bims-auttor Biomed News
on Autophagy and mTOR
Issue of 2025–02–02
67 papers selected by
Viktor Korolchuk, Newcastle University
  1. The Type III Intermediate Filament Protein Peripherin Regulates Lysosomal Degradation Activity and Autophagy.
  2. Beclin 1-Mediated Autophagy Is Potentiated by an Interaction with the Neuronal Adaptor FE65.
  3. Autophagic flux measurement: Cargo degradation versus generation of degradation products.
  4. Hierarchical inhibition of mTORC1 by glucose starvation-triggered AXIN lysosomal translocation and by AMPK.
  5. Phase-separated condensates in autophagosome formation and autophagy regulation.
  6. Pellino 3 E3 ligase promotes starvation-induced autophagy to prevent hepatic steatosis.
  7. Deacetylated SNAP47 recruits HOPS to facilitate autophagosome-lysosome fusion independent of STX17.
  8. Acetylation modification in the regulation of macroautophagy.
  9. Glucose-6-phosphate dehydrogenase regulates mitophagy by maintaining PINK1 stability.
  10. Regulation of autophagy by protein lipidation.
  11. Altered lipid homeostasis and autophagy precipitate diffuse alveolar hemorrhage in murine lupus.
  12. A novel uORF regulates folliculin to promote cell growth and lysosomal biogenesis during cardiac stress.
  13. Neuroprotective effects of phytochemicals through autophagy modulation in ischemic stroke.
  14. Role of autophagy in plant growth and adaptation to salt stress.
  15. Increased expression of the small lysosomal gene SVIP in the Drosophila gut suppresses pathophysiological features associated with a high-fat diet.
  16. Unraveling the role of autophagy regulation in Crohn's disease: from genetic mechanisms to potential therapeutics.
  17. New Atg9 Phosphorylation Sites Regulate Autophagic Trafficking in Glia.
  18. Simultaneous Live Mapping of pH and Hydrogen Peroxide Fluctuations in Autophagic Vesicles.
  19. Novel strategies targeting mitochondria-lysosome contact sites for the treatment of neurological diseases.
  20. Activation of lysophagy by a TBK1-SCFFBXO3-TMEM192-TAX1BP1 axis in response to lysosomal damage.
  21. Lactate Promotes Hypoxic Granulosa Cells' Autophagy by Activating the HIF-1α/BNIP3/Beclin-1 Signaling Axis.
  22. Drosophila aux orchestrates the phosphorylation-dependent assembly of the lysosomal V-ATPase in glia and contributes to SNCA/α-synuclein degradation.
  23. Inhibition of Src signaling induces autophagic killing of Toxoplasma gondii via PTEN-mediated deactivation of Akt.
  24. Aging-enhanced autophagy activity promotes fibrotic progression via the TGF-β2/Smad signaling pathway in trabecular meshwork cells-a new insight from POAG.
  25. WSB2 inhibits apoptosis and autophagy by targeting NOXA for degradation.
  26. Sestrin2 ameliorates age-related spontaneous benign prostatic hyperplasia via activation of AMPK/mTOR dependent autophagy.
  27. A novel rapalog shows improved safety vs. efficacy in a human organoid model of polycystic kidney disease.
  28. ATG-3 limits Orsay virus infection in C. elegans through regulation of collagen pathways.
  29. Saikosaponin D exacerbates acetaminophen-induced liver injury by sabotaging GABARAP-SNARE complex assembly in protective autophagy.
  30. What We Know About TMEM175 in Parkinson's Disease.
  31. Autophagy and Mitophagy in Diabetic Kidney Disease-A Literature Review.
  32. TFEB-dependent autophagy-lysosomal pathway is required for NRF2-driven antioxidative action in obstructive sleep apnea-induced neuronal injury.
  33. Hsa_circ_0001304 promotes vascular neointimal hyperplasia accompanied by autophagy activation.
  34. FOXS1, frequently inactivated by promoter methylation, inhibited colorectal cancer cell growth by promoting TGFBI degradation through autophagy-lysosome pathway.
  35. Changes to the Autophagy-Related Muscle Proteome Following Short-Term Treatment with Ectoine in the Duchenne Muscular Dystrophy Mouse Model mdx.
  36. Upregulated astrocyte HDAC7 induces Alzheimer-like tau pathologies via deacetylating transcription factor-EB and inhibiting lysosome biogenesis.
  37. Mechanisms of Copper-Induced Autophagy and Links with Human Diseases.
  38. Angiotensin-Converting Enzyme 2 Enhances Autophagy via the Consumption of miR-326 in a Mouse Model of Acute Lung Injury.
  39. H4K12 lactylation-regulated NLRP3 is involved in cigarette smoke-accelerated Alzheimer-like pathology through mTOR-regulated autophagy and activation of microglia.
  40. Human TSC2 mutant cells exhibit aberrations in early neurodevelopment accompanied by changes in the DNA Methylome.
  41. Endogenous LRRK2 and PINK1 function in a convergent neuroprotective ciliogenesis pathway in the brain.
  42. Stromal Cell Derived Factor-1 Promotes Hepatic Insulin Resistance via Inhibiting Hepatocyte Lipophagy.
  43. Knockdown of STAU1 inhibits inflammation and autophagy in in vitro chronic obstructive pulmonary disease model by regulating AMPK-mTOR signaling pathway.
  44. Apolipoprotein B100 acts as a tumor suppressor in ovarian cancer via lipid/ER stress axis-induced blockade of autophagy.
  45. VEXAS, Chediak-Higashi syndrome and Danon disease: myeloid cell endo-lysosomal pathway dysfunction as a common denominator?
  46. A Multi-Omics Analysis of a Mitophagy-Related Signature in Pan-Cancer.
  47. The link between ferroptosis and autophagy in myocardial ischemia/reperfusion injury: new directions for therapy.
  48. Studying plant autophagy: challenges and recommended methodologies.
  49. An mTOR inhibitor discovery system using drug-sensitized yeast.
  50. Micropeptide hSPAR regulates glutamine levels and suppresses mammary tumor growth via a TRIM21-P27KIP1-mTOR axis.
  51. The E3-ligase Siah2 activates mitochondrial quality control in neurons to maintain energy metabolism during ischemic brain tolerance.
  52. HER2 regulates autophagy and promotes migration in gastric cancer cells through the cGAS-STING pathway.
  53. m6A modified ATG9A is required in regulating autophagy to promote HSCs activation and liver fibrosis.
  54. Trehalose enhances macrophage autophagy to promote myelin debris clearance after spinal cord injury.
  55. Increasing cellular NAD+ protects hepatocytes against palmitate-induced lipotoxicity by preventing PARP-1 inhibition and the mTORC1-p300 pathway activation.
  56. VSTM2L protects prostate cancer cells against ferroptosis via inhibiting VDAC1 oligomerization and maintaining mitochondria homeostasis.
  57. Targeting the Interplay Between Autophagy and the Nrf2 Pathway in Parkinson's Disease with Potential Therapeutic Implications.
  58. HERC1 E3 Ubiquitin Ligase Is Necessary for Autophagy Processes and for the Maintenance and Homeostasis of Vesicles in Motor Nerve Terminals, but Not for Proteasomal Activity.
  59. The 40S ribosomal subunit recycling complex modulates mitochondrial dynamics and endoplasmic reticulum - mitochondria tethering at mitochondrial fission/fusion hotspots.
  60. Lysosomes finely control macrophage inflammatory function via regulating the release of lysosomal Fe2+ through TRPML1 channel.
  61. Actl6a regulates autophagy via Sox2-dependent Atg5 and Atg7 expression to inhibit apoptosis in spinal cord injury.
  62. ATG8 in single membranes: Fresh players of endocytosis and acidic organelle quality control in cancer, neurodegeneration, and inflammation.
  63. A cellular model of TDP-43 induces phosphorylated TDP-43 aggregation with distinct changes in solubility and autophagy dysregulation.
  64. Dysregulation of Mitochondrial Homeostasis in Cardiovascular Diseases.
  65. Limiting cap-dependent translation increases 20S proteasomal degradation and protects the proteomic integrity in autophagy-deficient skeletal muscle.
  66. CAV1 Exacerbates Renal Tubular Epithelial Cell Senescence by Suppressing CaMKK2/AMPK-Mediated Autophagy.
  67. NLRX1 deficiency exacerbates skin inflammation in atopic dermatitis by disrupting mitophagy.
  1. Int J Mol Sci. 2025 Jan 10. pii: 549. [Epub ahead of print]26(2):
    The Type III Intermediate Filament Protein Peripherin Regulates Lysosomal Degradation Activity and Autophagy.
    Roberta Romano, Paola Cordella, Cecilia Bucci.
      Peripherin belongs to heterogeneous class III of intermediate filaments, and it is the only intermediate filament protein selectively expressed in the neurons of the peripheral nervous system. It has been previously discovered that peripherin interacts with proteins important for the endo-lysosomal system and for the transport to late endosomes and lysosomes, such as RAB7A and AP-3, although little is known about its role in the endocytic pathway. Here, we show that peripherin silencing affects lysosomal abundance but also positioning, causing the redistribution of lysosomes from the perinuclear area to the cell periphery. Moreover, peripherin silencing affects lysosomal activity, inhibiting EGFR degradation and the degradation of a fluorogenic substrate for proteases. Furthermore, we demonstrate that peripherin silencing affects lysosomal biogenesis by reducing the TFEB and TFE3 contents. Finally, in peripherin-depleted cells, the autophagic flux is strongly inhibited. Therefore, these data indicate that peripherin has an important role in regulating lysosomal biogenesis, and positioning and functions of lysosomes, affecting both the endocytic and autophagic pathways. Considering that peripherin is the most abundant intermediate filament protein of peripheral neurons, its dysregulation, affecting its functions, could be involved in the onset of several neurodegenerative diseases of the peripheral nervous system characterized by alterations in the endocytic and/or autophagic pathways.
    Keywords:  autophagy; cytoskeleton; intermediate filaments; lysosome; peripherin
    DOI:  https://doi.org/10.3390/ijms26020549
  2. Biology (Basel). 2025 Jan 18. pii: 97. [Epub ahead of print]14(1):
    Beclin 1-Mediated Autophagy Is Potentiated by an Interaction with the Neuronal Adaptor FE65.
    Wai Wa Ray Chan, Jessica Chow, Dennis Dik-Long Chau, Yuqi Zhai, Kwok-Fai Lau.
      Autophagy is a vital cellular pathway in eukaryotic cells, including neurons, where it plays significant roles in neurodevelopment and maintenance. A crucial step in autophagy is the formation of the class III phosphatidylinositol 3-kinase complex 1 (PI3KC3-C1), which is essential for initiating autophagosome biogenesis. Beclin 1 is the key component of PI3KC3-C1, and its interactors have been reported to affect autophagy. The brain-enriched adaptor protein FE65 has been shown to interact with Alzheimer's disease amyloid precursor protein (APP) to alter the processing of APP. Additionally, FE65 has been implicated in various cellular pathways, including autophagy. We demonstrate here that FE65 positively regulates autophagy. FE65, through its C-terminus, has been shown to interact with Beclin 1. Notably, the overexpression of FE65 enhances Beclin 1-mediated autophagy, whereas this process is attenuated in FE65 knockout cells. Moreover, the stimulatory effect of FE65 on Beclin 1-mediated autophagy is diminished by an FE65 C-terminus deletion mutant that disrupts the FE65-Beclin 1 interaction. Lastly, we have found that the FE65-Beclin 1 interaction modulates the kinase activity of the PI3KC3-C1 complex. Together, we have identified FE65 as a novel Beclin 1 interactor, and this interaction potentiates autophagy.
    Keywords:  Beclin 1; FE65; macroautophagy
    DOI:  https://doi.org/10.3390/biology14010097
  3. Curr Opin Cell Biol. 2025 Jan 25. pii: S0955-0674(25)00001-8. [Epub ahead of print]93 102463
    Autophagic flux measurement: Cargo degradation versus generation of degradation products.
    Noboru Mizushima.
      Autophagy is the cellular processes that transport cytoplasmic components to lysosomes for degradation. It plays essential physiological roles, including in adaptation to environmental changes such as starvation and maintaining intracellular quality control. Recently, its links to aging and disease have garnered substantial attention. Although various methods to measure autophagic activity (autophagic flux) have been developed, accurate measurement remains challenging and often contentious. This review presents a discussion of techniques to measure the flux of autophagy, particularly macroautophagy, utilizing two contrasting approaches-assaying cargo degradation versus assaying the generation of degradation products-with an emphasis on the advantages of the latter.
    DOI:  https://doi.org/10.1016/j.ceb.2025.102463
  4. Life Metab. 2023 Jun;2(3): load005
    Hierarchical inhibition of mTORC1 by glucose starvation-triggered AXIN lysosomal translocation and by AMPK.
    Mengqi Li, Xiaoyan Wei, Jinye Xiong, Jin-Wei Feng, Chen-Song Zhang, Sheng-Cai Lin.
      When glucose is replete, mammalian/mechanistic target of rapamycin complex 1 (mTORC1) is active and anchored to the lysosomal surface via the two GTPases, Ras-related GTPase (RAG) and Ras homolog enriched in brain (Rheb), which are regulated by Ragulator and tuberous sclerosis complex 2 (TSC2), respectively. When glucose is low, aldolase senses low fructose-1,6-bisphosphate level and promotes the translocation of AXIN-liver kinase B1 (LKB1) to the lysosomal surface, which leads to the activation of AMP-activated protein kinase (AMPK) and the inhibition of RAGs, sundering mTORC1 from the lysosome and causing its inactivation. AMPK can also inactivate mTORC1 by phosphorylating Raptor and TSC2. However, the hierarchy of AXIN- and AMPK-mediated inhibition of mTORC1 remains poorly defined. Here, we show that AXIN translocation does not require AMPK expression or activity. In glucose starvation conditions, knockout of AXIN extended the half-life of mTORC1 inhibition from 15 to 60 min, whereas knockout of AMPK only extended it to 30 min. RAGBGTP (constitutively active RAGB) almost entirely blocked the lysosomal dissociation and inhibition of mTORC1 under glucose starvation, but it did not inhibit AMPK, indicating that under these conditions, it is AXIN lysosomal translocation that inhibits mTORC1, and it does so via inhibition of RAGs. 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), a mimetic of AMP, which activates both cytosolic AMPK and lysosomal AMPK, fully inhibited mTORC1 even when it is stably anchored to the lysosome by RAGBGTP, whereas glucose starvation mildly inhibited such anchored mTORC1. Together, we demonstrate that the lysosomal translocation of AXIN plays a primary role in glucose starvation-triggered inhibition of mTORC1 by inhibiting RAGs, and that AMPK activity inhibits mTORC1 through phosphorylating Raptor and TSC2, especially under severe stress.
    Keywords:  AMPK; glucose sensing; mTORC1
    DOI:  https://doi.org/10.1093/lifemeta/load005
  5. J Mol Biol. 2025 Jan 27. pii: S0022-2836(25)00030-0. [Epub ahead of print] 168964
    Phase-separated condensates in autophagosome formation and autophagy regulation.
    Zheng Wang, Hong Zhang.
      Biomacromolecules partition into numerous types of biological condensates or membrane-less organelles via liquid-liquid phase separation (LLPS). Newly formed liquid-like condensates may further undergo phase transition to convert into other material states, such as gel or solid states. Different biological condensates possess distinct material properties to fulfil their physiological functions in diverse cellular pathways and processes. Phase separation and condensates are extensively involved in the autophagy pathway. The autophagosome formation sites in both yeast and multicellular organisms are assembled as phase-separated condensates. TORC1, one of the core regulators of the autophagy-lysosome pathway, is subject to nonconventional regulation by multiple biological condensates. TFEB, the master transcription factor of the autophagy-lysosome pathway, phase separates to assemble liquid-like condensates involved in transcription of autophagic and lysosomal genes. The behaviors and transcriptional activity of TFEB condensates are governed by their material properties, thus suggesting novel autophagy intervention strategies. The phase separation process and the resulting condensates are emerging therapeutic targets for autophagy-related diseases.
