bims-auttor Biomed News
on Autophagy and mTOR
Issue of 2025–03–23
57 papers selected by
Viktor Korolchuk, Newcastle University
  1. Advances in mitophagy initiation mechanisms.
  2. The primate-specific Nedd4-1(NE) localizes to late endosomes in response to amino acids to suppress autophagy.
  3. ATG2A-WDR45/WIPI4-ATG9A complex-mediated lipid transfer and equilibration during autophagosome formation.
  4. Critical role of microRNAs in cellular quality control during brain aging and neurological disorders: Interplay between autophagy and proteostasis.
  5. Targeting autophagy in autoimmune glomerular diseases.
  6. Investigation of dynamic regulation of TFEB nuclear shuttling by microfluidics and quantitative modelling.
  7. The Whi2-Psr1-Psr2 complex selectively regulates TORC1 and autophagy under low leucine conditions but not nitrogen depletion.
  8. Molecular mechanism on autophagy associated cardiovascular dysfunction in Drosophila melanogaster.
  9. TBK1 is a signaling hub in coordinating stress-adaptive mechanisms in head and neck cancer progression.
  10. PPM1D ameliorates Alzheimer's disease by promoting mitophagy.
  11. DNA damage response regulator ATR licenses PINK1-mediated mitophagy.
  12. Mitochondrial quality control in cardiomyocytes: safeguarding the heart against disease and ageing.
  13. H3K36me2 methyltransferase NSD2/WHSC1 promotes triple-negative breast cancer metastasis via activation of ULK1-dependent autophagy.
  14. Chaperone-mediated autophagy degrades SERPINA1E342K/α1-antitrypsin Z variant and alleviates cell stress.
  15. Enhanced alpha-synuclein pathology and exacerbated motor dysfunction in alpha-synuclein transgenic mice with autophagy deficiency.
  16. Natural Compounds and their Nano-formulations in Combating Autophagy-mediated Drug Resistance in Human Cancers.
  17. Targeting PI3K inhibitor resistance in breast cancer with metabolic drugs.
  18. Autophagy in tumor immune escape and immunotherapy.
  19. Gallic acid relieved bortezomib-induced peripheral neurotoxicity by restoring Schwann cell lysosomal activity.
  20. UXT oligomerization is essential for its role as an autophagy adaptor.
  21. Protein kinase-mediated inhibition of autophagy by palmitic acid in hepatocytes.
  22. Adsl-produced fumarate increases BECN1 dimethylation to promote autophagy and liver tumor growth.
  23. Tau degradation in Alzheimer's disease: Mechanisms and therapeutic opportunities.
  24. Autophagy related genes polymorphisms in Parkinson's Disease; A systematic review of literature.
  25. Mitochondria-Lysosome Contact Sites: Emerging Players in Cellular Homeostasis and Disease.
  26. Bioengineering the metabolic network of CAR T cells with GLP-1 and Urolithin A increases persistence and long-term anti-tumor activity.
  27. ROS Regulate Rotenone-induced SH-SY5Y Dopamine Neuron Death Through Ferroptosis-mediated Autophagy and Apoptosis.
  28. The autophagy protein ATG14 safeguards against unscheduled pyroptosis activation to enable embryo transport during early pregnancy.
  29. Disruption of Oligodendroglial Autophagy Leads to Myelin Morphological Deficits, Neuronal Apoptosis, and Cognitive Decline in Aged Mice.
  30. Endosomal-lysosomal organellar assembly (ELYSA) structures coordinate lysosomal degradation systems through mammalian oocyte-to-embryo transition.
  31. Kit-mediated autophagy suppression driven by a viral oncoprotein emerges as a crucial survival mechanism in Merkel cell carcinoma.
  32. mTORC1 activation drives astrocyte reactivity in cortical tubers and brain organoid models of TSC.
  33. SIRT3-PINK1-PKM2 axis prevents osteoarthritis via mitochondrial renewal and metabolic switch.
  34. PTK6 drives HNRNPH1 phase separation to activate autophagy and suppress apoptosis in colorectal cancer.
  35. The structure-function relationship of ATE1 R-transferase of the autophagic Arg/N-degron pathway.
  36. Injectable sustainable andrographolide-releasing hydrogel for long-lasting alleviation of osteoarthritis and regulation of chondrocyte autophagy via PRKCA/EGFR.
  37. Highly spatial-temporal electrochemical profiling of molecules trafficking at a single mitochondrion in one living cell.
  38. FP receptor inhibits autophagy to aggravate aging-related cardiac fibrosis through PI3K/AKT/mTOR signaling pathway.
  39. Identification of lysosomal lipolysis as an essential noncanonical mediator of adipocyte fasting and cold-induced lipolysis.
  40. What are the ethical limits of claimed scientific authorship? a case report of relevance.
  41. Murine Leukemia Virus GlycoGag Antagonizes SERINC5 via ER-phagy Receptor RETREG1.
  42. AMPK-dependent Parkin activation suppresses macrophage antigen presentation to promote tumor progression.
  43. Candida glabrata subverts intracellular trafficking and modulates autophagy to replicate in human epithelial cells.
  44. Inhibition of autophagy promotes ultrasound‑targeted microbubble destruction-induced apoptosis of pancreatic cancer cells.
  45. MicroRNA-124a/Sirtuin 1 pathway inhibits autophagy to promote hepatocyte apoptosis in acute-on-chronic liver failure.
  46. The Alpha-coronavirus E protein inhibits the JAK-STAT pathway signaling by triggering STAT2 degradation through OPTN- and NBR1-mediated selective autophagy.
  47. TOR and heat shock response pathways regulate peroxisome biogenesis during proteotoxic stress.
  48. Acute Restraint Stress Induces Long-Lasting Synaptic Enhancement by Inhibiting AMPK Activation in AD Model Mice.
  49. N-acetylserotonin derivative ameliorates hypoxic-ischemic brain damage by promoting PINK1/Parkin-dependent mitophagy to inhibit NLRP3 inflammasome-induced pyroptosis.
  50. Pten Loss Triggers Progressive Photoreceptor Degeneration in an mTORC1-Independent Manner.
  51. Atg5 in microglia regulates sex-specific effects on postnatal neurogenesis in Alzheimer's disease.
  52. Extracellular vesicles derived from mesenchymal stem cells alleviate renal fibrosis via the miR-99b-5p/mTOR/autophagy axis in diabetic kidney disease.
  53. Mitochondrial oxidative stress or decreased autophagy in osteoblast lineage cells is not sufficient to mimic the deleterious effects of aging on bone mechanoresponsiveness.
  54. Luteolin Inhibits Dexamethasone-Induced Osteoporosis by Autophagy Activation Through miR-125b-5p/SIRT3/AMPK/mTOR Axis, an In Vitro and In Vivo Study.
  55. TBCK-deficiency leads to compartment-specific mRNA and lysosomal trafficking defects in patient-derived neurons.
  56. Optogenetic tools for inducing organelle membrane rupture.
  57. PTBP2 promotes cell survival and autophagy in chronic myeloid leukemia by stabilizing BNIP3.
  1. Curr Opin Cell Biol. 2025 Mar 20. pii: S0955-0674(25)00031-6. [Epub ahead of print]94 102493
    Advances in mitophagy initiation mechanisms.
    Catharina Küng, Michael Lazarou, Thanh Ngoc Nguyen.
      Mitophagy is an important lysosomal degradative pathway that removes damaged or unwanted mitochondria to maintain cellular and organismal homeostasis. The mechanisms behind how mitophagy is initiated to form autophagosomes around mitochondria have gained a lot of interest since they can be potentially targeted by mitophagy-inducing therapeutics. Mitophagy initiation can be driven by various autophagy receptors or adaptors that respond to different cellular and mitochondrial stimuli, ranging from mitochondrial damage to metabolic rewiring. This review will cover recent advances in our understanding of how mitophagy is initiated, and by doing so reveal the mechanistic plasticity of how autophagosome formation can begin.
    DOI:  https://doi.org/10.1016/j.ceb.2025.102493
  2. Nat Commun. 2025 Mar 18. 16(1): 2682
    The primate-specific Nedd4-1(NE) localizes to late endosomes in response to amino acids to suppress autophagy.
    G Kefalas, A Priya, A Astori, A Persaud, L Jing, A M Sydor, H H Y Yao, N Warner, Y Zhang, J H Brumell, A M Muise, S Sari, H C Su, M J Lenardo, W H A Kahr, B Raught, D Rotin.
      The ubiquitin ligase Nedd4 (Nedd4-1), comprised of C2-WW(n)-HECT domains, regulates protein trafficking. We recently described a primate-specific Nedd4-1 splice isoform with an extended N-terminus replacing the C2 domain, called Nedd4-1(NE). Here, we show that while canonical Nedd4-1 is primarily localized to the cytosol, Nedd4-1(NE) localizes to late endosomes. This localization is mediated by the NE region, is dependent on amino acid availability, is independent of mTORC1, and is inhibited by the autophagy inducer IKKβ. We further demonstrate that VPS16B, which regulates late endosome to lysosome maturation, is a unique Nedd4-1(NE) substrate that co-localizes with Nedd4-1(NE) in the presence of nutrients. Importantly, a potentially pathogenic homozygous variant identified in the NE region (E70Q) of a patient with lymphangiectasia and protein-losing enteropathy leads to reduced VPS16B ubiquitination by Nedd4-1(NE). Finally, we report that Nedd4-1(NE) inhibits autophagy, likely by disrupting late endosome to autophagosome maturation. This work identified an mTORC1-independent, IKK-driven mechanism to regulate Nedd4-1(NE) localization to late endosomes in primates in response to nutrient availability, and uncovered suppression of autophagy by this ubiquitin ligase.
    DOI:  https://doi.org/10.1038/s41467-025-57944-x
  3. Autophagy. 2025 Mar 21. 1-3
    ATG2A-WDR45/WIPI4-ATG9A complex-mediated lipid transfer and equilibration during autophagosome formation.
    Yang Wang, Goran Stjepanovic.
      Macroautophagy/autophagy is a highly conserved cellular process, spanning from yeast to humans, and plays a vital role in maintaining cellular homeostasis. Dysregulation of autophagy has been linked to a wide range of diseases. A hallmark of autophagy is the formation of double-membrane vesicles called autophagosomes. Autophagosome biogenesis requires a large number of phospholipids, with the endoplasmic reticulum (ER) being the main lipid source. The ATG2A-WDR45/WIPI4-ATG9A complex serves as the core machinery responsible for lipid transfer and equilibration during this process. In our recent study, we resolved the cryo-electron microscopy (cryo-EM) structures of the ATG2A-WDR45/WIPI4 and ATG2A-WDR45/WIPI4-ATG9A complexes, providing critical insights into their architecture and function. Additionally, molecular dynamics simulations were employed to investigate the mechanism by which ATG2A mediates lipid extraction from donor membranes. Our findings offer structural and mechanistic insights into the spatially coupled processes of lipid transfer and re-equilibration, which are essential for phagophore membrane expansion.Abbreviation: ATG: autophagy related; ATG2A: autophagy related 2A; ATG2A[NR]: ATG2A N-terminal region; ATG9A: autophagy related 9A; cryo-EM: cryo-electron microscopy; cryo-ET: cryo-electron tomography; ER: endoplasmic reticulum; PtdIns3P: phosphatidylinositol-3-phosphate; SpAtg2[NR]: Schizosaccharomyces pombe Atg2 N-terminal region; SUVs: small unilamellar vesicles; TGN: trans-Golgi network; TMEM41B: transmembrane protein 41B; VMP1: vacuole membrane protein 1; WDR45/WIPI4: WD repeat domain 45.
    Keywords:  ATG2A-ATG9A complex; Cryo-EM; autophagosome formation; phospholipid scramblases; phospholipid transfer
    DOI:  https://doi.org/10.1080/15548627.2025.2473388
  4. Life Sci. 2025 Mar 13. pii: S0024-3205(25)00197-3. [Epub ahead of print]369 123563
    Critical role of microRNAs in cellular quality control during brain aging and neurological disorders: Interplay between autophagy and proteostasis.
    Rajesh Tamatta, Abhishek Kumar Singh.
      A decline in cellular quality control mechanisms is one of the processes of brain aging. Autophagy and proteostasis are two regulatory mechanisms that maintain cellular component turnover to preserve cellular homeostasis, optimal function, and neuronal health by eliminating damaged and aggregated proteins and preventing neurodegenerative disorders (NDDs). Impaired autophagy and proteostasis are significant hallmarks of aging and many age-related NDDs. MicroRNAs are noncoding RNA molecules that have recently been shown to be essential for regulating several biological processes, such as autophagy, proteostasis, cellular differentiation, and development by targeting mRNA's 3'untranslated region (3'UTR). During brain aging, miRNAs have been shown to dysregulate proteostasis and autophagy, resulting in abnormal cellular activity and protein aggregation, a characteristic of age-related NDDs. This review highlights the complex interactions of miRNAs in the orchestration of proteostasis and autophagy. This dysregulation impairs autophagic flux and proteostasis and accelerates age-related disorders, neuroinflammation, and neurodegeneration. Understanding the complex interactions among miRNAs, autophagy, and proteostasis in the aging brain is essential for novel therapeutics development for age-related NDDs.
    Keywords:  Autophagy; Neurodegeneration; Neuroinflammation; Proteostasis; miRNA
    DOI:  https://doi.org/10.1016/j.lfs.2025.123563
  5. J Nephrol. 2025 Mar 19.
    Targeting autophagy in autoimmune glomerular diseases.
    Ponticelli Claudio, Moroni Gabriella.
      Autophagy is a natural process whereby damaged or dying parts of a cell are eliminated and recycled. The term autophagy usually refers to macroautophagy, which is one of three types of autophagy, alongside microautophagy and chaperone-mediated autophagy. Autophagy is activated by adenosine monophosphate-activated protein kinase (AMPK) and inhibited by mammalian target of rapamycin (mTOR) through their interference with Unc-51-like kinase 1 (ULK1). Dysregulated autophagy is deeply involved in autoimmune glomerular diseases. Upregulated autophagy can induce inflammation and activate innate and adaptive immunity. However, autophagy may also exert a protective role on podocytes, enhance endothelial cell function, and preserve proximal tubular epithelial cells during ischemic or endotoxic acute kidney injury (AKI). Hydroxychloroquine (HCQ) can downregulate increased autophagy and is widely used in lupus nephritis. HCQ causes alkalinization, which results in vacuolization of lysosomes and inhibition of their functions. By inhibiting autophagic activity, HCQ may reduce inflammation and innate immunity, inhibit the activation of T cells, restore the T helper 17/T regulator balance, restrict the production of pro-inflammatory cytokines, and modulate co-stimulatory molecules. This reduces the risk of flares, spares the dosage of glucocorticoids, improves lupus activity, and prevents the thrombotic effects of anti-phospholipid antibodies. Recent studies showed that HCQ can also reduce proteinuria in IgA nephropathy (IgAN) and membranous nephropathy (MN). Drugs that improve mitochondrial function or enhance autophagy, such as metformin, sodium-glucose co-transporter 2 (SGLT2) inhibitors or mTOR inhibitors, may exert protective effects on podocytes and reduce proteinuria in MN or focal segmental glomerulosclerosis (FSGS).
