although autophagy reduces tauopathy, whether it can proactively restrict early tau pathology via post-translational modifications (PTMs) has remained unclear. In a recent paper, we have identified a mitophagy-based metabolic signaling mechanism linking the autophagy-initiating kinase Unc-51-like autophagy activating kinase 1 (ULK1) to the inhibition of pathogenic tau acetylation via the ULK1-NAD+/SIRT1 axis. Analyses of human biofluidic to postmortem and transcriptomic data reveal an age-associated decline of ULK1; this situation gets worse in AD with the extent of ULK1 reduction positively correlates with Tau-based Braak stage progression, consistent with a bidirectional vicious cycle in which pathological tau disrupts mitochondrial homeostasis and impairs autophagy. Restoring ULK1-dependent mitophagy breaks this cycle in the upstream: in the hTau.P301S mice, ULK1 overexpression reduces ac‑tauK174 leading to reduced tau pathology and improved cognition. Mechanistically, ULK1 activates PINK1- and FUNDC1- as well as AMBRA1-dependent mitophagy to eliminate damaged mitochondria, restore bioenergetics, and elevate intracellular NAD+, which activates the deacetylase SIRT1 to directly deacetylate tau at Lys174. Pharmacological ULK1 activation with a small molecule Rac‑BL‑918 phenocopies these protective effects in a mitophagy- and SIRT1-dependent manner. Collectively, our recent findings position mitophagy as a metabolic signaling hub that couples mitochondrial turnover to NAD+/SIRT1 activity to shape neuronal tau PTMs, supporting ULK1-mitophagy activation as an upstream strategy to limit tauopathy before overt aggregation.
    Keywords:  Ac‑tauK174; Mitophagy; NAD+; SIRT1; ULK1
    DOI:  https://doi.org/10.1080/15548627.2026.2689031
  5. iScience. 2026 Jul 17. 29(7): 116345
    BCAS-3 is required for the progression of autophagosome formation to degrade paternal mitochondria in Caenorhabditis elegans.
    Takuya Norizuki, Taeko Sasaki, Yuji Suehiro, Shohei Mitani, Waka Kojima, Koji Yamano, Noriyuki Matsuda, Miyuki Sato.
      In the nematode Caenorhabditis elegans, autophagy degrades paternal mitochondria after fertilization to ensure the maternal inheritance of mitochondrial DNA. We previously showed that the autophagy adaptor ALLO-1 is first targeted to paternal mitochondria and then recruits the autophagy machinery. However, the mechanisms underlying local autophagosome formation remain unclear. Here, our forward genetic screen identified a WD40 repeat domain-containing protein, BCAS-3, and its interactor, PHAF-1, as essential factors for paternal mitochondrial degradation. After fertilization, BCAS-3 and PHAF-1 are recruited to the paternal mitochondria, and the loss of these genes impairs the progression of autophagosome formation. We further show that BCAS-3 recruitment is regulated downstream of the WD40 repeat domain-containing core autophagy proteins, ATG-18 and EPG-6, but BCAS-3 also contributes to further ATG-18 accumulation around paternal mitochondria. These findings suggest that the interplay between BCAS-3 and ATG-18 underlies the progression of autophagosome formation during paternal mitochondrial degradation.
    Keywords:  cell biology; developmental biology; molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2026.116345
  6. bioRxiv. 2026 Jun 10. pii: 2026.06.09.731146. [Epub ahead of print]
    Lipid transfer protein ORP3 mediates lysosomal repair via LC3B and ubiquitin-TAK1-p38 signaling.
    Christopher J Bott, Martyna O Iwaniek, James E Casanova.
      Lysosomal membrane damage triggers a multi-stage repair response essential for cellular homeostasis. Here we identify the oxysterol-binding protein-related protein ORP3 as a critical mediator of late-stage lysosomal membrane repair. Following lysosomal damage induced by L-leucine-leucine methyl ester (LLOME) or cationic amphiphilic drugs (CADs), ORP3 is phosphorylated and recruited to ER-lysophagosome contact sites via a signaling cascade initiated by lysosomal membrane ubiquitination, TAK1, p38 MAPK, and, to a lesser extent, IKK. p38-dependent phosphorylation promotes direct interaction between ORP3 and LC3B, which together with PI(4,5)P₂ binding, is required for autophagic lysosome recruitment. ORP3 depletion impairs late-stage lysosomal recovery, elevates lysosomal lipid peroxidation, and reduces cell survival. A lipid transfer-deficient ORP3 mutant fails to restore lysosome function despite normal recruitment, indicating that ER-to-lysophagosome transfer of phosphatidylcholine by ORP3 is functionally required. ORP3 activity is subsequently terminated by VCP/p97-mediated deubiquitination of lysosomes. These findings define ORP3 as a MAPK regulated lipid transfer protein during the late autophagic phase of the endolysosomal damage response.
    Summary: Lysosomal membrane damage triggers ubiquitination that activates a TAK1-p38 signaling cascade, phosphorylating the lipid transfer protein ORP3 and recruiting it to damaged lysosomes via LC3B interaction. ORP3-mediated phosphatidylcholine transfer from the ER is essential for late-stage lysosomal repair and cell survival.
    Abstract Figure:
    DOI:  https://doi.org/10.64898/2026.06.09.731146
  7. Cancers (Basel). 2026 Jun 15. pii: 1944. [Epub ahead of print]18(12):
    mTOR Substrate Phosphorylation in Growth Control: An Update.
    Don Benjamin, Michael N Hall.
      Background: The mechanistic target of rapamycin (mTOR) is a highly conserved serine/threonine protein kinase that integrates inputs on nutrient status, energy levels, and growth factor stimulation to accordingly regulate cell growth and metabolism. It does this by activating or repressing target proteins covering a broad array of cellular processes. mTOR nucleates two structurally and functionally distinct protein complexes, mTORC1 and mTORC2. Because of their wide-ranging effects in the cell, both mTOR complexes are presumed to have a large number of targets. However, only a relatively small number have been conclusively identified. Methods: With emphasis on mammalian mTOR, we previously reviewed the extensive mTOR literature (1991-2021) and compiled a list of all reported substrates of mTORC1 and mTORC2. We have updated this list for the period 2022-2025. Results/Conclusions: Many of the targets are involved in autophagy, underscoring the major role of mTOR in the regulation of this process. From the perspective of this Special Issue, targets linked to cancer may be responsible for executing an mTOR-driven pro-oncogenic program and merit future study.
    Keywords:  autophagy; cancer; cell signaling; mTOR; metabolism; phosphorylation
    DOI:  https://doi.org/10.3390/cancers18121944
  8. Mol Biol Rep. 2026 Jun 23. pii: 975. [Epub ahead of print]53(1):
    Regulatory mechanisms of post-translational modifications on autophagic flux in neurons following ischemic stroke.
    Liling Yu, Wenting Zhuang, Xiong Liu, Hongqiong He, Yihao Deng, Hongyun He.
      Ischemic stroke, a serious disease that threatens to human health, is caused by insufficient blood supply due to cerebrovascular occlusion, leading to severe brain damage and neurological deficits. Numerous investigations have revealed that autophagy is extensively involved in the pathophysiological processes of ischemic stroke. Autophagy is a vital mechanism to maintain neuronal homeostasis by degradation and recycling of cytoplasmic components. It comprises a series of consecutive processes, including autophagy initiation, autophagosome formation, fusion of autophagosomes with lysosomes, and degradation of autophagic substrates within autolysosomes. Thus, autophagy is termed as autophagic flux, as well as autophagic/lysosomal signaling pathway. Several key steps in autophagic signaling pathway are prominently regulated by post-translational modifications, thereby significantly affecting neurological outcomes after ischemic stroke. However, how the post-translational modifications regulate autophagic flux to mitigate ischemic neuronal injury remains to be systematically expounded. To provide insights into the researches on the pathogenesis and neuroprotection of ischemic stroke, this article is to summarize the post-translational modifications involved in autophagic/lysosomal signaling pathway in neurons after ischemic stroke, especially highlighting the effects of acetylation and phosphorylation on post-stroke pathophysiological processes.
    Keywords:  Autophagy; Ischemic stroke; Neuron; Post-translational modification
    DOI:  https://doi.org/10.1007/s11033-026-12177-z
  9. Autophagy. 2026 Jun 24.
    Robust and sensitive ELISA detection of total and activated PRKN.
    Jens O Watzlawik, Bernardo A Bustillos, Claudia Rodriguez Martinez, Dennis W Dickson, Zbigniew K Wszolek, Owen A Ross, Wolfdieter Springer, Fabienne C Fiesel.
      Parkinson disease (PD) is closely linked to disruptions in mitochondrial quality control, a process regulated by the ubiquitin kinase PINK1 and the E3 ubiquitin ligase PRKN/parkin. Upon mitochondrial damage, PINK1 phosphorylates ubiquitin, which in turn recruits and activates PRKN. Full activation of PRKN is mediated by PINK1-dependent phosphorylation of PRKN at serine 65, which leads to widespread ubiquitination of mitochondrial substrates and amplifies the mitophagy response. Disruption of this pathway results in mitochondrial accumulation, oxidative stress, and neuronal death, all key mechanisms of PD pathogenesis. Genetic studies have shown biallelic loss-of-function mutations in PRKN are the most common cause of early-onset PD. Although the role of haploinsufficiency remains under investigation, PRKN protein becomes insoluble and inactive with aging or post-translational modifications, indicating that functional protein levels are a key determinant of disease risk. Reliable quantification of total and activated PRKN in samples has not been feasible, limiting research and clinical assessment. To address this, we developed and validated knockout (KO)-verified sandwich ELISA assays that quantify both total PRKN and PINK1-phosphorylated p-S65-PRKN. These assays provide absolute quantification of PRKN, improving functional diagnosis, and patient stratification in PD. Application of these methods established the concentration of PRKN in cells and in brain and revealed significant effects of a common genetic PRKN variant, further highlighting the importance of determining functional PRKN protein levels. The developed immunoassays complement previously established PINK1 and p-S65-Ub measurements, enhancing mechanistic insight into mitophagy and enabling effective monitoring of PD therapies and other neurodegenerative diseases.
    Keywords:  Autophagy; P-S65-PRKN; PARK2; PINK1; biomarker; mitochondria; mitophagy; parkin; parkinson disease; ubiquitin
    DOI:  https://doi.org/10.1080/15548627.2026.2694658
  10. J Cell Biol. 2026 Sep 07. pii: e202507087. [Epub ahead of print]225(9):
    PIKfyve influences inter-organelle contacts with lysosomes to modulate the endoplasmic reticulum.
    Nicala Jenkins, Zainab Adamji, Maria R Narciso, Nourhan R Almasri, Sharifa Lomiyev, Roberto J Botelho.
      Lysosomes clear unwanted cellular material delivered by constant membrane fusion. Membrane fission is thus required to balance lysosome size, number, and composition. PIKfyve is a lipid kinase that converts phosphatidylinositol-3-phosphate [PtdIns(3)P] to phosphatidylinositol-3,5-bisphosphate [PtdIns(3,5)P2] and promotes lysosome fission since lysosomes coalesce into larger, but fewer, organelles in its absence. Here, we reveal a role for PIKfyve in regulating ER dynamics. We show the ER is less reticulated and motile in cells inhibited for PIKfyve. Partly, this arises because lysosomes cluster perinuclearly and are less motile, which appears to arrest ER hitchhiking, a process in which lysosomes pull and form ER tubules. Secondly, the ER morphology is distorted because of hyper-tethering of protrudin, an ER transmembrane protein, to lysosomes via excess PtdIns(3)P and protrudin's FYVE domain. Our findings reveal that PIKfyve balances phosphoinositides at ER-lysosome contact sites to govern ER properties and have significant implications for our understanding of PIKfyve function and of diseases linked to its dysfunction.
    DOI:  https://doi.org/10.1083/jcb.202507087
  11. Biochim Biophys Acta Mol Basis Dis. 2026 Jun 24. pii: S0925-4439(26)00198-5. [Epub ahead of print] 168335
    The irisin-PINK1/Parkin axis plays an essential role in mediating microglial mitophagy: A crucial mechanism for exercise-induced neuroprotection against Parkinson's disease.
    Bin Wang, Xin Liu, Xin Tian, Junjie Lin, Qian Li, Yue Wu, Renqing Zhao.
      The progression of Parkinson's disease (PD) is primarily driven by chronic neuroinflammation in microglia and impaired mitochondrial quality control. Here, we show that 10 weeks of treadmill running ameliorates motor deficits, dopaminergic neuron loss, and α-synuclein (α-syn) pathology in MPTP-induced PD mice. Exercise enhances PINK1/Parkin-dependent mitophagy in microglia, evidenced by increased LC3/Iba1 colocalization, p62 clearance, and direct LC3/Tom20 colocalization, thereby suppressing proinflammatory activation. These effects are mediated by exercise-induced upregulation of FNDC5/irisin. In vitro, recombinant irisin rescues impaired mitophagy and alleviates neuroinflammation in α-syn-exposed microglia. Crucially, pharmacological blockade of irisin receptors with RGDyk abolishes exercise-induced neuroprotection, mitophagy restoration, and behavioral improvements. Our findings reveal: (1) Exercise alleviates PD pathology by enhancing mitochondrial autophagy to reprogram microglial function; (2) Irisin is a key myokine activating microglial mitochondrial autophagy via the PINK1/Parkin pathway; (3) The irisin-mitochondrial autophagy axis represents a novel and promising therapeutic target for PD. This work provides the first evidence that exercise-induced irisin directly regulates microglial mitochondrial homeostasis, establishing a mechanistic basis for exercise-based PD interventions.
    Keywords:  Exercise; Irisin; Microglial mitophagy; Neuroinflammation; Parkinson's disease
    DOI:  https://doi.org/10.1016/j.bbadis.2026.168335
  12. Vet Sci. 2026 Jun 09. pii: 567. [Epub ahead of print]13(6):
    The Dual Roles of Autophagy in Important Picornaviruses Infecting Livestock and Poultry.