    Keywords:  TFEB; TORC1; autophagosome formation site; autophagy; phase separation
    DOI:  https://doi.org/10.1016/j.jmb.2025.168964
  6. Sci Adv. 2025 Jan 17. 11(3): eadr2450
    Pellino 3 E3 ligase promotes starvation-induced autophagy to prevent hepatic steatosis.
    Srinivasa P Kolapalli, Carsten J Beese, Steven E Reid, Sólveig H Brynjólfsdóttir, Maria H Jørgensen, Ashish Jain, Joyceline Cuenco, Monika Lewinska, Ahmad Abdul-Al, Aida R López, Marja Jäättelä, Kei Sakamoto, Jesper B Andersen, Kenji Maeda, Tor E Rusten, Anders H Lund, Lisa B Frankel.
      Nutrient deprivation is a major trigger of autophagy, a conserved quality control and recycling process essential for cellular and tissue homeostasis. In a high-content image-based screen of the human ubiquitome, we here identify the E3 ligase Pellino 3 (PELI3) as a crucial regulator of starvation-induced autophagy. Mechanistically, PELI3 localizes to autophagic membranes, where it interacts with the ATG8 proteins through an LC3-interacting region (LIR). This facilitates PELI3-mediated ubiquitination of ULK1, driving ULK1's subsequent proteasomal degradation. PELI3 depletion leads to an aberrant accumulation and mislocalization of ULK1 and disrupts the early steps of autophagosome formation. Genetic deletion of Peli3 in mice impairs fasting-induced autophagy in the liver and enhances starvation-induced hepatic steatosis by reducing autophagy-mediated clearance of lipid droplets. Notably, PELI3 expression is decreased in the livers of patients with metabolic dysfunction-associated steatotic liver disease (MASLD), suggesting its role in hepatic steatosis development in humans. The findings suggest that PELI3-mediated control of autophagy plays a protective role in liver health.
    DOI:  https://doi.org/10.1126/sciadv.adr2450
  7. Nat Commun. 2025 Jan 09. 16(1): 543
    Deacetylated SNAP47 recruits HOPS to facilitate autophagosome-lysosome fusion independent of STX17.
    Fenglei Jian, Shen Wang, Wenmin Tian, Yang Chen, Shixuan Wang, Yan Li, Cong Ma, Yueguang Rong.
      Autophagy, a conserved catabolic process implicated in a diverse array of human diseases, requires efficient fusion between autophagosomes and lysosomes to function effectively. Recently, SNAP47 has been identified as a key component of the dual-purpose SNARE complex mediating autophagosome-lysosome fusion in both bulk and selective autophagy. However, the spatiotemporal regulatory mechanisms of this SNARE complex remain unknown. In this study, we found that SNAP47 undergoes acetylation followed by deacetylation during bulk autophagy and mitophagy. The acetylation status of SNAP47 is regulated by the acetyltransferase CBP and the deacetylase HDAC2. Notably, the spatiotemporal regulatory dynamics of SNAP47 acetylation differ between bulk autophagy and mitophagy due to distinct regulation on the activity of acetyltransferase and deacetylase. Acetylated SNAP47 inhibits autophagosome-lysosome fusion by indirectly impeding SNARE complex assembly. Mechanistically, deacetylated SNAP47 recruits HOPS components to autophagic vacuoles independently of STX17 and STX17-SNAP47 interaction, while acetylated SNAP47 inhibits this recruitment, consequently leading to the failure of SNARE complex assembly. Taken together, our study uncovers a SNAP47 acetylation-dependent regulatory mechanism governing autophagosome-lysosome fusion by modulating the recruitment of HOPS to autophagic vacuoles without involving STX17, SNAP47-STX17 interaction and ternary SNARE complex formation.
    DOI:  https://doi.org/10.1038/s41467-025-55906-x
  8. Adv Biotechnol (Singap). 2024 Jun 07. 2(2): 19
    Acetylation modification in the regulation of macroautophagy.
    Li Huang, Hongwei Guo.
      Macroautophagy, commonly referred to as autophagy, is an evolutionarily conserved cellular process that plays a crucial role in maintaining cellular homeostasis. It orchestrates the delivery of dysfunctional or surplus cellular materials to the vacuole or lysosome for degradation and recycling, particularly during adverse conditions. Over the past few decades, research has unveiled intricate regulatory mechanisms governing autophagy through various post-translational modifications (PTMs). Among these PTMs, acetylation modification has emerged as a focal point in yeast and animal studies. It plays a pivotal role in autophagy by directly targeting core components within the central machinery of autophagy, including autophagy initiation, nucleation, phagophore expansion, and autophagosome maturation. Additionally, acetylation modulates autophagy at the transcriptional level by modifying histones and transcription factors. Despite its well-established significance in yeast and mammals, the role of acetylation in plant autophagy remains largely unexplored, and the precise regulatory mechanisms remain enigmatic. In this comprehensive review, we summarize the current understanding of the function and underlying mechanisms of acetylation in regulating autophagy across yeast, mammals, and plants. We particularly highlight recent advances in deciphering the impact of acetylation on plant autophagy. These insights not only provide valuable guidance but also inspire further scientific inquiries into the intricate role of acetylation in plant autophagy.
    Keywords:  Acetylation; Autophagy; Deacetylation; Lysine; Post-translational modification
    DOI:  https://doi.org/10.1007/s44307-024-00027-7
  9. Life Metab. 2025 Feb;4(1): loae040
    Glucose-6-phosphate dehydrogenase regulates mitophagy by maintaining PINK1 stability.
    Yik-Lam Cho, Hayden Weng Siong Tan, Jicheng Yang, Basil Zheng Mian Kuah, Nicole Si Ying Lim, Naiyang Fu, Boon-Huat Bay, Shuo-Chien Ling, Han-Ming Shen.
      Glucose-6-phosphate dehydrogenase (G6PD) is the rate-limiting enzyme in the pentose phosphate pathway (PPP) in glycolysis. Glucose metabolism is closely implicated in the regulation of mitophagy, a selective form of autophagy for the degradation of damaged mitochondria. The PPP and its key enzymes such as G6PD possess important metabolic functions, including biosynthesis and maintenance of intracellular redox balance, while their implication in mitophagy is largely unknown. Here, via a whole-genome CRISPR-Cas9 screening, we identified that G6PD regulates PINK1 (phosphatase and tensin homolog [PTEN]-induced kinase 1)-Parkin-mediated mitophagy. The function of G6PD in mitophagy was verified via multiple approaches. G6PD deletion significantly inhibited mitophagy, which can be rescued by G6PD reconstitution. Intriguingly, while the catalytic activity of G6PD is required, the known PPP functions per se are not involved in mitophagy regulation. Importantly, we found a portion of G6PD localized at mitochondria where it interacts with PINK1. G6PD deletion resulted in an impairment in PINK1 stabilization and subsequent inhibition of ubiquitin phosphorylation, a key starting point of mitophagy. Finally, we found that G6PD deletion resulted in lower cell viability upon mitochondrial depolarization, indicating the physiological function of G6PD-mediated mitophagy in response to mitochondrial stress. In summary, our study reveals a novel role of G6PD as a key positive regulator in mitophagy, which bridges several important cellular processes, namely glucose metabolism, redox homeostasis, and mitochondrial quality control.
    Keywords:  G6PD; NADPH; PINK1; PPP; ROS; mitophagy
    DOI:  https://doi.org/10.1093/lifemeta/loae040
  10. Adv Biotechnol (Singap). 2024 Sep 20. 2(4): 33
    Regulation of autophagy by protein lipidation.
    Yuqian Shao, Junchao Hu, Huihui Li, Kefeng Lu.
      Autophagy is a conserved catabolic recycling pathway that can eliminate cytosolic materials to maintain homeostasis and organelle functions. Many studies over the past few decades have demonstrated that abnormal autophagy is associated with a variety of diseases. Protein lipidation plays an important role in the regulation of autophagy by affecting protein trafficking, localization, stability, interactions and signal transduction. Here, we review recent advances in the understanding of the role of lipidation in autophagy, including S-palmitoylation, N-myristoylation, S-prenylation, glycosylphosphatidylinositol (GPI) anchor modification and cholesterylation. We comprehensively review the enzymes and catalytic mechanisms of lipidation and discuss the relationship between lipidation and autophagy, aiming to deepen the understanding of lipidation and promote the discovery of drug targets for the treatment of autophagy-related diseases.
    Keywords:  Autophagy; Cholesterylation; Glycosylphosphatidylinositol (GPI) anchor; Lipidation; N-myristoylation; S-palmitoylation; S-prenylation
    DOI:  https://doi.org/10.1007/s44307-024-00040-w
  11. Autophagy Rep. 2024 ;pii: 2379193. [Epub ahead of print]3(1):
    Altered lipid homeostasis and autophagy precipitate diffuse alveolar hemorrhage in murine lupus.
    Shuhong Han, Haoyang Zhuang, Yanpeng Diao, Mark Segal, Tanzia Islam Tithi, Weizhou Zhang, Westley H Reeves.
      Abnormal autophagy regulation is implicated in lupus and other autoimmune diseases. We investigated autophagy in the murine pristane-induced lupus model. Pristane causes monocyte/macrophage-mediated endoplasmic reticulum (ER) stress in lung endothelial cells and diffuse alveolar hemorrhage (DAH) indistinguishable from DAH in lupus patients. Enlarged macrophages with abundant lipid droplets containing neutral lipid and exhibiting increased autophagosome staining were observed in the lung and peritoneal macrophages after pristane treatment. Cellular overload of neutral lipid can lead to selective autophagy (lipophagy) of lipid droplets and transport to lysosomes. The autophagy inducer rapamycin decreased neutral lipid staining but aggravated DAH, while an autophagy inhibitor (3-methyladenine) blocked the onset of DAH. Pristane-induced autophagy in macrophages was confirmed by acridine orange assay and LC3 western blot. Pristane also enlarged lysosomal volume and enhanced cathepsin S, D, and K expression while decreasing lysosomal acid lipase activity. If the capacity to degrade neutral lipid into free cholesterol and fatty acids is overwhelmed, lysosomes enlarge and can release cathepsins into the cytoplasm promoting cell death. Increasing lysosomal cholesterol content by blocking the Niemann-Pick C disease protein NPC1 protects against lysosome-dependent cell death. Treatment with NPC1 inhibitors U18666A or cepharanthine, which stabilize lysosomes, normalized lysosomal volume, reversed ER stress, and prevented DAH in pristane-treated mice. We conclude that pristane disrupts lipid homeostasis, promoting autophagy, lysosomal dysfunction, ER stress, and cell death leading to DAH. NPC1 inhibition reverses these abnormalities, preventing DAH. The findings shed light on the role of autophagy and lysosomal dysfunction in the pathogenesis of lupus.
    Keywords:  Cholesterol; Endoplasmic reticulum stress; Lipid droplets; Lung; Lysosomes; Macrophages; Niemann-Pick C disease; Pristane; Rapamycin; Systemic lupus erythematosus
    DOI:  https://doi.org/10.1080/27694127.2024.2379193
  12. Sci Rep. 2025 Jan 27. 15(1): 3319
    A novel uORF regulates folliculin to promote cell growth and lysosomal biogenesis during cardiac stress.
    Maja Bencun, Laura Spreyer, Etienne Boileau, Jessica Eschenbach, Norbert Frey, Christoph Dieterich, Mirko Völkers.
      Pathological cardiac remodeling is a maladaptive response that leads to changes in the size, structure, and function of the heart. These changes occur due to an acute or chronic stress on the heart and involve a complex interplay of hemodynamic, neurohormonal and molecular factors. As a critical regulator of cell growth, protein synthesis and autophagy mechanistic target of rapamycin complex 1 (mTORC1) is an important mediator of pathological cardiac remodeling. The tumor suppressor folliculin (FLCN) is part of the network regulating non-canonical mTORC1 activity. FLCN activates mTORC1 by functioning as a guanosine triphosphatase activating protein (GAP). Our work has identified a regulatory upstream open reading frame (uORF) localized in the 5'UTR of the FLCN mRNA. These small genetic elements are important regulators of protein expression. They are particularly important for the regulation of stress-responsive protein synthesis. We have studied the relevance of the FLCN uORF in the regulation of FLCN translation. We show that FLCN downregulation through the uORF is linked to cardiomyocyte growth and increased lysosomal activity. In summary, we have identified uORF-mediated control of RNA translation as another layer of regulation in the complex molecular network controlling cardiomyocyte hypertrophy.
    Keywords:  Folliculin; Hypertrophic growth; Lysosome; TFEB; Translation; Upstream open reading frame
    DOI:  https://doi.org/10.1038/s41598-025-87107-3
  13. Inflammopharmacology. 2025 Jan 30.
    Neuroprotective effects of phytochemicals through autophagy modulation in ischemic stroke.
    Amir Mahmoud Ahmadzadeh, Ali Mohammad Pourbagher-Shahri, Fatemeh Forouzanfar.
      Stroke is a serious life-threatening medical condition. Understanding the underlying molecular mechanisms of this condition is crucial to identifying novel therapeutic targets that can improve patient outcomes. Autophagy is an essential mechanism for the destruction of damaged intracellular components that maintains homeostasis in physiological or pathological conditions. This process is involved in the pathophysiology of stroke. Phytochemicals are bioactive naturally occurring compounds present in plants. This paper reviews the neuroprotective roles of phytochemicals in ischemic stroke through autophagy modulation. It summarizes the interactions of various phytochemicals with key molecular targets of the autophagy pathway in ischemic stroke, including PI3K/Akt/mTOR, Beclin-1, and AMPK. Due to the ability of various phytochemicals to alter autophagic flux, they may provide promising opportunities in the development of new treatments and the improvement of stroke management.
    Keywords:  Autophagy; Carotenoids; Complementary medicine; Ischemic stroke; Medicinal plants; Polyphenols
    DOI:  https://doi.org/10.1007/s10787-024-01606-9
  14. Planta. 2025 Jan 31. 261(3): 49
    Role of autophagy in plant growth and adaptation to salt stress.
    Syed Inzimam Ul Haq, Faheem Tariq, Noor Us Sama, Hadiqa Jamal, Heba I Mohamed.
       MAIN CONCLUSION: Under salt stress, autophagy regulates ionic balance, scavenges ROS, and supports nutrient remobilization, thereby alleviating osmotic and oxidative damage. Salt stress is a major environmental challenge that significantly impacts plant growth and agricultural productivity by disrupting nutrient balance, inducing osmotic stress, and causing the accumulation of toxic ions like Na+. Autophagy, a key cellular degradation and recycling pathway, plays a critical role in enhancing plant salt tolerance by maintaining cellular homeostasis and mitigating stress-induced damage. While autophagy has traditionally been viewed as a response to nutrient starvation, recent research has highlighted its importance under various environmental stresses, particularly salt stress. Under such conditions, plants activate autophagy through distinct signaling pathways involving autophagy-related genes (ATGs), Target of Rapamycin (TOR) proteins, and reactive oxygen species (ROS). Salt stress induces the expression of ATG genes and promotes the formation of autophagosomes, which facilitate the degradation of damaged organelles, denatured proteins, and the sequestration of Na+ into vacuoles, thereby improving stress tolerance. Recent studies have also suggested that autophagy may play a direct role in salt stress signaling, linking it to the regulation of metabolic processes. This review discusses the molecular mechanisms underlying autophagy induction in plants under salt stress, including the roles of ATGs and TOR, as well as the physiological significance of autophagy in mitigating oxidative damage, maintaining ion balance, and enhancing overall salt tolerance. In addition, we discussed the metabolic changes related to autophagy in stressed plants and examined the broader implications for managing plant stress and improving crops.
    Keywords:  Autophagosome; Autophagy; Reactive oxygen species; Salt stress; Target of rapamycin
    DOI:  https://doi.org/10.1007/s00425-025-04615-2
  15. Biol Open. 2025 Feb 15. pii: BIO061601. [Epub ahead of print]14(2):
    Increased expression of the small lysosomal gene SVIP in the Drosophila gut suppresses pathophysiological features associated with a high-fat diet.
    Brennan M Mercola, Tatiana V Villalobos, Jocelyn E Wood, Ankita Basu, Alyssa E Johnson.