    Keywords:  Autophagy; Glomerulonephritis; Hydroxychloroquine; Lupus nephritis; Podocyte
    DOI:  https://doi.org/10.1007/s40620-025-02267-9
  6. Commun Biol. 2025 Mar 15. 8(1): 443
    Investigation of dynamic regulation of TFEB nuclear shuttling by microfluidics and quantitative modelling.
    Iacopo Ruolo, Sara Napolitano, Lorena Postiglione, Gennaro Napolitano, Andrea Ballabio, Diego di Bernardo.
      Transcription Factor EB (TFEB) controls lysosomal biogenesis and autophagy in response to nutritional status and other stress factors. Although its regulation by nuclear translocation is known to involve a complex network of well-studied regulatory processes, the precise contribution of each of these mechanisms is unclear. Using microfluidics technology and real-time imaging coupled with mathematical modelling, we explored the dynamic regulation of TFEB under different conditions. We found that TFEB nuclear translocation upon nutrient deprivation happens in two phases: a fast one characterised by a transient boost in TFEB dephosphorylation dependent on transient calcium release mediated by mucolipin 1 (MCOLN1) followed by activation of the Calcineurin phosphatase, and a slower one driven by inhibition of mTORC1-dependent phosphorylation of TFEB. Upon refeeding, TFEB cytoplasmic relocalisation kinetics are determined by Exportin 1 (XPO1). Collectively, our results show how different mechanisms interact to regulate TFEB activation and the power of microfluidics and quantitative modelling to elucidate complex biological mechanisms.
    DOI:  https://doi.org/10.1038/s42003-025-07870-x
  7. Autophagy. 2025 Mar 18.
    The Whi2-Psr1-Psr2 complex selectively regulates TORC1 and autophagy under low leucine conditions but not nitrogen depletion.
    Yitao Wang, Yang Ping, Rui Zhou, Guiqin Wang, Yu Zhang, Xueyu Yang, Mingjun Zhao, Dongsheng Liu, Madhura Kulkarni, Heather Lamb, Qingwei Niu, J Marie Hardwick, Xinchen Teng.
      Amino acids and ammonia serve as sources of nitrogen for cell growth and were previously thought to have similar effects on yeast. Consistent with this idea, depletion of either of these two nitrogen sources inhibits the target of rapamycin complex 1 (TORC1), leading to induction of macroautophagy/autophagy and inhibition of cell growth. In this study, we show that Whi2 and the haloacid dehalogenase (HAD)-type phosphatases Psr1 and Psr2 distinguish between these two nitrogen sources in Saccharomyces cerevisiae, as the Whi2-Psr1-Psr2 complex inhibits TORC1 in response to low leucine but not in the absence of nitrogen. In contrast, a parallel pathway controlled by Npr2 and Npr3, components of the Seh1-associated complex inhibiting TORC1 (SEACIT), suppress TORC1 under both low leucine- and nitrogen-depletion conditions. Co-immunoprecipitations with mutants of Whi2, Psr1, Psr2 and fragments of Tor1 support the model that Whi2 recruits Psr1 and Psr2 to TORC1. In accordance, the interaction between Whi2 and Tor1 appears to increase under low leucine but decreases under nitrogen-depletion conditions. Although the targets of Psr1 and Psr2 phosphatases are not known, mutation of their active sites abolishes their inhibitory effects on TORC1. Consistent with the conservation of HAD phosphatases across species, human HAD phosphatases CTDSP1 (CTD small phosphatase 1), CTDSP2, and CTDSPL can functionally replace Psr1 and Psr2 in yeast, restoring TORC1 inhibition and autophagy activation in response to low leucine conditions.
    Keywords:  Autophagy; CTDSP; TORC1; Whi2-Psr1-Psr2; low leucine; nitrogen depletion
    DOI:  https://doi.org/10.1080/15548627.2025.2481014
  8. Front Cell Dev Biol. 2025 ;13 1512341
    Molecular mechanism on autophagy associated cardiovascular dysfunction in Drosophila melanogaster.
    Wei Zhang, Rong Zhou, Xinjuan Lei, Mofei Wang, Qinchun Duan, Yuanlin Miao, Tingting Zhang, Xinjie Li, Zhang Zutong, Liyang Wang, Odell D Jones, Mengmeng Xu, Joseph Bryant, Jianjie Ma, Yingli Liu, Xuehong Xu.
      As a highly conserved cellular process, autophagy has been the focus of extensive research due to its critical role in maintaining cellular homeostasis and its implications in cardiovascular pathogenesis. The decline in muscular function, along with the neuronal system, and increased sensitivity to stress have been recognized in multiple animal models. Autophagic defects in cardiovascular architecture and cellular dysfunction have been linked to both physiological and pathological conditions of the heart in mammals and Drosophila. In this review, we systematically analyze the autophagy-associated pathways in the hearts of fruit flies and aim to provide a comprehensive understanding for developing potential treatments for patients and effective strategies for agricultural applications. This analysis elucidates the molecular mechanisms of autophagy in cardiovascular function under both physiological and pathological conditions in Drosophila, offering significant insights into the development of cardiovascular diseases. The loss of key autophagy-associated proteins, including the transmembrane protein Atg9 and its partners Atg2 or Atg18, along with DmSestrin, leads to cardiac hypertrophy and structural abnormalities in Drosophila, resembling the age-dependent deterioration of cardiac function. Members of the autophagy-related (Atg) gene family, cellular or nuclear skeletal lamins, and the mechanistic or mammalian target of rapamycin (mTOR) signaling pathways are critically influential in heart function in Drosophila, with autophagy activation shown to suppress cardiac laminopathy. The mTORC1/C2 complexes, along with axis of Atg2-AMPK/Sirt1/PGC-1α pathway, are essential in the hearts of both mammals and fruit flies, governing cardiac development, growth, maturation, and the maintenance of cardiac homeostasis. The beneficial effects of several interventions that enhance cardiac function, including exercise and cold stress, can influence autophagy-dependent TOR activity of the serine/threonine protein kinase signaling in both mammals and Drosophila. Exercise has been shown to increase autophagy when it is deficient and to inhibit it when it is excessive, highlighting the dual role of autophagy in cardiac health. This review evaluates the functional significance of autophagy in the heart, particularly in the context of Drosophila, in relation to mTORC-associated autophagy and the axis of Atg2-AMPK/Sirt1/PGC-1α pathways. It systematically contrasts the molecular mechanisms underlying autophagy-related cardiovascular physiological and pathological conditions in both fruit flies and mammals. The evolutionary conservation of autophagy underscores the value of Drosophila as a model for understanding broader mechanisms of autophagy across species. This study not only deepens our understanding of autophagy's role in cardiovascular function but also provides a theoretical foundation for the potential application of autophagy in agricultural pest control.
    Keywords:  Autophagy; Cardiovascular dysfunction; Drosophila melanogaster; cardiac laminopathy; interference; mTOR pathway
    DOI:  https://doi.org/10.3389/fcell.2025.1512341
  9. Autophagy. 2025 Mar 20.
    TBK1 is a signaling hub in coordinating stress-adaptive mechanisms in head and neck cancer progression.
    Hyo Jeong Kim, Haeng-Jun Kim, Sun-Yong Kim, Jin Roh, Ju Hyun Yun, Chul-Ho Kim.
      Tumorigenesis is closely linked to the ability of cancer cells to activate stress-adaptive mechanisms in response to various cellular stressors. Stress granules (SGs) play a crucial role in promoting cancer cell survival, invasion, and treatment resistance, and influence tumor immune escape by protecting essential mRNAs involved in cell metabolism, signaling, and stress responses. TBK1 (TANK binding kinase 1) functions in antiviral innate immunity, cell survival, and proliferation in both the tumor microenvironment and tumor cells. Here, we report that MUL1 loss results in the hyperactivation of TBK1 in both HNC cells and tissues. Mechanistically, under proteotoxic stress induced by proteasomal inhibition, HSP90 inhibition, or Ub+ stress, MUL1 promotes the degradation of active TBK1 through K48-linked ubiquitination at lysine 584. Furthermore, TBK1 facilitates autophagosome-lysosome fusion and phosphorylates SQSTM1, regulating selective macroautophagic/autophagic clearance in HNC cells. TBK1 is required for SG formation and cellular protection. Moreover, we found that MAP1LC3B is partially localized within SGs. TBK1 depletion enhances the sensitivity of HNC cells to cisplatin-induced cell death. GSK8612, a novel TBK1 inhibitor, significantly inhibits HNC tumorigenesis in xenografts. In summary, our study reveals that TBK1 facilitates the rapid removal of ubiquitinated proteins within the cell through protective autophagy under stress conditions and assists SG formation through the use of the autophagy machinery. These findings highlight the potential of TBK1 as a therapeutic target in HNC treatment.
    Keywords:  Autophagic flux; GSK8612; MUL1; TBK1; head and neck cancer; stress granule formation
    DOI:  https://doi.org/10.1080/15548627.2025.2481661
  10. Exp Neurol. 2025 Mar 14. pii: S0014-4886(25)00082-2. [Epub ahead of print] 115218
    PPM1D ameliorates Alzheimer's disease by promoting mitophagy.
    Aiming Wang, Fan Zhang, Wenqiang Zhang, Jian Gong, Xiaohong Sun.
      Mitochondrial autophagy (mitophagy) plays an essential role in the maintenance of mitochondrial homeostasis. Defective mitophagy triggered by amyloid beta (Aβ) is linked to neuronal deterioration and neurodegeneration in Alzheimer's disease (AD). However, the molecular mechanism underlying the defective mitophagy in AD is still not fully illustrated. Protein phosphatase Mn2+/Mg2+-dependent 1D (PPM1D) triggers autophagy in mouse embryonic fibroblasts. Downregulated PPM1D in the hippocampus of APP/PS1 mice. This study aims to investigate the role of PPM1D in the progression of AD. Here, APP/PS1 mice were used to mimic AD, and rAAV2 vectors expressing PPM1D were injected into the bilateral hippocampus. In vitro, the mouse hippocampal neuron cell line HT22 was stimulated by Aβ1-42 to trigger neuronal damage. High PPM1D expression alleviated the impairments of spatial cognition and memory in APP/PS1 mice. Additionally, PPM1D enhanced autophagosome formation, lysosomal degradation of impaired mitochondria, amyloid plaque deposition, and neuronal degeneration and apoptosis in the hippocampus of APP/PS1 mice. Similar effects of PPM1D on neuronal apoptosis and mitophagy were observed in Aβ1-42-treated HT22 cells, and the effects could be reversed by the mitophagy inhibitor cyclosporine A. In conclusion, PPM1D facilitates mitophagy to inhibit the progression of AD-like disease. Taken together, the present work uncovers defective mitophagy in AD may be associated with down-regulated PPM1D, and PPM1D may be a potential therapeutic target for AD treatment.
    Keywords:  Alzheimer's disease; Mitophagy; Neuronal damage; Neurotoxicity; PPM1D
    DOI:  https://doi.org/10.1016/j.expneurol.2025.115218
  11. Nucleic Acids Res. 2025 Feb 27. pii: gkaf178. [Epub ahead of print]53(5):
    DNA damage response regulator ATR licenses PINK1-mediated mitophagy.
    Christian Marx, Xiaobing Qing, Yamin Gong, Joanna Kirkpatrick, Kanstantsin Siniuk, Galina V Beznoussenko, Gururaj Rao Kidiyoor, Murat Kirtay, Katrin Buder, Philipp Koch, Martin Westermann, Christopher Bruhn, Eric J Brown, Xingzhi Xu, Marco Foiani, Zhao-Qi Wang.
      Defective DNA damage response (DDR) and mitochondrial dysfunction are a major etiology of tissue impairment and aging. Mitochondrial autophagy (mitophagy) is a mitochondrial quality control (MQC) mechanism to selectively eliminate dysfunctional mitochondria. ATR (ataxia-telangiectasia and Rad3-related) is a key DDR regulator playing a pivotal role in DNA replication stress response and genomic stability. Paradoxically, the human Seckel syndrome caused by ATR mutations exhibits premature aging and neuropathies, suggesting a role of ATR in nonreplicating tissues. Here, we report a previously unknown yet direct role of ATR at mitochondria. We find that ATR and PINK1 (PTEN-induced kinase 1) dock at the mitochondrial translocase TOM/TIM complex, where ATR interacts directly with and thereby stabilizes PINK1. ATR deletion silences mitophagy initiation thereby altering oxidative phosphorylation functionality resulting in reactive oxygen species overproduction that attack cytosolic macromolecules, in both cells and brain tissues, prior to nuclear DNA. This study discloses ATR as an integrated component of the PINK1-mediated MQC program to ensure mitochondrial fitness. Together with its DDR function, ATR safeguards mitochondrial and genomic integrity under physiological and genotoxic conditions.
    DOI:  https://doi.org/10.1093/nar/gkaf178
  12. Nat Rev Cardiol. 2025 Mar 20.
    Mitochondrial quality control in cardiomyocytes: safeguarding the heart against disease and ageing.
    Rishith Ravindran, Åsa B Gustafsson.
      Mitochondria are multifunctional organelles that are important for many different cellular processes, including energy production and biosynthesis of fatty acids, haem and iron-sulfur clusters. Mitochondrial dysfunction leads to a disruption in these processes, the generation of excessive reactive oxygen species, and the activation of inflammatory and cell death pathways. The consequences of mitochondrial dysfunction are particularly harmful in energy-demanding organs such as the heart. Loss of terminally differentiated cardiomyocytes leads to cardiac remodelling and a reduced ability to sustain contraction. Therefore, cardiomyocytes rely on multilayered mitochondrial quality control mechanisms to maintain a healthy population of mitochondria. Mitochondrial chaperones protect against protein misfolding and aggregation, and resident proteases eliminate damaged proteins through proteolysis. Irreparably damaged mitochondria can also be degraded through mitochondrial autophagy (mitophagy) or ejected from cells inside vesicles. The accumulation of dysfunctional mitochondria in cardiomyocytes is a hallmark of ageing and cardiovascular disease. This accumulation is driven by impaired mitochondrial quality control mechanisms and contributes to the development of heart failure. Therefore, there is a strong interest in developing therapies that directly target mitochondrial quality control in cardiomyocytes. In this Review, we discuss the current knowledge of the mechanisms involved in regulating mitochondrial quality in cardiomyocytes, how these pathways are altered with age and in disease, and the therapeutic potential of targeting mitochondrial quality control pathways in cardiovascular disease.