    Haibin Ma, Rongchang Liu, Ming Liao.
      Autophagy is a conserved catabolic process that degrades damaged proteins and organelles to preserve cellular homeostasis. Autophagy plays two opposing roles during viral infection. On the one hand, it can be subverted by viruses to facilitate replication and immune evasion. On the other hand, it limits viral infection by delivering viral components to lysosomes. The interaction between autophagy and important picornaviruses that infect cattle and poultry, such as SVV, EMCV, FMDV, and DHAV, is the main topic of this paper. However, comprehensive summaries focusing specifically on livestock and poultry remain limited. We summarize current research showing that these viruses evade host protection by manipulating several steps of the autophagic pathway, from initiation to lysosomal fusion, to produce replication-favorable environments. Notably, by directing the breakdown of viral capsid proteins, specific autophagy receptors such as SQSTM1/p62, NDP52, and optineurin (OPTN) serve as antiviral effectors. In response, picornaviruses have developed proteolytic strategies to inactivate these receptors, such as SVV 3C-mediated cleavage of SQSTM1 and OPTN. Moreover, different immune evasion tactics are shown by virus-specific engagement of organelle-selective autophagy, such as ER-phagy (SVV) or mitophagy (DHAV). The development of broad-spectrum antiviral treatments and autophagy-based biomarkers for livestock disease progression may benefit from an understanding of the convergent and different ways picornaviruses take advantage of the autophagic machinery.
    Keywords:  immune evasion; livestock; picornaviruses; poultry; selective autophagy; viral receptors
    DOI:  https://doi.org/10.3390/vetsci13060567
  13. FASEB J. 2026 Jun 30. 40(12): e72070
    RRAGD p.(Ser76Leu) Variant Causes Dysregulated Expression of Muscle Development and Cytoskeleton Genes in Cardiomyocytes.
    Anastasia Adella, Sara B van Katwijk, Pieter A Leermakers, Willem B van Ham, Hesther de Ruiter, Judita Ilgutytė, Suzanne Hendrickx, Levi Nijland, Teun P de Boer, Eva van Rooij, Joost G J Hoenderop, Jeroen H F de Baaij.
      Autosomal dominant kidney hypomagnesemia with RRAGD variants (ADKH-RRAGD) is a hereditary disorder characterized by kidney tubulopathy and dilated cardiomyopathy (DCM). RagD, encoded by the RRAGD gene, is a small GTPase involved in activating the mechanistic target of rapamycin complex 1 (mTORC1) by amino acids. Although several gain-of-function variants in the RRAGD gene have been identified, their contributions to DCM remain unclear. Here, we hypothesize that these RRAGD variants induce mTORC1 overactivation, thereby contributing to the manifestation of DCM. To investigate this, we established T-REx HeLa cell lines that overexpress the RRAGD p.(Ser76Leu) or the wild-type (WT) variant to assess the effects on mTORC1 signaling. Additionally, we developed the first cellular model of ADKH-RRAGD utilizing genetically edited human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) that express the mutated variant. Our data indicate that the RRAGD p.(Ser76Leu) variant maintains the phosphorylation of mTORC1 targets (i.e., S6K, 4E-BP1, and TFEB) during amino acid starvation, in contrast to RRAGD WT in T-REx HeLa cells. The pharmacological inhibition of mTOR with Torin1 reversed these changes. In 2D-cultured RRAGDWT/p.(Ser76Leu) hiPSC-CMs, mTORC1 remained responsive to amino acid starvation. Results from bulk RNA sequencing showed an upregulation of pathways associated with cytoskeletal organization and a downregulation of muscle development in RRAGDWT/p.(Ser76Leu) hiPSC-CMs. Moreover, a prolonged duration of Ca2+ transients was observed in the mutant cardiomyocytes. Altogether, our data demonstrate that gain-of-function variants in RRAGD cause mTORC1 activation in T-REx HeLa cells. Consequently, cardiomyocytes develop impaired intracellular Ca2+ clearance and activation of transcriptional programs, suggesting dedifferentiation.
    Keywords:   RRAGD ; ADKH‐RRAGD; cardiomyocytes; dilated cardiomyopathy; mTORC1
    DOI:  https://doi.org/10.1096/fj.202501099RR
  14. Cells. 2026 Jun 10. pii: 1058. [Epub ahead of print]15(12):
    Cell Death by Holocrine Secretion: The Final Step of Epithelial Differentiation in Sebaceous Glands.
    Leopold Eckhart, Supawadee Sukseree, Heinz Fischer.
      Sebaceous glands consist of epithelial cells, known as sebocytes, that undergo differentiation to deliver the components of sebum into the sebaceous duct and eventually to the hair and skin surface. The final step of the terminal differentiation program is called holocrine secretion because the entire cell content is converted into sebum. Holocrine secretion is a mode of programmed cell death, which involves the degradation of the nucleus and other organelles and the rupture of the cell membrane. Here, we review the current knowledge of differentiation-associated death of sebocytes and discuss open questions regarding its mechanism and functions. In vivo studies have provided evidence for degradation of nuclear and mitochondrial DNA by lysosomal deoxribonuclease 2 (DNase 2), indicating a key role of lysosomes in holocrine secretion. We discuss the influence of tight junctions on the spatial localization of holocrine secretion within glands, the regulation of holocrine cell death by autophagy and potential mediators of membrane lysis. Further studies of holocrine secretion are needed to fully uncover its molecular control and to determine potential clinical implications.
    Keywords:  autophagy; deoxyribonuclease; epithelial cell; exocrine gland; holocrine secretion; keratinocyte; lysosome; programmed cell death; sebaceous gland; skin
    DOI:  https://doi.org/10.3390/cells15121058
  15. Cell Death Dis. 2026 Jun 23.
    YIF1A activates mTORC1 signaling to promote cellular senescence.
    Xiaogang Zhang, Luying Liu, Mengdi Shang, Bin Hu, Shu Zhu, Xi Wang, Jieying Liu, Yanchun Han, Xiaodan Wei, Qi Cao, Fan Li, Lijie Gao, Jingyu Sun, Jiaqi Yu, Chentai Tan, Menghua Dong, Tie-Shan Tang, Jiu-Qiang Wang.
      The mechanistic target of rapamycin complex 1 (mTORC1) serves as a central metabolic hub that integrates nutrient signals and orchestrates cellular metabolism to regulate many fundamental cell processes. While mTORC1 activation is known to occur both on lysosomal membranes and at the Golgi apparatus in response to environmental cues, the molecular mechanisms governing its Golgi-associated activation remain poorly understood. In this study, we identified YIF1A as a novel Golgi-localized regulator of growth factor-mediated mTORC1 signaling. Mechanistically, YIF1A interacted with the E3 ubiquitin ligase RNF126 to facilitate K48-linked polyubiquitination of G3BP1/2, thereby promoting mTORC1 activation. Genetic depletion of either YIF1A or RNF126 stabilized G3BP1/2 proteins and significantly impaired mTORC1 activity. Notably, YIF1A knockdown conferred resistance to etoposide- and doxorubicin-induced cellular senescence. The evolutionary conservation of this pathway was demonstrated by extended or shortened lifespan in Caenorhabditis elegans lacking or overexpressing yif-1, the invertebrate ortholog of YIF1A. Our findings not only elucidate a previously unrecognized Golgi-specific regulatory axis for mTORC1 activation but also suggest YIF1A as a potential therapeutic target for modulating aging-related pathologies.
    DOI:  https://doi.org/10.1038/s41419-026-09034-z
  16. Channels (Austin). 2026 Dec;20(1): 2687246
    mTORC2-Nav1.2 signaling drives early hyperexcitability in Alzheimer's disease mouse model.
    Nolan M Dvorak, Jeffrey L Noebels.
      Hyperexcitability is a biomarker of early-stage Alzheimer's Disease (AD) and hastens cognitive decline later in its course. Mechanistic target of rapamycin (mTOR) signaling contributes to the slope of this trajectory, as evidenced by early increased brain expression and the rescue of hyperexcitability by genetic deletion of mTOR complex 2 (mTORC2); however, a molecular mechanism directly linking mTOR signaling to membrane hyperexcitability in early-stage AD remains elusive. Here, we show that hyperactive mTOR signaling stimulates the voltage-gated Na+ channel 1.2 (Nav1.2), a previously identified downstream phosphorylation target of mTORC2 and a key regulator of membrane electrogenesis. Augmented Nav1.2 channel function induced by hyperactive mTOR signaling requires the action of mTORC2 and is selective among major brain Nav channel isoforms. In a murine AD model, neocortical pyramidal neurons display augmented Nav1.2 channel function and hyperexcitability through a mechanism that requires mTORC2 activity. These results highlight the mTORC2-Nav1.2 interaction as a therapeutic target for attenuating pathogenic hyperexcitability in early-stage AD.
    Keywords:  Alzheimer’s disease; Voltage-gated Na+ channel; hyperexcitability; mechanistic target of rapamycin; patch-clamp electrophysiology
    DOI:  https://doi.org/10.1080/19336950.2026.2687246
  17. bioRxiv. 2026 Jun 09. pii: 2026.06.04.729996. [Epub ahead of print]
    PINK1 loss in astrocytes triggers inflammatory dysfunction and neuronal death.
    Gabriella Fiorino, Damian N Di Florio, Deshaun H Hadley, Owen A Ross, Fabienne C Fiesel, Wolfdieter Springer.
      Genetic loss of the mitochondrial control enzyme PINK1 leads to Parkinson's disease, characterized by dopaminergic neuron degeneration and neuroinflammation, yet its role in glia remains poorly understood. To address this gap, we investigated how the function of astrocytes and their ability to support neurons is influenced by PINK1 deficiency. For the first time, we demonstrate that human astrocytes exhibit robust PINK1 activity. Next, the first bulk transcriptomic study of human PINK1 mutant astrocytes was performed followed by biochemical validation at the protein level, uncovering homeostatic collapse. Co-culture experiments demonstrated that this astrocyte dysfunction drives neuronal damage through non-cell-autonomous mechanisms. Notably, pharmacological enhancement of autophagy successfully mitigated this inflammatory secretome, indicating that mitochondrial quality control deficits are reversible. These findings establish an unexpected role for PINK1 in glial biology, reveal that astrocytes are vulnerable to mitophagy deficits, and highlight a novel mechanistic link connecting mitochondrial dysfunction, neuroinflammation, and neurodegeneration.
    DOI:  https://doi.org/10.64898/2026.06.04.729996
  18. EMBO J. 2026 Jun 22.
    mRAVE governs lysosomal catabolism through basal and mTORC1-regulated V-ATPase assembly.
    Nora S Siefert, Andrea Zanotti, Anastasija Paneva, Martin Schneider, Dominic Helm, Wilhelm Palm.
      Acidification of lysosomes, endosomes and the Golgi underpins organelle-specific functions within the endomembrane system. This process is driven by vacuolar-type H + -ATPases (V-ATPases), proton pumps that reversibly assemble from peripheral V1 and membrane-integral Vo domains to regulate organelle pH. In yeast, V1-Vo assembly at the vacuole is mediated by the RAVE complex, but V-ATPase assembly in mammalian cells remains less well understood. Here, we systematically characterize physiological roles of the mammalian RAVE complex, composed of the subunits Dmxl1 or Dmxl2, Wdr7 and Rogdi. Under basal conditions, mRAVE broadly promotes V-ATPase assembly and luminal acidification of endomembrane organelles. Upon mTORC1 inactivation, mRAVE is recruited to lysosomes and required for the resulting increase in V-ATPase assembly and catabolic activity. Loss of mRAVE disrupts organelle acidification, leading to suppression of lysosomal catabolism, accumulation of dysfunctional lysosomes and lysosomal exocytosis. Restoring lysosomal pH rescues basal function in mRAVE-deficient cells but not the mTORC1-regulated increase in catabolic activity. Thus, mRAVE is an essential V-ATPase assembly factor that couples acidification to organelle function and nutrient signaling.
    DOI:  https://doi.org/10.1038/s44318-026-00838-5
  19. Front Physiol. 2026 ;17 1836651
    Physical exercise as a precision strategy for targeted PINK1 recruitment- a mechanistic review.
    Jing Zhu, Ligang Tong, Anand Thirupathi.
      PTEN-induced kinase 1 (PINK1) is a mitochondrial serine/threonine kinase that orchestrates ubiquitin-dependent mitophagy together with the E3 ligase Parkin. Both physiological and pathological conditions rapidly recruit PINK1, and timely PINK1 degradation in healthy mitochondria determines whether it supports or harms the cell. Thus, the tight regulation of PINK1 balances its negative effects. In this context, introducing physical exercise as one of the strategies can fine-tune PINK1/Parkin pathways by triggering transient energy stress and moderate increases in reactive oxygen species (ROS) that promote PINK1 stabilization on the outer mitochondrial membrane, enhance Parkin recruitment via sensitizing various molecular signaling, such as AMPK-PGC-1α and FOXOs. However, the mechanism underlying a specific exercise mode that triggers PINK1-mediated selective removal of mitochondrial damage remains unknown. Therefore, this review will synthesize mechanistic approaches to how different exercise paradigms modulate PINK1 function, recruit PINK1 dynamics, and regulate downstream signaling, to define exercise prescriptions as adjunctive strategies.
    Keywords:  PINK1; Parkin; mitochondria; mitophagy; neurons; physical exercise
    DOI:  https://doi.org/10.3389/fphys.2026.1836651
  20. bioRxiv. 2026 Jun 14. pii: 2026.06.10.731244. [Epub ahead of print]
    Lysosomal ion homeostasis drives delayed hair cell death after aminoglycoside uptake.