      Lysosomes are digestive organelles that are crucial for nutrient sensing and metabolism. Lysosome impairment is linked to a broad spectrum of metabolic disorders, underscoring their importance to human health. Thus, lysosomes are an attractive target for metabolic disease therapies. In previous work, we discovered a novel class of tubular lysosomes that are morphologically and functionally distinct from traditionally described vesicular lysosomes. Tubular lysosomes are present in multiple tissues, are broadly conserved from invertebrates to mammals, are more proficient at degrading autophagic cargo than vesicular lysosomes, and delay signs of tissue aging when induced ectopically. Thus, triggering tubular lysosome formation presents one mechanism to increase lysosome activity and, notably, overproduction of the small lysosomal protein, SVIP, is a robust genetic strategy for triggering lysosomal tubulation on demand. In this study, we examine whether SVIP overexpression in the fly gut can suppress pathophysiological phenotypes associated with an obesogenic high-fat diet. Indeed, our results indicate that increasing SVIP expression in the fly gut reduces lipid accumulation, suppresses body mass increase, and improves survival in flies fed a high-fat diet. Collectively, these data hint that increasing lysosomal activity through induction of tubular lysosomal networks, could be one strategy to combat obesity-related pathologies.
    Keywords:   Drosophila ; Autophagy; High-fat diet; Lysosomes; Obesity; SVIP
    DOI:  https://doi.org/10.1242/bio.061601
  16. Adv Biotechnol (Singap). 2024 Mar 21. 2(2): 14
    Unraveling the role of autophagy regulation in Crohn's disease: from genetic mechanisms to potential therapeutics.
    Ziyue Yuan, Jing Ye, Bo Liu, Lan Zhang.
      Autophagy serves as the primary intracellular degradation mechanism in which damaged organelles and self-cytoplasmic proteins are transported to the lysosome for degradation. Crohn's disease, an idiopathic chronic inflammatory disorder of the gastrointestinal tract, manifests in diverse regions of the digestive system. Recent research suggests that autophagy modulation may be a new avenue for treating Crohn's disease, and several promising small-molecule modulators of autophagy have been reported as therapeutic options. In this review, we discuss in detail how mutations in autophagy-related genes function in Crohn's disease and summarize the modulatory effects on autophagy of small-molecule drugs currently used for Crohn's disease treatment. Furthermore, we delve into the therapeutic potential of small-molecule autophagy inducers on Crohn's disease, emphasizing the prospects for development in this field. We aim to highlight the significance of autophagy modulation in Crohn's disease, with the aspiration of contributing to the development of more efficacious treatments that can alleviate their suffering, and improve their quality of life.
    Keywords:  Autophagy; Autophagy-related genes; Crohn's disease; Small-molecule modulators
    DOI:  https://doi.org/10.1007/s44307-024-00021-z
  17. ASN Neuro. 2025 ;17(1): 2443442
    New Atg9 Phosphorylation Sites Regulate Autophagic Trafficking in Glia.
    Linfang Wang, Shuanglong Yi, Shiping Zhang, Yu-Ting Tsai, Yi-Hsuan Cheng, Yu-Tung Lin, Chia-Ching Lin, Yi-Hua Lee, Honglei Wang, Margaret S Ho.
      We previously identified a role for dAuxilin (dAux), the fly homolog of Cyclin G-associated kinase, in glial autophagy contributing to Parkinson's disease (PD). To further dissect the mechanism, we present evidence here that lack of glial dAux enhanced the phosphorylation of the autophagy-related protein Atg9 at two newly identified threonine residues, T62 and T69. The enhanced Atg9 phosphorylation in the absence of dAux promotes autophagosome formation and Atg9 trafficking to the autophagosomes in glia. Whereas the expression of the non-phosphorylatable Atg9 variants suppresses the lack of dAux-induced increase in both autophagosome formation and Atg9 trafficking to autophagosome, the expression of the phosphomimetic Atg9 variants restores the lack of Atg1-induced decrease in both events. In relation to pathophysiology, Atg9 phosphorylation at T62 and T69 contributes to dopaminergic neurodegeneration and locomotor dysfunction in a Drosophila PD model. Notably, increased expression of the master autophagy regulator Atg1 promotes dAux-Atg9 interaction. Thus, we have identified a dAux-Atg1-Atg9 axis relaying signals through the Atg9 phosphorylation at T62 and T69; these findings further elaborate the mechanism of dAux regulating glial autophagy and highlight the significance of protein degradation pathway in glia contributing to PD.
    Keywords:  Atg1; Atg9; Parkinson’s disease; dAuxilin; glia
    DOI:  https://doi.org/10.1080/17590914.2024.2443442
  18. JACS Au. 2025 Jan 27. 5(1): 343-352
    Simultaneous Live Mapping of pH and Hydrogen Peroxide Fluctuations in Autophagic Vesicles.
    Smitaroopa Kahali, Ranojoy Baisya, Sayani Das, Ankona Datta.
      Hydrogen peroxide (H2O2) plays a critical role in the regulation and progress of autophagy, an essential recycling process that influences cellular homeostasis and stress response. Autophagy is characterized by the formation of intracellular vesicles analogous to recycle "bags" called autophagosomes, which fuse with lysosomes to form autolysosomes, eventually ending up as lysosomes. We have developed two novel autophagic vesicle-targeted peptide-based sensors, ROSA for H2O2 and pHA for pH, to simultaneously track H2O2 and pH dynamics within autophagic vesicles as autophagy advances. Since pH values progressively decrease within autophagic vesicles with the progress of autophagy, we utilized information on vesicular pH to identify stages of autophagic vesicles in live cells. Fluorescence intensities of the H2O2 sensor, ROSA, within autophagic compartments at different autophagic stages, which were identified by simultaneous pH mapping, revealed that H2O2 levels vary significantly within autophagic vesicles as autophagy progresses, with maximum H2O2 levels in the autolysosomal stage. This study provides the first detailed observation of H2O2 fluctuations within autophagic vesicles throughout the entire process of autophagy in living mammalian cells, offering insights into the oxidative changes associated with this vital cellular process.
    DOI:  https://doi.org/10.1021/jacsau.4c01021
  19. Front Mol Neurosci. 2024 ;17 1527013
    Novel strategies targeting mitochondria-lysosome contact sites for the treatment of neurological diseases.
    Yinyin Xie, Wenlin Sun, Aoya Han, Xinru Zhou, Shijie Zhang, Changchang Shen, Yi Xie, Cui Wang, Nanchang Xie.
      Mitochondria and lysosomes are critical for neuronal homeostasis, as highlighted by their dysfunction in various neurological diseases. Recent studies have identified dynamic membrane contact sites between mitochondria and lysosomes, independent of mitophagy and the lysosomal degradation of mitochondrial-derived vesicles (MDVs), allowing bidirectional crosstalk between these cell compartments, the dynamic regulation of organelle networks, and substance exchanges. Emerging evidence suggests that abnormalities in mitochondria-lysosome contact sites (MLCSs) contribute to neurological diseases, including Parkinson's disease, Charcot-Marie-Tooth (CMT) disease, lysosomal storage diseases, and epilepsy. This article reviews recent research advances regarding the tethering processes, regulation, and function of MLCSs and their role in neurological diseases.
    Keywords:  lysosomal dynamics; mitochondria-lysosome contact sites; mitochondrial network; mitophagy; neurological diseases; substance exchanges
    DOI:  https://doi.org/10.3389/fnmol.2024.1527013
  20. Nat Commun. 2025 Jan 28. 16(1): 1109
    Activation of lysophagy by a TBK1-SCFFBXO3-TMEM192-TAX1BP1 axis in response to lysosomal damage.
    Na Yeon Park, Doo Sin Jo, Jae-Yoon Yang, Ji-Eun Bae, Joon Bum Kim, Yong Hwan Kim, Seong Hyun Kim, Pansoo Kim, Dong-Seok Lee, Tamotsu Yoshimori, Eun-Kyeong Jo, Eunbyul Yeom, Dong-Hyung Cho.
      Lysophagy eliminates damaged lysosomes and is crucial to cellular homeostasis; however, its underlying mechanisms are not entirely understood. We screen a ubiquitination-related compound library and determine that the substrate recognition component of the SCF-type E3 ubiquitin ligase complex, SCFFBXO3(FBXO3), which is a critical lysophagy regulator. Inhibition of FBXO3 reduces lysophagy and lysophagic flux in response to L-leucyl-L-leucine methyl ester (LLOMe). Furthermore, FBXO3 interacts with TMEM192, leading to its ubiquitination in LLOMe-treated cells. We also identify TAX1BP1 as a critical autophagic adaptor that recognizes ubiquitinated TMEM192 during lysophagy and find that TBK1 activation is crucial for lysophagy, as it phosphorylates FBXO3 in response to lysosomal damage. Knockout of FBXO3 significantly impairs lysophagy, and its reconstitution with a loss-of-function mutant (V221I) further confirms its essential role in lysophagy regulation. Collectively, our findings highlight the significance of the TBK1-FBXO3-TMEM192-TAX1BP1 axis in lysophagy and emphasize the critical role of FBXO3 in lysosomal integrity.
    DOI:  https://doi.org/10.1038/s41467-025-56294-y
  21. Genes (Basel). 2024 Dec 26. pii: 14. [Epub ahead of print]16(1):
    Lactate Promotes Hypoxic Granulosa Cells' Autophagy by Activating the HIF-1α/BNIP3/Beclin-1 Signaling Axis.
    Yitong Pan, Gang Wu, Min Chen, Xiumei Lu, Ming Shen, Hongmin Li, Honglin Liu.
       BACKGROUND/OBJECTIVES: The avascular nature of the follicle creates a hypoxic microenvironment, establishing a niche where granulosa cells (GCs) rely on glycolysis to produce energy in the form of lactate (L-lactate). Autophagy, an evolutionarily conserved stress-response process, involves the formation of autophagosomes to encapsulate intracellular components, delivering them to lysosomes for degradation. This process plays a critical role in maintaining optimal follicular development. However, whether hypoxia regulates autophagy in GCs via lactate remains unclear.
    METHODS: In this study, we investigated lactate-induced autophagy under hypoxia by utilizing glycolysis inhibitors or silencing related genes.
    RESULTS: We observed a significant increase in autophagy in ovarian GCs under hypoxic conditions, indicated by elevated LC3II levels and reduced P62 levels. Suppressing lactate production through glycolytic inhibitors (2-DG and oxamate) or silencing lactate dehydrogenase (LDHA/LDHB) effectively reduced hypoxia-induced autophagy. Further investigation revealed that the HIF1-α/BNIP3/Beclin-1 axis is essential for lactate-induced autophagy under hypoxic conditions. Inhibiting HIF-1α activity using siRNAs or PX-478 downregulated BNIP3 expression and subsequently suppressed autophagy. Similarly, BNIP3 silencing with siRNAs repressed lactate-induced autophagy in hypoxic conditions. Mechanistically, immunoprecipitation experiments showed that BNIP3 disrupted pre-existing Bcl-2/Beclin-1 complexes by competing with Bcl-2 to form Bcl-2/BNIP3 complexes. This interaction released Beclin-1, which subsequently triggered lactate-induced autophagy under hypoxic conditions.
    CONCLUSIONS: These findings unveil a novel mechanism by which hypoxia regulates GC autophagy through lactate production, highlighting its potential role in sustaining follicular development under hypoxic conditions.
    Keywords:  BNIP3; Beclin-1; HIF-1α; granulosa cell; lactate
    DOI:  https://doi.org/10.3390/genes16010014
  22. Autophagy. 2025 Jan 29. 1-20
    Drosophila aux orchestrates the phosphorylation-dependent assembly of the lysosomal V-ATPase in glia and contributes to SNCA/α-synuclein degradation.
    Shiping Zhang, Linfang Wang, Shuanglong Yi, Yu-Ting Tsai, Yi-Hsuan Cheng, Yu-Tung Lin, Chia-Ching Lin, Yi-Hua Lee, Honglei Wang, Shuhua Li, Ruiqi Wang, Yang Liu, Wei Yan, Chang Liu, Kai-Wen He, Margaret S Ho.
      Glia contribute to the neuropathology of Parkinson disease (PD), but how they react opposingly to be beneficial or detrimental under pathological conditions, like promoting or eliminating SNCA/α-syn (synuclein alpha) inclusions, remains elusive. Here we present evidence that aux (auxilin), the Drosophila homolog of the PD risk factor GAK (cyclin G associated kinase), regulates the lysosomal degradation of SNCA/α-syn in glia. Lack of glial GAK/aux increases the lysosome number and size, regulates lysosomal acidification and hydrolase activity, and ultimately blocks the degradation of substrates including SNCA/α-syn. Whereas SNCA/α-syn accumulates prominently in lysosomes devoid of glial aux, levels of injected SNCA/α-syn preformed fibrils are further enhanced in the absence of microglial GAK. Mechanistically, aux mediates phosphorylation at the serine 543 of Vha44, the V1 C subunit of the vacuolar-type H+-translocating ATPase (V-ATPase), and regulates its assembly to control proper acidification of the lysosomal milieu. Expression of Vha44, but not the Vha44 variant lacking S543 phosphorylation, restores lysosome acidity, locomotor deficits, and DA neurodegeneration upon glial aux depletion, linking this pathway to PD. Our findings identify a phosphorylation-dependent switch controlling V-ATPase assembly for lysosomal SNCA/α-syn degradation in glia. Targeting the clearance of glial SNCA/α-syn inclusions via this lysosomal pathway could potentially be a therapeutic approach to ameliorate the disease progression in PD.Abbreviation: aux: auxilin; GAK: cyclin G associated kinase; LTG: LysoTracker Green; LTR: LysoTracker Red; MR: Magic Red; PD: Parkinson disease; SNCA/a-syn: synuclein alpha; V-ATPase: vacuolar-type H+-translocating ATPase.
    Keywords:  GAK/Aux; SNCA/α-syn degradation; V-ATPase; lysosomal acidification; microglia; parkinson disease
    DOI:  https://doi.org/10.1080/15548627.2024.2442858
  23. PLoS Pathog. 2025 Jan 27. 21(1): e1012907
    Inhibition of Src signaling induces autophagic killing of Toxoplasma gondii via PTEN-mediated deactivation of Akt.
    Alyssa Hubal, Anusha Vendhoti, Charles N Shaffer, Sarah Vos, Yalitza Lopez Corcino, Carlos S Subauste.
      The intracellular protozoan Toxoplasma gondii manipulates host cell signaling to avoid targeting by autophagosomes and lysosomal degradation. Epidermal Growth Factor Receptor (EGFR) is a mediator of this survival strategy. However, EGFR expression is limited in the brain and retina, organs affected in toxoplasmosis. This raises the possibility that T. gondii activates a signaling mechanism independently of EGFR to avoid autophagic targeting. We report T. gondii activates Src to promote parasite survival even in cells that lack EGFR. Blockade of Src triggered LC3 and LAMP-1 recruitment around the parasitophorous vacuole (PV) and parasite killing dependent on the autophagy protein, ULK1, and lysosomal enzymes. Src promoted PI3K activation and recruitment of activated Akt to the PV membrane. T. gondii promoted Src association with PTEN, and PTEN phosphorylation at Y240, S380, T382, and T383, hallmarks of an inactive PTEN conformation known to maintain Akt activation. Blockade of parasite killing was dependent of activated Akt. Src knockdown or treatment with the Src family kinase inhibitor, Saracatinib, impaired these events, leading to PTEN accumulation around the PV and a reduction in activated Akt recruitment at this site. Saracatinib treatment in mice with pre-established cerebral and ocular toxoplasmosis promoted PTEN recruitment around tachyzoites in neural tissue impairing recruitment of activated Akt, profoundly reducing parasite load and neural histopathology that were dependent of the autophagy protein, Beclin 1. Our studies uncovered an EGFR-independent pathway activated by T. gondii that enables its survival and is central to the development of neural toxoplasmosis.
    DOI:  https://doi.org/10.1371/journal.ppat.1012907
  24. Front Med (Lausanne). 2024 ;11 1534120
    Aging-enhanced autophagy activity promotes fibrotic progression via the TGF-β2/Smad signaling pathway in trabecular meshwork cells-a new insight from POAG.