    DOI:  https://doi.org/10.1038/s41569-025-01142-1
  13. Autophagy. 2025 Mar 17.
    H3K36me2 methyltransferase NSD2/WHSC1 promotes triple-negative breast cancer metastasis via activation of ULK1-dependent autophagy.
    Danyang Chen, Xiaohui Chen, Mingqiang Yang, Qiunuo Li, Shaojuan Weng, Siyue Kou, Xi Liu, Guanmin Jiang, Hao Liu.
      Metastasis is the primary cause for treatment failure and poor prognosis in patients with triple-negative breast cancer (TNBC). Macroautophagy/autophagy plays a crucial role in tumor growth and metastasis. Genetic or epigenetic regulation of autophagy-related factors alters autophagy levels, which subsequently promotes cancer progression and affects the therapeutic effectiveness. However, the molecular basis for the transcriptional and epigenetic regulation of autophagy in TNBC progression is poorly understood. In this study, we reveal the histone methyltransferase NSD2/WHSC1 (nuclear receptor binding SET domain protein 2) as a novel epigenetic regulator of autophagy in TNBC progression. We demonstrate that the expression of NSD2 is significantly upregulated in TNBC cells and high NSD2 expression is correlated with poor TNBC survival. Elevated expression of NSD2 significantly promotes TNBC metastasis in multiple TNBC models. Mechanistically, ULK1 (unc-51 like autophagy activating kinase 1) is identified as a novel target of NSD2 and NSD2-mediated histone H3K36me2 methylation directly activates ULK1 transcription in TNBC cells. Notably, NSD2-induced ULK1 expression facilitates autophagosome maturation and increases autophagic flux, thus promoting autophagy-related malignancy progression in TNBC. Furthermore, pharmacological inhibition of NSD2 using MS159 and MCTP-39 significantly suppresses TNBC autophagy, growth, and metastasis both in vivo and in vitro. In conclusion, our findings demonstrate a pivotal epigenetic role for the NSD2-H3K36me2 axis in regulating ULK1 expression and identify a novel NSD2-ULK1-autophagy signaling axis in the promotion of TNBC progression, suggesting that NSD2 inhibition may be an effective treatment strategy for TNBC.
    Keywords:  Autophagy; H3K36me2; NSD2; ULK1; metastasis; triple-negative breast cancer
    DOI:  https://doi.org/10.1080/15548627.2025.2479995
  14. Autophagy. 2025 Mar 20.
    Chaperone-mediated autophagy degrades SERPINA1E342K/α1-antitrypsin Z variant and alleviates cell stress.
    Jiayu Lin, Xinyue Wei, Yan Dai, Haorui Lu, Yajian Song, Jiansong Ju, Rihan Wu, Qichen Cao, Hao Yang, Lang Rao.
      Chaperone-mediated autophagy (CMA) is a specific form of autophagy that selectively targets proteins containing a KFERQ-like motif and relies on the chaperone protein HSPA8/HSC70 for substrate recognition. In SERPINA1/a1-antitrypsin deficiency (AATD), a disease characterized by the hepatic buildup of the SERPINA1E342K/ATZ, CMA's role had been unclear. This work demonstrates the critical role that CMA plays in preventing SERPINA1E342K/ATZ accumulation; suppressing CMA worsens SERPINA1E342K/ATZ accumulation while activating it through chemical stimulation or LAMP2A overexpression promotes SERPINA1E342K/ATZ breakdown. Specifically, SERPINA1E342K/ATZ's 121QELLR125 motif is critical for HSPA8/HSC70 recognition and LAMP2A's charged C-terminal cytoplasmic tail is vital for substrate binding, facilitating CMA-mediated degradation of SERPINA1E342K/ATZ. This selective activation of CMA operates independently from other autophagy pathways and alleviates SERPINA1E342K/ATZ aggregate-induced cellular stress. In vivo administration of AR7 promotes hepatic SERPINA1E342K/ATZ elimination and mitigates hepatic SERPINA1E342K/ATZ aggregation pathology. These findings highlight CMA's critical function in cellular protein quality control of SERPINA1E342K/ATZ and place it as a novel target for AATD treatment approaches.
    Keywords:  Cellular stress; HSPA8/HSC70; LAMP2A; chaperone-mediated autophagy; protein degradation
    DOI:  https://doi.org/10.1080/15548627.2025.2480037
  15. Biochem Biophys Res Commun. 2025 Feb 19. pii: S0006-291X(25)00228-1. [Epub ahead of print]758 151514
    Enhanced alpha-synuclein pathology and exacerbated motor dysfunction in alpha-synuclein transgenic mice with autophagy deficiency.
    Sachiko Noda, Shigeto Sato, Hodaka Yamakado, Ryosuke Takahashi, Nobutaka Hattori.
      Alpha-synuclein (α-synuclein), a key component of Lewy body pathology, is a hallmark of Parkinson's disease. In previous studies, we examined dopaminergic neuron-specific Atg7 autophagy-deficient mice and observed α-synuclein aggregation in vivo. Notably, p62 accumulation preceded synuclein deposition, resulting in the formation of inclusions containing both α-synuclein and p62. This pathological process led to dopamine neuron loss and age-related motor impairments, such as hindlimb defects in 120-week-old mice. In this study, we developed a mouse model by crossing human α-synuclein bacterial artificial chromosome transgenic mice with dopaminergic neuron-specific Atg7 conditional knockout mice to investigate these mechanisms further. The mice exhibited accelerated Lewy body-like pathology and motor dysfunction, providing additional evidence that autophagy deficiency exacerbates synuclein toxicity in vivo. Phosphorylated synuclein deposits were detected in the substantia nigra, hippocampus, and cortical regions reliant on dopaminergic pathways. Degeneration of dopaminergic neurons in the substantia nigra pars compacta was also observed, with neuron numbers declining with age. Interestingly, this mouse model displayed more severe motor deficits than Atg7 autophagy-deficient mice. This novel model offers a valuable platform for studying the interplay between α-synuclein expression, autophagy dysfunction, and neurodegeneration, as well as for testing therapeutic strategies targeting synucleinopathies. Our findings highlight the importance of aging in the manifestation of synuclein toxicity, mirroring the progression observed in patients with Parkinson's disease.
    Keywords:  Atg7; Autophagy; Dopamine; Parkinson's disease; p62; α-synuclein
    DOI:  https://doi.org/10.1016/j.bbrc.2025.151514
  16. Curr Top Med Chem. 2025 Mar 18.
    Natural Compounds and their Nano-formulations in Combating Autophagy-mediated Drug Resistance in Human Cancers.
    Fahad Khan, Prashant Chauhan, Seema Ramniwas, Meenakshi Verma, Shivam Pandey, Suhas Ballal, Sanjay Kumar, Mahakshit Bhat, Shilpa Sharma, M Ravi Kumar, Sorabh Lakhanpal, Pratibha Pandey.
      Autophagy is a crucial mechanism that maintains cellular homeostasis and has emerged as a pivotal factor in cancer progression and drug resistance. Despite autophagic regulations being a complex process, convincing evidence shows that PI3K-Akt-mTOR, LKB1-AMPK-mTOR, and p53 pathways are the primary upstream regulators of the autophagy process. Currently, there is an immense amount of evidence demonstrating that autophagy plays a crucial role in cancer. It is worth noting that autophagy increases cancer cells' resistance to chemotherapy and anticancerous drugs. According to studies, cancer cells employ autophagy to evade the cytotoxic impacts of several anticancer drugs, resulting in autophagy-mediated drug resistance. This resistance brings a significant challenge to cancer management, emphasising the need for improved therapeutic strategies to overcome this obstacle and enhance the efficacy of cancer treatments. Therefore, this review gathers current data and findings to understand the intricate mechanism between autophagymediated drug resistance and cancer progression. Moreover, this study highlights the intriguing role of natural compounds and nano-formulations in combating autophagy-mediated drug resistance in various carcinomas, presenting a promising avenue for the effective management of cancer treatment.
    Keywords:  Autophagy; cancer; drug resistance; nano-formulations.; natural compound
    DOI:  https://doi.org/10.2174/0115680266345188250304064600
  17. Signal Transduct Target Ther. 2025 Mar 21. 10(1): 92
    Targeting PI3K inhibitor resistance in breast cancer with metabolic drugs.
    Niklas Gremke, Isabelle Besong, Alina Stroh, Luise von Wichert, Marie Witt, Sabrina Elmshäuser, Michael Wanzel, Martin F Fromm, R Verena Taudte, Sabine Schmatloch, Thomas Karn, Mattea Reinisch, Nader Hirmas, Sibylle Loibl, Thomas Wündisch, Anne-Sophie Litmeyer, Paul Jank, Carsten Denkert, Sebastian Griewing, Uwe Wagner, Thorsten Stiewe.
      Activating PIK3CA mutations, present in up to 40% of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (Her2-) breast cancer (BC) patients, can be effectively targeted with the alpha isoform-specific PI3K inhibitor Alpelisib. This treatment significantly improves outcomes for HR+, Her2-, and PIK3CA-mutated metastatic BC patients. However, acquired resistance, often due to aberrant activation of the mTOR complex 1 (mTORC1) pathway, remains a significant clinical challenge. Our study, using in vitro and orthotopic xenograft mouse models, demonstrates that constitutively active mTORC1 signaling renders PI3K inhibitor-resistant BC exquisitely sensitive to various drugs targeting cancer metabolism. Mechanistically, mTORC1 suppresses the induction of autophagy during metabolic perturbation, leading to energy stress, a critical depletion of aspartate, and ultimately cell death. Supporting this mechanism, BC cells with CRISPR/Cas9-engineered knockouts of canonical autophagy genes showed similar vulnerability to metabolically active drugs. In BC patients, high mTORC1 activity, indicated by 4E-BP1T37/46 phosphorylation, correlated with p62 accumulation, a sign of impaired autophagy. Together, these markers predicted poor overall survival in multiple BC subgroups. Our findings reveal that aberrant mTORC1 signaling, a common cause of PI3K inhibitor resistance in BC, creates a druggable metabolic vulnerability by suppressing autophagy. Additionally, the combination of 4E-BP1T37/46 phosphorylation and p62 accumulation serves as a biomarker for poor overall survival, suggesting their potential utility in identifying BC patients who may benefit from metabolic therapies.
    DOI:  https://doi.org/10.1038/s41392-025-02180-4
  18. Mol Cancer. 2025 Mar 19. 24(1): 85
    Autophagy in tumor immune escape and immunotherapy.
    Huan Wang, Peng Sun, Xijing Yuan, Zhiyong Xu, Xinyuan Jiang, Mingshu Xiao, Xin Yao, Yueli Shi.
      The immunotherapy targeting tumor immune escape mechanisms has become a critical strategy in anticancer treatment; however, the challenge of immune resistance remains significant. Autophagy, a cellular response to various stressors, involves the degradation of damaged proteins and organelles via lysosomal pathways, maintaining cellular homeostasis. This process not only supports tumor cell survival but also profoundly impacts the efficacy of cancer immunotherapies. The modulation of autophagy in tumor cells or immune cells exerts dual effects on tumor immune escape and immunotherapy. However, the mechanistic details of how autophagy influences the immune system and therapy remain inadequately understood. Given this complexity, a deeper understanding of the role of autophagy in the tumor-immune landscape could reveal novel therapeutic avenues. By manipulating autophagy appropriately, it may be possible to overcome immune resistance and enhance the effectiveness of immunotherapeutic strategies. This article summarizes the role of autophagy in tumor immunity, its relationship with immunotherapy, and the potential therapeutic benefits of targeting autophagy to strengthen antitumor immune responses and optimize the outcomes of immunotherapy.
    Keywords:  Autophagy; Cancer; Immune escape; Immune resistance; Tumor immune microenvironment
    DOI:  https://doi.org/10.1186/s12943-025-02277-y
  19. Toxicol Sci. 2025 Mar 20. pii: kfaf032. [Epub ahead of print]
    Gallic acid relieved bortezomib-induced peripheral neurotoxicity by restoring Schwann cell lysosomal activity.
    Xiaoliang Liu, Ke Wang, Xingxian Zhang, Jiayu Qi, Danyan Zhu, Zechao Wang, Zhi He, Jianbiao Yao, Xiangnan Zhang, Jiaying Wu.
      Bortezomib (BTZ) serves as a first-line medication for multiple myeloma (MM) therapy. Unfortunately, despite its prominent efficacy in MM therapy, BTZ-induced peripheral neuropathy (BIPN) presents a significant challenge for patients lacks an established therapeutic solution. Previous research has demonstrated the involvement of lysosomal dysfunction in Schwann cells as a key in the pathological process of BIPN, suggesting that agents enhancing lysosomal activity could hold promise as a treatment for BIPN. Gallic acid (GA) is a natural compound known to preserve lysosomal integrity. However, it remains unidentified whether GA is effective in ameliorating BIPN. The administration of GA in mice demonstrated a significant reversal of BTZ-induced mechanical hypersensitivity, reduction in tail nerve conduction velocity, and demyelination of sciatic nerve. GA counteracted BTZ-induced lysosomal dysfunction as evidenced by DQ-Red-BSA staining in RSC96 Schwann cells. BTZ-induced lysosomal proteins loss and autophagic flux blockage were also hindered by GA. Further analysis revealed that BTZ resulted in the increased phosphorylation of transcription factor EB (TFEB) and reduced nuclear translocation of TFEB in RSC96 cells, and these effects that were reversed upon GA treatment. Importantly, GA did not compromise the cytotoxic effects of BTZ on RPMI 8226 cells, indicating little interference with the pharmacological effects of BTZ. In summary, this study provides compelling evidence that GA can ameliorate BIPN in mice. GA activated TFEB signaling, promoted the lysosomal activity and thus restore autophagy flux in Schwann cells exposed to BTZ. These findings underscore the potential of GA as a promising therapeutic intervention for BIPN.
    Keywords:  Autophagy; Bortezomib; Gallic Acid; Lysosome; Peripheral Neuropathy
    DOI:  https://doi.org/10.1093/toxsci/kfaf032
  20. iScience. 2025 Mar 21. 28(3): 112013
    UXT oligomerization is essential for its role as an autophagy adaptor.
    Min Ji Yoon, Jugeon Park, MinHyeong Lee, Jiyeon Ohk, Tae Su Choi, Eun Jung Choi, Hosung Jung, Chungho Kim.