    Francisco A Barros Becker, Ananya Cholkar, Tor H Linbo, David W Raible.
      Aminoglycoside ototoxicity has been widely reported and remains an important public health issue. Unfortunately, the molecular mechanisms of ototoxicity are not well understood. Here, we report the lysosome compartment as the main driver of delayed cell death triggered by aminoglycosides. By labeling early and late endosomes we show that endocytosis is not an significant path of aminoglycoside uptake. Instead, we show that aminoglycosides are delivered to lysosomes primarily through autophagy. Hair cells can be protected from damage by activation of the dual function lysosomal Two-Pore-Channel 2 (TPC2), stimulated by NAADP agonist but not by phosphoinositide PI(3,5,)P2 agonist. These treatments neutralize lysosomal pH. Moreover, luminal pH changes are also accompanied by changes in ferrous iron availability, though classical ferroptosis inhibitors do not prevent a delayed hair cell death. These findings reveal that lysosomal-driven delayed hair cell death is ferroptosis independent, suggesting that toxicity relies on a distinct mechanism that based on the internal conditions of the lysosomal compartment.
    DOI:  https://doi.org/10.64898/2026.06.10.731244
  21. PLoS One. 2026 ;21(6): e0352120
    Omipalisib reduces hyperphosphorylated tau protein by modulating mTOR-autophagy pathway.
    Haeun Hwang, Namkwon Kim, Subyn Jeon, Yoojin Lee, Jeongmin Son, Seung Ho Jeon, Yeongae Lee, Min Sung Gee, Kyung-Soo Inn, Jong Kil Lee.
      Tauopathies are neurodegenerative diseases characterized by the presence of hyperphosphorylated tau (p-tau) and neurofibrillary tangles. Autophagy is a critical self-degradation mechanism that preserves cellular homeostasis and function, including the clearance of misfolded proteins. Autophagy is impaired in tauopathies, resulting in excessive accumulation of p-tau. Omipalisib, a dual phosphatidylinositol 3-kinase/mammalian target of rapamycin (PI3K/mTOR) inhibitor, was explored in a phase I clinical trial involving solid tumors and lymphoma. In this study, we aimed to investigate the effects of omipalisib on tauopathy both in vitro and in vivo. Omipalisib increased the levels of protein LC3B and decreased that of p62 in human tau (P301L)-expressing SH-SY5Y stable (SH-Tau) cells by inhibiting mTOR activation in a time-dependent manner. In our study, we hypothesized that omipalisib, a PI3K/mTOR inhibitor, could remove accumulated tau and inhibit memory decline by activating autophagy. Additionally, omipalisib reduced tau phosphorylation in SH-Tau cells without inducing cytotoxicity. Upon administration of 6-month-old PS19 mice with omipalisib (1 mg/kg) for 2 months, the levels of both RIPA-soluble and RIPA-insoluble p-tau were decreased, and spatial memory dysfunction was alleviated in omipalisib-treated PS19 mice. Overall, these results show that omipalisib decreases the expression of p-tau by modulation mTOR-autophagy pathway, resulting in the amelioration of spatial memory deficits. This study highlighted the potential of omipalisib as a candidate treatment for tauopathies.
    DOI:  https://doi.org/10.1371/journal.pone.0352120
  22. Sci Signal. 2026 Jun 23. 19(943): eadw1017
    Diacylglycerol kinase ζ in B lymphocytes supports CD40-mediated immune synapse formation, mTORC1 signaling, and plasma cell fate.
    Ana Fernández-Barrecheguren, Adrián Fernández-Rego, Lucía Fuentes-Cantos, Tirso Pons, Belén S Estrada, Marta Iborra-Pernichi, María Velasco de la Esperanza, Tahmineh Ebrahimi, Ana Sagrega-Aparisi, Sara Cogliati, Nuria Martínez-Martín, Rodrigo Jiménez-Saiz, Yolanda R Carrasco.
      To mount a robust T cell-dependent immune response, antigen-specific B lymphocytes require the stimulation of the transmembrane receptor CD40 through immune synapse formation with CD4+ T follicular helper cells. CD40 stimulates the activation of mammalian target of rapamycin complex 1 (mTORC1) and remodels mitochondria to meet the increased bioenergetic and anabolic demands of activated B cells. Here, we found that diacylglycerol kinase ζ (DGKζ) supported mTORC1 activation downstream of CD40 stimulation in mouse B cells. We showed that DGKζ was required for organellar translocation to the CD40-mediated immune synapse and for the recruitment of mTORC1 to lysosomes, the latter of which was necessary for mTORC1 activation and function. The production of phosphatidic acid by DGKζ was crucial for these processes. DGKζ-/- B cells exhibited defects in protein biosynthesis, metabolite transporter expression, and cell cycle progression, together with dysregulation of the transcriptional network that determines B cell fate. To sustain their bioenergetic and metabolic demands, DGKζ-/- B cells enhanced their mitochondrial function. Together, these effects of DGKζ loss led to decreases in germinal center responses and in the generation of long-lived plasma cells and memory B cells in mice. Thus, our data identify DGKζ as an essential mediator of CD40 functions in the B cell immune response.
    DOI:  https://doi.org/10.1126/scisignal.adw1017
  23. Genes (Basel). 2026 Jun 09. pii: 673. [Epub ahead of print]17(6):
    Comparative Genomics Reveals Recurrent Loss of Autophagy-Related 9B (ATG9B) in Amniotes.
    Supawadee Sukseree, Leopold Eckhart.
      Background/Objectives: Autophagy is an evolutionarily conserved intracellular degradation mechanism that is regulated by a set of autophagy-related (ATG) proteins. The only transmembrane protein among ATGs is the lipid scramblase ATG9, which exists in the form of two paralogs, ATG9A and ATG9B, in humans and other vertebrates. Methods: Here, we analyzed human and murine skin transcriptome and proteome datasets for the expression of ATG9 paralogs and performed comparative genomics to determine their conservation during the evolution of amniotes (mammals and sauropsids). Results: The expression of ATG9B, but not of ATG9A, is enriched in differentiated epidermal keratinocytes and in skin appendages of humans and mice. In contrast to the conservation of ATG9A in all major clades of amniotes, ATG9B has been lost in at least three phylogenetic lineages. Cetaceans, which have unique skin adaptations to aquatic life, harbor mutations that disrupt the open reading frame of ATG9B. Many or all species of turtles (Testudines) and crocodilians (Crocodylia) have entirely lost the ATG9B gene. Conclusions: ATG9B has undergone independent pseudogenization or gene loss in different subgroups of amniotes. In mammalian species that have retained the gene, its expression pattern indicates functions of ATG9B in the skin and skin appendages.
    Keywords:  autophagy; cetaceans; evolution; gene loss; hair; keratinocytes; pseudogenization; sebaceous gland; skin; vesicle
    DOI:  https://doi.org/10.3390/genes17060673
  24. Nat Commun. 2026 Jun 21.
    Sensing centrosome amplification: the interface between centriole duplication and autophagy.
    Paula A Coelho, Agnieszka Fatalska, Marco Geymonat, Ramona Lattao, David M Glover.
      Multipolar mitotic spindles with extra centrosomes, first observed in cancer cells in the late nineteenth century, remain poorly understood. Here, to address how cells overcome proliferation arrest imposed by centrosome amplification, we describe a genome-wide screen revealing that downregulation of the Wnt, Hippo, Tpr53, PIDDosome, ciliary biogenesis, or autophagy pathways enables proliferation of mouse embryonic stem cells having PLK4-mediated centrosome amplification. We select the tumor suppressor, Guanine-nucleotide Activating Protein ARHGAP15, for further study as its depletion activates autophagy, overcomes centrosome amplification, and enables embryonic fibroblast proliferation. Reduction of centrosomes following ARHGAP15 depletion requires autophagy protein, ATG16L1, which associates with ARHGAP15 when the autophagy pathway is inactive. ARHGAP15 is opposed by Guanine-nucleotide Exchange Factor ARHGEF2, which is activated by the centriolar protein CEP170 to generate RAC1-GTP and promote autophagy. Together our findings add extra dimensions to the roles of RAC1 in cytoskeletal regulation and ARHGAP15 as a potential tumor suppressor.
    DOI:  https://doi.org/10.1038/s41467-026-74702-9
  25. Int J Biol Sci. 2026 ;22(11): 6132-6148
    Deciphering the Neuroautophagic Interactome: Molecular Circuits Linking Selective Autophagy to Neuropathological Cascades in Neurological Disorders.
    Pengfei Luo, Zachary D Travis, Cameron Lenahan, Haijian Wu, Jianmin Zhang, Jun Yu, Weilin Xu.
      Selective autophagy, a lysosome-dependent degradation pathway targeting specific substrates (e.g., mitochondria, protein aggregates), plays a pivotal role in maintaining neuronal homeostasis. Its dysregulation is intricately linked to neurodegenerative diseases, acute brain injuries, and neuroinflammatory disorders. This review elucidates the crosstalk between selective autophagy and key neuropathophysiological processes, including apoptosis, neuroinflammation, oxidative stress, and blood-brain barrier disruption. We delineate the dual roles of selective autophagy through the framework of the neuroautophagic interactome-a network in which kinases (ULK1, TBK1) and effectors (PINK1/Parkin, SQSTM1/p62) collaboratively interpret ubiquitin codes. This integrated signaling nexus functions as a decisive hub that bidirectionally modulates disease progression. Furthermore, we evaluate emerging therapeutic strategies targeting selective autophagy to mitigate neuronal damage, emphasizing its dual role as both a protector and a contributor to disease progression.
    Keywords:  neuroautophagic interactome; neurological disorders; selective autophagy; therapeutic targets
    DOI:  https://doi.org/10.7150/ijbs.127431
  26. bioRxiv. 2026 Jun 10. pii: 2026.06.08.731026. [Epub ahead of print]
    Structural Mechanism and Cellular Restriction of Tau Seeding from Endolysosomes.
    Eric Herrmann, Shuixia Tan, Kevin M Rose, Richard M Hooy, James H Hurley.
      The prion-like spread of tau from cell to cell in the central nervous system involves escape from the endolysosomal network, which is counteracted by the lysosomal repair activity of the ESCRT system. Here, we investigate whether other components of the lysosomal damage sensing and repair system, namely the ESCRT-recruiting Ca 2+ sensor ALG-2, conjugation of ATG8s to single membranes (CASM), the phosphoinositide-initiated tethering and lipid transport (PITT) pathway, and the Parkinson's disease-related lipid transporter VPS13C are involved in tau spread. We found that the PITT pathway and VPS13C are strongly implicated in tau seeding by pre-formed fibrils (PFFs) in both neurons and astrocytes, CASM has a major role in astrocytes but not neurons, and ALG-2 has a lesser role in both. We then investigated the mechanism of damage and seeding by tau PFFs using cryo-electron tomography. Unlike the classical lysosome damage agent LLOMe, tau PFFs were not seen to directly interact with the lysosomal membrane, nor do they distort local membrane curvature. Lysosomes in PFF-treated cells were structurally intact. Extensive protein aggregates of similar character were seen in both the lysosomal lumen and in the cytosol proximal to lysosomes. The observations are consistent with the PFF-induced co-aggregation of tau with other cellular materials within lysosomes, with leakage to the cytosol attributed to reversible holes in the lysosome membrane.
    DOI:  https://doi.org/10.64898/2026.06.08.731026
  27. Proteomes. 2026 May 27. pii: 28. [Epub ahead of print]14(2):
    Diverse Forms of Autophagy and Their Roles in Liver Disease and Aging: A Comprehensive Review.
    Seoyoon Heo, Min Young Lee, Che Yeon Jeong, Dong Ha Kim, Ji Hye Jun.
      The liver is a central metabolic organ that integrates nutrient sensing, lipid handling, and detoxification to maintain systemic homeostasis. In metabolic dysfunction-associated steatotic liver disease (MASLD), chronic metabolic overload accelerates hepatocyte senescence, impairing regenerative capacity and promoting progression toward fibrosis and hepatocellular carcinoma. While transcriptomic studies have provided important insights into stress-responsive pathways, they incompletely capture the proteome remodeling and proteoform-level alterations that govern hepatocyte function during aging and disease. Recent mass spectrometry-based proteomics studies have revealed that disruption of autophagy-dependent proteome homeostasis is a defining feature of senescent hepatocytes. Quantitative analyses demonstrate coordinated alterations in selective autophagy pathways-including lipophagy, mitophagy, ferritinophagy, ER-phagy, and pexophagy-accompanied by organelle-specific protein abundance signatures and remodeling of autophagy-related proteoforms. These findings position proteomics as an essential tool for resolving the spatial and functional reorganization of hepatocyte proteomes that cannot be inferred from transcript abundance alone. In this review, we synthesize proteomics-driven evidence defining selective autophagy dysfunction in aging and MASLD livers, critically evaluate methodological limitations, and propose a conceptual framework in which impaired selective autophagy acts as a proteome-level driver of hepatocyte senescence. We further outline future directions for proteoform-resolved and spatial proteomics approaches aimed at identifying actionable targets for therapeutic intervention in liver disease.
    Keywords:  MASLD; hepatocyte senescence; organelle proteome remodeling; proteoforms; quantitative proteomics; selective autophagy
    DOI:  https://doi.org/10.3390/proteomes14020028
  28. Biosci Biotechnol Biochem. 2026 Jun 26. pii: zbag087. [Epub ahead of print]
    TORC1 inactivation induces a noncanonical, separase-independent cohesin degradation.
    Chihiro Yamada, Honoka Goto, Ayana Futaguchi, Kohana Maeshima, Maho Morikawa, Kozo Tanaka, Takashi Ushimaru.