    Jin Han, Jun Wang, Ling Shen, Yiting Cai, Xuze Wang, Ailixiati Wumaier, Wei Chen, Wei Han.
       Introduction: Glaucoma, a leading cause of irreversible blindness, is characterized by optic neuropathy and retinopathy, with primary open-angle glaucoma (POAG) being the most prevalent form. The primary pathogenic mechanism of POAG involves elevated intraocular pressure caused by chronic fibrosis of the trabecular meshwork (TM). Autophagy, a critical process for maintaining cellular homeostasis, has been implicated in fibrosis across various organs. However, its precise role in the fibrosis associated with POAG pathogenesis remains unclear. This study investigates the involvement of autophagy in TM fibrosis and explores its potential impact on POAG development, aiming to provide insights into new therapeutic targets.
    Methods: To assess autophagy activity and its relationship with fibrosis, we analyzed TM tissues from POAG patients and healthy donors. Autophagic activity in human TM tissues was measured through immunohistochemical analyses. An in vitro aging model using chronic H2O2 treatment was established to investigate the change of fibrosis in TM cells. Additionally, we used dexamethasone-treated TM cells as a POAG model to explore the role of autophagy in fibrotic progression. The involvement of the TGF-β2/Smad signaling pathway was investigated through western blot analysis and quantitative real-time PCR.
    Results: This study reveals increased autophagic activity in tissues from POAG patients and an age-related upregulation of autophagy in healthy human TM tissues. In the H2O2-induced aging model, TM cells displayed both elevated autophagic activity and fibrosis. Further investigation showed that enhanced autophagy activity promoted fibrotic progression via activation of the TGF-β2/Smad signaling pathway. Similarly, in the dexamethasone-treated TM cell model, autophagy was found to exacerbate fibrosis, aligning with observations in the aging model.
    Discussion: In this study, we uncover the interplay between autophagy and the TGF-β2/Smad pathway in the pathogenesis of POAG. We observed increased autophagic activity in TM tissues from POAG patients and in TM tissues of aging healthy individuals. In human primary TM cells, we confirmed that autophagy becomes activated in the context of cellular senescence and the development of POAG, which further facilitates fibrotic progression via the TGF-β2/Smad signaling pathway. These findings underscore the important role of autophagy in POAG pathogenesis and confirm senescence as a pivotal risk factor.
    Keywords:  POAG; aging; autophagy; fibrosis; trabecular meshwork
    DOI:  https://doi.org/10.3389/fmed.2024.1534120
  25. MedComm (2020). 2025 Feb;6(2): e70071
    WSB2 inhibits apoptosis and autophagy by targeting NOXA for degradation.
    Shengpeng Shao, Danrui Cui, Chutian Zheng, Xiufang Xiong, Yongchao Zhao.
      
    Keywords:  CUL5; NOXA; WSB2; degradation; ubiquitylation
    DOI:  https://doi.org/10.1002/mco2.70071
  26. Biogerontology. 2025 Jan 24. 26(1): 48
    Sestrin2 ameliorates age-related spontaneous benign prostatic hyperplasia via activation of AMPK/mTOR dependent autophagy.
    Hui-Ju Lee, Yae-Ji Kim, Hwan-Woo Park, Hae-Il Kim, Hyun-Tae Kim, Geum-Lan Hong, Sung-Pil Cho, Kyung-Hyun Kim, Ju-Young Jung.
      Benign prostatic hyperplasia (BPH), characterized as a chronic disease with unregulated enlargement of prostatic gland, is commonly observed in elderly men leading to lower urinary tract dysfunction. Sestrin2 plays a role in the maintenance of cellular homeostasis and protects organisms from various stimuli. The exact role of Sestrin2 in the etiology of BPH, a common age-related disease, remains unknown. Here, we explored the regulatory function of Sestrin2 in modulating autophagy and its therapeutic role in spontaneous BPH. In vivo study, the 3-month-old (3 M) and 24-month-old (24 M) mice were used, and the 24 M mice were additionally administered recombinant Sestrin2 protein (rp-Sestrin2) for consecutive 14 days. In vitro, BPH-1 cells were transfected with an empty or Sestrin2 overexpression vector. Sestrin2 expression in mice prostate was gradually declined with age. Administration of rp-Sestrin2 to these mice suppressed prostatic hyperplasia, restored the balance between proliferation and apoptosis, and reduced prostatic fibrosis. Moreover, rp-Sestrin2 treatment enhanced autophagy by activating AMP-activated protein kinase (AMPK)/ mammalian target of rapamycin (mTOR) signaling pathway, as evidenced by increased autophagosome and autolysosome formation, along with a decrease in degradation marker such as p62. Our findings were further supported by in vitro studies, where Sestrin2 overexpression induced autophagy via AMPK/mTOR signaling pathway. These results suggest that Sestrin2 plays a critical role in attenuating spontaneous BPH by regulating autophagy through AMPK/mTOR signaling pathway. This study provides novel insights into the therapeutic potential of Sestrin2 in age-related spontaneous BPH.
    Keywords:  Aging; Autophagy; Benign prostatic hyperplasia; Sestrin2
    DOI:  https://doi.org/10.1007/s10522-025-10184-4
  27. Stem Cell Reports. 2025 Jan 09. pii: S2213-6711(24)00355-2. [Epub ahead of print] 102395
    A novel rapalog shows improved safety vs. efficacy in a human organoid model of polycystic kidney disease.
    Ramila E Gulieva, Parvaneh Ahmadvand, Benjamin S Freedman.
      The mammalian target of rapamycin (mTOR) pathway is a therapeutic target in polycystic kidney disease (PKD), but mTOR inhibitors such as everolimus have failed to show efficacy at tolerated doses in clinical trials. Here, we introduce AV457, a novel rapalog developed to reduce side effects, and assess its dose-dependent safety and efficacy versus everolimus in PKD1-/- and PKD2-/- human kidney organoids, which form cysts in a PKD-specific way. Both AV457 and everolimus reduce cyst growth over time. At intermediate doses, AV457 exhibits an improved safety profile relative to everolimus, with comparable efficacy. Target engagement assays confirm mTOR pathway inhibition and greater selectivity of AV457 for mTOR complex 1 versus complex 2, compared to everolimus. AV457 thus provides a more favorable balance of safety and efficacy for PKD compared to everolimus and merits further consideration as an investigational therapeutic.
    Keywords:  Akt; IC50; S6; ciliopathy; drug discovery; immunoblot; mTORC1; mTORC2; sirolimus; therapeutic screening
    DOI:  https://doi.org/10.1016/j.stemcr.2024.102395
  28. bioRxiv. 2025 Jan 13. pii: 2025.01.13.632696. [Epub ahead of print]
    ATG-3 limits Orsay virus infection in C. elegans through regulation of collagen pathways.
    Gowri Kalugotla, Vivien Marmerstein, Lawrence A Schriefer, Leran Wang, Stephanie Morrison, Luis Casorla Perez, Tim Schedl, Stephen C Pak, Megan T Baldridge.
      Autophagy is an essential cellular process which functions to maintain homeostasis in response to stressors such as starvation or infection. Here, we report that a subset of autophagy factors including ATG-3 play an antiviral role in Orsay virus infection of Caenorhabditis elegans. Orsay virus infection does not modulate autophagic flux, and re-feeding after starvation limits Orsay virus infection and blocks autophagic flux, suggesting that the role of ATG-3 in Orsay virus susceptibility is independent of its role in maintaining autophagic flux. atg-3 mutants phenocopy rde-1 mutants, which have a defect in RNA interference (RNAi), in susceptibility to Orsay virus infection and transcriptional response to infection. However, atg-3 mutants do not exhibit defects in RNAi. Additionally, atg-3 limits viral infection at a post-entry step, similar to rde-1 mutants. Differential expression analysis using RNA sequencing revealed that antiviral sqt-2, which encodes a collagen trimer protein, is depleted in naïve and infected atg-3 mutants, as well as in infected WT animals, as are numerous other collagen genes. These data suggest that ATG-3 has a role in collagen organization pathways that function in antiviral defense in C. elegans.
    DOI:  https://doi.org/10.1101/2025.01.13.632696
  29. Phytomedicine. 2025 Jan 17. pii: S0944-7113(25)00048-0. [Epub ahead of print]138 156409
    Saikosaponin D exacerbates acetaminophen-induced liver injury by sabotaging GABARAP-SNARE complex assembly in protective autophagy.
    Guifang Fan, Xiaojiaoyang Li, Fanghong Li, Ranyun Chen, Xiaoyong Xue, Le Wang, Qi Zheng, Shuni Duan, Ranyi Luo, Rong Sun, Runping Liu.
       BACKGROUND: Radix Bupleuri (RB) and acetaminophen (APAP) are two popular medications having potential hepatotoxicity and substantial risks of irrational co-administration and excessive use, posing an overlooked danger of drug-induced liver injury (DILI). Autophagy is a protective mechanism against APAP-induced DILI, yet, saikosaponin d (SSd) in RB has been characterized to regulate autophagy, although the current findings are controversial.
    PURPOSE: We aim to elucidate whether SSd promoted APAP-induced liver injury by regulating autophagy.
    METHODS: UPLC-MS analysis was employed to measure the hepatic abundance of APAP-cysteine protein adducts. Multiple techniques such as fluorescence probe, proteinase K protection assay, immunoprecipitation-coupled proteomic analysis, surface plasmon resonance, molecular docking and et.al were applied to evaluate the SSd on autophagy flux.
    RESULTS: We discovered that, by inhibiting autophagy, SSd impaired the removal of APAP-cysteine protein adducts and delayed the compensation of damaged mitochondria. This ultimately potentiated the development of severe liver toxicity induced by subtoxic APAP. The use of autophagy probes, transmission electron microscopy, membrane curative assay, and protein K assay collectively revealed that SSd predominately disrupted autophagosome-lysosome fusion, without affecting other stages of autophagic flux. Immunoprecipitation-coupled proteomic analysis and surface plasmon resonance further found that SSd directly bound to GABARAP, thus preventing the recruitment and autoactivation of STX17 and the following assembly of STX17-SNAP29-VAMP8 complex.
    CONCLUSION: In conclusion, our findings not only highlight the significant risk of drug-induced liver injury associated with the co-administration of RB and APAP in clinical practice but also unveils that GABARAP-SNARE complex is a novel druggable target for the treatment of autophagy-related diseases.
    Keywords:  GABARAP; Hepatotoxicity; Mitophagy; Radix Bupleuri; SNARE complex; Saikosaponin
    DOI:  https://doi.org/10.1016/j.phymed.2025.156409
  30. CNS Neurosci Ther. 2025 Jan;31(1): e70195
    What We Know About TMEM175 in Parkinson's Disease.
    Jing Wang, Xuechun Sun, Lufeng Cheng, Meijie Qu, Chanyuan Zhang, Xueting Li, Lingyan Zhou.
       BACKGROUND: Lysosome is a highly heterogeneous membranous organelle in eukaryotic cells, which regulates many physiological processes in the cell. Studies have found that lysosomal dysfunction disrupts cellular homeostasis and is associated with Parkinson's disease (PD). Transmembrane protein 175 (TMEM175) is a lysosomal cation channel whose activity is essential for lysosomal homeostasis. At present, it has been confirmed that TMEM175 is related to the pathogenesis of PD, but the relationship between the two remains unclear.
    AIMS: A thorough comprehension of the structure and function of TMEM175 would greatly contribute to elucidating the achievement of this objective. In this paper, the structure, composition, and function of TMEM175 and its relationship with PD will be reviewed.
    Keywords:  TMEM175; lysosome; parkinson's disease; proton channel
    DOI:  https://doi.org/10.1111/cns.70195
  31. Int J Mol Sci. 2025 Jan 18. pii: 806. [Epub ahead of print]26(2):
    Autophagy and Mitophagy in Diabetic Kidney Disease-A Literature Review.
    Alina Mihaela Stanigut, Liliana Tuta, Camelia Pana, Luana Alexandrescu, Adrian Suceveanu, Nicoleta-Mirela Blebea, Ileana Adela Vacaroiu.
      Autophagy and mitophagy are critical cellular processes that maintain homeostasis by removing damaged organelles and promoting cellular survival under stress conditions. In the context of diabetic kidney disease, these mechanisms play essential roles in mitigating cellular damage. This review provides an in-depth analysis of the recent literature on the relationship between autophagy, mitophagy, and diabetic kidney disease, highlighting the current state of knowledge, existing research gaps, and potential areas for future investigations. Diabetic nephropathy (DN) is traditionally defined as a specific form of kidney disease caused by long-standing diabetes, characterized by the classic histological lesions in the kidney, including mesangial expansion, glomerular basement membrane thickening, nodular glomerulosclerosis (Kimmelstiel-Wilson nodules), and podocyte injury. Clinical markers for DN are albuminuria and the gradual decline in glomerular filtration rate (GFR). Diabetic kidney disease (DKD) is a broader and more inclusive term, for all forms of chronic kidney disease (CKD) in individuals with diabetes, regardless of the underlying pathology. This includes patients who may have diabetes-associated kidney damage without the typical histological findings of diabetic nephropathy. It also accounts for patients with other coexisting kidney diseases (e.g., hypertensive nephrosclerosis, ischemic nephropathy, tubulointerstitial nephropathies), even in the absence of albuminuria, such as a reduction in GFR.
    Keywords:  AMPK-mTOR-Sirt1 pathway; PINK1/Parkin pathway; autophagy; diabetic nephropathy; mitochondrial dysfunction; mitophagy
    DOI:  https://doi.org/10.3390/ijms26020806
  32. Cell Signal. 2025 Jan 26. pii: S0898-6568(25)00043-9. [Epub ahead of print] 111630
    TFEB-dependent autophagy-lysosomal pathway is required for NRF2-driven antioxidative action in obstructive sleep apnea-induced neuronal injury.
    Junxiu Song, Tian Wang, Jau-Shyong Hong, Yubao Wang, Jing Feng.
      Nearly one billion individuals worldwide suffer from obstructive sleep apnea (OSA) and are potentially impacted by related neurodegeneration. TFEB is considered a master regulator of autophagy and lysosomal biogenesis, but little is known about its role in neuronal oxidative stress and resultant injury induced by OSA. This study aimed to investigate these issues. Here, we demonstrated that neuronal TFEB induction is repressed in OSA mouse models. Activation of a TFEB-dependent autophagy-lysosomal pathway (ALP) reduces hippocampal neuronal cell death and mitigates OSA-related cognitive impairment. Neuronal NRF2 induction was also found to be defective in OSA mouse models. A series of staining assays for HO1, SOD3, ROS, GSH, 8-OHdG, MDA and PI revealed that enhancement of NRF2 expression restores neuronal redox balance and protects hippocampal neurons. We then identified a novel interplay between TFEB-dependent ALP and NRF2-mediated relief of oxidative stress. Inhibition of NRF2 hinders TFEB expression and lysosomal biogenesis. Conversely, knockdown of TFEB or blocking autophagy dampens the antioxidative effect of NRF2. Our findings highlight the unexpected and crucial role of TFEB-dependent ALP as a downstream event of NRF2 in NRF2-promoted redox balance. This study provides novel insights into the mechanism behind NRF2-driven antioxidative action and the regulation of TFEB-dependent ALP.
    Keywords:  Autophagy-lysosomal pathway; Cognitive impairment; Nuclear factor erythroid 2-related factor 2; Obstructive sleep apnea; Oxidative stress; Transcription factor EB
    DOI:  https://doi.org/10.1016/j.cellsig.2025.111630
  33. Commun Biol. 2025 Jan 30. 8(1): 146
    Hsa_circ_0001304 promotes vascular neointimal hyperplasia accompanied by autophagy activation.
    Shi-Qing Mu, Jia-Jie Lin, Yu Wang, Li-Yun Yang, Sen Wang, Zhao-Yi Wang, An-Qi Zhao, Wen-Jun Luo, Zi-Qi Dong, Yu-Guang Cao, Ze-An Jiang, Si-Fan Wang, Shan-Hu Cao, Li Meng, Yang Li, Shu-Yan Yang, Shao-Guang Sun.