      SQSTM1/p62 serves as an autophagy receptor that binds to ubiquitinated misfolded proteins and delivers them to the phagophores for removal. This function can be augmented by autophagy adaptors, such as UXT. Here, by in silico structural homology modeling, we demonstrated that UXT can potentially form a hexameric structure to bind to misfolded proteins. Importantly, the UXT hexamer can assemble into a high-order oligomer via β hairpins positioned outside of each hexamer, facilitating the formation and efficient removal of protein aggregates. Consistently, the high-order oligomer of UXT was found to be essential for inducing the efficient clearance of SOD1(A4V) aggregates, in both in vitro and in vivo. Collectively, our research emphasizes the crucial importance of UXT oligomerization in its role as an autophagy adaptor and explains why the structurally and functionally similar prefoldin, which lacks such high-order oligomerization capacity, is employed for the refolding of individual misfolded proteins, but not autophagy.
    Keywords:  Biochemistry; Molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2025.112013
  21. Eur J Pharmacol. 2025 Mar 18. pii: S0014-2999(25)00282-1. [Epub ahead of print] 177528
    Protein kinase-mediated inhibition of autophagy by palmitic acid in hepatocytes.
    Yeon Jeong Kim, Jae Rim Lee, Myeong Ryeo Kim, Jin Ah Jeong, Jung Ju Kim, Kwang Won Jeong.
      Steatosis is characterized by an increase in free fatty acids, such as palmitic acid (PA), in hepatocytes and the accumulation of triglycerides in the liver. However, the role of intracellular autophagy in PA accumulation-induced hepatotoxicity is not clearly understood. Therefore, in this study, we investigated the effects of PA on autophagy in hepatocytes and its underlying mechanism of action. Treatment of HepG2 cells with PA induced a significant increase in intracellular p62 and LC3-II levels, suggesting inhibition of autophagy. Furthermore, PA inhibited autophagic flux in HepG2 cells, as monitored using GFP-RFP-LC3. Mechanistically, PA increased the phosphorylation of the Ser12 and Thr29 residues of LC3, which are autophagy inhibition markers, through protein kinase A (PKA) and protein kinase C (PKC) signaling. Finally, PKA and PKC inhibitors restored PA-induced autophagic flux inhibition, reduced intracellular lipid accumulation, and rescued the altered expression of lipogenic genes, such as SREBP-1c, in HepG2 cells. Thus, our study demonstrates the mechanism of autophagy inhibition by PA in hepatocytes and provides a potential therapeutic approach for preventing and treating hepatic steatosis.
    Keywords:  HepG2; LC3; Palmitic acid; autophagy; protein kinase A; protein kinase C
    DOI:  https://doi.org/10.1016/j.ejphar.2025.177528
  22. Autophagy. 2025 Mar 18.
    Adsl-produced fumarate increases BECN1 dimethylation to promote autophagy and liver tumor growth.
    Lei Wang, Guimei Ji, Yuran Duan, Peixiang Zheng, Zhiqiang Hu, Zheng Wang, Daqian Xu.
      Cancer cells depend on the reprogramming of cell metabolism to constantly adapt metabolically to the tumor microenvironment. ADSL (adenylosuccinate lyase), a rate-limiting enzyme in de novo purine synthesis, is overexpressed in various cancer cells. However, whether ADSL functions in other oncogenic signaling is largely unknown. Here, our recent study shows that ADSL interacts with BECN1 (beclin 1) to regulate macroautophagy/autophagy upon lipid deprivation. Mechanistically, ADSL is phosphorylated at S140 by EIF2AK3/PERK (eukaryotic translation initiation factor 2 alpha kinase 3) in response to lipid deprivation, which enhances the association between ADSL and BECN1. ADSL-produced fumarate reduces the BECN1-associated KDM8 activity, leading to increased BECN1 K117 dimethylation. BECN1 K117 dimethylation inhibits its interaction with BCL2 to initiate autophagy. Targeting the ADSL-BECN1 axis by knock-in mutation or a cell-penetrating peptide inhibits autophagy and blunts liver tumor growth in mice. These findings broaden the physiological significance of ADSL in autophagy and liver tumor development.
    Keywords:  ADSL; Beclin1; autophagy; fumarate
    DOI:  https://doi.org/10.1080/15548627.2025.2481125
  23. Alzheimers Dement. 2025 Mar;21(3): e70048
    Tau degradation in Alzheimer's disease: Mechanisms and therapeutic opportunities.
    Lisha Wang, Banesh Sooram, Rajnish Kumar, Sophia Schedin-Weiss, Lars O Tjernberg, Bengt Winblad.
      In Alzheimer's disease (AD), tau undergoes abnormal post-translational modifications and aggregations. Impaired intracellular degradation pathways further exacerbate the accumulation of pathological tau. A new strategy - targeted protein degradation - recently emerged as a modality in drug discovery where bifunctional molecules bring the target protein close to the degradation machinery to promote clearance. Since 2016, this strategy has been applied to tau pathologies and attracted broad interest in academia and the pharmaceutical industry. However, a systematic review of recent studies on tau degradation mechanisms is lacking. Here we review tau degradation mechanisms (the ubiquitin-proteasome system and the autophagy-lysosome pathway), their dysfunction in AD, and tau-targeted degraders, such as proteolysis-targeting chimeras and autophagy-targeting chimeras. We emphasize the need for a continuous exploration of tau degradation mechanisms and provide a future perspective for developing tau-targeted degraders, encouraging researchers to work on new treatment options for AD patients. HIGHLIGHTS: Post-translational modifications, aggregation, and mutations affect tau degradation. A vicious circle exists between impaired degradation pathways and tau pathologies. Ubiquitin plays an important role in complex degradation pathways. Tau-targeted degraders provide promising strategies for novel AD treatment.
    Keywords:  Alzheimer's disease; autophagy; autophagy‐targeting chimeras (AUTOTACs); degradation; proteolysis‐targeting chimeras (PROTACs); targeted protein degradation; tau; ubiquitin–proteasome system
    DOI:  https://doi.org/10.1002/alz.70048
  24. Clin Park Relat Disord. 2025 ;12 100312
    Autophagy related genes polymorphisms in Parkinson's Disease; A systematic review of literature.
    Parastoo Yousefi, Shahrzad Ghadirian, Maryam Mobedi, Mehrzad Jafarzadeh, Adib Alirezaei, Ali Gholami, Alireza Tabibzadeh.
       Background: Neurodegenerative diseases are mainly a consequence of degenerated proteins in neurons. Parkinson's disease (PD) is one of the most common neurodegenerative disorders and is characterized by Lewy body deposition. Autophagy is known as one of the cell maintenance mechanisms. Autophagy targets are damaged or degenerated macromolecules and organelles for lysosomal degradation. The role of disrupted autophagy in PD was established earlier. In this regard, the current study aimed to evaluate the frequency and status of the autophagy gene polymorphisms in PD by a systematic review approach.
    Materials and methods: In the current study, electronic databases including Scopus, PubMed, and Science Direct were used for the search. The search was performed by using Parkinson's disease, autophagy, autophagy-related gene, ATG, Single-nucleotide polymorphisms, variant, Sequence variants, and with a date limitation of 2010 to 2023. All original research papers in the English language that evaluate the ATG polymorphisms in PD were included in the study.
    Results: The conducted search leads to 2626 primary studies screened based on the inclusion criteria. After the screening stage, 8 studies were included. ATG7 rs1375206 and ATG5 rs510432, rs573775 and rs17587319 were associated with PD. However, some other polymorphisms in ATGs that were not associated with PD were listed.
    Conclusion: In conclusion, regardless of the critical role of autophagy in PD pathogenesis, it seems that ATG16 and ATG7 polymorphisms are not associated with PD; however, ATG7 rs1375206 needs more evaluation for a clearer conclusion in future studies. ATG5 and ATG12 polymorphisms seem to be more important in PD. More comprehensive studies about all ATG5, 7, 12, and 16 seem to be urgently required for a conclusive judgment about their role in PD or even other neurodegenerative disorders.
    Keywords:  ATG; Autophagy; Autophagy-related gene; Parkinson’s disease; Single-nucleotide polymorphisms; Variant
    DOI:  https://doi.org/10.1016/j.prdoa.2025.100312
  25. Contact (Thousand Oaks). 2025 Jan-Dec;8:8 25152564251329250
    Mitochondria-Lysosome Contact Sites: Emerging Players in Cellular Homeostasis and Disease.
    Francesca Rizzollo, Patrizia Agostinis.
      Mitochondria and lysosomes regulate a multitude of biological processes that are essential for the maintenance of nutrient and metabolic homeostasis and overall cell viability. Recent evidence reveals that these pivotal organelles, similarly to others previously studied, communicate through specialized membrane contact sites (MCSs), hereafter referred to as mitochondria-lysosome contacts (or MLCs), which promote their dynamic interaction without involving membrane fusion. Signal integration through MLCs is implicated in key processes, including mitochondrial fission and dynamics, and the exchange of calcium, cholesterol, and amino acids. Impairments in the formation and function of MLCs are increasingly associated with age-related diseases, specifically neurodegenerative disorders and lysosomal storage diseases. However, MLCs may play roles in other pathological contexts where lysosomes and mitochondria are crucial. In this review, we introduce the methodologies used to study MLCs and discuss known molecular players and key factors involved in their regulation in mammalian cells. We also argue other potential regulatory mechanisms depending on the acidic lysosomal pH and their impact on MLC's function. Finally, we explore the emerging implications of dysfunctional mitochondria-lysosome interactions in disease, highlighting their potential as therapeutic targets in cancer.
    Keywords:  lysosome; membrane contact sites; mitochondria; mitochondria-lysosome contacts
    DOI:  https://doi.org/10.1177/25152564251329250
  26. Cell Rep Med. 2025 Mar 18. pii: S2666-3791(25)00094-1. [Epub ahead of print]6(3): 102021
    Bioengineering the metabolic network of CAR T cells with GLP-1 and Urolithin A increases persistence and long-term anti-tumor activity.
    Areej Akhtar, Md Shakir, Mohammad Sufyan Ansari, Divya, Md Imam Faizan, Varnit Chauhan, Aashi Singh, Ruquaiya Alam, Iqbal Azmi, Sheetal Sharma, Mehak Pracha, Insha Mohi Uddin, Uzma Bashir, Syeda Najidah Shahni, Rituparna Chaudhuri, Sarah Albogami, Rik Ganguly, Shakti Sagar, Vijay Pal Singh, Gaurav Kharya, Amit Kumar Srivastava, Ulaganathan Mabalirajan, Soumya Sinha Roy, Irfan Rahman, Tanveer Ahmad.
      Constant tumor antigen exposure disrupts chimeric antigen receptor (CAR) T cell metabolism, limiting their persistence and anti-tumor efficacy. To address this, we develop metabolically reprogrammed CAR (MCAR) T cells with enhanced autophagy and mitophagy. A compound screening identifies a synergy between GLP-1R agonist (semaglutide [SG]) and Urolithin A (UrA), which activate autophagy through mTOR (mechanistic target of rapamycin) inhibition and mitophagy via Atg4b activation, maintaining mitochondrial metabolism in CAR T cells (MCAR T-1). These changes increase CD8+ T memory cells (Tm), enhancing persistence and anti-tumor activity in vitro and in xenograft models. GLP-1R knockdown in CAR T cells diminishes autophagy/mitophagy induction, confirming its critical role. We further engineer GLP-1-secreting cells (MCAR T-2), which exhibited sustained memory, stemness, and long-term persistence, even under tumor re-challenge. MCAR T-2 cells also reduce cytokine release syndrome (CRS) risks while demonstrating potent anti-tumor effects. This strategy highlights the potential of metabolic reprogramming via targeting autophagy/mitophagy pathways to improve CAR T cell therapy outcomes, ensuring durability and efficacy.
    Keywords:  CAR T cells; GLP-1 peptide; T cell persistence; Urolithin A; anti-tumor activity; autophagy; metabolism; mitochondrial health; mitophagy
    DOI:  https://doi.org/10.1016/j.xcrm.2025.102021
  27. Mol Neurobiol. 2025 Mar 18.
    ROS Regulate Rotenone-induced SH-SY5Y Dopamine Neuron Death Through Ferroptosis-mediated Autophagy and Apoptosis.
    Xinying Li, Weiran Li, Xinying Xie, Ting Fang, Jingwen Yang, Yue Shen, Yicheng Wang, Hongyan Wang, Liqing Tao, Heng Zhang.
      Rotenone, a plant-derived natural insecticide, is widely used to induce Parkinson's disease (PD) models. However, the mechanisms of rotenone-induced cell death remain unclear. Here, we found that rotenone (0.01, 0.1, or 1 μmol/L) suppressed SH-SY5Y dopamine neuron viability and led to PD-like pathological changes, such as reduced tyrosine hydroxylase (TH) but increased α-synuclein. Rotenone increased the levels of intracellular reactive oxygen species (ROS) and mitochondrial ROS, as well as the levels of the antioxidants nuclear factor E2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1), ultimately resulting in oxidative stress. Moreover, rotenone significantly downregulated the expression of GPX4 and xCT but upregulated the expression of COX2 and NCOA4, which are markers of ferroptosis. Furthermore, rotenone decreased phosphorylated mTOR level but increased Beclin-1, ATG5, LC3 and p62 expression, suggesting that rotenone enhances autophagy and reduces autophagy flux. Additionally, rotenone reduced Bcl-2 levels and the mitochondrial membrane potential (MMP) while promoting BAX and Caspase-3 expression, thus initiating cell apoptosis. N-acetylcysteine (NAC), a ROS scavenger, and ferrostatin-1 (Fer-1) and deferoxamine (DFO), two ferroptosis inhibitors, significantly eliminated rotenone-induced autophagy and apoptosis. Moreover, ML385, a specific inhibitor of Nrf2, suppressed rotenone-induced ferroptosis. Our results demonstrated that ROS might mediate rotenone-induced PD-like pathological changes by regulating iron death, autophagy, and apoptosis. Inhibiting ferroptosis blocked the rotenone-induced increase in autophagy and apoptosis. Thus, the ability of ROS to regulate rotenone-induced death through autophagy and apoptosis is dependent on ferroptosis. The findings require validation in multiple neuronal cell lines and in vivo.
    Keywords:  Apoptosis; Autophagy; Ferroptosis; Oxidative stress; Parkinson’s disease; Rotenone
    DOI:  https://doi.org/10.1007/s12035-025-04824-6
  28. Elife. 2025 Mar 18. pii: RP97325. [Epub ahead of print]13
    The autophagy protein ATG14 safeguards against unscheduled pyroptosis activation to enable embryo transport during early pregnancy.
    Pooja Popli, Arin K Oestreich, Vineet K Maurya, Marina N Rowen, Yong Zhang, Michael J Holtzman, Ramya Masand, John P Lydon, Shizuo Akira, Kelle Moley, Ramakrishna Kommagani.