      Target of rapamycin complex 1 (TORC1) integrates nutrient signals with cell growth. While its inactivation is known to trigger mitotic slippage via APC/C-Cdh1-dependent securin degradation and separase activation, the molecular basis of cohesion loss during nutrient stress has remained incompletely defined. In budding yeast, we show that TORC1 inactivation elicits a noncanonical, proteasome-dependent degradation of cohesin that is independent of securin and separase. Separase was itself destabilized upon TORC1 inactivation, yet Scc1 degradation persisted even in a separase-resistant mutant. Cohesin degradation proceeds when APC/C is impaired, indicating involvement of an atypical ubiquitin ligase. These results reveal a second, aberrant route to sister chromatid dissociation upon TORC1 inactivation, operating in parallel with the previously reported APC/C-Cdh1 pathway, via the unconventional degradation of mitotic key factors.
    Keywords:  Cohesin; securin; separase; spindle assembly checkpoint (SAC); target of rapamycin complex 1 (TORC1)
    DOI:  https://doi.org/10.1093/bbb/zbag087
  29. Cells. 2026 Jun 15. pii: 1082. [Epub ahead of print]15(12):
    Ketone-Dependent Restoration of Autophagy and Mitochondrial Quality Control Through VPS35 in a Drosophila Model of C99-Induced Neurodegeneration.
    Hao Huang, Kaijing Xu, Michael Lardellia.
       BACKGROUND: Early endolysosomal and autophagic defects are among the earliest cellular alterations observed in Alzheimer's disease (AD). However, the molecular mechanisms linking amyloid precursor protein (APP) metabolism to vesicle trafficking dysfunction remain incompletely understood. The APP-derived fragment C99 has emerged as a potential upstream mediator of intracellular toxicity, but its impact on organelle homeostasis and its modulation by metabolic interventions remain unclear.
    METHODS: To investigate these mechanisms, we expressed human C99 in Drosophila neurons and examined intracellular pathology using ultrastructural analysis, fluorescent reporters of autophagy and mitochondrial turnover, and proteomic interactome mapping. The effects of the ketone body β-hydroxybutyrate (BHB) were evaluated to assess the impact of metabolic intervention.
    RESULTS: Neuronal C99 expression induced pronounced vesicular abnormalities, impaired autophagic turnover, and disrupted mitochondrial quality control. Transmission electron microscopy revealed extensive accumulation of enlarged vesicular compartments, accompanied by reduced mitochondrial turnover and accumulation of aged mitochondria. BHB treatment restored autophagic cargo clearance, improved mitochondrial turnover, and normalized vesicular ultrastructure. These protective effects required neuronal ketone transport, indicating a neuron-intrinsic metabolic mechanism. Proteomic analysis of the C99-associated interactome revealed that ketone treatment remodels networks enriched for vesicle trafficking and proteostasis pathways. Network prioritization identified the retromer component VPS35 as a candidate regulatory hub. Functional analyses demonstrated that depletion of VPS35 abolished the BHB-dependent restoration of autophagy, mitochondrial turnover, and vesicle morphology.
    CONCLUSIONS: Ketone treatment restores mitochondrial quality control and autophagic homeostasis through a VPS35-dependent mechanism in C99-induced neurodegeneration. These findings provide mechanistic insight into how metabolic interventions may restore intracellular homeostasis in Alzheimer's disease.
    Keywords:  Alzheimer’s disease; C99; β-hydroxybutyrate
    DOI:  https://doi.org/10.3390/cells15121082
  30. J Fungi (Basel). 2026 Jun 04. pii: 410. [Epub ahead of print]12(6):
    The Role of ATG8 in Promoting Lipid Accumulation in the Oleaginous Fungus Mucor circinelloides During Nitrogen Limitation.
    Hequn Li, Hongjuan Yuan, Bushra Iqbal, Tianyu Wang, Zhen Wang, Huaiyuan Zhang.
      Autophagy is a central cellular process that recycles intracellular components and supplies precursors for biosynthesis. As a key regulator of autophagosome formation, autophagy-related protein 8 (ATG8) plays an essential role in macromolecular degradation and in the availability of lipid precursors. However, whether enhanced autophagic flux promotes lipid accumulation in oleaginous fungi remains unclear. In this study, atg8-1 and atg8-2 were homologously overexpressed in the oleaginous fungus Mucor circinelloides to evaluate their roles in lipid biosynthesis. The engineered strains McATG8-1T2 and McATG8-2T2 showed significantly increased total fatty acid (TFA) contents (32.9% and 32.5%), representing improvements of 15.0% and 13.7% compared with the control. γ-Linolenic acid levels were also elevated to 16.9% and 16.5%, relative increases of 25.2% and 22.0%, respectively. RT-qPCR analysis revealed coordinated upregulation of genes involved in autophagy, central carbon metabolism, lipid biosynthesis, and the pentose phosphate pathway. Ethanolamine supplementation further enhanced lipid accumulation, increasing TFA contents by 12.2-14.6%. In addition, inhibition of target of rapamycin complex 1 using rapamycin produced a strong synergistic effect with atg8 overexpression, leading to substantial lipid increases under nitrogen-limited and nitrogen-rich conditions. Collectively, these findings demonstrated that ATG8-mediated autophagy enhanced lipid accumulation and acted as a key determinant of lipid synthesis flux.
    Keywords:  ATG8; Mucor circinelloides; autophagy; lipid accumulation; oleaginous microorganism
    DOI:  https://doi.org/10.3390/jof12060410
  31. Int J Mol Sci. 2026 Jun 16. pii: 5413. [Epub ahead of print]27(12):
    Regulation of Innate Immune Signaling by Autophagy.
    Daniel Oña-Sánchez, Julia Bandera-Linero, Felipe X Pimentel-Muiños.
      The first line of defense against infection is provided by the innate immune system, which is able to recognize molecular patterns in a variety of infectious agents through the action of different families of pattern recognition receptors (PRRs). These effectors detect the invading agent and trigger powerful inflammatory responses that help fight the infection from the very beginning. However, inflammatory reactions can be damaging for the host and must be properly controlled to prevent pathological consequences. Here we provide a comprehensive review of the important role of autophagy, a catabolic pathway that degrades cellular components for quality control and regulatory purposes, in the regulation of innate immune responses, and the underlying mechanisms involved. Inflammatory pathways discussed in this review include those triggered by Toll-like receptors (TLRs), Retinoic acid-Inducible Gene (RIG)-I-like receptors (RLRs), Nucleotide-binding Oligomerization Domain (NOD)-like receptors (NLRs), and the receptor for cyclic GMP-AMP Stimulator of Interferon Genes (STING). Finally, we also consider examples where autophagy plays context-dependent or even pro-inflammatory roles, reflecting a complex involvement that remains to be fully characterized.
    Keywords:  danger associated molecular patterns (DAMPs); inflammation; innate immunity; pathogen-associated molecular patterns (PAMPs); pattern recognition receptors (PRRs); protein degradation; selective autophagy
    DOI:  https://doi.org/10.3390/ijms27125413
  32. Cell Death Discov. 2026 Jun 25.
    Molecular diversity of mitochondrial autophagy receptors: context-dependent effects in human health and disease.
    Ana Rožić, Mija Marinković, Ivana Novak.
      Mitophagy receptors are central regulators of mitochondrial quality control, integrating metabolic, stress-related, and developmental cues to maintain cellular homeostasis. Accumulating evidence indicates that their dysregulation contributes to a broad spectrum of human diseases through highly context-dependent mechanisms. In cardiovascular and neurological disorders, receptor-mediated mitophagy shapes cell survival, synaptic function, stress adaptation, and tissue integrity, with both insufficient and excessive activity proving detrimental. In cancer, mitophagy receptors display dual and stage-specific roles, acting as tumor suppressors in early disease while later supporting metabolic adaptation, stemness, and therapy resistance. Metabolic diseases highlight the tissue-specific complexity of mitophagy regulation, where precise control of mitochondrial turnover is essential for insulin sensitivity, calcium signaling, and energy homeostasis. In hematological, inflammatory, and autoimmune disorders, receptor-mediated mitophagy emerges as a fundamental determinant of lineage commitment, immune cell function, and inflammatory balance. Collectively, these findings position mitophagy receptors not as uniform stress responders, but as dynamic modulators of disease progression, whose precise and context-sensitive targeting may offer novel therapeutic opportunities across diverse pathological conditions.
    DOI:  https://doi.org/10.1038/s41420-026-03207-7
  33. Mol Neurodegener Adv. 2026 ;2(1): 31
    miRNA family miR-29 inhibits PINK1-PRKN signaling via ATG9A.
    Briana N Markham, Chloe Ramnarine, Songeun Kim, William E Grever, Alexandra I Soto-Beasley, Michael G Heckman, Yingxue Ren, Andrew C Osborne, Mohammed Kehili, Aditya V Bhagwate, Yuanhang Liu, Chen Wang, Jungsu Kim, Zbigniew K Wszolek, Owen A Ross, Wolfdieter Springer, Fabienne C Fiesel.
      Loss-of-function mutations in the genes encoding PINK1 and PRKN result in early-onset Parkinson disease (EOPD). Together, the encoded enzymes direct a neuroprotective pathway that ensures the elimination of damaged mitochondria via autophagy. We performed a genome-wide high-content imaging miRNA screen for inhibitors of the PINK1-PRKN pathway and identified all three members of the miRNA family 29 (miR-29). RNA sequencing revealed target genes regulated by miR-29 and identified ATG9A as a candidate gene. SiRNA-mediated ATG9A silencing phenocopied the effects of miR-29 and suppressed the initiation of PINK1-PRKN-mediated mitophagy. In addition, expression of ATG9A was able to rescue the effects of miR-29a, suggesting that ATG9A is primarily responsible for the inhibitory effect of miR-29. In an EOPD patient cohort, we further discovered two rare, potentially deleterious, ATG9A missense variants (p.R631W and p.S828L) and tested them experimentally in cells. Strikingly, neither EOPD ATG9A variant was able to rescue the phenotype suggesting they both act as loss-of-function mutations and might contribute to the etiology of disease. Together, our study validates miR-29 and its target gene ATG9A as novel regulators of PINK1-PRKN signaling. It further serves as proof-of-concept with the identification of novel, potentially disease-relevant EOPD variants specifically in mitophagy-regulating genes. The nomination of biological pathways is important for the stratification and treatment of patients that suffer from devastating diseases, such as EOPD.
    Supplementary Information: The online version contains supplementary material available at 10.1186/s44477-026-00029-w.
    Keywords:  ATG9A; Hsa-miR-29; Mitophagy; PINK1; PRKN; Parkin; Parkinson’s disease
    DOI:  https://doi.org/10.1186/s44477-026-00029-w
  34. Genes (Basel). 2026 Jun 05. pii: 660. [Epub ahead of print]17(6):
    Biallelic ATG9B Variants Define a Novel Autophagy-Related Neurodevelopmental Disorder with Cerebellar Ataxia.
    Seval Kılıç, Kerem Esmen, Jean-Loup Méreaux, Ayşe Miray Oto, Tansu Bilge Kose, Melike Sever-Bahcekapili, Emine Eren-Koçak, Şeyda Demir, A Semra Hız, Erum Afzal, Zahra Firoozfar, Gökhan Karakülah, H Alper Bagriyanik, Léna Guillot-Noel, Giulia Coarelli, Henry Houlden, Stephanie Efthymiou, Alexandra Durr, Mehmet Öztürk, M Kasim Diril.
       BACKGROUND/OBJECTIVES: Autophagy is a highly conserved eukaryotic cellular process whose dysfunction results in human pathologies including cancer and neurodegenerative disease. First identified in yeast, ATG genes are central players in autophagy. Mutations in core autophagy genes ATG5 and ATG7 have been previously reported to cause rare genetic disorders with autosomal recessive inheritance.
    METHODS: Here we report, for the first time, variants in human ATG9B gene as causative factors for a rare neurodevelopmental disease with autosomal recessive inheritance. Three distinct mutations were detected in three independent families with consanguinity, five patients affected in total.
    RESULTS: The first variant is an 11-nucleotide deletion resulting in a frameshift. A premature stop codon is added and the C-terminal cytosolic domain of ATG9B protein is truncated. The second one is a point mutation that changes a critical amino acid in the transmembrane domain. The third variant is a 2-nucleotide deletion causing a different truncation product. Patients presented with diverse neurodevelopmental anomalies including intellectual disability, behavioral abnormalities, congenital cerebellar ataxia, mild cerebellar atrophy, and microcephaly. Since human ATG9B is expressed specifically in the placenta, we hypothesized that the disease pathology originates during placental development. To characterize the effects of the first frameshift mutation and gain insight into the specific functions of ATG9B in a physiological setting, we used mammalian cells and a knock-in mouse model. Truncated ATG9B was not stable when expressed in cells. It was localized to perinuclear vesicles like the WT protein, but not to peripheral vesicles. Homozygous knock-in mice were viable, fertile, and displayed no gross phenotypical abnormalities. Histomorphometry analysis of the placenta layers did not reveal a significant difference between mutant and control embryos. The assessments of neurobehavioral tests were similar in wild-type and homozygous knock-in mice. However, knock-in mice had a reduced fear memory trend, which is an amygdala-involved response.
    CONCLUSIONS: In this study, we describe a new rare disease linked to ATG9, including cerebellar ataxia and atrophy, as described for ATG5 and ATG7.
    Keywords:  ATG9B; autophagy; genetically engineered mouse models; rare disease
    DOI:  https://doi.org/10.3390/genes17060660
  35. Science. 2026 Jun 25. 392(6805): 1363-1368
    Reversible suppression of autophagy in a mouse model reveals neuronal resilience.
    Tomoya Eguchi, Manabu Abe, Takuya Tomita, Hideaki Morishita, Yasushi Saeki, Kenji Sakimura, Kenji F Tanaka, Noboru Mizushima.