      Aberrant autophagy in vascular smooth muscle cells (VSMCs) is associated with the progression of vascular remodeling diseases caused by neointimal hyperplasia. Platelet-derived growth factor-BB (PDGF-BB)-induced vascular remodeling is accompanied by autophagy activation, however, the involvement of circular RNAs (circRNAs) remains unclear. Here, we show the role of PDGF-BB-regulated hsa_circ_0001304 (circ-1304) in neointimal hyperplasia and its potential involvement in VSMC autophagy, while also elucidating the potential mechanisms. Functionally, overexpression of circ-1304 promotes VSMC autophagy in vitro and exacerbates neointimal hyperplasia in vivo, and this exacerbation is accompanied by autophagy activation. Mechanistically, circ-1304 acts as a sponge for miR-636, resulting in increased protein levels of YTHDF2. Subsequently, the YTHDF2 protein promotes the degradation of mTOR mRNA by binding to the latter's m6A modification sites. We demonstrate that PDGF-BB activates VSMC autophagy via circRNA regulation. Therefore, circ-1304 may serve as a potential therapeutic target for vascular remodeling diseases.
    DOI:  https://doi.org/10.1038/s42003-025-07580-4
  34. J Adv Res. 2025 Jan 24. pii: S2090-1232(25)00056-6. [Epub ahead of print]
    FOXS1, frequently inactivated by promoter methylation, inhibited colorectal cancer cell growth by promoting TGFBI degradation through autophagy-lysosome pathway.
    Yeye Kuang, Yijian Yu, Chan Wang, Hui Li, Yiru Zhou, Lijuan Pan, Yi Zhang, Xiaoqing Cheng, Zhinong Jiang, Xiaotong Hu.
       INTRODUCTION: Tumor suppressor gene (TSG) inactivation by epigenetic modifications contributes to the carcinogenesis and progression of colorectal cancer (CRC). Expression profiling and CpG methylomics revealed that a forkhead-box transcriptional factor, FOXS1, is downregulated and methylated in CRC.
    OBJECTIVES: To assess the biological functions and underlying mechanisms of FOXS1 in colorectal cancer.
    METHODS: Public databases, semi-quantitative RT-PCR, immunohistochemistry, MSP, and BGS were used to analyze FOXS1 expression and promoter methylation in CRC. Stable FOXS1-overexpressing or knockdown cell lines were established. Cell growth, colony formation, flow cytometry, GFP-LC3 puncta detection, Ad-mCherry-GFP-LC3B, qPCR, in vivo subcutaneous tumor model, RNA-seq, western blotting, immunofluorescence, Co-IP assays, and protein stability analysis were performed to investigate the underlying molecular mechanisms of FOXS1.
    RESULTS: In CRC, FOXS1 was frequently downregulated due to promoter CpG methylation, acting as an independent prognostic marker. Moreover, FOXS1 exerts inhibitory effects on the growth of CRC cells in vitro and in vivo, while concurrently promoting CRC cell autophagy. Intriguingly, we found that FOXS1 interacted with transforming growth factor beta induced (TGFBI) and FOXS1 promoted TGFBI degradation through the autophagy-lysosome pathway rather than the ubiquitin-proteasome system. FOXS1 was also found to facilitate the interaction between TGFBI and lysosomal associated membrane protein 2A (LAMP2A), leading to the translocation of TGFBI into lysosomes for degradation. Additionally, FOXS1 regulates AKT phosphorylation and FOXO3a nuclear translocation, promoting the transcription of autophagy-related genes downstream of FOXO3a. Restoration of TGFBI expression reversed the suppressive effect exerted by FOXS1 on the growth of colorectal cancer cells.
    CONCLUSION: FOXS1 functions as a tumor suppressor that is methylated in CRC and promotes the lysosomal degradation of TGFBI, regulates cell growth and promotes autophagy in CRC through the TGFBI/AKT/FOXO3a signaling pathway. These findings indicate that FOXS1 exhibits potential as a promising biomarker and therapeutic target for colorectal cancer.
    Keywords:  Autophagy; Colorectal cancer; FOXS1; Methylation; TGFBI
    DOI:  https://doi.org/10.1016/j.jare.2025.01.037
  35. Int J Mol Sci. 2025 Jan 07. pii: 439. [Epub ahead of print]26(2):
    Changes to the Autophagy-Related Muscle Proteome Following Short-Term Treatment with Ectoine in the Duchenne Muscular Dystrophy Mouse Model mdx.
    Eulàlia Gómez Armengol, Caroline Merckx, Hanne De Sutter, Jan L De Bleecker, Boel De Paepe.
      The most severe form of muscular dystrophy (MD), known as Duchenne MD (DMD), remains an incurable disease, hence the ongoing efforts to develop supportive therapies. The dysregulation of autophagy, a degradative yet protective mechanism activated when tissues are under severe and prolonged stress, is critically involved in DMD. Treatments that harness autophagic capacities therefore represent a promising therapeutic approach. Osmolytes are protective organic molecules that regulate osmotic pressure and cellular homeostasis and may support tissue-repairing autophagy. We therefore explored the effects of the osmolyte ectoine in the standard mouse model of DMD, the mdx, focusing on the autophagy-related proteome. Mice were treated with ectoine in their drinking water (150 mg/kg) or through daily intraperitoneal injection (177 mg/kg) until they were 5.5 weeks old. Hind limb muscles were dissected, and samples were prepared for Western blotting for protein quantification and for immunofluorescence for an evaluation of tissue distribution. We report changes in the protein levels of autophagy-related 5 (ATG5), Ser366-phosphorylated sequestosome 1 (SQSTM1), heat shock protein 70 (HSP70), activated microtubule-associated protein 1A/1B-light chain 3 (LC3 II) and mammalian target of rapamycin (mTOR). Most importantly, ectoine significantly improved the balance between LC3 II and SQSTM1 levels in mdx gastrocnemius muscle, and LC3 II immunostaining was most pronounced in muscle fibers of the tibialis anterior from treated mdx. These findings lend support for the further investigation of ectoine as a potential therapeutic intervention for DMD.
    Keywords:  autophagy; mitophagy; muscular dystrophy; osmolytes
    DOI:  https://doi.org/10.3390/ijms26020439
  36. Mol Neurodegener. 2025 Jan 13. 20(1): 5
    Upregulated astrocyte HDAC7 induces Alzheimer-like tau pathologies via deacetylating transcription factor-EB and inhibiting lysosome biogenesis.
    Jinwang Ye, Suyue Zhong, Huali Wan, Xing Guo, Xuanbao Yao, Qiong Liu, Liming Chen, Jian-Zhi Wang, Shifeng Xiao.
       BACKGROUND: Astrocytes, the most abundant glial cell type in the brain, will convert into the reactive state in response to proteotoxic stress such as tau accumulation, a characteristic feature of Alzheimer's disease (AD) and other tauopathies. The formation of reactive astrocytes is partially attributed to the disruption of autophagy lysosomal signaling, and inhibiting of some histone deacetylases (HDACs) has been demonstrated to reduce the molecular and functional characteristics of reactive astrocytes. However, the precise role of autophagy lysosomal signaling in astrocytes that regulates tau pathology remains unclear.
    METHODS: We investigated the expression of class IIa HDAC7 in astrocytes from AD patients and PS19 mice. PS19 mice were treated with AAVs expressing shRNA for HDAC7 with astrocyte-specific promoter and with a selective class IIa HDAC inhibitor, TMP195, and the effects on tau pathology, gliosis, synaptic plasticity and cognition-related behavioral performance were measured. Tau uptake and degradation assays in cultured astrocytes were utilized to investigate the role of HDAC7 on astrocyte-mediated tau clearance. Immunoprecipitation, immunofluorescence, western blotting, RT-qPCR, mass spectrometric, and luciferase reporter assay were used to identify HDAC7 substrates, modification site and related signaling pathways in astrocyte-tau clearance. We generated a new antibody to clarify the role of HDAC7-mediated signaling in AD patients and PS19 mice.
    RESULTS: Here, we found that the level of histone deacetylase 7 (HDAC7) was remarkably increased in the astrocytes of AD patients and P301S tau transgenic (PS19) mice. Genetic or pharmacological inhibition of HDAC7 effectively enhanced astrocytic clearance of tau with improved cognitive functions in PS19 mice. HDAC7 could modulate astrocytic uptake and lysosomal degradation of tau proteins through a transcriptional factor EB (TFEB) acetylation-dependent manner. Specifically, deacetylation of TFEB at K310 site by HDAC7 prevented TFEB nuclear translocation with reduced lysosomal biogenesis and tau clearance in astrocytes, whereas inhibiting HDAC7 restored astrocytic TFEB acetylation level at K310 with improved tau pathology and cognitive functions in PS19 mice.
    CONCLUSIONS: Our findings suggest that upregulation of HDAC7 induces AD-like tau pathologies via deacetylating TFEB and inhibiting lysosomal biogenesis in astrocytes, and downregulating HDAC7-TFEB signaling is promising for arresting AD and other tauopathies.
    Keywords:  Astrocytes; HDAC7; Lysosomal biogenesis; TFEB; Tau pathology
    DOI:  https://doi.org/10.1186/s13024-025-00796-2
  37. Pharmaceuticals (Basel). 2025 Jan 15. pii: 99. [Epub ahead of print]18(1):
    Mechanisms of Copper-Induced Autophagy and Links with Human Diseases.
    Yuanyuan Fu, Shuyan Zeng, Zhenlin Wang, Huiting Huang, Xin Zhao, Min Li.
      As a structural and catalytic cofactor, copper is involved in many biological pathways and is required for the biochemistry of all living organisms. However, excess intracellular copper can induce cell death due to its potential to catalyze the generation of reactive oxygen species, thus copper homeostasis is strictly regulated. And the deficiency or accumulation of intracellular copper is connected with various pathological conditions. Since the success of platinum-based compounds in the clinical treatment of various types of neoplasias, metal-based drugs have shown encouraging perspectives for drug development. Compared to platinum, copper is an essential intracellular trace element that may have better prospects for drug development than platinum. Recently, the potential therapeutic role of copper-induced autophagy in chronic diseases such as Parkinson's, Wilson's, and cardiovascular disease has already been demonstrated. In brief, copper ions, numerous copper complexes, and copper-based nano-preparations could induce autophagy, a lysosome-dependent process that plays an important role in various human diseases. In this review, we not only focus on the current advances in elucidating the mechanisms of copper or copper-based compounds/preparations on the regulation of autophagy but also outline the association between copper-induced autophagy and human diseases.
    Keywords:  autophagy; copper; copper-based agents; human diseases; therapeutic potential
    DOI:  https://doi.org/10.3390/ph18010099
  38. Biochem Genet. 2025 Jan 27.
    Angiotensin-Converting Enzyme 2 Enhances Autophagy via the Consumption of miR-326 in a Mouse Model of Acute Lung Injury.
    Xingsheng Lin, Fengying Gao.
      Angiotensin-converting enzyme 2 (ACE2) has been reported to exert a protective effect in acute lung injury (ALI), though its underlying mechanism remains incompletely understood. In this study, ACE2 expression was found to be upregulated in a mouse model of ALI induced by lipopolysaccharide (LPS) injection. ACE2 knockdown modulated the severity of ALI, the extent of autophagy, and the mTOR pathway in this model. ACE2 regulated liver kinase B1 (LKB1) gene expression by sequestering miR-326, thereby alleviating ALI severity through enhanced autophagy. In cell-based experiments, miR-326 was shown to regulate ACE2 and LKB1 expression and autophagy. Overexpression of ACE2 disrupted miR-326's regulatory effect on LKB1, suggesting that LKB1 may function as an endogenous sponge for miR-326. These findings imply that elevated ACE2 expression in lung could play enhance the autophagy via the consumption of miR-326.
    Keywords:  Acute lung injury; Angiotensin-converting enzyme 2; Autophagy; Lung vascular endothelial cells; MiRNA
    DOI:  https://doi.org/10.1007/s10528-025-11040-3
  39. J Hazard Mater. 2025 Jan 21. pii: S0304-3894(25)00222-5. [Epub ahead of print]488 137310
    H4K12 lactylation-regulated NLRP3 is involved in cigarette smoke-accelerated Alzheimer-like pathology through mTOR-regulated autophagy and activation of microglia.
    Hailan Wang, Haibo Xia, Jun Bai, Zhongyue Wang, Yue Wang, Jiaheng Lin, Cheng Cheng, Weiyong Chen, Jingshu Zhang, Qingbi Zhang, Qizhan Liu.
      Cigarette smoke (CS), an indoor environmental pollution, is an environmental risk factor for diverse neurological disorders. However, the neurotoxicological effects and mechanisms of CS on Alzheimer's disease (AD) progression remain unclear. We found that CS accelerated the progression of AD, including increasing β-amyloid (Aβ) plaque deposition and exacerbating cognitive decline. Mechanistically, CS exposure increased the levels of NOD-like receptor protein 3 (NLRP3), which impaired autophagic flux in microglia by activating the mammalian target of rapamycin (mTOR) signal. Metabolomics analysis revealed an upregulation of lactate levels and an increase in global protein lysine lactylation in the brain tissue of CS-exposed AD-transgenic mice. Immunoprecipitation-Mass Spectrometry and chromatin immunoprecipitation assays demonstrated that CS elevates H4K12 lactylation (H4K12la) levels, which accumulate at the promoter region of NLRP3, leading to the activation of its transcription. Via inhibiting lactate or NLRP3 activation, oxamate and MCC950 alleviates these CS-induced effects. Therefore, our data suggest that the CS-induced increase in lactate levels triggers NLRP3 transcriptional activation through H4K12la, which subsequently leads to mTOR-mediated autophagy dysfunction in microglia, promoting microglial activation and resulting in Aβ plaque accumulation in AD-transgenic mice. This provides a new mechanism and potential therapeutic target for AD associated with environmental factors.
    Keywords:  Alzheimer's disease; Cigarette smoke; Lactylation; Microglial autophagy; NLRP3/mTOR axis
    DOI:  https://doi.org/10.1016/j.jhazmat.2025.137310
  40. Hum Mol Genet. 2025 Jan 29. pii: ddae199. [Epub ahead of print]
    Human TSC2 mutant cells exhibit aberrations in early neurodevelopment accompanied by changes in the DNA Methylome.
    Mary-Bronwen L Chalkley, Lindsey N Guerin, Tenhir Iyer, Samantha Mallahan, Sydney Nelson, Mustafa Sahin, Emily Hodges, Kevin C Ess, Rebecca A Ihrie.
      Tuberous Sclerosis Complex (TSC) is a debilitating developmental disorder characterized by a variety of clinical manifestations. While benign tumors in the heart, lungs, kidney, and brain are all hallmarks of the disease, the most severe symptoms of TSC are often neurological, including seizures, autism, psychiatric disorders, and intellectual disabilities. TSC is caused by loss of function mutations in the TSC1 or TSC2 genes and consequent dysregulation of signaling via mechanistic Target of Rapamycin Complex 1 (mTORC1). While TSC neurological phenotypes are well-documented, it is not yet known how early in neural development TSC1/2-mutant cells diverge from the typical developmental trajectory. Another outstanding question is the contribution of homozygous-mutant cells to disease phenotypes and whether phenotypes are also present in the heterozygous-mutant populations that comprise the vast majority of cells in patients. Using TSC patient-derived isogenic induced pluripotent stem cells (iPSCs) with defined genetic changes, we observed aberrant early neurodevelopment in vitro, including misexpression of key proteins associated with lineage commitment and premature electrical activity. These alterations in differentiation were coincident with hundreds of differentially methylated DNA regions, including loci associated with key genes in neurodevelopment. Collectively, these data suggest that mutation or loss of TSC2 affects gene regulation and expression at earlier timepoints than previously appreciated, with implications for whether and how prenatal treatment should be pursued.
    Keywords:  DNA methylation; iPS cells; neurodevelopment; tuberous sclerosis
    DOI:  https://doi.org/10.1093/hmg/ddae199
  41. Proc Natl Acad Sci U S A. 2025 Feb 04. 122(5): e2412029122
    Endogenous LRRK2 and PINK1 function in a convergent neuroprotective ciliogenesis pathway in the brain.