      Recurrent pregnancy loss, characterized by two or more failed clinical pregnancies, poses a significant challenge to reproductive health. In addition to embryo quality and endometrial function, proper oviduct function is also essential for successful pregnancy establishment. Therefore, structural abnormalities or inflammation resulting from infection in the oviduct may impede the transport of embryos to the endometrium, thereby increasing the risk of miscarriage. However, our understanding of the biological processes that preserve the oviductal cellular structure and functional integrity is limited. Here, we report that autophagy-related protein ATG14 plays a crucial role in maintaining the cellular integrity of the oviduct by controlling inflammatory responses, thereby supporting efficient embryo transport. Specifically, the conditional depletion of the autophagy-related gene Atg14 in the oviduct causes severe structural abnormalities compromising its cellular integrity, leading to the abnormal retention of embryos. Interestingly, the selective loss of Atg14 in oviduct ciliary epithelial cells did not impact female fertility, highlighting the specificity of ATG14 function in distinct cell types within the oviduct. Mechanistically, loss of Atg14 triggered unscheduled pyroptosis via altering the mitochondrial integrity, leading to inappropriate embryo retention and impeded embryo transport in the oviduct. Finally, pharmacological activation of pyroptosis in pregnant mice phenocopied the genetically induced defect and caused impairment in embryo transport. Together, we found that ATG14 safeguards against unscheduled pyroptosis activation to enable embryo transport from the oviduct to uterus for the successful implantation. Of clinical significance, these findings provide possible insights into the underlying mechanism(s) of early pregnancy loss and might aid in developing novel prevention strategies using autophagy modulators.
    Keywords:  Atg14; autophagy; developmental biology; inflammation; mouse; oviduct; pregnancy
    DOI:  https://doi.org/10.7554/eLife.97325
  29. Glia. 2025 Mar 19.
    Disruption of Oligodendroglial Autophagy Leads to Myelin Morphological Deficits, Neuronal Apoptosis, and Cognitive Decline in Aged Mice.
    Niki Ktena, Dimitrios Spyridakos, Alexandros Georgilis, Ilias Kalafatakis, Efstathia Thomoglou, Angeliki Kolaxi, Vassiliki Nikoletopoulou, Maria Savvaki, Domna Karagogeos.
      The aging central nervous system (CNS) is often marked by myelin degeneration, yet the underlying mechanisms remain elusive. This study delves into the previously unexplored role of autophagy in maintaining CNS myelin during aging. We generated the transgenic mouse line plpCreERT2; atg5f/f, enabling selective deletion of the core autophagic component Atg5 in oligodendrocytes (OLs) following tamoxifen administration in adulthood, while analysis was conducted on aged mice. Our findings reveal that oligodendroglial autophagy inactivation leads to significant alterations in myelin protein levels. Moreover, the ultrastructural analysis revealed pronounced myelin deficits and increased degeneration of axons, accompanied by apoptosis, as confirmed by immunohistochemistry. Behaviorally, aged knockout (cKO) mice exhibited marked deficits in learning and memory tasks, indicative of cognitive impairment. Additionally, we observed increased activation of microglia, suggesting an inflammatory response linked to the absence of autophagic activity in OLs. These results underscore the critical role of autophagy in OLs for the preservation of CNS myelin and axonal integrity during aging. Our study highlights autophagy as a vital mechanism for neural maintenance, offering potential therapeutic avenues for combating age-related neurodegenerative diseases.
    Keywords:  CNS; aging; autophagy; myelin; neurodegeneration
    DOI:  https://doi.org/10.1002/glia.70012
  30. Elife. 2025 Mar 17. pii: RP99358. [Epub ahead of print]13
    Endosomal-lysosomal organellar assembly (ELYSA) structures coordinate lysosomal degradation systems through mammalian oocyte-to-embryo transition.
    Yuhkoh Satouh, Takaki Tatebe, Isei Tanida, Junji Yamaguchi, Yasuo Uchiyama, Ken Sato.
      Mouse oocytes undergo drastic changes in organellar composition and their activities during maturation from the germinal vesicle (GV) to metaphase II (MII) stage. After fertilization, the embryo degrades parts of the maternal components via lysosomal degradation systems, including autophagy and endocytosis, as zygotic gene expression begins during embryogenesis. Here, we demonstrate that endosomal-lysosomal organelles form large spherical assembly structures, termed endosomal-lysosomal organellar assemblies (ELYSAs), in mouse oocytes. ELYSAs are observed in GV oocytes, attaining sizes up to 7-8 μm in diameter in MII oocytes. ELYSAs comprise tubular-vesicular structures containing endosomes and lysosomes along with cytosolic components. Most ELYSAs are also positive for an autophagy regulator, LC3. These characteristics of ELYSA resemble those of ELVA (endolysosomal vesicular assemblies) identified independently. The signals of V1-subunit of vacuolar ATPase tends to be detected on the periphery of ELYSAs in MII oocytes. After fertilization, the localization of the V1-subunit on endosomes and lysosomes increase as ELYSAs gradually disassemble at the 2-cell stage, leading to further acidification of endosomal-lysosomal organelles. These findings suggest that the ELYSA/ELVA maintain endosomal-lysosomal activity in a static state in oocytes for timely activation during early development.
    Keywords:  cell biology; developmental biology; endosome; lysosomal maturation; mouse; oocyte activation; oocyte dormancy; ubiquitination; vacuolar ATPase
    DOI:  https://doi.org/10.7554/eLife.99358
  31. Autophagy. 2025 Mar 19. 1-21
    Kit-mediated autophagy suppression driven by a viral oncoprotein emerges as a crucial survival mechanism in Merkel cell carcinoma.
    Hao Shi, Yajie Yang, Jiwei Gao, Satendra Kumar, Hong Xie, Ziqing Chen, Jiawen Lyu, Harri Sihto, Virve Koljonen, Silvia Vega-Rubin-de-Celis, Vladana Vukojevic, Filip Farnebo, Viveca Björnhagen, Anders Höög, C Christofer Juhlin, Linkiat Lee, Malin Wickström, Jürgen C Becker, John Inge Johnsen, Catharina Larsson, Weng-Onn Lui.
      The KIT/c-KIT proto-oncogene is frequently over-expressed in Merkel cell carcinoma (MCC), an aggressive skin cancer commonly caused by Merkel cell polyomavirus (MCPyV). Here, we demonstrated that truncated MCPyV-encoded large T-antigen (LT) suppressed macroautophagy/autophagy by stabilizing and sequestering KIT in the paranuclear compartment via binding VPS39. KIT engaged with phosphorylated BECN1, thereby enhancing its association with BCL2 while diminishing its interaction with the PIK3C3 complex. This process ultimately resulted in the suppression of autophagy. Depletion of KIT triggered both autophagy and apoptosis, and decreased LT expression. Conversely, blocking autophagy in KIT-depleted cells restored LT levels and rescued apoptosis. Additionally, stimulating autophagy efficiently increased cell death and inhibited tumor growth of MCC xenografts in mice. These insights into the interplay between MCPyV LT and autophagy regulation reveal important mechanisms by which viral oncoproteins are essential for MCC cell viability. Thus, autophagy-inducing agents represent a therapeutic strategy in advanced MCPyV-associated MCC.Abbreviation: 3-MA, 3-methyladenine; AL, autolysosome; AP, autophagosome; Baf-A1, bafilomycin A1; BARA, β-α repeated autophagy specific domain; BH3, BCL2 homology 3 domain; CCD, coiled-coil domain; CHX, cycloheximide; Co-IP, co-immunoprecipitation; CQ, chloroquine; CTR, control; DAPI, 4',6-diamidino-2-phenylindole; EBSS, Earle's balanced salt solution; ECD, evolutionarily conserved domain; EEE, three-tyrosine phosphomimetic mutations Y229E Y233E Y352E; ER, endoplasmic reticulum; FFF, three-tyrosine non-phosphomimetic mutations; FFPE, formalin-fixed paraffin-embedded; FL, full-length; GIST, gastrointestinal stromal tumor; IB, immunoblotting; IHC, immunohistochemistry; KIT-HEK293, KIT stably expressing HEK293 cells; KRT20/CK20, keratin 20; LT, large T-antigen; LT339, MCPyV truncated LT antigen; LTco, codon-optimized MCPyV LT antigen; MCC, Merkel cell carcinoma; MCPyV-, MCPyV-negative; MCPyV, Merkel cell polyomavirus; MCPyV+, MCPyV-positive; PARP1, poly(ADP-ribose) polymerase 1; PCI, pan-caspase inhibitor; PI, propidium iodide; PtdIns3K, class III phosphatidylinositol 3-kinase; PtdIns3P, phosphatidylinositol-3-phosphate; RB1, RB transcriptional corepressor 1; RTKs, receptor tyrosine kinases; KITLG/SCF, KIT ligand; sT, small T-antigen; sTco, codon-optimized MCPyV sT antigen; T-B, Tat-BECN1; T-S, Tat-scrambled; TEM, transmission electron microscopy.
    Keywords:  Autophagy; BECN1; KIT; Merkel cell carcinoma; Merkel cell polyomavirus; large T antigen
    DOI:  https://doi.org/10.1080/15548627.2025.2477385
  32. bioRxiv. 2025 Mar 05. pii: 2025.02.28.640914. [Epub ahead of print]
    mTORC1 activation drives astrocyte reactivity in cortical tubers and brain organoid models of TSC.
    Thomas L Li, John D Blair, Taesun Yoo, Gerald A Grant, Dirk Hockemeyer, Brenda E Porter, Helen S Bateup.
      Tuberous Sclerosis Complex (TSC) is a genetic neurodevelopmental disorder associated with early onset epilepsy, intellectual disability and neuropsychiatric disorders. A hallmark of the disorder is cortical tubers, which are focal malformations of brain development that contain dysplastic cells with hyperactive mTORC1 signaling. One barrier to developing therapeutic approaches and understanding the origins of tuber cells is the lack of a model system that recapitulates this pathology. To address this, we established a genetically mosaic cortical organoid system that models a somatic "second-hit" mutation, which is thought to drive the formation of tubers in TSC. With this model, we find that loss of TSC2 cell-autonomously promotes the differentiation of astrocytes, which exhibit features of a disease-associated reactive state. TSC -/- astrocytes have pronounced changes in morphology and upregulation of proteins that are risk factors for neurodegenerative diseases, such as clusterin and APOE. Using multiplexed immunofluorescence in primary tubers from TSC patients, we show that tuber cells with hyperactive mTORC1 activity also express reactive astrocyte proteins, and we identify a unique population of cells with expression profiles that match the those observed in organoids. Together, this work reveals that reactive astrogliosis is a primary feature of TSC that arises early in cortical development. Dysfunctional glia are therefore poised to be drivers of pathophysiology, nominating a potential therapeutic target for treating TSC and related mTORopathies.
    DOI:  https://doi.org/10.1101/2025.02.28.640914
  33. Bone Res. 2025 Mar 14. 13(1): 36
    SIRT3-PINK1-PKM2 axis prevents osteoarthritis via mitochondrial renewal and metabolic switch.
    Yaoge Deng, Mingzhuang Hou, Yubin Wu, Yang Liu, Xiaowei Xia, Chenqi Yu, Jianfeng Yu, Huilin Yang, Yijian Zhang, Xuesong Zhu.
      Maintaining mitochondrial homeostasis is critical for preserving chondrocyte physiological conditions and increasing resistance against osteoarthritis (OA). However, the underlying mechanisms governing mitochondrial self-renewal and energy production remain elusive. In this study, we demonstrated mitochondrial damage and aberrant mitophagy in OA chondrocytes. Genetically overexpressing PTEN-induced putative kinase 1 (PINK1) protects against cartilage degeneration by removing defective mitochondria. PINK1 knockout aggravated cartilage damage due to impaired mitophagy. SIRT3 directly deacetylated PINK1 to promote mitophagy and cartilage anabolism. Specifically, PINK1 phosphorylated PKM2 at the Ser127 site, preserving its active tetrameric form. This inhibited nuclear translocation and the interaction with β-catenin, resulting in a metabolic shift and increased energy production. Finally, a double-knockout mouse model demonstrated the role of the SIRT3-PINK1-PKM2 axis in safeguarding the structural integrity of articular joints and improving motor functions. Overall, this study provides a novel insight into the regulation of mitochondrial renewal and metabolic switches in OA.
    DOI:  https://doi.org/10.1038/s41413-025-00413-4
  34. Autophagy. 2025 Mar 18.
    PTK6 drives HNRNPH1 phase separation to activate autophagy and suppress apoptosis in colorectal cancer.
    Bingyuan Chen, Bowen Liu, Junnan Chen, Wenjing Li, Ning Ma, Jianquan Liu, Ruizhi Fan, Qihang Hu, Hu Song, Yixin Xu, Tao Jiang, Jun Song.
      Macroautophagy/autophagy is the principal mechanism that mediates the delivery of various cellular cargoes to lysosomes for degradation and recycling, and has been reported to play a crucial role in colorectal cancer (CRC) pathogenesis and progression. Targeting autophagy may be a promising therapeutic strategy for CRC. However, the specific functions and potential mechanisms of autophagy in CRC remain unclear. In the present study, we discovered that PTK6 (protein tyrosine kinase 6) could activate autophagy and inhibit CRC apoptosis. PTK6 physically interacted with HNRNPH1 and mediated tyrosine phosphorylation at Y210 of HNRNPH1, which promoted the latter's liquid-liquid phase separation (LLPS). Furthermore, LLPS of HNRNPH1 formed biomolecular condensates and triggered splicing-switching of the NBR1 exon 10 inclusion transcript, thereby activating autophagy and suppressing apoptosis of CRC. Additionally, PDO and CDX models indicated that tilfrinib, an inhibitor targeting PTK6, could inhibit CRC growth. Overall, our findings reveal the novel PTK6-HNRNPH1-NBR1 regulatory autophagy axis and provide a potential therapy target for CRC.
    Keywords:  Alternative splicing; LLPS; PTK6; autophagy; colorectal cancer
    DOI:  https://doi.org/10.1080/15548627.2025.2481001
  35. Autophagy. 2025 Mar 18. 1-3
    The structure-function relationship of ATE1 R-transferase of the autophagic Arg/N-degron pathway.
    Su Bin Kim, Ji Su Lee, Xin Lan, Wei Huang, Derek J Taylor, Yong Tae Kwon, Yi Zhang, Chang Hoon Ji.