      Impairments in intracellular quality-control mechanisms, including autophagy, affect neuronal integrity and function. Despite numerous studies aimed at slowing neuronal deterioration, it remains unclear whether neuronal function and intracellular quality can be restored once impaired. We developed a mouse model in which autophagy could be rapidly and reversibly regulated to investigate the reversibility of such defects. Suppressing autophagy led to proteome and transcriptome changes, inclusion body accumulation, and axonal swelling, all of which were largely ameliorated after autophagy restoration. Consistent with these cellular abnormalities, autophagy suppression induced motor and cognitive dysfunction, which was also reversed on autophagy restoration. Our findings elucidate the potential resilience of neuronal function and quality enabled by intracellular clearance.
    DOI:  https://doi.org/10.1126/science.ady3911
  36. Cancer Metab. 2026 Jun 24.
    CRISPR screen identifies autophagy inhibition (GNS561) as a PARP inhibitor (AZD5305) combination strategy in small cell lung cancer.
    Tony Yu, Ranya Barayan, Lifang Song, Vidhyasagar Venkatasubramanian, Janvi Tamakuwala, Sree N Nair, Vivek Philip, Benjamin H Lok.
       BACKGROUND: Small cell lung cancer (SCLC) is a deadly cancer with few treatment options and poor prognosis, creating a dire need for improving therapies. Poly (ADP-ribose) polymerase inhibitors (PARPi) have been tested as a treatment strategy, but patient response varies. We aimed to identify novel approaches to sensitize SCLC to PARPi through a genome-wide CRISPR dropout screen.
    METHODS: Genome-wide CRISPR dropout screening was conducted in two SCLC cell lines using the PARPi, olaparib, as the selection pressure. Stable shRNA-mediated knockdown cell lines were validated by Western blotting and tested for olaparib sensitivity by assaying for cell viability. Synergy between PARPi and autophagy inhibition was tested by treating SCLC cell lines and analyzing cell viability using SynergyFinder+. The therapeutic strategy combining AZD5305 (PARPi) and GNS561 (novel autophagy inhibitor) was tested in cell line-derived xenograft mouse models.
    RESULTS: CRISPR screening identified the loss of mTOR negative regulators as a mechanism of PARPi sensitivity in SCLC, and knockdown of TSC1 and TSC2 sensitized SCLC cell lines to olaparib. Therapeutic strategies combining PARPi and autophagy inhibition demonstrated synergy in SCLC cell lines, and combination therapy with AZD5305 and GNS561 was effective in cell line-derived xenograft mouse models.
    CONCLUSIONS: Autophagy inhibition downstream of the mTOR pathway is a mechanism of PARPi sensitivity in SCLC. This suggests that a therapeutic combination of autophagy inhibition and PARPi is a promising treatment strategy in SCLC, paving the way for the adoption of novel treatments in this disease context.
    Keywords:  Autophagy; Cancer therapy; Combination therapy; PARP inhibitors; Small cell lung cancer; Therapeutic resistance
    DOI:  https://doi.org/10.1186/s40170-026-00443-4
  37. Antioxidants (Basel). 2026 Jun 10. pii: 739. [Epub ahead of print]15(6):
    Aminochrome-Induced Disruption of Autophagosome-Lysosome Fusion: Implications for Protein Aggregation in Parkinson's Disease.
    Andrea Briceño, Cipriano Núñez, Karina Cortés, Patricia Pallacán, Nicole Salinas, Carola Millán, Juan F Vivanco, Nelson Caro, Juan Segura-Aguilar, Irmgard B Paris.
      Aminochrome, an endogenous neurotoxin, has been implicated in the loss of neuromelanin-containing dopaminergic neurons in the nigrostriatal system in Parkinson's disease. Although aminochrome-induced oxidative stress and its inhibitory effects on microtubule polymerization are well documented, its impact on protein aggregation remains poorly understood. The aim of this research was to evaluate the effects of aminochrome on protein aggregate accumulation in SH-SY5Y cells differentiated into dopaminergic neurons. While the role of aminochrome in autophagy has been described, its direct effect on autophagosome-lysosome fusion has not been studied. Our findings reveal that aminochrome, like vinblastine, delays autophagosome-lysosome fusion and induces cell death. This inhibitory effect was also observed in the presence of autophagy inducers, which partially attenuated aminochrome-induced cell death. Under these conditions of disruptions in autophagosome-lysosome fusion, a marked accumulation of perinuclear vimentin and ubiquitin aggregates was observed. Aminochrome also increased colocalization between vimentin and ubiquitin. Interestingly, ubiquitin aggregates were also detected within the nucleus. These findings suggest that aminochrome-induced disruption of the microtubule network, particularly its impairment of autophagosome-lysosome fusion and promotion of protein aggregation, may represent a critical mechanism leading to cell death. In addition, inhibition of autophagosome-lysosome fusion may contribute to the accumulation of perinuclear and nuclear protein aggregates, which may be associated with either toxic or non-toxic pathways. Our findings underscore the therapeutic potential of targeting both microtubule stabilization and proteostasis pathways, including autophagy and the ubiquitin-proteasome system (UPS), in Parkinson's disease, highlighting the need for further research into nuclear proteotoxicity mechanisms.
    Keywords:  Parkinson’s disease; aminochrome; autophagy; microtubules; protein aggregation; ubiquitin; vimentin
    DOI:  https://doi.org/10.3390/antiox15060739
  38. Mol Immunol. 2026 Jun 20. pii: S0161-5890(26)00150-1. [Epub ahead of print]196 133-147
    Cordycepin attenuates diabetic nephropathy by dual-pathway activation of TFEB to restore autophagy and ameliorate podocyte injury.
    Jiaqi Li, Shuang Chen, Jialiang Suo, Yuanbiao Ma, Zhengxin Lu, Shenlin Cai, Haoyu Chen, Zhiyu Chen, Zhewen Deng, Chenglun Tang, Qi Zhang, Bo Ma.
      Currently, effective therapeutic strategies to halt the irreversible decline of renal function in diabetic nephropathy (DN) are limited. This study aimed to investigate the renoprotective effects of Cordycepin (COR), a bioactive adenosine analog derived from Cordyceps militaris, in a mouse model of DN and to elucidate its underlying mechanisms. In a type II diabetic mouse model induced by a high-fat diet and streptozotocin, COR treatment attenuated hyperglycemia and renal dysfunction, ameliorated glomerular injury, and restored the expression of Nephrin, a critical slit-diaphragm protein in podocytes. In vitro, in palmitic acid (PA)-induced podocyte injury, COR treatment elevated cell viability and upregulated Nephrin expression dose-dependently. Mechanistically, COR restored impaired autophagic flux under diabetic conditions by improving autophagosome maturation, autophagosome-lysosome fusion, and lysosomal degradation, as demonstrated by the normalized profile of autophagy markers (LC3-II/I, p62, Beclin-1, LAMP1). This pro-autophagic activity was essential for its protection, which was abolished by 3-MA and enhanced by rapamycin. Subsequently, we identified transcription factor EB (TFEB) as the central mediator of COR's action. COR dually regulates TFEB through two synchronized pathways: it inhibits the mTORC1 axis to promote TFEB nuclear translocation and transcriptional activity, while simultaneously suppressing K48-linked polyubiquitination to prevent its proteasomal degradation, and enhancing its stability. TFEB was essential for restoring autophagic flux and podocyte integrity, with overexpression reversing and knockdown exacerbating PA‑induced injury. In summary, our findings demonstrate that COR alleviates DN by coordinately enhancing the activity and stability of TFEB. This work reveals a novel dual-targeting mechanism and proposes a promising therapeutic strategy for diabetic nephropathy.
    Keywords:  Autophagy Flux; Cordycepin (COR); Diabetic nephropathy (DN); Podocyte; TFEB
    DOI:  https://doi.org/10.1016/j.molimm.2026.06.010
  39. Cell Death Dis. 2026 Jun 26.
    GPR107 promotes autophagy secretion in psoriatic keratinocytes by inhibiting BECN1 K48-linked ubiquitination.
    Kainan Liao, Junyan Wang, Jinjin Chen, Dandan Zang, Tiantian Zhou, Nominzul Altankhuyag, Moru Puseletso, Jing Wang, Chunlin Cai, Fusheng Zhou, Deping Xu, Haisheng Zhou.
      Psoriasis is a chronic inflammatory skin disease driven by excessive proliferation and aberrant differentiation of keratinocytes. Autophagy-based unconventional secretory pathway (secretory autophagy) plays key roles in regulating cell proliferation and autosecretion in psoriatic keratinocytes; however, their upstream regulators remain poorly defined. The orphan G protein-coupled receptor 107 (GPR107) mediates signal transduction via clathrin-dependent endocytosis. Here, we report that upregulation of GPR107 in psoriatic keratinocytes promotes both cell proliferation and the secretion of chemokines and antimicrobial peptides through BECN1-dependent autophagy. Mechanistically, internalized GPR107 activates the β-arrestin/ERK/NF-κB pathway. This activation not only drives the direct transcription of inflammatory factors but also negatively regulates the expression of E3-ubiquitin ligase CUL3. The reduction of CUL3 decreases K48-linked ubiquitination at K206 of BECN1, preventing its proteasomal degradation. Stabilization of BECN1 facilitates secretory autophagy in psoriatic keratinocytes, further enhancing their proliferation and inflammatory responses. These findings highlight a novel function of GPR107 in psoriasis, and suggest that the integrated β-arrestin/ERK/NF-κB/CUL3/BECN1 axis may serve as a potential therapeutic target for this disease.
    DOI:  https://doi.org/10.1038/s41419-026-09038-9
  40. Mol Metab. 2026 Jun 25. pii: S2212-8778(26)00093-1. [Epub ahead of print] 102409
    RNASET2 degrades mRNAs that protect against lipotoxicity.
    Shuiling Zhao, Stevens Bontemps, Ryan M Nottingham, Jun Yao, Mariana Acuña, David E Cohen, Alan M Lambowitz, Jean E Schaffer.
       ABSTRACT/OBJECTIVE: RNASET2 is a lysosomal RNase whose enzymatic function is required for early events in lipotoxicity. However, the endogenous RNA substrates of RNASET2 that modulate lipid-induced cell death are not known. The purpose of this study was to identify RNASET2 substrates that impact lipotoxic stress.
    METHODS: RNA sequencing was used to identify RNAs that increase in abundance in human cells upon RNASET2 knockdown, and actinomycin D assays were used to show that RNASET2 impacted decay rates of these RNAs. We tested for the presence of these RNAs in immunoisolated lysosomes and determined the contribution of the lysosomal membrane transporter SIDT2 in delivery of these RNAs to the lysosome. A role for these RNAs in lipotoxic cell death was directly tested in loss- and gain of function analysis.
    RESULTS: RNASET2 knockdown increased steady-state abundance of UCHL3, PFN2 and PRDX3 mRNAs and prolonged their decay rate, leading to increased protein expression. These mRNAs were delivered to the lysosomal lumen by the lysosomal membrane transporter SIDT2 that mediates RNautophagy. While UCHL3 and PFN2 have not previously been implicated in lipotoxic responses, expression of these proteins protected against lipid-induced cell death.
    CONCLUSIONS: Our study identified specific mRNA substrates of RNASET2 and uncovered a previously unexplored function for lysosomes and RNautophagy in regulation of the response to metabolic stress. Moreover, we demonstrated that RNautophagy selectively regulates turnover of specific endogenous RNAs and thereby impacts regulation of gene expression.
    Keywords:  RNA degradation; autophagy; gene expression; lipotoxicity; lysosomes
    DOI:  https://doi.org/10.1016/j.molmet.2026.102409
  41. bioRxiv. 2026 Jun 09. pii: 2026.06.05.730503. [Epub ahead of print]
    Myofibroblast- specific autophagy drives cyst growth in autosomal dominant polycystic kidney disease.
    Abeda Jamadar, Viji Remadevi, Meekha M Varghese, Haichun Yang, Vedant P Thakkar, Indra Chandrasekar, Wen-Xing Ding, Volker H Haase, Darren P Wallace, Reena Rao.
       Background: Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive cyst expansion, fibrosis and inflammation, leading to kidney failure. Myofibroblasts (MFs) often accumulate around cysts and promote fibrosis and cyst growth, but the cellular mechanisms enabling their pro-cystogenic activity remain unclear. Here we examined the role of autophagy within MFs, on their paracrine stimulation of cyst expansion in ADPKD.
    Methods: Autophagy was assessed in human ADPKD nephrectomy tissue, primary human ADPKD renal myofibroblasts (ADPKD-MFs) and male RC/RC mouse model of ADPKD using immunostaining, LC3/p62 analyses, and transmission electron microscopy. Autophagy in MFs was inhibited pharmacologically in ADPKD-MFs, or by conditional Atg5 deletion in PDGFRβ-expressing renal stromal cells in RC/RC (RC/RC;Atg5KO) and wild type (WT;Atg5KO) mice.
    Results: In human and mouse ADPKD kidneys, we detected LC3 puncta and autophagic organelles within αSMA-expressing MFs. Inhibition of autophagy in ADPKD-MFs blocked their paracrine stimulation of cyst epithelial cell proliferation in vitro . RC/RC;Atg5KO mice showed significantly reduced cystic growth, fibrosis, MF abundance, and improved kidney function. WT;Atg5KO mice showed no abnormalities in kidney structure or function. Targeted metabolomics performed on ADPKD cyst epithelial-cell conditioned media (ADPKD-ECs CM) revealed moderate increase in lactate levels compared to normal human kidney epithelial-cell conditioned media. Furthermore, lactate treatment stabilized hypoxia-inducible factor-1α (HIF1α) in myofibroblasts, while pharmacological inhibition of HIF1α reduced the expression of autophagy-related genes and impaired autophagic flux.
    Conclusion: These findings reveal that autophagy in MFs is a previously unrecognized driver of cyst expansion and fibrosis in ADPKD. Lactate-mediated HIF1α stabilization in MFs promotes autophagy that is required for their paracrine stimulation of cyst epithelial growth. Targeting MF-specific autophagy or its upstream regulators may represent a therapeutic strategy to limit cyst growth and fibrosis in ADPKD.