    Enrico Bagnoli, Yu-En Lin, Sophie Burel, Ebsy Jaimon, Odetta Antico, Christos Themistokleous, Jonas M Nikoloff, Samuel Squires, Ilaria Morella, Jens O Watzlawik, Fabienne C Fiesel, Wolfdieter Springer, Francesca Tonelli, Pawel Lis, Simon P Brooks, Stephen B Dunnett, Riccardo Brambilla, Dario R Alessi, Suzanne R Pfeffer, Miratul M K Muqit.
      Mutations in Leucine-rich repeat kinase 2 (LRRK2) and PTEN-induced kinase 1 (PINK1) are associated with familial Parkinson's disease (PD). LRRK2 phosphorylates Rab guanosine triphosphatase (GTPases) within the Switch II domain while PINK1 directly phosphorylates Parkin and ubiquitin (Ub) and indirectly induces phosphorylation of a subset of Rab GTPases. Herein we have crossed LRRK2 [R1441C] mutant knock-in mice with PINK1 knock-out (KO) mice and report that loss of PINK1 does not impact endogenous LRRK2-mediated Rab phosphorylation nor do we see significant effect of mutant LRRK2 on PINK1-mediated Rab and Ub phosphorylation. In addition, we observe that a pool of the Rab-specific, protein phosphatase family member 1H phosphatase, is transcriptionally up-regulated and recruited to damaged mitochondria, independent of PINK1 or LRRK2 activity. Parallel signaling of LRRK2 and PINK1 pathways is supported by assessment of motor behavioral studies that show no evidence of genetic interaction in crossed mouse lines. Previously we showed loss of cilia in LRRK2 R1441C mice and herein we show that PINK1 KO mice exhibit a ciliogenesis defect in striatal cholinergic interneurons and astrocytes that interferes with Hedgehog induction of glial derived-neurotrophic factor transcription. This is not exacerbated in double-mutant LRRK2 and PINK1 mice. Overall, our analysis indicates that LRRK2 activation and/or loss of PINK1 function along parallel pathways to impair ciliogenesis, suggesting a convergent mechanism toward PD. Our data suggest that reversal of defects downstream of ciliogenesis offers a common therapeutic strategy for LRRK2 or PINK1 PD patients, whereas LRRK2 inhibitors that are currently in clinical trials are unlikely to benefit PINK1 PD patients.
    Keywords:  LRRK2; PINK1; brain; ciliogenesis; phosphorylation
    DOI:  https://doi.org/10.1073/pnas.2412029122
  42. J Cell Mol Med. 2025 Jan;29(2): e70352
    Stromal Cell Derived Factor-1 Promotes Hepatic Insulin Resistance via Inhibiting Hepatocyte Lipophagy.
    Chunfeng Lu, Yuting Zhang, Cuilian Sun, Yuhang Na, Haotian Sun, Jianhua Ma, Xueqin Wang, Xiaomin Cang.
      Saturated fatty acid (SFA) accumulation in liver decreases hepatocyte lipophagy, a type of selective autophagy that degrades intracellular lipid droplets, leading to hepatic insulin resistance (IR), which contributes to simultaneous increases in liver glucose production and fat synthesis, resulting in hyperglycemia and dyslipidemia traits of type 2 diabetes mellitus (T2DM). Stromal cell derived factor-1 (SDF-1), a cytokine produced by hepatocytes, inhibits autophagy. In this study, we evaluated the hypothesis that SDF-1 promoted hepatic IR via inhibiting hepatocyte lipophagy during T2DM. Furthermore, we probed the downstream pathway participating in the role of SDF-1. The results showed that the neutralising of SDF-1 improved hepatic IR via promoting hepatocyte lipophagy in a mouse high-fat and high sucrose diet (HFHSD)-induced T2DM model. In vitro, SDF-1 expression and release increased in palmitic acid (PA, a kind of SFA)-treated hepatocytes. Meanwhile, SDF-1 bound to up-regulated C-X-C chemokine receptor type 4 (CXCR4) and C-X-C chemokine receptor type 7 (CXCR7) on PA-treated hepatocytes. Subsequently, SDF-1 inhibited lipophagy in PA-treated hepatocytes via CXCR4, rather than CXCR7. Finally, SDF-1/CXCR4/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) pathway-inhibited lipophagy promotes PA-induced hepatocyte IR. Collectively, this study discovered that SDF-1 might inhibit lipophagy in SFA-treated hepatocytes to promote hepatic IR via CXCR4/AKT/mTOR pathway.
    Keywords:  hepatic insulin resistance; hepatocyte; lipophagy; stromal cell derived factor‐1
    DOI:  https://doi.org/10.1111/jcmm.70352
  43. Allergol Immunopathol (Madr). 2025 ;53(1): 146-152
    Knockdown of STAU1 inhibits inflammation and autophagy in in vitro chronic obstructive pulmonary disease model by regulating AMPK-mTOR signaling pathway.
    Rixi Xie, Fang Wang.
      Chronic obstructive pulmonary disease (COPD) is characterized by chronic inflammation, airway obstruction, and lung damage, often triggered by cigarette smoke. Dysregulated autophagy and inflammation are key contributors to its progression. Although double-stranded RNA-binding protein Staufen homolog 1 (STAU1), a multifunctional protein primarily involved in mRNA transport and localization, is identified as a potential biomarker, its role in COPD pathogenesis remains unclear. This study investigates the effects of STAU1 knockdown on inflammation and autophagy in an in vitro COPD model. We found that STAU1 expression was significantly elevated in the in vitro COPD model. Knockdown of STAU1 led to a marked reduction in inflammation in cigarette smoke extract (CSE)-induced non-tumorigenic human bronchial epithelial cells (BEAS-2B). Additionally, STAU1 knockdown suppressed autophagy in CSE-induced BEAS-2B cells. Mechanistically, it inhibited the activation of the adenosine monophosphate-activated protein kinase-mechanistic target of rapamycin (AMPK/mTOR) pathway. In summary, STAU1 knockdown inhibits inflammation and autophagy by modulating the AMPK/mTOR axis. Targeting STAU1 could provide new avenues for the treatment of COPD.
    Keywords:  AMPK/mTOR pathway; COPD; STAU1; autophagy; inflammation
    DOI:  https://doi.org/10.15586/aei.v53i1.1218
  44. Acta Pharmacol Sin. 2025 Jan 29.
    Apolipoprotein B100 acts as a tumor suppressor in ovarian cancer via lipid/ER stress axis-induced blockade of autophagy.
    Ze-Yuan Yin, Shi-Min He, Xin-Yuan Zhang, Xiao-Chen Yu, Kai-Xuan Sheng, Tong Fu, Yi-Xue Jiang, Liu Xu, Bing-Xuan Hu, Jing-Bo Zhang, Yan-Yu Li, Qing Wang, Bei-Bei Zhang, Yun-Meng Qi, Joseph Adu-Amankwaah, Xue-Yan Zhou, Qi Qi, Bei Zhang, Cheng-Lin Li.
      Ovarian cancer presents a significant treatment challenge due to its insidious nature and high malignancy. As autophagy is a vital cellular process for maintaining homeostasis, targeting the autophagic pathway has emerged as an avenue for cancer therapy. In the present study, we identify apolipoprotein B100 (ApoB100), a key modulator of lipid metabolism, as a potential prognostic biomarker of ovarian cancer. ApoB100 functioned as a tumor suppressor in ovarian cancer, and the knockdown of ApoB100 promoted ovarian cancer progression in vivo. Moreover, ApoB100 blocked autophagic flux, which was dependent on interfering with the lipid accumulation/endoplasmic reticulum (ER) stress axis. The effects of LFG-500, a novel synthetic flavonoid, on ApoB100 induction were confirmed using proteomics and lipidomics analyses. Herein, LFG-500 induced lipid accumulation and ER stress and subsequently blocked autophagy by upregulating ApoB100. Moreover, data from in vivo experiments further demonstrated that ApoB100, as well as the induction of the lipid/ER stress axis and subsequent blockade of autophagy, were responsible for the anti-tumor effects of LFG-500 on ovarian cancer. Hence, our findings support that ApoB100 is a feasible target of ovarian cancer associated with lipid-regulated autophagy and provide evidence for using LFG-500 for ovarian cancer treatment.
    Keywords:  ApoB100; ER stress; LFG-500; autophagy; lipid metabolism; ovarian cancer
    DOI:  https://doi.org/10.1038/s41401-024-01470-x
  45. Cell Mol Biol Lett. 2025 Jan 26. 30(1): 12
    VEXAS, Chediak-Higashi syndrome and Danon disease: myeloid cell endo-lysosomal pathway dysfunction as a common denominator?
    Coline Savy, Maxence Bourgoin, Thomas Cluzeau, Arnaud Jacquel, Guillaume Robert, Patrick Auberger.
      Vacuolization of hematopoietic precursors cells is a common future of several otherwise non-related clinical settings such as VEXAS, Chediak-Higashi syndrome and Danon disease. Although these disorders have a priori nothing to do with one other from a clinical point of view, all share abnormal vacuolization in different cell types including cells of the erythroid/myeloid lineage that is likely the consequence of moderate to drastic dysfunctions in the ubiquitin proteasome system and/or the endo-lysosomal pathway. Indeed, the genes affected in these three diseases UBA1, LYST or LAMP2 are known to be direct or indirect regulators of lysosome trafficking and function and/or of different modes of autophagy. Furthermore, all three genes are highly expressed in the more mature myeloid cells pointing out their likely important function in these cells. LAMP2 deficiency for instance is known to be associated with alterations of lysosome architecture and function. It is thus well established that different cell types from Danon disease patients that harbor invalidating mutations in LAMP2 exhibit giant lysosomes containing undigested materials characteristic of defects in the fusion of lysosomes with autophagosomes, a feature also found in VEXAS and CHS. Other similarities regarding these three diseases include granulocyte and monocyte dysfunctions and a recurrent inflammatory climate. In the present review we discuss the possibility that some common clinical manifestations of these diseases, notably the hematopoietic ones are consecutive to a dysfunction of the endo-lysosomal pathway in myeloid/erythroid progenitors and in mature myeloid cells including neutrophiles, monocytes and macrophages. Finally, we propose reacidification as a way of reinducing lysosome functionalities and autophagy as a potential approach for a better management of these diseases.
    Keywords:  Chediak–Higashi disease; Danon disease; Inflammation; Lysosomes; Macrophages; Monocytes; Neutrophiles; VEXAS; pH
    DOI:  https://doi.org/10.1186/s11658-025-00691-0
  46. Int J Mol Sci. 2025 Jan 07. pii: 448. [Epub ahead of print]26(2):
    A Multi-Omics Analysis of a Mitophagy-Related Signature in Pan-Cancer.
    Nora Agir, Ilias Georgakopoulos-Soares, Apostolos Zaravinos.
      Mitophagy, an essential process within cellular autophagy, has a critical role in regulating key cellular functions such as reproduction, metabolism, and apoptosis. Its involvement in tumor development is complex and influenced by the cellular environment. Here, we conduct a comprehensive analysis of a mitophagy-related gene signature, composed of PRKN, PINK1, MAP1LC3A, SRC, BNIP3L, BECN1, and OPTN, across various cancer types, revealing significant differential expression patterns associated with molecular subtypes, stages, and patient outcomes. Pathway analysis revealed a complex interplay between the expression of the signature and potential effects on the activity of various cancer-related pathways in pan-cancer. Immune infiltration analysis linked the mitophagy signature with certain immune cell types, particularly OPTN with immune infiltration in melanoma. Methylation patterns correlated with gene expression and immune infiltration. Mutation analysis also showed frequent alterations in PRKN (34%), OPTN (21%), PINK1 (28%), and SRC (15%), with implications for the tumor microenvironment. We also found various correlations between the expression of the mitophagy-related genes and sensitivity in different drugs, suggesting that targeting this signature could improve therapy efficacy. Overall, our findings underscore the importance of mitophagy in cancer biology and drug resistance, as well as its potential for informing treatment strategies.
    Keywords:  BECN1; BNIP3L; MAP1LC3; OPTN; PARK2; PINK1; PRKN; SRC; drug resistance; drug sensitivity; mitophagy; multi-omics; pan-cancer
    DOI:  https://doi.org/10.3390/ijms26020448
  47. J Cardiovasc Transl Res. 2025 Jan 30.
    The link between ferroptosis and autophagy in myocardial ischemia/reperfusion injury: new directions for therapy.
    Xiaoting Yang, Hui Wu, Di Liu, Gang Zhou, Dong Zhang, Qingzhuo Yang, Yanfang Liu, Yi Li.
      Myocardial ischemia/reperfusion (I/R)-induced cell death, such as autophagy and ferroptosis, is a major contributor to cardiac injury. Regulating cell death may be key to mitigating myocardial ischemia/reperfusion injury (MI/RI). Autophagy is a crucial physiological process involving cellular self-digestion and compensation, responsible for degrading excess or malfunctioning long-lived proteins and organelles. During MI/RI, autophagy plays both "survival" and "death" roles. A growing body of research indicates that ferroptosis is a type of autophagy-dependent cell death. This article provides a comprehensive review of the functions of autophagy and ferroptosis in MI/RI, as well as the molecules mediating their interaction. Understanding the link between autophagy and ferroptosis may offer new therapeutic directions for MI/RI, bearing significant clinical implications.
    Keywords:  Autophagy; Autophagy-dependent cell death; Autophagy-dependent ferroptosis; Ferroptosis; Myocardial ischemia/reperfusion injury; Selective autophagy
    DOI:  https://doi.org/10.1007/s12265-025-10590-6
  48. Adv Biotechnol (Singap). 2023 Oct 26. 1(4): 2
    Studying plant autophagy: challenges and recommended methodologies.
    Hua Qi, Yao Wang, Yan Bao, Diane C Bassham, Liang Chen, Qin-Fang Chen, Suiwen Hou, Inhwan Hwang, Li Huang, Zhibing Lai, Faqiang Li, Yule Liu, Rongliang Qiu, Hao Wang, Pengwei Wang, Qingjun Xie, Yonglun Zeng, Xiaohong Zhuang, Caiji Gao, Liwen Jiang, Shi Xiao.
      In plants, autophagy is a conserved process by which intracellular materials, including damaged proteins, aggregates, and entire organelles, are trafficked to the vacuole for degradation, thus maintaining cellular homeostasis. The past few decades have seen extensive research into the core components of the central autophagy machinery and their physiological roles in plant growth and development as well as responses to biotic and abiotic stresses. Moreover, several methods have been established for monitoring autophagic activities in plants, and these have greatly facilitated plant autophagy research. However, some of the methodologies are prone to misuse or misinterpretation, sometimes casting doubt on the reliability of the conclusions being drawn about plant autophagy. Here, we summarize the methods that are widely used for monitoring plant autophagy at the physiological, microscopic, and biochemical levels, including discussions of their advantages and limitations, to provide a guide for studying this important process.
    Keywords:  ATG8 lipidation; Autophagy; GFP-ATG8 cleavage; Methodology; Microscopy analysis
    DOI:  https://doi.org/10.1007/s44307-023-00002-8
  49. Geroscience. 2025 Jan 30.
    An mTOR inhibitor discovery system using drug-sensitized yeast.
    Anna K Breen, Sarah Thomas, David Beckett, Matthew Agsalud, Graham Gingras, Judd Williams, Brian M Wasko.