      ATE1 (arginyltransferase 1; EC 2.3.2) transfers the amino acid arginine (Arg) from Arg-tRNAArg to the N-terminal (Nt) residues of proteins, such as aspartate (Asp), glutamate (Glu), and oxidized cysteine (Cys). The resulting Nt-Arg acts as an N-degron that regulates the degradation of various biomaterials via the ubiquitin/Ub-proteasome system (UPS) or the autophagy-lysosome system (ALS). In the UPS, Arg/N-degrons are recognized by cognate N-recognins, leading to substrate ubiquitination and proteasomal degradation. In the ALS, the same degrons bind the macroautophagy/autophagy receptor SQSTM1/p62 (sequestosome 1) to facilitate self-polymerization of SQSTM1 associated with cargoes and SQSTM1 interaction with LC3-II on phagophores. A key unresolved question is why only a small subset of proteins acquires Arg/N-degrons, given the rather weak binding affinity of ATE1 for Nt-substrates. In this study, we determined the cryo-EM structures of human ATE1 in complex with Arg-tRNAArg and an Nt-Asp peptide. ATE1 harbors two adjacent pockets that each bind an Nt-substrate or Arg-tRNAArg, the latter being wrapped by a long, unstructured loop. In the apo state, two ATE1 monomers form a homodimer. ATE1 achieves the selectivity for its peptidyl-ligands through these multivalent interactions, with Kd values in the micro-molar range. These results reveal the structural principle of Nt-arginylation at the crossroads of the UPS and ALS.Abbreviations: ALS: autophagy-lysosome system; Arg: arginine; Asp: aspartate; ATE1: arginyltransferase 1; Cys: cysteine; CysO2(H): Cys sulfinic acid; Glu: glutamate; Nt: N-terminal; UBR: ubiquitin protein ligase E3 component n-recognin; UPS: ubiquitin-proteasome system; ZZ: ZZ-type zinc finger.
    Keywords:  ATE1; N-degron; N-recognin; Nt-arginylation; SQSTM1/p62/sequestosome 1; arginyltransferase
    DOI:  https://doi.org/10.1080/15548627.2025.2473393
  36. Mater Today Bio. 2025 Apr;31 101610
    Injectable sustainable andrographolide-releasing hydrogel for long-lasting alleviation of osteoarthritis and regulation of chondrocyte autophagy via PRKCA/EGFR.
    Yang Chen, Peipei He, Siyi Tao, Jintao Zhong, Kai Jiang, Yuching Hsu, Guang Xia, Xinzhan Mao, Hongxun Sang, Ke Lu.
      Osteoarthritis is one of the most prevalent age-related joint diseases, with chondrocyte inflammation and autophagy dysregulation serving as pivotal pathogenesis factors. Andrographolide (AD), a phytochemical identified in Andrographis paniculata, exhibits anti-inflammatory properties and regulates autophagy to safeguard cells from damage. Nevertheless, the precise mechanism underlying the influence of AD on autophagy in osteoarthritis (OA) chondrocytes remains unelucidated. Concurrently, sustained efficacy of andrographolide typically necessitates prolonged administration, posing a challenge for its clinical application. We engineered an injectable 4-arm PEG-Mix-Hydrogel/PF system capable of encapsulating lipophilic drugs and achieving sustained release over a period of up to 24 days, substantially reducing the frequency of medication. Our findings indicate that andrographolide augments chondrocyte autophagy via the PRKCA/EGFR pathway and modulates chondrocyte inflammation as well as extracellular matrix degradation. Subsequent experimentation revealed that the injectable 4-arm PEG-Mix-Hydrogel/PF@AD (PHPF@AD) exhibited excellent biocompatibility with chondrocytes, possessed a rapid in-situ gelation time, and a single injection was sufficient to alleviate joint degeneration, abnormal gait, and weakened chondrocyte autophagy in OA mice, while ameliorating inflammation, matrix degradation, and apoptosis levels, and maintaining a certain degree of bone mass around the joints. In summary, this injectable hydrogel with spontaneous andrographolide release is anticipated to be a promising therapeutic modality for OA.
    Keywords:  Andrographolide; Autophagy; Hydrogel; Micelle; Osteoarthritis
    DOI:  https://doi.org/10.1016/j.mtbio.2025.101610
  37. Proc Natl Acad Sci U S A. 2025 Mar 25. 122(12): e2424591122
    Highly spatial-temporal electrochemical profiling of molecules trafficking at a single mitochondrion in one living cell.
    Kang Liu, Lina Wu, Yuanyuan Ma, Desheng Chen, Rujia Liu, Xiaobo Zhang, Dechen Jiang, Rongrong Pan.
      Simultaneous profiling of multiple molecules trafficking at a single organelle and the surrounding cytosol within a living cell is crucial for elucidating their functions, necessitating advanced techniques that provide high spatial-temporal resolution and molecule specificity. In this study, we present an electrochemical nanodevice based on a θ-nanopipette designed to coanalyze calcium ions (Ca2+) and reactive oxygen species (ROS) at a single mitochondrion and its surrounding cytosol, thereby enhancing our understanding of their trafficking within the signaling pathways of cellular autophagy. Two independent nanosensors integrated within the channels of the θ-nanopipette spatially isolate a single target mitochondrion from the cytosol and simultaneously measure the release of Ca2+ and ROS with high spatial-temporal resolution. Dynamic tracking reveals the direct trafficking of lysosomal Ca2+ to the mitochondrion rather than to the cytosol, which triggers ROS-induced ROS release within the mitochondria. Furthermore, highly temporal and concurrent observations revealed a second burst of Ca2+ in both the mitochondrion and the cytosol, which is not consistent with the change in ROS. These dynamic data elucidate the potential role of a beneficial feedback loop between the Ca2+ signaling pathway and the subsequent generation of mitochondrial ROS in ML-SA-induced autophagy. More importantly, this innovative platform facilitates detailed profiling of the molecular interactions between trafficking molecules within the mitochondria and the adjacent cytosolic environment, which is hardly realized using the current superresolution optical microscopy.
    Keywords:  electrochemical analysis; highly spatial–temporal profiling; molecule trafficking; single living cell; single mitochondrion
    DOI:  https://doi.org/10.1073/pnas.2424591122
  38. Arch Gerontol Geriatr. 2025 Mar 08. pii: S0167-4943(25)00081-0. [Epub ahead of print]133 105824
    FP receptor inhibits autophagy to aggravate aging-related cardiac fibrosis through PI3K/AKT/mTOR signaling pathway.
    Jia Qi, Bin Lu, Cheng-Wei Jin, Yuan-Yuan Shang, Hui Pan, Hao Li, Zhou-Jie Tong, Wei Zhang, Lu Han, Ming Zhong.
       BACKGROUND: F-prostanoid receptor (FP receptor), a receptor for Prostaglandin F2α(PGF2α), is involved in the process of tissue fibrosis, but its exact role in the aging heart remains unclear.
    METHODS: We investigated cardiac function, myocardial fibrosis levels, autophagy levels and related mechanistic pathways in different groups of mice using gene silencing. At the cellular level, we simulated the senescence process of cardiac fibroblasts and investigated the related mechanisms using relevant inhibitors.
    RESULTS: In aging mice, FP receptor and PI3K/AKT/mTOR pathways are increased and autophagy levels are decreased, ultimately leading to cardiac fibrosis. FP receptor gene silencing slows down the above process. We found similar changes at the cellular level.
    CONCLUSION: FP receptor could activate PI3K/AKT/mTOR pathway and inhibit cardiac autophagy, which resulted in aging-related cardiac fibrosis. Thus, the inhibition of FP receptor could improve aging-related cardiac remodeling, implicating its potential therapeutic application to treat cardiovascular diseases associated with aging.
    Keywords:  Aging process; Autophagy; Cardiac fibrosis; FP receptor; PI3K/AKT/mTOR pathway
    DOI:  https://doi.org/10.1016/j.archger.2025.105824
  39. J Clin Invest. 2025 Mar 17. pii: e185340. [Epub ahead of print]135(6):
    Identification of lysosomal lipolysis as an essential noncanonical mediator of adipocyte fasting and cold-induced lipolysis.
    Yu-Sheng Yeh, Trent D Evans, Mari Iwase, Se-Jin Jeong, Xiangyu Zhang, Ziyang Liu, Arick Park, Ali Ghasemian, Borna Dianati, Ali Javaheri, Dagmar Kratky, Satoko Kawarasaki, Tsuyoshi Goto, Hanrui Zhang, Partha Dutta, Francisco J Schopfer, Adam C Straub, Jaehyung Cho, Irfan J Lodhi, Babak Razani.
      Adipose tissue lipolysis is the process by which triglycerides in lipid stores are hydrolyzed into free fatty acids (FFAs), serving as fuel during fasting or cold-induced thermogenesis. Although cytosolic lipases are considered the predominant mechanism of liberating FFAs, lipolysis also occurs in lysosomes via lysosomal acid lipase (LIPA), albeit with unclear roles in lipid storage and whole-body metabolism. We found that adipocyte LIPA expression increased in adipose tissue of mice when lipolysis was stimulated during fasting, cold exposure, or β-adrenergic agonism. This was functionally important, as inhibition of LIPA genetically or pharmacologically resulted in lower plasma FFAs under lipolytic conditions. Furthermore, adipocyte LIPA deficiency impaired thermogenesis and oxygen consumption and rendered mice susceptible to diet-induced obesity. Importantly, lysosomal lipolysis was independent of adipose triglyceride lipase, the rate-limiting enzyme of cytosolic lipolysis. Our data suggest a significant role for LIPA and lysosomal lipolysis in adipocyte lipid metabolism beyond classical cytosolic lipolysis.
    Keywords:  Adipose tissue; Endocrinology; Lysosomes; Metabolism; Obesity; Therapeutics
    DOI:  https://doi.org/10.1172/JCI185340
  40. Cell Mol Life Sci. 2025 Mar 17. 82(1): 120
    What are the ethical limits of claimed scientific authorship? a case report of relevance.
    Juan-Carlos Argüelles.
      Since its discovery in the middle of the XX century, research into autophagy has undergone a spectacular expansion, particularly in the early 1990s. A number of physiological processes involving autophagy have been revealed and important human pathologies have been associated with perturbations in autophagy. In 2008 the "Guidelines for the use and interpretation of assays for monitoring autophagy" was launched with the purpose of collecting in a single document all the available information to monitor autophagy, which, it was thought, might be useful for established groups and any new scientists attracted by this field. The usefulness and success of this Guidelines has led to the subsequent publication of editions every 4 years, a task in which a growing number of authors have become involved and consequently included in the list of contributors. However, this worthy initiative and closely associated metric parameters has led to important scholarly repercussions in terms of perceived merits, grants and financial support obtained, professional careers and other areas concerning scientific activity. All these aspects are carefully examined in this contribution.
    Keywords:  Authorship; Autophagy; Ethics; Metric parameters; Scholar repercussions
    DOI:  https://doi.org/10.1007/s00018-025-05650-8
  41. bioRxiv. 2025 Mar 06. pii: 2025.03.06.641798. [Epub ahead of print]
    Murine Leukemia Virus GlycoGag Antagonizes SERINC5 via ER-phagy Receptor RETREG1.
    Iqbal Ahmad, Jing Zhang, Rongrong Li, Wenqiang Su, Weiqi Liu, You Wu, Ilyas Khan, Xiaomeng Liu, Lian-Feng Li, Sunan Li, Yong-Hui Zheng.
      Serine incorporator 5 (SERINC5) is a host restriction factor that targets certain enveloped viruses, including human immunodeficiency virus type 1 (HIV-1) and murine leukemia virus (MLV). It integrates into the viral envelope from the cell surface, inhibiting viral entry. SERINC5 is transported to the cell surface via polyubiquitination, while a single K130R mutation retains it in the cytoplasm. Both HIV-1 Nef and MLV glycoGag proteins antagonize SERINC5 by reducing its expression in producer cells. Here, we report that MLV glycoGag employs selective autophagy to downregulate SERINC5, demonstrating a more potent mechanism for decreasing its cell surface expression. Although glycoGag is a type II integral membrane protein, it primarily localizes to the cytoplasm and undergoes rapid proteasomal degradation. Employing the K130R mutant, we show that Nef, primarily associated with the plasma membrane, downregulates SERINC5 only after it has trafficked to the cell surface, whereas glycoGag can reduce its expression before reaching the plasma membrane while still in the cytoplasm. Nonetheless, an interaction with SERINC5 stabilizes and recruits glycoGag to the plasma membrane, enabling it to downregulate SERINC5 from the cell surface. Through affinity-purified mass spectrometry analysis combined with CRISPR/Cas9 knockouts, we find that glycoGag's activity depends on reticulophagy regulator 1 (RETREG1), an ER-phagy receptor. Further knockout experiments of critical autophagy genes demonstrate that glycoGag downregulates cytoplasmic SERINC5 via micro-ER-phagy. These findings provide crucial new insights into the ongoing arms race between retroviruses and SERINC5 during infection.
    AUTHOR SUMMARY: HIV-1 Nef and MLV glycoGag are unrelated viral proteins, yet both counteract the same host restriction factor, SERINC5, to facilitate productive infection. In this study, we report a novel pathway through which glycoGag downregulates SERINC5. We demonstrate that while Nef downregulates SERINC5 only after it has trafficked to the cell surface, glycoGag can directly downregulate SERINC5 in the cytoplasm before it reaches the plasma membrane. Furthermore, we show that this pathway is mediated by the ER-phagy receptor RETREG1, which targets SERINC5 for degradation via micro-ER-phagy. This mechanism provides a more effective means of blocking SERINC5 antiviral activity. These findings reveal that retroviruses have evolved different strategies to antagonize SERINC5, highlighting the critical role of SERINC5 in restricting retroviral infections.
    DOI:  https://doi.org/10.1101/2025.03.06.641798
  42. Sci Adv. 2025 Mar 21. 11(12): eadn8402
    AMPK-dependent Parkin activation suppresses macrophage antigen presentation to promote tumor progression.
    Xinyu Wang, Yiyi Li, Yan Li, Xiumei Wang, Hongrui Song, Yingzhao Wang, Chunliu Huang, Chengzhou Mao, Lixiang Wang, Cheng Zhong, Di Yu, Zijin Xia, Yongyi Feng, Jingjing Duan, Yujia Liu, Juanjuan Ou, Congzhou Luo, Wenhao Mai, Hai Hong, Weibin Cai, Limin Zheng, Jean-François Trempe, Edward A Fon, Jing Liao, Wei Yi, Jun Chen.
      The constrained cross-talk between myeloid cells and T cells in the tumor immune microenvironment (TIME) restricts cancer immunotherapy efficacy, whereas the underlying mechanism remains elusive. Parkin, an E3 ubiquitin ligase renowned for mitochondrial quality control, has emerged as a regulator of immune response. Here, we show that both systemic and macrophage-specific ablations of Parkin in mice lead to attenuated tumor progression and prolonged mouse survival. By single-cell RNA-seq and flow cytometry, we demonstrate that Parkin deficiency reshapes the TIME through activating both innate and adaptive immunities to control tumor progression and recurrence. Mechanistically, Parkin activation by AMP-activated protein kinase rather than PTEN-induced kinase 1 mediated major histocompatibility complex I down-regulation on macrophages via Autophagy related 5-dependent autophagy. Furthermore, Parkin deletion synergizes with immune checkpoint blockade treatment and Park2-/- signature aids in predicting the prognosis of patients with solid tumor. Our findings uncover Parkin's involvement in suppressing macrophage antigen presentation for coordinating the cross-talk between macrophages and T cells.