    DOI:  https://doi.org/10.64898/2026.06.05.730503
  42. CNS Neurosci Ther. 2026 06;32(6): e70995
    STING Modulating ER-Phagy in the Prelimbic Cortex Neurons Contributed to Neuropathic Pain and Emotional Comorbidity.
    Yongda Liu, Xu Yang, Shihui Kuai, Xi Chen, Zhibin Wang, Zhongsheng Yang, Xiaochuan Guo, Xin He, Ping Zhao.
       BACKGROUND: Our previous data suggested that autophagy is crucial for neuropathic pain. The different cell types and varying degrees of regulation of STING may lead to a paradoxical effect on pain and emotions in the neuropathic pain model. Up to now, whether STING modulates neuropathic pain in PrL neurons via ER-phagy is still unknown.
    METHOD: In this study, we investigated the effect of ER-phagy in the prefrontal cortex (PrL) on neuropathic pain. We administered 4-phenylbutyric acid, tunicamycin, 3-methyladenine, and rapamycin to evaluate the interaction between endoplasmic reticulum (ER) stress and autophagy in the PrL of SNL (spinal nerve ligation). We injected AAV to investigate whether ER-phagy modulated pain and emotional behaviors. We further explored whether STING and its pathway as a modulation target for ER-phagy to participate in the pain process. We injected 2'3-cGAMP and RU521 to modulate the cGAS/STING pathway in ER-phagy in SNL mice. Moreover, we modulated STING expression and regulated the levels of ER-phagy and the interaction between STING and LC3 in neurons through PrL AAV injections.
    RESULTS: The data indicated that ER-phagy alleviated the excessive ER stress induced by SNL in PrL through the cGAS/STING pathway. Regulating ER-phagy in PrL neurons through AAV tools altered pain and emotion-related behaviors. In addition, regulating STING in PrL neurons altered the comorbidity of pain and emotion. Importantly, the binding interaction between STING and LC3 in PrL neurons provides a novel target for PrL ER-phagy.
    CONCLUSION: Enhanced ER-phagy of PrL neurons provides analgesic, anti-anxiety, and antidepressant effects through modulating STING in SNL mice.
    Keywords:  ER‐phagy; antidepressants; cGAS/STING pathway; neuropathic pain; prelimbic cortex
    DOI:  https://doi.org/10.1002/cns.70995
  43. Proc Natl Acad Sci U S A. 2026 Jun 30. 123(26): e2610001123
    IRE1 regulates the proteostasis of TDP-43/TARDBP in ALS/FTD through ribosome-associated quality control.
    Dongyue Liu, Yu Li, Shuai Huang, Yufang Xu, Lei Sun, Wen Li, Cahir J O'Kane, David C Rubinsztein, Bingwei Lu, Shuangxi Li.
      Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are progressive neurodegenerative disorders characterized by motor neuron degeneration, leading to muscle weakness, atrophy, and cognitive impairments. A defining pathological hallmark of ALS/FTD is the cytosolic mislocalization and accumulation of TAR DNA-binding protein 43 (TDP-43), highlighting its critical role in ALS pathogenesis. However, the molecular mechanisms underlying TDP-43 proteostasis remain poorly understood. Through a genetic screening approach, we identify inositol-requiring enzyme 1 (IRE1), an endoplasmic reticulum-resident transmembrane protein, as a potent suppressor of TDP-43 protein levels. Furthermore, we show that ribosome-associated quality control (RQC) factors play a crucial role in regulating TDP-43 proteostasis and cellular toxicity. Activation of the RQC pathway prevents excessive accumulation of TDP-43 and associated toxicity. Mechanistically, our findings suggest that IRE1 regulates TDP-43 protein level by promoting the degradation of aberrant TDP-43 translation product through the RQC pathway. IRE1 acts canonically to enhance the transcription of the RQC core component Clbn/NEMF and noncanonically to physically interact with Clbn/NEMF, thereby ameliorating TDP-43-induced proteotoxicity. Moreover, ectopic expression or pharmacological activation of IRE1 alleviates TDP-43 pathology and restores cognitive function in the TDP-43 A315T ALS mouse models. Collectively, our study identifies a role for IRE1 in the translational quality control of TDP-43 and establishes its potential as a therapeutic target for ALS/FTD.
    Keywords:  IRE1; TDP-43/TARDBP; ribosome-associated quality control (RQC)
    DOI:  https://doi.org/10.1073/pnas.2610001123
  44. Chin Med J (Engl). 2026 Jun 24.
    Mitochondrial quality control in health and disease: Updates 2026.
    Zhengzhao Liu, Wenbao Hu, Lin Sun, Huafeng Liu.
       ABSTRACT: Mitochondria are central to cellular energy metabolism, and their functional integrity is essential for maintaining cellular homeostasis and life processes. Mitochondrial quality control (MQC) encompasses a complex network of mechanisms-including mitochondrial biogenesis, mitochondrial dynamics, mitophagy, mitochondrial proteostasis, and mitochondrial-derived vesicles-that collectively preserve the structural and functional balance of mitochondria. Recent studies have revealed that dysregulation of MQC is closely associated with a broad spectrum of diseases, such as neurodegenerative disorders, cardiovascular diseases, kidney diseases, metabolic syndrome, and cancers, highlighting its critical role in pathological processes. Despite significant progress in elucidating the molecular regulation of MQC, many aspects of its complexity and multilayered regulatory mechanisms remain unresolved. This review provides a comprehensive overview of the major molecular pathways involved in MQC and their functional alterations under physiological and pathological conditions. It emphasizes the abnormalities of MQC in various diseases and explores potential therapeutic targets. Moreover, integrating the latest research advances, this article discusses emerging treatment strategies aimed at restoring and optimizing MQC, with the goal of offering theoretical insights and clinical translation avenues for future disease prevention and management.
    Keywords:  Cardiovascular disease; Kidney disease; Mitochondria; Mitochondrial dynamics; Mitochondrial quality control; Mitophagy; Neurodegenerative disease; Therapeutic strategies
    DOI:  https://doi.org/10.1097/CM9.0000000000004169
  45. Degener Neurol Neuromuscul Dis. 2026 ;16 608341
    Spermidine in Alzheimer's Disease: Evidence from Animal Models and Human Studies.
    Francesco Angelucci, Jiří Cerman, Jana Amlerova, Katerina Sheardova, Jan Pavlik, Jakub Hort.
      Spermidine is a naturally occurring polyamine involved in multiple cellular processes, including growth regulation, protein translation, and autophagy. Increasing attention has been devoted to its potential neuroprotective effects, particularly in Alzheimer's disease (AD), a neurodegenerative disorder characterized by β-amyloid and phosphorylated tau accumulation, synaptic dysfunction, and progressive neuronal loss. In this narrative review, we examine potential mechanisms through which spermidine may influence AD pathophysiology and summarize available preclinical and clinical evidence. Preclinical studies indicate that spermidine induces autophagy, a key cellular clearance pathway responsible for removing damaged organelles and aggregated proteins. Because impaired neuronal autophagy contributes to the accumulation of β-amyloid and tau in AD, increasing intracellular spermidine levels may enhance the degradation of these toxic species. In addition, spermidine exhibits anti-inflammatory and antioxidant properties, attenuates microglial activation, and supports mitochondrial function. In animal models of AD and brain aging, spermidine administration has been associated with improvements in cognitive performance and synaptic function. However, human clinical evidence remains limited and largely inconclusive. Observational studies suggest associations between higher dietary spermidine intake and better cognitive outcomes, but do not establish causality. Randomized clinical trials to date are few, include small and heterogeneous populations, and have not demonstrated consistent effects on primary cognitive endpoints. Overall, spermidine represents a biologically plausible modulator of pathways relevant to neurodegeneration, but translation of preclinical findings into clinical benefit remains uncertain. Current evidence is insufficient to support its use as a therapeutic or preventive intervention in AD, and further well-designed clinical studies are required to clarify its efficacy and mechanisms of action.
    Keywords:  Alzheimer’s disease; autophagy; cognition; diet; neuroinflammation; spermidine
    DOI:  https://doi.org/10.2147/DNND.S608341
  46. Molecules. 2026 Jun 11. pii: 2055. [Epub ahead of print]31(12):
    Research Progress and Prospects of Flavonoids in the Treatment of Diseases by Regulating Autophagy: A Narrative Review.
    Shuang Xue, Qiao Wang, Xuan Guo, Xingtong Chen, Yunyue Zhou, Jinbiao Yang, Yukun Zhang, Wenying Niu.
      Autophagy is an essential mechanism through which cells break down and reuse intracellular proteins and organelles to preserve cellular homeostasis. Under physiological conditions, autophagy primarily exerts a cytoprotective effect; however, aberrant activation or deficiency of autophagy pathways can disturb cellular balance and even trigger apoptosis, thereby contributing to the occurrence and progression of multiple diseases. Flavonoids are natural bioactive components widely distributed in plants, characterized by distinct benefits of synergistic regulation via multiple targets and pathways. This review summarizes the primary mechanisms of flavonoids, focusing on their potential underlying mechanisms against various diseases-including atherosclerosis, cardiovascular diseases, liver diseases, lung diseases, Parkinson's disease, leukemia, and malignant tumors-via regulating autophagy (including selective autophagy), and sorts out the latest advances in related experimental research over the past five years. In conclusion, flavonoids can effectively ameliorate the pathological processes of multiple diseases by modulating autophagy pathways with favorable biosafety. Nevertheless, low bioavailability remains the core bottleneck restricting their clinical translation. Further optimization of pharmaceutical formulations is warranted to enhance their uptake efficacy in vivo, and rigorous clinical trials are needed to assess their prolonged effectiveness and potential drug interactions, so as to offer new feasible approaches and research directions for the prophylaxis and therapy of various diseases.
    Keywords:  autophagy; disease; flavonoids; research progress; selective autophagy
    DOI:  https://doi.org/10.3390/molecules31122055
  47. Acta Neuropathol. 2026 Jun 26. pii: 73. [Epub ahead of print]151(1):
    VMA21 deficiency leads to autophagic dysregulation and altered vesicle trafficking in X-linked myopathy with excessive autophagy.
    Christian A Suarez, Sara K Pittman, Michio Inoue, Eileen M Lynch, Andrew Moran, Angèle N Merlet, Emmanuelle Lacenne, Teresinha Evangelista, Conrad C Weihl.
      X-Linked myopathy with excessive autophagy (XMEA) is a rare vacuolar myopathy caused by mutations in Vma21, an assembly chaperone required for vacuolar H⁺-ATPase (V-ATPase) function. However, the mechanisms linking Vma21 deficiency to progressive muscle pathology remain poorly understood, in part due to the lack of suitable animal models. To address this gap, we generated conditional Vma21 knockout mouse models to investigate the consequences of Vma21 loss in striated muscle. Combined deletion of Vma21 in skeletal and cardiac muscle resulted in early lethality driven by severe cardiomyopathy associated with autophagic dysregulation, preceding the development of skeletal muscle pathology. In contrast, inducible skeletal muscle-specific deletion of Vma21 produced progressive muscle weakness and myopathy characterized by centralized nuclei, fiber splitting, and increased fiber size variability. Affected skeletal muscle also recapitulated defining pathological hallmarks of XMEA, including basal lamina reduplication and autophagic vacuoles with sarcolemmal features (AVSFs). Ultrastructural analysis revealed membrane-bound vacuoles containing partially undegraded material that frequently accumulated at the subsarcolemmal region, together with clusters of vesicular structures. Notably, mutant muscle exhibited increased staining for the late endosomal/exosomal marker CD63, which strongly colocalized with the complement membrane attack complex C5b-9. A similar increase in CD63 staining and its colocalization with C5b-9 were observed in skeletal muscle biopsies from patients with XMEA. Together, these models faithfully recapitulate key pathological features of XMEA and identify the accumulation of CD63-positive structures and their colocalization with C5b-9 as previously unrecognized features of Vma21-deficient skeletal muscle, implicating altered vesicle trafficking in XMEA pathogenesis.
    Keywords:  Autophagy; Membrane attack complex; VMA21; Vacuolar myopathy; Vesicle trafficking; XMEA
    DOI:  https://doi.org/10.1007/s00401-026-03044-z
  48. Mol Cell Biochem. 2026 Jun 23.
    RBM15 promotes hyperglycemia-induced retinal endothelial cell injury by regulating FOXO3 stability via m6A modification.
    Yang Yu, Yuqing Ren, Su Dong, Jiaqi Yao, Zhijun Chen.
      Diabetic retinopathy (DR), a common microvascular complication of diabetes mellitus, is a leading cause of vision loss among working-age adults. Although N6-methyladenosine (m6A), a prevalent post-transcriptional mRNA modification, is emerging as a key regulator in DR, the specific role of the m6A writer RBM15 in hyperglycemia-induced retinal endothelial cell injury remains poorly defined. Here, we found that RBM15 is upregulated in the retinas of diabetic mice as well as in endothelial cells (ECs) challenged with high glucose (HG). Knockdown of RBM15 significantly mitigated HG-induced apoptosis and rescued autophagy deficiency in retinal ECs. In vivo, downregulation of RBM15 effectively attenuated retinal thinning, acellular capillary formation, and vascular leakage in diabetic mice. Mechanistically, we demonstrated that RBM15 regulates HG-induced apoptosis and autophagy deficiency in ECs by modulating FOXO3 mRNA stability in an m6A-dependent manner. In conclusion, our findings identify the RBM15/m6A/FOXO3 signaling pathway as a critical regulator of HG-induced retinal microvascular dysfunction and highlight RBM15 as a potential therapeutic target for the treatment of DR.