      Inhibition of the target of rapamycin (TOR/mTOR) protein kinase by the drug rapamycin extends lifespan and health span across diverse species. However, rapamycin has potential off-target and side effects that warrant the discovery of additional TOR inhibitors. TOR was initially discovered in Saccharomyces cerevisiae (yeast) which contains two TOR paralogs, TOR1 and TOR2. Yeast lacking functional Tor1 are viable but are hypersensitive to growth inhibition by TORC1 inhibitors, which is a property of yeast that can be exploited to identify TOR inhibitors. Additionally, yeast lacking FK506-sensitive proline rotamase (FPR1) or containing a tor1-1 allele (a mutation in the Fpr1-rapamycin binding domain of Tor1) are robustly and selectively resistant to rapamycin and analogs that allosterically inhibit TOR activity via an FPR1-dependent mechanism. To facilitate the identification of TOR inhibitors, we generated a panel of yeast strains with mutations in TOR pathway genes combined with the removal of 12 additional genes involved in drug efflux. This creates a drug-sensitive strain background that can sensitively and effectively identify TOR inhibitors. In a wild-type yeast strain background, 25 µM of Torin1 and 100 µM of GSK2126458 (omipalisib) are necessary to observe TOR1-dependent growth inhibition by these known TOR inhibitors. In contrast, 100 nM Torin1 and 500 nM GSK2126458 (omipalisib) are sufficient to identify TOR1-dependent growth inhibition in the drug-sensitized background. This represents a 200-fold and 250-fold increase in detection sensitivity for Torin1 and GSK2126458, respectively. Additionally, for the TOR inhibitor AZD8055, the drug-sensitive system resolves that the compound results in TOR1-dependent growth sensitivity at 100 µM, whereas no growth inhibition is observed in a wild-type yeast strain background. Our platform also identifies the caffeine analog aminophylline as a TOR1-dependent growth inhibitor via selective tor1 growth sensitivity. We also tested nebivolol, isoliquiritigenin, canagliflozin, withaferin A, ganoderic acid A, and taurine and found no evidence for TOR inhibition using our yeast growth-based model. Our results demonstrate that this system is highly effective at identifying compounds that inhibit the TOR pathway. It offers a rapid, cost-efficient, and sensitive tool for drug discovery, with the potential to expedite the identification of new TOR inhibitors that could serve as geroprotective and/or anti-cancer agents.
    Keywords:  Rapamycin; Yeast; mTOR
    DOI:  https://doi.org/10.1007/s11357-025-01534-8
  50. EMBO J. 2025 Jan 28.
    Micropeptide hSPAR regulates glutamine levels and suppresses mammary tumor growth via a TRIM21-P27KIP1-mTOR axis.
    Yan Huang, Hua Lu, Yao Liu, Jiabei Wang, Qingan Xia, Xiangmin Shi, Yan Jin, Xiaolin Liang, Wei Wang, Xiaopeng Ma, Yangyi Wang, Meng Gong, Canjun Li, Chunlei Cang, Qinghua Cui, Ceshi Chen, Tao Shen, Lianxin Liu, Xiangting Wang.
      mTOR plays a pivotal role in cancer growth control upon amino acid response. Recently, CDK inhibitor P27KIP1 has been reported as a noncanonical inhibitor of mTOR signaling in MEFs, via unclear mechanisms. Here, we find that P27KIP1 degradation via E3 ligase TRIM21 is inhibited by human micropeptide hSPAR through its C-terminus (hSPAR-C), causing P27KIP1's cytoplasmic accumulation in breast cancer cells. Furthermore, hSPAR/hSPAR-C also serves as an inhibitor of glutamine transporter SLC38A2 expression and thereby decreases the cellular glutamine levels specifically in cancer cells. The resultant glutamine deprivation sequentially triggers translocation of cytoplasmic P27KIP1 to lysosomes, where P27KIP1 disrupts the Ragulator complex and suppresses mTORC1 assembly. Administration of hSPAR or hSPAR-C significantly impedes breast cancer cell proliferation and tumor growth in xenograft models. These findings define hSPAR as an intrinsic control factor for cellular glutamine levels and as a novel tumor suppressor inhibiting mTORC1 assembly.
    Keywords:  Breast Cancer; Micropeptide/microprotein; P27KIP1; TRIM21; mTOR
    DOI:  https://doi.org/10.1038/s44318-024-00359-z
  51. Cell Death Dis. 2025 Jan 28. 16(1): 52
    The E3-ligase Siah2 activates mitochondrial quality control in neurons to maintain energy metabolism during ischemic brain tolerance.
    Maria Josè Sisalli, Elena D'Apolito, Ornella Cuomo, Giovanna Lombardi, Michele Tufano, Lucio Annunziato, Antonella Scorziello.
      Mitochondrial quality control is crucial for the homeostasis of the mitochondrial network. The balance between mitophagy and biogenesis is needed to reduce cerebral ischemia-induced cell death. Ischemic preconditioning (IPC) represents an adaptation mechanism of CNS that increases tolerance to lethal cerebral ischemia. It has been demonstrated that hypoxia-induced Seven in absentia Homolog 2 (Siah2) E3-ligase activation influences mitochondrial dynamics promoting the degradation of mitochondrial proteins. Therefore, in the present study, we investigated the role of Siah2 in the IPC-induced neuroprotection in in vitro and in vivo models of IPC. To this aim, cortical neurons were exposed to 30-min oxygen and glucose deprivation (OGD, sublethal insult) followed by 3 h OGD plus reoxygenation (lethal insult). Our results revealed that the mitochondrial depolarization induced by hypoxia activates Siah2 at the mitochondrial level and increases LC3-II protein expression, a marker of mitophagy, an effect counteracted by the reoxygenation phase. By contrast, hypoxia reduced the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), a marker of mitochondrial biogenesis, whereas its expression was increased after reoxygenation thus improving mitochondrial membrane potential, mitochondrial calcium content, and mitochondrial morphology, hence leading to neuroprotection in IPC. Furthermore, Siah2 silencing confirmed these results. Collectively, these findings indicate that the balance between mitophagy and mitochondrial biogenesis, due to the activation of the Siah2-E3-ligase, might play a role in IPC-induced neuroprotection.
    DOI:  https://doi.org/10.1038/s41419-025-07339-z
  52. Anticancer Drugs. 2025 Jan 28.
    HER2 regulates autophagy and promotes migration in gastric cancer cells through the cGAS-STING pathway.
    Panping Liang, Zedong Li, Zhengwen Chen, Zehua Chen, Fengjun He, Tao Jin, Yuwei Cao, Kun Yang.
      In gastric cancer, the relationship between human epidermal growth factor receptor 2 (HER2), the cyclic GMP-AMP synthase-stimulator of the interferon genes (cGAS-STING) pathway, and autophagy remains unclear. This study examines whether HER2 regulates autophagy in gastric cancer cells via the cGAS-STING signaling pathway, influencing key processes such as cell proliferation and migration. Understanding this relationship could uncover new molecular targets for diagnosis and treatment. Through lentiviral transfection, cell counting kit-8 assays, colony formation, transwell migration, scratch assays, and siRNA, we found that HER2 overexpression suppresses the cGAS-STING pathway, inhibits autophagy, and enhances the migratory ability of gastric cancer cells. In contrast, HER2 knockdown activates the cGAS-STING pathway, promotes autophagy, and reduces cell migration. We further observed that the inhibition of autophagy using chloroquine (CQ) increases the migration ability of HER2-overexpressing cells. Moreover, interfering with STING expression reversed the migration defects caused by HER2 knockdown, underscoring the critical role of the cGAS-STING pathway in HER2-regulated cell migration. We also revealed that high STING expression in gastric cancer is significantly associated with poor prognosis. STING expression was identified as an independent prognostic factor for survival (hazard ratio, 1.942; 95% confidence interval, 1.06-3.54; P = 0.031). These results highlight the importance of HER2-driven regulation of autophagy through the cGAS-STING pathway in gastric cancer progression and its potential as a therapeutic target.
    DOI:  https://doi.org/10.1097/CAD.0000000000001680
  53. Cell Signal. 2025 Jan 26. pii: S0898-6568(25)00032-4. [Epub ahead of print]127 111619
    m6A modified ATG9A is required in regulating autophagy to promote HSCs activation and liver fibrosis.
    Tingjuan Huang, Ziyi Shang, Lina Nie, Haichao Diao, Qizhi Shuai, Junjie Ren, Jun Xu, Jun Xie.
      Hepatic stellate cells (HSCs) are the central link of the occurrence and development of hepatic fibrosis, and autophagy promotes HSCs activation. N6-methyladenosine (m6A) RNA modification can also control autophagy by targeting selected autophagy-associated genes. but up to now, little research has been done on the m6A modification autophagy-related genes (ATGs) in hepatic fibrosis. Here, we identify ATG9A as a previously unrecognized m6A modified ATG using m6A-sequencing (m6A-seq). Importantly, ATG9A is upregulated in liver fibrosis mice and primary biliary cirrhosis (PBC) patient liver tissue. Mechanistically, based on the presence of m6A binding sites on ATG9A, ATG9A promotes HSCs autophagy in an m6A dependent manner, thereby enhancing HSCs activation. Noteworthy, FTO is identified as the upstream of ATG9A, and knockdown of ATG9A can prevent FTO-induced HSCs autophagy and activation. In bile duct ligation (BDL) or CCL4-induced liver fibrosis mouse models, lowering ATG9A alleviated liver fibrosis through PI3K/AKT/mTOR pathway and TGFβ1/smad3 pathway. Taken together, our results provided that ATG9A is a potential prognostic biomarker and therapeutic target for patients with liver fibrosis.
    Keywords:  ATG9A; Autophagy; Hepatic stellate cells; Liver fibrosis; m6A
    DOI:  https://doi.org/10.1016/j.cellsig.2025.111619
  54. Cell Biosci. 2025 Jan 29. 15(1): 11
    Trehalose enhances macrophage autophagy to promote myelin debris clearance after spinal cord injury.
    Zhida Ma, Congpeng Meng, Xiang Wang, Yuanzhe Zhao, Jingwen Wang, Yihao Chen, Yiteng Li, Yan Jiang, Fangru Ouyang, Jianjian Li, Meige Zheng, Li Cheng, Juehua Jing.
       BACKGROUND: Myelin-laden foamy macrophages accumulate extensively in the lesion epicenter, exhibiting characteristics of autophagolysosomal dysfunction, which leads to prolonged inflammatory responses after spinal cord injury (SCI). Trehalose, known for its neuroprotective properties as an autophagy inducer, has yet to be fully explored for its potential to mitigate foamy macrophage formation and exert therapeutic effects in the context of SCI.
    RESULTS: We observed that trehalose significantly enhances macrophage phagocytosis and clearance of myelin in a dose-dependent manner in vitro. In vivo, trehalose administration markedly reduced myelin debris accumulation, inhibited foamy macrophage formation, suppressed inflammatory responses, decreased fibrotic scarring, and promoted axonal growth and motor function recovery after SCI. These beneficial effects of trehalose may be related to the overexpression of transcription factor EB (TFEB), a key regulator of the autophagy-lysosomal system, which can rescue autophagic dysfunction in foamy macrophages and inhibit inflammatory responses. Additionally, the effects of trehalose on macrophages were abolished by chloroquine, an autophagy inhibitor, suggesting trehalose's potential as a therapeutic candidate for enhancing myelin debris clearance post-SCI.
    CONCLUSIONS: Our findings underscore the pivotal role of trehalose in modulating myelin debris clearance within macrophages, providing new perspectives for the treatment of spinal cord injury.
    Keywords:  Autophagy; Foamy macrophages; Myelin debris; Spinal cord injury; Trehalose
    DOI:  https://doi.org/10.1186/s13578-025-01357-2
  55. Am J Physiol Cell Physiol. 2025 Jan 27.
    Increasing cellular NAD+ protects hepatocytes against palmitate-induced lipotoxicity by preventing PARP-1 inhibition and the mTORC1-p300 pathway activation.
    Rui Guo, Yanhui Li, Qing Song, Rong Huang, Xiaodong Ge, Natalia Nieto, Yuwei Jiang, Zhenyuan Song.
      Hepatic lipotoxicity, resulting from excessive lipid accumulation in hepatocytes, plays a central role in the pathogenesis of various metabolic liver diseases. Despite recent progress, the precise mechanisms remain incompletely understood. Employing excessive exposure to palmitate in hepatocytes as our primary experimental model and mice studies, we aimed to uncover the mechanisms behind hepatic lipotoxicity, thereby developing potential treatments. Our data reveal for the first time that exposure to palmitate leads to downregulated expression of poly(ADP-ribose) polymerase 1 (PARP-1) in hepatocytes, inhibiting its enzymatic activity. While inhibiting PARP-1 worsens palmitate-induced hepatotoxicity, preventing PARP-1 suppression, using NAD+ precursors, nicotinamide N-methyltransferase (NNMT) inhibitors, or a poly(ADP-ribose) glycohydrolase (PARG) inhibitor, prevents it. Moreover, we uncover that PARP-1 suppression contributes to palmitate-triggered mTORC1 activation, which has been previously reported by us to contribute to palmitate-induced hepatocyte cell death. Furthermore, our results identify p300 as a downstream target of mTORC1 activation upon palmitate exposure. Importantly, p300 inhibition via either pharmacological or genetic approaches protects against palmitate hepatotoxicity. Additionally, we provide evidence that the TLR4-NF-κB pathway activation in response to palmitate plays a mechanistic role in mediating palmitate-induced PARP-1 downregulation in that both TLR4 antagonist and NF-κB inhibitors prevent palmitate induced PARP-1 reduction and protect against hepatocyte cell death. In conclusion, our study presents new evidence that the PARP-1-mTORC1-p300 pathway serves as a novel molecular mechanism underlying palmitate-induced hepatic lipotoxicity. Targeting the PARP-1 pathway by increasing cellular NAD+ availability either through its precursor supplementation or by inhibiting its degradation represents a promising therapeutic approach for treating hepatic lipotoxicity.
    Keywords:  NAD+; NNMT; PARP-1; Palmitate; mTORC1
    DOI:  https://doi.org/10.1152/ajpcell.00946.2024
  56. Nat Commun. 2025 Jan 29. 16(1): 1160
    VSTM2L protects prostate cancer cells against ferroptosis via inhibiting VDAC1 oligomerization and maintaining mitochondria homeostasis.
    Juan Yang, Xiao Lu, Jing-Lan Hao, Lan Li, Yong-Tong Ruan, Xue-Ni An, Qi-Lai Huang, Xiao-Ming Dong, Ping Gao.
      Ferroptosis is a form of iron-dependent programmed cell death, which is distinct from apoptosis, necrosis, and autophagy. Mitochondria play a critical role in initiating and amplifying ferroptosis in cancer cells. Voltage-Dependent Anion Channel 1 (VDAC1) embedded in the mitochondrial outer membrane, exerts roles in regulation of ferroptosis. However, the mechanisms of VDAC1 oligomerization in regulating ferroptosis are not well elucidated. Here, we identify that a VDAC1 binding protein V-Set and Transmembrane Domain Containing 2 Like (VSTM2L), mainly localized to mitochondria, is positively associated with prostate cancer (PCa) progression, and a key regulator of ferroptosis. Moreover, VSTM2L knockdown in PCa cells enhances the sensitivity of RSL3-induced ferroptosis. Mechanistically, VSTM2L forms complex with VDAC1 and hexokinase 2 (HK2), enhancing their binding affinity and preventing VDAC1 oligomerization, thereby inhibiting ferroptosis and maintaining mitochondria homeostasis in vitro and in vivo. Collectively, our findings reveal a pivotal role for mitochondria-localized VSTM2L in driving ferroptosis resistance and highlight its potential as a ferroptosis-inducing therapeutic target for the treatment of PCa.
    DOI:  https://doi.org/10.1038/s41467-025-56494-6
  57. Biomolecules. 2025 Jan 19. pii: 149. [Epub ahead of print]15(1):
    Targeting the Interplay Between Autophagy and the Nrf2 Pathway in Parkinson's Disease with Potential Therapeutic Implications.
    Mengru Liu, Siqi Liu, Zihan Lin, Xi Chen, Qian Jiao, Xixun Du, Hong Jiang.
      Parkinson's disease (PD) is a prevalent neurodegenerative disorder marked by the progressive degeneration of midbrain dopaminergic neurons and resultant locomotor dysfunction. Despite over two centuries of recognition as a chronic disease, the exact pathogenesis of PD remains elusive. The onset and progression of PD involve multiple complex pathological processes, with dysfunctional autophagy and elevated oxidative stress serving as critical contributors. Notably, emerging research has underscored the interplay between autophagy and oxidative stress in PD pathogenesis. Given the limited efficacy of therapies targeting either autophagy dysfunction or oxidative stress, it is crucial to elucidate the intricate mechanisms governing their interplay in PD to develop more effective therapeutics. This review overviews the role of autophagy and nuclear factor erythroid 2-related factor 2 (Nrf2), a pivotal transcriptional regulator orchestrating cellular defense mechanisms against oxidative stress, and the complex interplay between these processes. By elucidating the intricate interplay between these key pathological processes in PD, this review will deepen our comprehensive understanding of the multifaceted pathological processes underlying PD and may uncover potential strategies for its prevention and treatment.