    DOI:  https://doi.org/10.1126/sciadv.adn8402
  43. Microb Pathog. 2025 Mar 13. pii: S0882-4010(25)00204-9. [Epub ahead of print]203 107479
    Candida glabrata subverts intracellular trafficking and modulates autophagy to replicate in human epithelial cells.
    Juan Castillo-Cruz, Samara Palacios-Barreto, Manuel Alejandro Mosso-Pani, Amanda Belén Serna-Pérez, Aída Verónica Rodríguez-Tovar, Jeanet Serafin-López, Nayeli Shantal Castrejón-Jiménez, Blanca Estela García-Pérez.
      In recent years, Candida glabrata (C. glabrata) has emerged as a pathogen responsible for systemic mortal infections. C. glabrata invades nonphagocytic cells, but the mechanisms involved in its internalization and its intracellular fate in these cells remain poorly understood. Here, it was shown that endocytosis of C. glabrata in epithelial cells partially depends on actin and microtubule rearrangements; importantly, C. glabrata promotes its uptake. The analysis of intracellular fate determined that C. glabrata avoids the fusion of endocytic vacuoles with lysosomes and replicates in epithelial cells. Additionally, C. glabrata downregulates host cell autophagy in the first hour of infection, which correlates with its intracellular replication. Remarkably, the ectopic activation of autophagy contributed to the control of intracellular growth of this yeast. These findings highlight the ability of C. glabrata to manipulate host proteins involved in endocytic processes and intracellular trafficking. Likewise, these results suggest a strong role of host autophagy in controlling fungal pathogens such as C. glabrata.
    Keywords:  A549 human epithelial cells; Autophagy; Candida glabrata; Cytoskeleton; Intracellular trafficking; Nakaseomyces glabrata
    DOI:  https://doi.org/10.1016/j.micpath.2025.107479
  44. Int J Med Sci. 2025 ;22(7): 1708-1719
    Inhibition of autophagy promotes ultrasound‑targeted microbubble destruction-induced apoptosis of pancreatic cancer cells.
    Nan Chen, Xiaoyu Zhang, Ping Yang, Xuemei He.
      In therapeutic studies of pancreatic cancer, ultrasound-targeted microbubble destruction (UTMD) has shown potential in promoting apoptosis as a safe and non-invasive adjuvant therapy. Autophagy, a regulatory mechanism for cellular stress response and survival, plays a dual role in tumor development, progression, and treatment. However, the role of autophagy in UTMD-induced apoptosis in pancreatic cancer cells remains unclear. In this study, chloroquine (CQ), an autophagy inhibitor, was combined with UTMD to treat pancreatic cancer both in vitro and in vivo, with changes in apoptosis assessed through Western blot and TUNEL staining. The results showed that UTMD induced both apoptosis and autophagy in pancreatic cancer cells. Notably, inhibiting autophagy significantly enhanced UTMD-induced apoptosis, while the inhibition of apoptosis did not affect UTMD-induced autophagy. These findings suggest that autophagy reduces the effectiveness of UTMD in treating pancreatic cancer. This study offers a new perspective on UTMD for treating pancreatic cancer, suggesting that combining autophagy inhibitors could be a promising strategy to enhance the effectiveness of pancreatic cancer therapy.
    Keywords:  apoptosis; chloroquine (CQ); ultrasound-targeted microbubble destruction (UTMD)
    DOI:  https://doi.org/10.7150/ijms.106509
  45. Mol Biol Rep. 2025 Mar 15. 52(1): 314
    MicroRNA-124a/Sirtuin 1 pathway inhibits autophagy to promote hepatocyte apoptosis in acute-on-chronic liver failure.
    Hongrui Xu, Xin Wang, Yadong Wang, Chuan Shen, Luyuan Ma, Caiyan Zhao.
       BACKGROUND: The roles of microRNAs in the regulation of autophagy and apoptosis in hepatic cells suggest that they may serve as novel biomarkers or therapeutic targets for various liver injuries. In this study, we aim to analyze whether miR-124a regulates autophagy and apoptosis in hepatic cells, particularly in acute-on-chronic liver failure (ACLF).
    MATERIALS AND METHODS: The plasma and liver tissues from the healthy control (HC) and ACLF patients were included. Moreover, LO2 cells were used to perform in vitro experiments. To measure hepatocyte apoptosis, a TUNEL kit was used. LPS, over-expression or knockdown, 3-methyladenine (3-MA) were used in vitro experiments. The expression levels of the autophagy related proteins (Beclin-1 and LC3), anti-apoptotic proteins (BAX and Bcl-2), Sirtuin 1 (SIRT1), and miR-124a were assessed using western blotting, ELISA, and qRT-PCR.
    RESULTS: ACLF patients had significantly decreased expressions of SIRT1, Bcl-2, LC3, and Beclin-1 and significant upregulation of miR-124a and BAX in both plasma and liver tissues in comparison with the HC group. miR-124a was inversely correlated with autophagy markers and SIRT1, but positively correlated with apoptosis. Upon exposure to LPS, the levels of BAX and miR-124a were notably elevated, while Beclin-1, LC3, SIRT1, and Bcl-2 were notably downregulated in LO2 cells. These changes were further exaggerated in the presence of the miR-124a mimic and EX-527 compared to the miR-124a inhibitor and SRT1720 groups. Co-transfection of miR-124a inhibitor was able to partly counteract the pro-apoptotic effects of the autophagy inhibitor 3-MA.
    CONCLUSION: miR-124a downregulates SIRT1, thereby suppressing hepatocyte autophagy and consequently inducing apoptosis.
    Keywords:  Acute-on-chronic liver failure; Apoptosis; Autophagy; Sirtuin 1; miR-124a
    DOI:  https://doi.org/10.1007/s11033-025-10373-x
  46. Autophagy. 2025 Mar 16.
    The Alpha-coronavirus E protein inhibits the JAK-STAT pathway signaling by triggering STAT2 degradation through OPTN- and NBR1-mediated selective autophagy.
    Zhao Huang, Chenyang Gao, Shaohong Huang, Sizhan Lin, WenBo Zhang, Jianyi You, Xiongnan Chen, Pei Zhou, Guihong Zhang, Lang Gong.
      The zoonotic transmission of coronaviruses continues to pose a considerable threat to humans. Swine acute diarrhea syndrome coronavirus (SADS-CoV), a bat coronavirus related to HKU2, causes severe economic losses in the pig industry and has the potential to trigger outbreaks in humans. However, our understanding of how SADS-CoV evades the host's innate immunity remains limited, hindering effective responses to potential human outbreaks. In this study, we demonstrate that the SADS-CoV envelope protein (E) inhibits type I interferon (IFN-I) signaling by inducing the degradation of STAT2 via the macroautophagy/autophagy-lysosome pathway. Mechanistically, the E protein evades host innate immunity by promoting STAT2 degradation through autophagy, mediated by the NBR1 and OPTN receptors. Notably, ubiquitination of E protein is required for the autophagic degradation of STAT2. Additionally, lysine residue K61 of the E protein is crucial for its stable expression; however, it is not involved in its ubiquitination. In conclusion, our study reveals a novel mechanism by which the E protein disrupts IFN-I signaling by targeting STAT2 via autophagy, enhancing our understanding of SADS-CoV's immune evasion strategies and providing potential drug targets for controlling viral infections.
    Keywords:  Alpha-coronaviruses; STAT2; envelope; innate immunity; selective autophagy host
    DOI:  https://doi.org/10.1080/15548627.2025.2479671
  47. bioRxiv. 2025 Jan 02. pii: 2024.12.31.630809. [Epub ahead of print]
    TOR and heat shock response pathways regulate peroxisome biogenesis during proteotoxic stress.
    Nandini Shukla, Maxwell L Neal, Jean-Claude Farré, Fred D Mast, Linh Truong, Theresa Simon, Leslie R Miller, John D Aitchison, Suresh Subramani.
      Peroxisomes are versatile organelles mediating energy homeostasis and redox balance. While peroxisome dysfunction is linked to numerous diseases, the molecular mechanisms and signaling pathways regulating peroxisomes during cellular stress remain elusive. Using yeast, we show that perturbations disrupting protein homeostasis including loss of ER or cytosolic chaperone function, impairments in ER protein translocation, blocking ER N-glycosylation, or reductive stress, cause peroxisome proliferation. This proliferation is driven by increased de novo biogenesis from the ER as well as increased fission of pre-existing peroxisomes, rather than impaired pexophagy. Notably, peroxisome biogenesis is essential for cellular recovery from proteotoxic stress. Through comprehensive testing of major signaling pathways, we determine this response to be mediated by activation of the heat shock response and inhibition of Target of Rapamycin (TOR) signaling. Finally, the effects of proteotoxic stress and TOR inhibition on peroxisomes are also captured in human fibroblasts. Overall, our findings reveal a critical and conserved role of peroxisomes in cellular response to proteotoxic stress.
    DOI:  https://doi.org/10.1101/2024.12.31.630809
  48. CNS Neurosci Ther. 2025 Mar;31(3): e70335
    Acute Restraint Stress Induces Long-Lasting Synaptic Enhancement by Inhibiting AMPK Activation in AD Model Mice.
    Ming Wang, Baoyuan Jin, Jihoon Jo.
       BACKGROUND: Alzheimer's disease (AD) is characterized by a gradual synaptic loss. The progression of AD severely affects late-phase long-term potentiation (L-LTP), which is essential for long-term memory consolidation.
    AIM: We have previously demonstrated the beneficial effects of acute restraint stress (ARS) on hippocampal LTP in AD mouse models. This study aimed to verify the effects and potential mechanisms of ARS on the maintenance of hippocampal L-LTP in two AD mouse models.
    MATERIALS AND METHODS: 5xFAD and Tg2576 mice underwent a 30-min body immobilization protocol to induce ARS, followed by electrophysiological recordings of L-LTP (> 3 h) in the CA1 region of thehippocampus.
    RESULTS: The ARS-exposed group exhibited significantly enhanced L-LTP compared to the control group. Maintenance of L-LTP requires new protein synthesis and signaling via the mammalian target of rapamycin (mTOR) pathway. Our findings revealed that ARS increased hippocampal adenosine triphosphate (ATP) production and reduced AMPK activity. Inactivation of AMPK and subsequent activation of the mTOR pathway were strongly associated with the ARS-facilitated enhancement of L-LTP. Furthermore, our experiments using the mTOR inhibitor rapamycin demonstrated that it effectively prevented the enhancement of L-LTP following ARS, underscoring the pivotal role of mTOR in this process.
    CONCLUSION: ARS may significantly modify AMPK activation and mTOR regulation in L-LTP, potentially triggering the mechanisms of long-term memory consolidation in AD mouse model mice. Identifying these underlying mechanisms could help promote the development of novel pharmaceutical agents for the treatment of AD.
    Keywords:  AMPK; Alzheimer's disease; hippocampus; long term potentiation; stress
    DOI:  https://doi.org/10.1111/cns.70335
  49. Int Immunopharmacol. 2025 Mar 18. pii: S1567-5769(25)00459-X. [Epub ahead of print]153 114469
    N-acetylserotonin derivative ameliorates hypoxic-ischemic brain damage by promoting PINK1/Parkin-dependent mitophagy to inhibit NLRP3 inflammasome-induced pyroptosis.
    Fang Fang, Jiaxin Tang, Jiaqing Geng, Chengzhi Fang, Binghong Zhang.
      Neonatal hypoxic-ischemic brain damage is the main cause of hypoxic-ischemic encephalopathy and cerebral palsy, whose clinical treatment is still limited to therapeutic hypothermia with limited efficacy. N-[2-(5-hydroxy-1H-indol-3-yl) ethyl]-2-oxopiperidine-3-carboxamide (HIOC), a derivative of N-acetylserotonin, has shown neuroprotective properties. This study was conducted to evaluate the neuroprotective and molecular mechanisms of HIOC. We established an in vitro model using Oxygen-glucose deprivation/reoxygenation (OGD/R) in HT22 cells, alongside an in vivo model via the modified Rice-Vannucci method. The results showed that HIOC reduced OGD/R-induced HT22 cell pyroptosis and inhibited NOD-like receptor pyrin domain- containing protein 3 (NLRP3) inflammasome activation. With the addition of the mitophagy inhibitor 3-MA, we demonstrated that HIOC promoted PTEN-induced putative kinase 1 (PINK1)/Parkin-mediated mitophagy to reduce HT22 cell pyroptosis. Mechanistically, HIOC stimulated mitophagy to remove damaged mitochondria. The clearance of injured mitochondria reduced reactive oxygen species generation, which consequently inhibited NLRP3 inflammasome expression. In vivo, HIOC remarkably lessened cerebral blood flow, infarct volume, neuronal injury by activating mitophagy. HIOC activated mitophagy to produce antipyroptosis effects. Together, our finding demonstrated that HIOC improves brain injury by promoting PINK1/Parkin-dependent mitophagy to inhibit NLRP3 inflammasome activation and pyroptosis, suggesting its potential for hypoxic-ischemic brain damage treatment.
    Keywords:  Hypoxic-ischemic brain damage (HIBD); Mitophagy; N-[2-(5-hydroxy-1H-indol-3-yl) ethyl]-2-oxopiperidine-3-carboxamide (HIOC); N-acetylserotonin derivative; Pyroptosis
    DOI:  https://doi.org/10.1016/j.intimp.2025.114469
  50. Invest Ophthalmol Vis Sci. 2025 Mar 03. 66(3): 45
    Pten Loss Triggers Progressive Photoreceptor Degeneration in an mTORC1-Independent Manner.
    Joseph Hanna, Yacine Touahri, Alissa Pak, Luke Ajay David, Edwin van Oosten, Rajiv Dixit, Laura M Vecchio, Dhruv Nimesh Mehta, Ren Minamisono, Isabelle Aubert, Carol Schuurmans.
       Purpose: Silencing Phosphatase and tensin homolog (Pten) is a proposed therapeutic strategy for tissue regeneration to treat neurological disorders. However, Pten is pleiotropic, inhibiting several signaling and metabolic pathways, including mTORC1 and glycolysis, both pro-regenerative in certain contexts. This study aims to assess the long-term impact of inactivating Pten on photoreceptor survival in the retina and to identify downstream pathway(s).
    Methods: We assessed retinal integrity in Pten conditional knock-outs (cKOs) that were retinal progenitor cell (RPC)-specific (Pten RPC-cKO), a congenital model, or rod-specific (Pten Rho-cKO). We examined early changes in photoreceptor gene expression and used immunostaining to assess photoreceptors, reactive astrocytes, microglia, angiogenesis, and subretinal deposit formation from postnatal day (P) 21 to 1 year of age. Pten RPC-cKO retinal explants were treated with rapamycin, an mTOR inhibitor, or 2-deoxy-D-glucose (2DG), a glycolysis inhibitor.