    Keywords:  Apoptosis; Autophagy; Diabetic retinopathy; Endothelial cell; N6-methyladenosine; RBM15
    DOI:  https://doi.org/10.1007/s11010-026-05613-y
  49. Methods Enzymol. 2026 ;pii: S0076-6879(26)00125-4. [Epub ahead of print]731 335-351
    Organelle-directed metabolic glycan labeling.
    Shixiong Wen, Yilong Shi, Enkang Zhang, Jiahuai Han, Shoufa Han.
      Metabolic Glycan Labeling (MGL) is a powerful tool to introduce diverse functional entities on cell surface by bioorthogonal labeling of abiotic sugars expressed on the glycocalyx. Akin to the plasma membrane, the luminal face of the lysosomal membrane is covered with a dense layer of glycans. To date, MGL has been mostly executed to modify cell surfaces. Herein we detail organelle-specific MGL (OMGL) by selective labeling of 9-azidosialic acid (AzSia) residues on the lysosomal inner membrane while sparing those on the cell surface. OMGL entails: (1) metabolic incorporation of AzSia into the global cell glycome; (2) staining of the AzSia-expressing cells with dibenzocyclooctyne (DBCO)-bearing lyso-probes, which can promptly accumulate in lysosomes driven by the acidotropic effect; (3) bioorthogonal ligation of lyso-probes enriched in lysosomes with AzSia on the inner membrane of lysosomes. Overcoming the liability of conventional chemical probes to dissipation from stressed lysosomes, OMGL enables optical tracking of stressed lysosomes in exocytosis and cell death.
    DOI:  https://doi.org/10.1016/bs.mie.2026.05.010
  50. Sci Rep. 2026 Jun 26.
    Characterization of the lysosomal arginine transporter SLC7A14.
    Deborah Giudice, Francesca Barone, Tiziano Mazza, Mariafrancesca Scalise, Lara Console, Cesare Indiveri.
      SLC7A14 is a putative amino acid transporter whose physiological role remains poorly characterized, despite its association with retinal degeneration, auditory defects, and metabolic dysfunctions. Confocal microscopy was performed in HEK293 transiently transfected with the human SLC7A14 (hSLC7A14), demonstrating a lysosomal localization, as previously suggested. To carry on functional and kinetic characterization, the protein was overexpressed in E. coli, and purified from insoluble fraction through affinity chromatography followed by SEC with a yield of 156 mg/L of bacterial cell culture. The homogeneous hSLC7A14 showed an apparent molecular mass of 72 kDa on SDS-PAGE and was reconstituted into proteoliposomes for functional assays. hSLC7A14 showed high specificity towards arginine, not histidine or glutamine, with a measured Km of 1.2 ± 0.21 mM. The arginine transport was inhibited by cysteine and threonine, but not by other amino acids or GABA. Inhibition kinetics identified metformin as an inhibitor of the transporter showing a mixed type of inhibition with a measured Ki in the same order of that of arginine. These findings are in agreement with hSLC7A14 being a specific lysosomal arginine transporter, with potential involvement in the mTORC1 signalling. The described results represent a first step to further elucidate hSLC7A14 role in human physiology and disease. Moreover, the identification of experimental conditions for measuring specific transport activity will allow screening of ligands as inhibitors or functional modulators opening perspectives for structure/function relationship studies.
    Keywords:  Arginine; Lysosomes; Metabolic dysfunction; Metformin; SLC; mTORC1
    DOI:  https://doi.org/10.1038/s41598-026-57824-4
  51. bioRxiv. 2026 Jun 10. pii: 2026.06.09.731205. [Epub ahead of print]
    Mitochondrial degradation of metallothionein enables local zinc mobilization during zinc limitation.
    Austin K Murchison, Julia C Heiby, Hansen Tao, Matthew J Matrongolo, Alessandro Ori, Monther Abu-Remaileh.
      Zinc is an essential structural and enzymatic cofactor for roughly 10% of proteins, including transcription factors, metabolic enzymes, and cytoskeletal components. It also supports critical functions across organelles such as gene regulation in the nucleus, protein folding in the endoplasmic reticulum, and energy production and antioxidant defense in mitochondria. Despite these indispensable roles, the cellular mechanism that recycles zinc to maintain homeostasis during zinc deficiency remains poorly understood. Here, we identify a biphasic response to zinc limitation, which involves the rapid degradation of the zinc-storing metallothionein followed by the degradation, in an autophagy-dependent manner, of other zinc-binding proteins. We show that metallothionein is rapidly imported into the mitochondria to be degraded by the mitoprotease LONP1. Zinc starvation leads to severe mitochondrial dysfunction and metallothionein degradation allows local zinc release to alleviate nutrient stress. Our results reveal a non-canonical, mitochondria-mediated degradation pathway for a nutrient-storing protein that mobilizes zinc locally to maintain metabolic homeostasis and establish mitochondria as active hubs for nutrient recycling.
    DOI:  https://doi.org/10.64898/2026.06.09.731205
  52. Adv Sci (Weinh). 2026 Jun 22. e76239
    RBM12 Maintains Glioma Stem Cells by Activating Amino Acid-Dependent mTORC1 Signaling via SLC7A5 mRNA Stabilization.
    Hong Lei, Wenlong Luo, Shu Zhou, Lihao Wan, Peng Ling, Zhihua Huang, Zhihua Qian, Chenfei Lu, Mengyue Guo, Zhen Xue, Jun Qin, Ningwei Zhao, Jianghong Man, Wenchao Zhou, Zhiqiang Dong, Shutong Xu, Zhipeng Zhou, Xiuxing Wang, Weiwei Tao.
      Reprogramming of amino acid metabolism is crucial for the rapid proliferation of cancer cells, including cancer stem cells. However, the molecular mechanisms underlying this reprogramming in glioma stem cells (GSCs) remain poorly understood. Here, we report that the RNA-binding protein RBM12 increases the intracellular levels of large neutral amino acids, thereby activating the mTORC1 pathway and promoting GSC proliferation, self-renewal, and glioblastoma (GBM) growth. Mechanistically, RBM12 stabilizes the mRNA of the amino acid transporter SLC7A5, thereby increasing intracellular levels of large neutral amino acids, which subsequently activates the mTORC1 pathway. Further studies reveal that RBM12 enhances SLC7A5 mRNA stability by recruiting ALKBH5 to remove m6A modifications on SLC7A5 mRNA. Importantly, pharmacological inhibition of the RBM12-SLC7A5 axis using the SLC7A5 inhibitor JPH203 effectively suppresses GBM growth. These findings elucidate a novel role for RBM12-SLC7A5 signaling in the malignant growth of GBM and highlight the therapeutic potential of targeting this axis for GBM treatment.
    Keywords:  RBM12; SLC7A5; amino acid metabolism; glioblastoma; glioma stem cells; mTORC1 pathway
    DOI:  https://doi.org/10.1002/advs.76239
  53. Nat Commun. 2026 Jun 25. pii: 5135. [Epub ahead of print]17(1):
    Karyoptosis mediates cell death and neurodegeneration upon proteotoxic stress.
    Rebecca Casterton, Aitana Martinez-Cotrina, Jodi Barnard, Eleanor Wycherley, Yanling Hu, Rhys Anderson, Sebastien Janel, Jiin Byun, Olivia Houghton, Daniel A Solomon, Juan Alcalde, Frank Lafont, Marc-David Ruepp, Frank Hirth, Bart Tummers, Yong-Yeon Cho, Gian De Nicola, Sarah Mizielinska, Manolis Fanto.
      Neurodegenerative diseases are frequently associated with proteotoxic stress linked to disease specific proteins. The autophagy-lysosome system provides essential control of proteotoxic stress and its failure can lead to initiation of apoptosis. However, in aging and neurodegenerative diseases apoptosis is insufficient to account for all neuronal death, and several different cell death types have been reported in these contexts. Here we show that karyoptosis, a distinct form of cell death, can be induced by proteotoxic stress and then develops through nuclear degeneration and cellular expulsion of nuclear material. We establish that karyoptosis is regulated by the p38 kinase signalling pathway, which controls stability of the nuclear lamina protein LaminB1 via direct phosphorylation. We demonstrate that karyoptosis affects neurons in models of amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) pathology. Finally, we identify karyoptotic features in post-mortem frontal cortex of FTD and Alzheimer's disease (AD) patients. Together these findings characterise a form of cell death directly linked to proteotoxic stress and nuclear lamina stability that is associated with neurodegeneration.
    DOI:  https://doi.org/10.1038/s41467-026-73802-w
  54. Nature. 2026 Jun 24.
    Dietary cholesterol activates a Ral-dependent pathway driving LDLR turnover.
    Xue Feng, Shuo Zhang, Yuqi Wang, Twisha Kurlagunda, Allyssa Sit, Priyadarshini Jaishankar, Pusu Yang, Sadatsugu Sakane, Se Yong Park, Churaibhon Wisessaowapak, Kaylee Nguyen, Jamie Yan, Himani Pothulu, Catherine Dinh, Felicia Chu, Yuyao Ren, Bichen Zhang, Patrick Secrest, Linmeng Han, Chao-Wei Hung, Preethi Veeragandham, Yuliya Skorobogatko, Tatiana Kisseleva, Philip L S M Gordts, Adam R Renslo, Peng Zhao, Amit R Majithia, Alan R Saltiel.
      Metabolism of the hepatic low-density lipoprotein receptor (LDLR) is a key determinant of cholesterol homeostasis1,2. The molecular switches that coordinate LDLR trafficking and turnover in response to nutritional cues, including high dietary cholesterol, remain poorly defined3-6. Here we identify a new pathway regulated by Ral GTPases that links extracellular cholesterol signals to the intracellular trafficking machinery controlling LDLR turnover. Chronic dietary cholesterol activates the Ral proteins by increasing RAS activity, routing LDLR to lysosomes for degradation and inhibiting its recycling independently of transcriptional regulation or PCSK9. Constitutive activation of Ral via RalGAPB deletion or overexpression of constitutively active Ral mutants in hepatocytes reduces LDLR levels and impairs cholesterol clearance. Ral engages the endocytic RalBP1-REPS1 complex to promote LDLR internalization and lysosomal routing, where LDLR is degraded by the lysosomal protease cathepsin A (CTSA). Ral activation directs CTSA towards lysosomes for maturation while limiting its secretion, further promoting LDLR degradation in lysosomes. Genetic variants in this pathway significantly associate with altered cholesterol in humans. Pharmacological inhibition of CTSA activity increases hepatic LDLR function and improves cholesterol clearance, offering a potential new therapeutic strategy for hypercholesterolaemia and cardiovascular disease.
    DOI:  https://doi.org/10.1038/s41586-026-10697-z
  55. Autophagy. 2026 Jun 21.
    EGR1 mediates neuronal damage via suppressing HIF1A-induced mitophagy following traumatic brain injury.
    Xiaoxiang Hou, Danfeng Zhang, Xianzheng Sang, Chaogui Peng, Wen Chen, Jing Xu, Yichao Ye, Yangu Guo, Hantong Shi, Chengzi Yang, Hanzi Cai, Yijian Wang, Guangxin Chu, Haoxiang Xu, Liquan Lv, Hai Jin, Chunhui Wang, Xiaolin Qu.
      Traumatic brain injury (TBI) remains a leading cause of neurological morbidity and mortality, characterized by complex pathophysiological cascades. Here, we investigate the role of the transcription factor EGR1 (early growth response 1) in modulating mitochondrial homeostasis via the HIF1A (hypoxia inducible factor 1, alpha subunit)-BNIP3 (BCL2/adenovirus E1B interacting protein 3) axis following TBI. Using integrated transcriptomic and epigenomic analyses, we identified EGR1 as a critical regulator of TBI pathology, with its expression acutely upregulated in neurons post-injury. Genetic ablation of Egr1 in mice significantly reduced neuronal apoptosis, preserved dendritic integrity, and ameliorated cognitive and sensorimotor deficits. Mechanistically, chromatin immunoprecipitation and luciferase assays revealed that EGR1 directly binds to the Hif1a promoter, repressing its transcription. Loss of EGR1 enhanced HIF1A-BNIP3-mediated mitophagy, reducing mitochondrial dysfunction and oxidative stress both in vitro and in vivo. Conversely, silencing HIF1A or BNIP3 abrogated the neuroprotective effects of EGR1 deficiency. These findings establish a novel EGR1-HIF1A-mitophagy signaling axis as a key determinant of TBI outcomes, highlighting EGR1 as a potential therapeutic target. Abbreviations: AAV: adeno-associated virus; ACTB/β-actin: actin, beta; AIF1/IBA1: allograft inflammatory factor 1; BAF: bafilomycin A1; BNIP3: BCL2/adenovirus E1B interacting protein 3; CCI: controlled cortical impact; COX8: cytochrome c oxidase subunit 8; CUT&Tag: cleavage under targets and tagmentation; DAPI: 4,'6-diamidino-2-phenylindole; DEGs: differentially expressed genes; eGFP: enhanced green fluorescent protein; EGR1: early growth response 1; GFAP: glial fibrillary acidic protein; GO: gene ontology; GSEA: gene set enrichment analysis; HCQ: hydroxychloroquine; HIF1A/HIF-1α: hypoxia inducible factor 1, alpha subunit; IGV: integrative genomics viewer; KEGG: Kyoto encyclopedia of genes and genomes; KO: knockout; LAMP1: lysosomal-associated membrane protein 1; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; Lv: lentivirus; MAP2: microtubule-associated protein 2; mCherry: monomeric cherry fluorescent protein; mRFP: monomeric red fluorescent protein; MTOR: mechanistic target of rapamycin kinase; MUT: mutant; MWM: Morris water maze; NAB1: Ngfi-A binding protein 1; NAB2: Ngfi-A binding protein 2; RBFOX3/NeuN: RNA binding protein, fox-1 homolog (C. elegans) 3; OGD: oxygen-glucose deprivation; OLIG2: oligodendrocyte transcription factor 2; PBS: phosphate-buffered saline; PECAM1/CD31: platelet/endothelial cell adhesion molecule 1; PFA: paraformaldehyde; PPI: protein-protein interaction; Puro: puromycin; ROI: region of interest; ROS: reactive oxygen species; SEM: standard error of the mean; SQSTM1/p62: sequestosome 1; TBI: traumatic brain injury; TOMM20: translocase of outer mitochondrial membrane 20; TSA: tyramide signal amplification; TUNEL: terminal deoxynucleotidyl transferase dUTP nick end labeling; VDAC1: voltage-dependent anion channel 1; WT: wild-type.