    Results: In both Pten-cKO models, retinas display signs of early pathogenesis as photoreceptor-specific gene expression is downregulated at P0, before photoreceptor loss. Pten loss triggers progressive rod and cone degeneration beginning at P21 in Pten RPC-cKOs and at 6 months of age in Pten Rho-cKOs. Activated microglia and astrocytes, and increased angiogenesis, are observed in both Pten-cKO models, while subretinal amyloid-β deposits develop in Pten RPC-cKOs. Rapamycin accelerates photoreceptor degeneration in Pten RPC-cKOs, whereas 2DG has no effect.
    Conclusions: Our findings suggest that Pten loss, either in RPCs as a congenital model, or solely in mature rod photoreceptors, leads to progressive retinal degeneration that is exacerbated by mTORC1 suppression, drawing into question the therapeutic value of Pten-mTORC1 manipulations.
    DOI:  https://doi.org/10.1167/iovs.66.3.45
  51. NPJ Aging. 2025 Mar 16. 11(1): 18
    Atg5 in microglia regulates sex-specific effects on postnatal neurogenesis in Alzheimer's disease.
    Ellen Walter, Gabrielle Angst, Justin Bollinger, Linh Truong, Elena Ware, Eric S Wohleb, Yanbo Fan, Chenran Wang.
      Female Alzheimer's disease (AD) patients display greater cognitive deficits and worse AD pathology as compared to male AD patients. In this study, we found that conditional knockout (cKO) of Atg5 in female microglia failed to obtain disease-associated microglia (DAM) gene signatures in familiar AD mouse model (5xFAD). Next, we analyzed the maintenance and neurogenesis of neural stem cells (NSCs) in the hippocampus and subventricular zone (SVZ) from 5xFAD mice with Atg5 cKO. Our data indicated that Atg5 cKO reduced the NSC number in hippocampus of female but not male 5xFAD mice. However, in the SVZ, Atg5 cKO only impaired NSCs in male 5xFAD mice. Interestingly, female 5xFAD;Fip200 cKO mice and 5xFAD;Atg14 cKO mice did not show NSC defects. These autophagy genes cKO 5xFAD mice exhibited a higher neurogenesis activity in their SVZ. Together, our data indicate a sex-specific role for microglial Atg5 in postnatal neurogenesis in AD mice.
    DOI:  https://doi.org/10.1038/s41514-025-00209-0
  52. Stem Cell Res Ther. 2025 Mar 18. 16(1): 142
    Extracellular vesicles derived from mesenchymal stem cells alleviate renal fibrosis via the miR-99b-5p/mTOR/autophagy axis in diabetic kidney disease.
    Rongrong Li, Hongyan Tao, Kai Pan, Rui Li, Zhikun Guo, Xiaoniao Chen, Zongjin Li.
       BACKGROUND: Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease (ESRD) globally, presenting a significant therapeutic challenge. Extracellular vesicles (EVs) from mesenchymal stem cells (MSCs) have emerged as promising therapeutic agents. This study explored the therapeutic effects and mechanisms of EVs derived from human placental mesenchymal stem cells (hP-MSCs) on DKD.
    METHODS: EVs were isolated from cultured hP-MSCs and administered to streptozotocin (STZ)-induced diabetic mice and high glucose-treated glomerular mesangial cells. The therapeutic impact of EVs was assessed through histological analysis and biochemical assays. miR-99b-5p expression in EVs and its role in modulating the mechanistic target of rapamycin (mTOR)/autophagy pathway were examined via western blotting and RT‒qPCR.
    RESULTS: Treatment with hP-MSC-derived EVs significantly alleviated renal fibrosis and improved renal function in DKD models. These EVs were enriched with miR-99b-5p, which targeted and inhibited mTOR signaling, thereby increasing autophagic activity and reducing cellular proliferation and extracellular matrix accumulation in renal tissues.
    CONCLUSIONS: hP-MSC-derived EVs can mitigate renal injury in DKD by modulating the miR-99b-5p/mTOR/autophagy pathway. These findings suggest a potential cell-free therapeutic strategy for managing DKD.
    Keywords:  Diabetic kidney disease (DKD); Extracellular vesicles; Glomerular mesangial cells; Mesenchymal stem cells; mTOR; miR-99b-5p
    DOI:  https://doi.org/10.1186/s13287-025-04265-x
  53. Aging (Albany NY). 2025 Mar 18. 17
    Mitochondrial oxidative stress or decreased autophagy in osteoblast lineage cells is not sufficient to mimic the deleterious effects of aging on bone mechanoresponsiveness.
    Ana Resende-Coelho, Md Mohsin Ali, Alicen James, Aaron Warren, Landon Gatrell, Ilham Kadhim, Qiang Fu, Jinhu Xiong, Melda Onal, Maria Almeida.
      Exercise-induced mechanical load stimulates bone cells, including osteocytes, to promote bone formation. The bone response to loading is less effective with aging, but the cellular and molecular mechanisms responsible for the impaired mechanoresponsiveness remain unclear. Excessive mitochondrial reactive oxygen species (mtROS) and deficient autophagy are common aging mechanisms implicated in decreased bone formation in old mice. Here, we confirmed that the osteogenic effects of tibia compressive loading are lower in old versus young female mice. We also examined whether an increase in mtROS or decreased autophagy in osteoblast-lineage cells of adult female mice could mimic the deleterious effects of aging. To this end, we loaded mice lacking the antioxidant enzyme superoxide dismutase 2 (Sod2) or autophagy-related 7 (Atg7) in cells targeted by Osterix1 (Osx1)-Cre. Osteocytes in Atg7ΔOsx1 exhibited altered morphology and decreased osteocyte dendrite projections. Two weeks of loading increased cortical bone mass and bone formation rate at both periosteal and endosteal surfaces of Osx1-Cre control mice. Nonetheless, in both Atg7ΔOsx1 and Sod2ΔOsx1 mice the response to loading was identical to that observed in control mice, indicating that compromised Atg7-dependent autophagy or excessive mtROS are not sufficient to impair the bone response to tibial compressive loading. Thus, alternative mechanisms of aging might be responsible for the decreased response of the aged skeleton to mechanical stimuli. These findings also suggest that an intact osteocyte dendrite network is not required for the osteogenic response in this model of bone loading.
    Keywords:  Atg7; Osx1-Cre; Sod2; osteocytes; tibia compressive loading
    DOI:  https://doi.org/10.18632/aging.206213
  54. Food Sci Nutr. 2025 Mar;13(3): e70071
    Luteolin Inhibits Dexamethasone-Induced Osteoporosis by Autophagy Activation Through miR-125b-5p/SIRT3/AMPK/mTOR Axis, an In Vitro and In Vivo Study.
    Liang Tang, Xinyu Fan, Yongqing Xu, Yeming Zhang, Gang Li.
      Luteolin (LUT) has been suggested as an inhibitor of osteoporosis (OP). This investigation examines the pivotal role of the miR-125b-5p/SIRT3/AMPK/mTOR pathway in mediating luteolin-induced effects on OP. Mesenchymal stem cells derived from bone marrow (BMSCs) were exposed to dexamethasone (DEX) to create an in vitro model of OP. Following treatment with luteolin, the levels of miR-125b-5p and SIRT3 were quantified using reverse transcription polymerase chain reaction. Moreover, SIRT3, AMPK, mTOR protein levels, and osteogenesis (OPN, Runx2, OSX, and OCN), and autophagy (p62, ATG5, LC3, and BECN1) were evaluated using ELISA. Additionally, specific mimics and siRNA were constructed to overexpress miR-125b-5p or downregulate SIRT3. Furthermore, animal models of DEX-induced OP were constructed to assess the effects of LUT at doses of 50 and 100 mg/kg/day on bone histology, stereology, biochemistry, and the expression of the miR-125b-5p, SIRT3/AMPK/mTOR axis, and markers of osteogenesis and autophagy. The findings revealed that LUT suppressed miR-125b-5p expression, overexpressed SIRT3 and AMPK, and downregulated mTOR in BMSCs compared to DEX (p-value < 0.01). Interestingly, LUT restored the levels of markers for osteogenesis and autophagy (p-value < 0.001). The overexpression of SIRT3 or miR-125b-5p downregulation inhibited LUT therapeutic properties. In animals, LUT improved bone histology (p-value < 0.05) and inhibited miR-125b-5p and mTOR expression while overexpressing SIRT3 and AMPK (p-value < 0.001). RUNX2, OSX, OPN, and OCN levels were improved, and autophagy was enhanced in LUT-treated rats. The current findings revealed that LUT could promote osteogenesis and improve OP via autophagy activation through the miR-125b-5p/SIRT3/AMPK/mTOR pathway.
    Keywords:  SIRT3; autophagy; luteolin; miRNA; osteoprosis
    DOI:  https://doi.org/10.1002/fsn3.70071
  55. bioRxiv. 2025 Mar 07. pii: 2025.03.02.641041. [Epub ahead of print]
    TBCK-deficiency leads to compartment-specific mRNA and lysosomal trafficking defects in patient-derived neurons.
    Marco Flores-Mendez, Jesus A Tintos-Hernández, Leonardo Ramos-Rodriguez, Leann Miles, Tsz Y Lo, Yuanquan Song, Xilma R Ortiz-González.
      Monogenic pediatric neurodegenerative disorders can reveal fundamental cellular mechanisms that underlie selective neuronal vulnerability. TBCK-Encephaloneuronopathy (TBCKE) is a rare autosomal recessive disorder caused by stop-gain variants in the TBCK gene. Clinically, patients show evidence of profound neurodevelopmental delays, but also symptoms of progressive encephalopathy and motor neuron disease. Yet, the physiological role of TBCK protein remains unclear. We report a human neuronal TBCKE model, derived from iPSCs homozygous for the Boricua variant (p.R126X). Using unbiased proteomic analyses of human neurons, we find TBCK interacts with PPP1R21, C12orf4, and Cryzl1, consistent with TBCK being part of the FERRY mRNA transport complex. Loss of TBCK leads to depletion of C12ORF4 protein levels across multiple cell types, suggesting TBCK may also play a role regulating at least some members of the FERRY complex. We find that TBCK preferentially, but not exclusively, localizes to the surface of endolysosomal vesicles and can colocalize with mRNA in lysosomes. Furthermore, TBCK-deficient neurons have reduced mRNA content in the axonal compartment relative to the soma. TBCK-deficient neurons show reduced levels of the lysosomal dynein/dynactin adapter protein JIP4, which functionally leads to TBCK-deficient neurons exhibiting striking lysosomal axonal retrograde trafficking defects. Hence, our work reveals that TBCK can mediate endolysosomal trafficking of mRNA, particularly along lysosomes in human axonal compartments. TBCK-deficiency leads to compartment-specific mRNA and lysosomal trafficking defects in neurons, which likely contribute to the preferential susceptibility to neurodegeneration.
    DOI:  https://doi.org/10.1101/2025.03.02.641041
  56. J Biol Chem. 2025 Mar 18. pii: S0021-9258(25)00270-4. [Epub ahead of print] 108421
    Optogenetic tools for inducing organelle membrane rupture.
    Yuto Nagashima, Tomoya Eguchi, Ikuko Koyama-Honda, Noboru Mizushima.
      Disintegration of organelle membranes induces various cellular responses and has pathological consequences, including autoinflammatory diseases and neurodegeneration. Establishing methods to induce membrane rupture of specific organelles is essential to analyze the downstream effects of membrane rupture; however, the spatiotemporal induction of organelle membrane rupture remains challenging. Here, we develop a series of optogenetic tools to induce organelle membrane rupture by using engineered Bcl-2-associated X protein (BAX), which primarily functions to form membrane pores in the outer mitochondrial membrane (OMM) during apoptosis. When BAX is forced to target mitochondria, lysosomes, or the endoplasmic reticulum (ER) by replacing its C-terminal transmembrane domain (TMD) with organelle-targeting sequences, the BAX mutants rupture their targeted membranes. To regulate the activity of organelle-targeted BAX, the photosensitive light-oxygen-voltage-sensing 2 (LOV2) domain is fused to the N-terminus of BAX. The resulting LOV2-BAX fusion protein exhibits blue light-dependent membrane-rupture activity on various organelles, including mitochondria, the ER, and lysosomes. Thus, LOV2-BAX enables spatiotemporal induction of membrane rupture across a broad range of organelles, expanding research opportunities on the consequences of organelle membrane disruption.
    Keywords:  Bcl-2-associated X protein (BAX); Membrane rupture; light-oxygen-voltage-sensing 2 (LOV2) domain; lysosomal membrane permeabilization (LMP); mitochondrial outer membrane permeabilization (MOMP); optogenetics
    DOI:  https://doi.org/10.1016/j.jbc.2025.108421
  57. Cell Death Dis. 2025 Mar 20. 16(1): 195
    PTBP2 promotes cell survival and autophagy in chronic myeloid leukemia by stabilizing BNIP3.
    Bibhudev Barik, Shristi Lama, Sajitha Is, Sayantan Chanda, Sonali Mohapatra, Sutapa Biswas, Ghanashyam Biswas, Soumen Chakraborty.
      Polypyrimidine tract binding protein 2 (PTBP2) regulates alternative splicing in neuronal, muscle, and Sertoli cells. PTBP2 and its paralog, PTBP1, which plays a role in B-cell development, was found to be expressed aberrantly in myeloid leukemia. Genetic ablation of Ptbp2 in the cells resulted in decreased cellular proliferation and repopulating ability, decreased reactive oxygen species (ROS), and altered mitochondrial morphology. RNA immunoprecipitation followed by sequencing (RIP-seq) and functional assays confirmed that PTBP2 binds to Bcl-2 Interacting Protein 3 (Bnip3)-3'UTR and stabilizes its expression. Our study also suggests that PTBP2 promotes autophagy, as evidenced by the low levels of LC3-II expression in Ptbp2-knockout cells treated with Bafilomycin A1. This effect was restored upon overexpression of Bnip3 in the knockout cells. Notably, when KCL22-NTC cells were subcutaneously injected into the flanks of mice, they gave rise to malignant tumors, unlike Ptbp2-KO-KCL22 cells. Also, transplantation of KCL22 cells through the tail vein in NOD/SCID mice resulted in higher cell engraftment and increased infiltration of malignant cells in the extramedullary organs. Our study underscores the role of PTBP2 in promoting cell proliferation and tumor formation while enhancing autophagy through Bnip3, thereby supporting the role of PTBP2 as an oncogene in CML.
    DOI:  https://doi.org/10.1038/s41419-025-07529-9
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