    Keywords:  EGR1; HIF1A; mitophagy; neuron; traumatic brain injury
    DOI:  https://doi.org/10.1080/15548627.2026.2693261
  56. Autophagy. 2026 Jun 22.
    Emodin induces defensive autophagy against white spot syndrome virus infection via targeting the hemocyanin-mediated endoplasmic reticulum-mitochondrial crosstalk in shrimp.
    Xu Zhang, Li-Peng Shan, Lei Liu, Jiong Chen.
      White spot syndrome virus (WSSV) devastates shrimp aquaculture, yet safe antivirals remain scarce. Here we identify a druggable host-directed pathway centered on hemocyanin (HMC). This pathway coordinates endoplasmic reticulum (ER)-mitochondrial crosstalk to promote WSSV replication, which could be counteracted by the natural anthraquinone emodin. In Litopenaeus vannamei, emodin suppressed viral replication with a half maximal inhibitory concentration (IC50) of 1.174 μM, improved survival in both therapeutic and prophylactic regimens, remained effective after per os administration, and retained antiviral activity in water for up to 4 d. Target fishing, orthogonal biophysics, and docking analyses show that emodin binds HMC (Kd = 4.49 μM) and interferes with HMC-HSPA5/BiP (heat shock protein family A (Hsp70) member 5) association. Mechanistically, emodin weakens the ITPR/IP3R (inositol 1,4,5-trisphosphate receptor)-VDAC (voltage dependent anion channel)-MCU (mitochondrial calcium uniporter) conduit at ER-mitochondrial contact sites, thereby limiting Ca2+ transfer, restoring mitochondrial membrane potential and organelle spacing, and attenuating ER stress. Untargeted metabolomics revealed that WSSV induced phosphoinositide and amino acid dysregulation, whereas emodin selectively normalizes phosphatidylinositol (PtdIns) and phosphatidylinositol 1,4,5-trisphosphate (PtdIns[1,4,5]P3) signaling and rebalances amino acid, tricarboxylic acid (TCA) intermediates. Correspondingly, emodin inhibited phosphoinositide 3-kinase (PI3K)-AKT/protein kinase B-MTOR (mechanistic target of rapamycin kinase) complex 1 (MTORC1) signaling and restored lysosome-dependent macroautophagy/autophagy. HMC RNAi or ITPR and MCU inhibition phenocopied emodin, whereas exogenous HMC or ER stress activation exacerbated infection and was mitigated by emodin or MCU blockade. These findings establish HMC-anchored ER-mitochondrial contact as a central proviral vulnerability and position emodin as a practical scaffold for next-generation antivirals in aquaculture.
    Keywords:  Active monomer; Ca2+ homeostasis; MAMs; WSSV; antiviral; autophagy; hemocyanin
    DOI:  https://doi.org/10.1080/15548627.2026.2693254
  57. bioRxiv. 2026 Jun 10. pii: 2026.06.08.730917. [Epub ahead of print]
    The p97 adaptor p47/NSFL1C is necessary for stress granule dissolution after heat stress.
    Michelle A Johnson, Richa Khanna, Sirisha Mukkavalli, Ly Nguyen, Malavika Raman.
      Stress granules form in response to diverse cellular perturbations to sequester translation components until the stress is resolved. Stress granules are composed of RNA-protein assemblies in membrane delimited structures and must be rapidly disassembled to release components to allow translation to resume. Disassembly of stress granules formed in response to heat stress is dependent on ubiquitiylation of stress granule components such as G3BP1. Ubiquitylation of stress granule proteins recruits the AAA-ATPase p97 (also known as VCP) to enable ubiquitin-dependent disassembly of these structures. Loss of p97 activity leads to the persistence of stress granules and is implicated in several age-related neurodegenerative diseases. Here we show that p97 recruitment to stress granules is dependent on its ubiquitin binding co-factor p47. p47 translocates to stress granules in response to a variety of cellular stressors and is required for the recruitment of p97 to stress granules. Loss of p47 leads to an inhibition in stress granule disassembly. We further show that p47 associates with G3BP1 in response to heat stress in a ubiquitin-dependent manner. Taken together our data adds to the growing list of p97 adaptors that are implicated in the recruitment of p97 for dissolution of stress granules.
    DOI:  https://doi.org/10.64898/2026.06.08.730917
  58. Oncogene. 2026 Jun 20.
    Hypoxia-induced MIC19 myristoylation promotes PRKN-dependent VDAC2 ubiquitination and activates mitophagy in non-small cell lung cancer.
    Hua Huang, Chen Ding, Zexia Zhao, Wenhao Zhao, Guorui He, Hongbing Zhang, Peijie Chen, Yongwen Li, Hongyu Liu, Jun Chen.
      Tumor hypoxia drives mitophagy reprogramming to support mitochondrial quality control in non-small cell lung cancer (NSCLC) cells, yet the role of the mitochondrial cristae organizers remains poorly understood. Here, we identified MIC19, a key subunit of mitochondrial contact site and cristae organizing system complex, as an essential regulator of hypoxia-induced mitophagy in NSCLC. We demonstrate that prolonged hypoxia induces MIC19 protein expression in a HIF-1α-dependent manner and that elevated MIC19 promotes NSCLC cell proliferation and metastasis. MIC19 sustains mitochondrial morphology and mitophagy activation under hypoxic stress. Mechanistically, HIF-1α transcriptionally upregulates NMT1, an N-myristoyltransferase that catalyzes N-myristoylation at Gly2 of MIC19 protein, which is essential for the mitochondrial localization and protein stability of MIC19. MIC19 facilitates PRKN-dependent K48-linked ubiquitination of the outer mitochondrial membrane protein voltage-dependent anion channel 2 (VDAC2), thereby promoting mitophagy progression under hypoxic stress. Therapeutically, suppression of MIC19 via shRNA combined with pharmacological inhibition of autophagy using chloroquine synergistically impairs NSCLC tumor growth in vivo. Collectively, these findings uncover a previously unrecognized HIF-1α-NMT1-MIC19-VDAC2 axis that drives hypoxia-adaptive mitophagy and reveals a potential therapeutic vulnerability in hypoxic NSCLC.
    DOI:  https://doi.org/10.1038/s41388-026-03847-0
  59. Dev Cell. 2026 Jun 25. pii: S1534-5807(26)00198-X. [Epub ahead of print]
    The ALS- and FTD-associated proteins annexin A11 and CHMP2B act sequentially in plasma membrane repair.
    Catherine M Heffner, Georgina P Starling, Lorian C Straker, Philippa C Hawes, Adrian M Isaacs, Jeremy G Carlton.
      Maintenance of plasma membrane integrity is essential for compartmentalization of the cytosol and for cellular viability. Upon membrane damage, several factors including endosomal sorting complex required for transport-III (ESCRT-III) proteins, annexins, stress granules, lipids, and membrane fusion proteins are mobilized to orchestrate membrane repair. However, whether these factors operate independently or act together is unclear. Here, using human cell lines, we expose temporal differences and interdependencies in the recruitment of ESCRT-III and annexin proteins to sites of plasma membrane damage. We show that annexin proteins are recruited immediately and form a plug at the damage site, restricting membrane permeability. We find that ESCRT-III assembles later and acts to release plug-containing damaged membranes from the cell. Further, frontotemporal dementia (FTD)- and amyotrophic lateral sclerosis (ALS)-associated mutations in the ESCRT-III protein, CHMP2B, and the annexin protein, ANXA11, compromise plasma membrane repair, suggesting that defects in this process may contribute to these pathologies. These data present an integrated "sealing and healing" model of membrane repair.
    Keywords:  ALS; ANXA11; CHMP2B; ESCRT-III; FTD; annexin; membrane repair; pore-forming toxin
    DOI:  https://doi.org/10.1016/j.devcel.2026.05.014
  60. Nat Commun. 2026 Jun 22.
    AOC1 regulates labor initiation through spermidine-induced autophagy of placental trophoblast cells via EIF5A hypusination.
    Huaiyan Chen, Peihua Long, Zhe Wang, Ruoheng Du, Chagui Zheng, Zhuo Li, Yihuan Xu, Qiaozhen Peng, Xuesong Sui, Yanyu Sui, Xiang Jiang, Qin Li, Lu Gao.
      Parturition depends on precise communication between the mother and fetus. While fetal lung signals are known to help initiate labor, the role of the placenta has remained unclear. Here we show that in steroid receptor coactivator (Src)-1 and -2 double-knockout mice, reduced placental amine oxidase, copper-containing 1 (Aoc1) leads to increased spermidine levels. In trophoblast cells, spermidine induces autophagy via hypusination of eukaryotic translation initiation factor 5 A (EIF5A), reducing estrogen and prostaglandin production. Estrogen reciprocally increases Aoc1 expression via estrogen receptor-α (ERα) in concert with SRC-1/2, forming a feedback loop maintaining placental autophagy homeostasis. AOC1 levels are elevated in preterm labor placentas from both mice and humans. Placenta-specific Aoc1 knockout dramatically delays labor by increasing trophoblast autophagy. Importantly, spermidine supplementation rescues inflammation-induced preterm labor in mice. Our findings reveal that placental AOC1-spermidine-EIF5A-autophagy axis is essential for parturition timing and offer a potential therapeutic strategy for preterm birth.
    DOI:  https://doi.org/10.1038/s41467-026-74698-2
  61. Autophagy. 2026 Jun 25.
    TMEM184A-mediated autophagy in MHC-I degradation promotes tumor immune evasion.
    Wenyi Li, Kejun Li, Zhimin Shi, Yuehong Chen, Mingzhen Cheng, Bohou Zhao, Shunyi Wang, Shizhe Diao, Shengzhi Ye, Xianzhe Wang, Jin Li, Zijing Zhang, Yuanyuan Qiao, Wenjun Xiong, Wei Wang, Wenhui Ma.
      The dominance of immunotherapy-insensitive MSS colorectal cancers (CRCs), which represent most cases, contrasts sharply with the treatable MSI-H minority, making this disparity a key obstacle to progress. It is urgent to identify genes driving immune evasion in MSS CRCs. Here, using a genome-wide CRISPR screen in a syngeneic tumor model under immune pressure, we identify TMEM184A as a previously unknown tumor-intrinsic regulator of immune evasion. Its genetic deletion in murine models enhanced CD8+ T cell infiltration and increased surface MHC-I expression on cancer cells, as shown by flow cytometry, immunohistochemistry, immunofluorescence and RNA-seq. Mechanistically, TMEM184A functions as a novel macroautophagy/autophagy receptor by binding GABARAPL2, directly promoting the autophagic degradation of IFNG-induced MHC-I. In murine models, genetic deletion of Tmem184a led to a significant increase in both CD8+ T cell infiltration and surface MHC-I expression on cancer cells. Functional studies in vivo and in vitro confirmed that this impaired antigen presentation causally facilitates immune evasion. Our findings establish MHC-I autophagic degradation as a critical pathway regulating immune evasion and position TMEM184A as a pivotal molecular hub in this process. Notably, treatment with the autophagy inhibitor chloroquine significantly increased surface MHC-I levels and enhanced the efficacy of anti-PDCD1/PD-1 therapy specifically in TMEM184A-high tumors. This work suggests that targeting TMEM184A or its associated autophagic pathway could restore antigen presentation in MHC-I-deficient tumors, offering a potential combinatorial strategy to overcome adaptive immune resistance in multiple malignancies. Abbreviations: AKP organoids:apcandtrp53knockout, KRASG12Dmutation organoids; CRC: colorectal cancer; CQ: chloroquine; GABARAPL2/Atg8: GABA type A receptor associated protein like 2; IF: immunofluorescence; IFNG: interferon gamma; IHC: immunohistochemistry; MHC-I: major histocompatibility complex I; qRT-PCR: quantitative reverse transcription PCR; MSI-H: microsatellite instability-high; MSS: microsatellite-stable; TMEM184A: transmembrane proteins 184a.
    Keywords:  Chloroquine; MHC-I degradation; colorectal cancer; immune checkpoint blockade; immune evasion
    DOI:  https://doi.org/10.1080/15548627.2026.2695316
  62. Redox Biol. 2026 Jun 23. pii: S2213-2317(26)00268-5. [Epub ahead of print]95 104269
    Metabolism, autophagy, and cell death: The triangular axis in tumor survival and therapeutic resistance.
    Wen-Dong Wan, Muhammad Tufail, Can-Hua Jiang, Ning Li.
      Tumor cells face constant environmental and therapeutic stresses, relying on interconnected survival mechanisms involving autophagy, metabolism, and cell death regulation. This review explores the triangular relationship between these processes and how their dynamic interplay supports tumor growth and drives resistance to various treatments. We discuss key molecular pathways regulating autophagy and metabolic reprogramming, and their impact on different cell death modalities. Finally, we address current challenges in translating this knowledge into clinical therapies, emphasizing the need for precise biomarkers and combination strategies to overcome resistance. Understanding this complex network offers promising avenues for developing more effective cancer treatments.
    Keywords:  Autophagy; Cell death; Metabolic reprogramming; Therapeutic approaches; Tumor survival and resistance
    DOI:  https://doi.org/10.1016/j.redox.2026.104269
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