    Keywords:  Nrf2 pathway; Parkinson’s disease; autophagy; oxidative stress; p62
    DOI:  https://doi.org/10.3390/biom15010149
  58. Int J Mol Sci. 2025 Jan 18. pii: 793. [Epub ahead of print]26(2):
    HERC1 E3 Ubiquitin Ligase Is Necessary for Autophagy Processes and for the Maintenance and Homeostasis of Vesicles in Motor Nerve Terminals, but Not for Proteasomal Activity.
    Miguel Ángel Pérez-Castro, Francisco Hernández-Rasco, Isabel María Alonso-Bellido, María S Letrán-Sánchez, Eva María Pérez-Villegas, Joana Vitallé, Luis Miguel Real, Ezequiel Ruiz-Mateos, José Luis Venero, Lucía Tabares, Ángel Manuel Carrión, José Ángel Armengol, Sara Bachiller, Rocío Ruiz.
      The ubiquitin proteasome system (UPS) is implicated in protein homeostasis. One of the proteins involved in this system is HERC1 E3 ubiquitin ligase, which was associated with several processes including the normal development and neurotransmission at the neuromuscular junction (NMJ), autophagy in projection neurons, myelination of the peripheral nervous system, among others. The tambaleante (tbl) mouse model carries the spontaneous mutation Gly483Glu substitution in the HERC1 E3 protein. Using this model, we analyzed the implication of HERC1 E3 ubiquitin ligase in the activity of UPS, autophagy, and synaptic homeostasis in brain and muscle tissues. Regarding UPS, no differences were found in its activity nor in the specific gene expression in both brain and muscle tissues from tbl compared with the control littermates. Furthermore, the use of the specific UPS inhibitor (MG-132), did not alter the evoked neurotransmitter release in the levator auris longus (LAL) muscle. Interestingly, the expression of the autophagy-related gene p62 was significantly increased in the muscle of tbl compared to the control littermates. Indeed, impaired evoked neurotransmitter release was observed with the autophagy inhibitor Wortmannin. Finally, altered levels of Clathrin and Synaptophysin were detected in muscle tissues. Altogether, our findings show that HERC1 E3 ubiquitin ligase mutation found in tbl mice alters autophagy and vesicular recycling without affecting proteasomal function.
    Keywords:  autophagy; neuromuscular junction; proteasome; synapses; vesicles
    DOI:  https://doi.org/10.3390/ijms26020793
  59. Nat Commun. 2025 Jan 25. 16(1): 1021
    The 40S ribosomal subunit recycling complex modulates mitochondrial dynamics and endoplasmic reticulum - mitochondria tethering at mitochondrial fission/fusion hotspots.
    Foozhan Tahmasebinia, Yinglu Tang, Rushi Tang, Yi Zhang, Will Bonderer, Maisa de Oliveira, Bretton Laboret, Songjie Chen, Ruiqi Jian, Lihua Jiang, Michael Snyder, Chun-Hong Chen, Yawei Shen, Qing Liu, Boxiang Liu, Zhihao Wu.
      The 40S ribosomal subunit recycling pathway is an integral link in the cellular quality control network, occurring after translational errors have been corrected by the ribosome-associated quality control (RQC) machinery. Despite our understanding of its role, the impact of translation quality control on cellular metabolism remains poorly understood. Here, we reveal a conserved role of the 40S ribosomal subunit recycling (USP10-G3BP1) complex in regulating mitochondrial dynamics and function. The complex binds to fission-fusion proteins located at mitochondrial hotspots, regulating the functional assembly of endoplasmic reticulum-mitochondria contact sites (ERMCSs). Furthermore, it alters the activity of mTORC1/2 pathways, suggesting a link between quality control and energy fluctuations. Effective communication is essential for resolving proteostasis-related stresses. Our study illustrates that the USP10-G3BP1 complex acts as a hub that interacts with various pathways to adapt to environmental stimuli promptly. It advances our molecular understanding of RQC regulation and helps explain the pathogenesis of human proteostasis and mitochondrial dysfunction diseases.
    DOI:  https://doi.org/10.1038/s41467-025-56346-3
  60. Nat Commun. 2025 Jan 24. 16(1): 985
    Lysosomes finely control macrophage inflammatory function via regulating the release of lysosomal Fe2+ through TRPML1 channel.
    Yanhong Xing, Meng-Meng Wang, Feifei Zhang, Tianli Xin, Xinyan Wang, Rong Chen, Zhongheng Sui, Yawei Dong, Dongxue Xu, Xingyu Qian, Qixia Lu, Qingqing Li, Weijie Cai, Meiqin Hu, Yuqing Wang, Jun-Li Cao, Derong Cui, Jiansong Qi, Wuyang Wang.
      Lysosomes are best known for their roles in inflammatory responses by engaging in autophagy to remove inflammasomes. Here, we describe an unrecognized role for the lysosome, showing that it finely controls macrophage inflammatory function by manipulating the lysosomal Fe2+-prolyl hydroxylase domain enzymes (PHDs)-NF-κB-interleukin 1 beta (IL1B) transcription pathway that directly links lysosomes with inflammatory responses. TRPML1, a lysosomal cationic channel, is activated secondarily to ROS elevation upon inflammatory stimuli, which in turn suppresses IL1B transcription, thus limiting the excessive production of IL-1β in macrophages. Mechanistically, the suppression of IL1B transcription caused by TRPML1 activation results from its modulation on the release of lysosomal Fe2+, which subsequently activates PHDs. The activated PHDs then represses transcriptional activity of NF-κB, ultimately resulting in suppressed IL1B transcription. More importantly, in vivo stimulation of TRPML1 ameliorates multiple clinical signs of Dextran sulfate sodium-induced colitis in mice, suggesting TRPML1 has potential in treating inflammatory bowel disease.
    DOI:  https://doi.org/10.1038/s41467-025-56403-x
  61. J Adv Res. 2025 Jan 26. pii: S2090-1232(25)00057-8. [Epub ahead of print]
    Actl6a regulates autophagy via Sox2-dependent Atg5 and Atg7 expression to inhibit apoptosis in spinal cord injury.
    Jian Hao, Yubiao Yang, Li Xie, Zhenhan Li, Boyuan Ma, Bitao Wang, Jinyu Chen, Zhi Zeng, Xianhu Zhou.
       INTRODUCTION: Spinal cord injury (SCI) is a severe central nervous system disorder with limited treatment options. While autophagy plays a protective role in neural repair, its regulatory mechanisms in SCI remain unclear. Actin-like protein 6A (Actl6a) influences cell fate and neural development, yet its specific role in SCI repair is not well understood. This study investigates Actl6a's function in regulating autophagy and apoptosis via the transcription factor Sox2 in SCI.
    OBJECTIVES: This study aims to determine if Actl6a promotes neural survival post-SCI by regulating autophagy-related genes Atg5 and Atg7 through Sox2. It also examines how the demethylase Fto modulates Actl6a mRNA stability via m6A methylation.
    METHODS: In vitro experiments were conducted using primary neurons and HT-22 hippocampal cells exposed to hydrogen peroxide (H2O2)-induced oxidative stress. Actl6a expression was manipulated by knockdown or overexpression. For in vivo studies, a rat SCI model was established with AAV-Actl6a injected at the injury site to induce Actl6a overexpression. Autophagy and apoptosis markers were analyzed using immunofluorescence, Western blotting, and qPCR. Additionally, m6A dot blot and RNA immunoprecipitation (RIP) assays were performed to assess Fto's role in regulating Actl6a mRNA methylation and stability.
    RESULTS: Actl6a expression significantly decreased after SCI, resulting in increased apoptosis. Overexpressing Actl6a enhanced autophagy, reduced apoptosis, and improved neurological function in SCI models. Mechanistically, Actl6a and Sox2 collaboratively upregulated Atg5 and Atg7 expression, promoting autophagy. Fto's modulation of Actl6a mRNA stability via m6A demethylation further influenced autophagy and apoptosis.
    CONCLUSION: Actl6a, through interaction with Sox2, plays a critical role in modulating autophagy and reducing apoptosis in SCI, with Fto's m6A modification affecting Actl6a stability. This Fto/Actl6a/Sox2 axis is a promising therapeutic target for SCI repair.
    Keywords:  Atg5; Atg7; Autophagy; Neuron; Sox2; Spinal cord injury
    DOI:  https://doi.org/10.1016/j.jare.2025.01.038
  62. Biochem Biophys Res Commun. 2025 Jan 23. pii: S0006-291X(25)00098-1. [Epub ahead of print]749 151384
    ATG8 in single membranes: Fresh players of endocytosis and acidic organelle quality control in cancer, neurodegeneration, and inflammation.
    Wang B Ben, Apaja M Pirjo.
      Ubiquitin-like autophagy-related gene ATG8 proteins are typically associated with degradative quality control via canonical double-membrane macro-autophagosomes in the cell. ATG8 proteins have now stepped forward in non-canonical pathways in single membrane organelles. The growing interest in non-canonical ATG8 roles has been stimulated by recent links to human conditions, especially in the regulation of inflammation, neurodegeneration and cancers. Here, we summarize the evidence linking non-canonical ATG8s to human pathologies and the quality control of acidic V-ATPase-regulated organelles in the cell.
    Keywords:  Cancer; Endosome; Inflammation; Lysosome; Neurodegeneration; Organelle pH; Ubiquitin; Ubiquitin-like; V-ATPase
    DOI:  https://doi.org/10.1016/j.bbrc.2025.151384
  63. FEBS J. 2025 Jan 31.
    A cellular model of TDP-43 induces phosphorylated TDP-43 aggregation with distinct changes in solubility and autophagy dysregulation.
    Matthew B Dopler, Muhammad I Abeer, Sanaz Arezoumandan, Keyshawn Cox, Tyler L Petersen, Esther H Daniel, Carlton L Cannon, Angelica Bautista, Kennedy D Blancher, Alysia M Bland, Kylie J Bond, Dominque A Davis, Jessica M Francois, Eliana J McCray, Justin M Morgan, Jessica L Pulliam, Zymir A Robinson, Mykia J Taylor, James A Dowell, Nigel J Cairns, Michael A Gitcho.
      Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease that affects neurons in the brain and spinal cord, causing loss of muscle control, and eventually leads to death. Phosphorylated transactive response DNA binding protein-43 (TDP-43) is the major pathological protein in both sporadic and familial ALS, forming cytoplasmic aggregates in over 95% of cases. Of the 10-15% of ALS cases that are familial, mutations in TDP-43 represent about 5% of those with a family history. We have developed an in vitro overexpression model by introducing three familial ALS mutations (A315T, M337V, and S379P) in the TDP-43 (TARDBP) gene which we define as 3X-TDP-43. This overexpression model TDP-43 shows deficits in autophagy flux and colocalization of TDP-43 with stress granules. We also observe a progressive shift of TDP-43 to the cytoplasm in this model. This overexpression model shows a reduction in solubility of phosphorylated TDP-43 from RIPA to urea soluble. Four glycolytic enzymes, phosphoglycerate kinase one (PGK1), aldolase A (ALDOA), enolase 1 (ENO1), and pyruvate dehydrogenase kinase 1 (PDK1) show significant time-dependent decreases in 3X-TDP-43 expressing cells. Shotgun proteomic analysis shows global changes in the importin subunit alpha-1 (KPNA2), heat shock 70 kDa protein 1A (HSPA1A), and protein disulfide-isomerase A3 (PDIA3) expression levels and coimmunoprecipitation reveals that these proteins complex with TDP-43. Overall, these results suggest that the 3X-TDP-43 model may provide new insights into pathophysiology and an avenue for drug screening in vitro for those suffering from ALS and related TDP-43 proteinopathies.
    Keywords:  ALS; TDP‐43; aggregation; autophagy; glycolysis; stress granules
    DOI:  https://doi.org/10.1111/febs.17413
  64. Pharmaceuticals (Basel). 2025 Jan 16. pii: 112. [Epub ahead of print]18(1):
    Dysregulation of Mitochondrial Homeostasis in Cardiovascular Diseases.
    Ricky Patil, Hui Wang, Matthew Kazaleh, Gorav Ailawadi, Morgan Salmon.
      Mitochondria dysfunction plays a central role in the development of vascular diseases as oxidative stress promotes alterations in mitochondrial morphology and function that contribute to disease progression. Redox imbalances can affect normal cellular processes including mitochondrial biogenesis, electrochemical equilibrium, and the regulation of mitochondrial DNA. In this review, we will discuss these imbalances and, in particular, the potential role of mitochondrial fusion, fission, biogenesis, and mitophagy in the context of vascular diseases and how the dysregulation of normal function might contribute to disease progression. We will also discuss potential implications of targeting mitochondrial regulation as therapeutic targets to treat vascular disease formation.
    Keywords:  B-aminopropionitrile; aorta; aortic aneurysm; cardiac surgery; elastase; inflammation; mitochondria; murine model
    DOI:  https://doi.org/10.3390/ph18010112
  65. Autophagy. 2025 Jan 29.
    Limiting cap-dependent translation increases 20S proteasomal degradation and protects the proteomic integrity in autophagy-deficient skeletal muscle.
    Han Dong, Yifan Lyu, Chien-Yung Huang, Shih-Yin Tsai.
      Postmitotic skeletal muscle critically depends on tightly regulated protein degradation to maintain proteomic stability. Impaired macroautophagy/autophagy-lysosomal or ubiquitin-proteasomal protein degradation causes the accumulation of damaged proteins, ultimately accelerating muscle dysfunction with age. While in vitro studies have demonstrated the complementary nature of these systems, their interplay at the organism levels remains poorly understood. Here, our study reveals novel insights into this complex relationship in autophagy-deficient skeletal muscle. We demonstrated that despite a compensatory increase in proteasome level in response to autophagy impairment, 26S proteasome activity was not proportionally enhanced in autophagy-deficient skeletal muscle. This functional deficit was partly attributed to reduced ATP levels to fuel the 26S proteasome. Remarkably, we found that activation of EIF4EBP1, a crucial inhibitor of cap-dependent translation, restored and even augmented proteasomal function through dual mechanisms. First, genetically activating EIF4EBP1 enhanced both ATP-dependent 26S proteasome and ATP-independent 20S proteasome activities, thereby expanding overall protein degradation capacity. Second, EIF4EBP1 activation caused muscle fiber transformation and increased mitochondrial biogenesis, thus replenishing ATP levels for 26S proteasome activation. Notably, the improved performance of the 20S proteasome in EIF4EBP1-activated skeletal muscle was attributed to an increased abundance of the immunoproteasome, a subtype specially adapted to function under oxidative stress conditions. This dual action of EIF4EBP1 activation preserved proteomic integrity in autophagy-deficient skeletal muscle. Our findings uncover a novel role of EIF4EBP1 in improving protein quality control, presenting a promising therapeutic strategy for autophagy-related muscular disorders and potentially other conditions characterized by proteostatic imbalance.
    Keywords:  Autophagy; immunoproteasome; proteasome; protein quality control; skeletal muscle; translation
    DOI:  https://doi.org/10.1080/15548627.2025.2457925
  66. Aging Cell. 2025 Jan 30. e14501
    CAV1 Exacerbates Renal Tubular Epithelial Cell Senescence by Suppressing CaMKK2/AMPK-Mediated Autophagy.
    Liya Sun, Lujun Xu, Tongyue Duan, Yiyun Xi, Zebin Deng, Shilu Luo, Chongbin Liu, Chen Yang, Huafeng Liu, Lin Sun.
      Renal proximal tubular epithelial cell (PTEC) senescence and defective autophagy contribute to kidney aging, but the mechanisms remain unclear. Caveolin-1 (CAV1), a crucial component of cell membrane caveolae, regulates autophagy and is associated with cellular senescence. However, its specific role in kidney aging is poorly understood. In this study, we generated Cav1 gene knockout mice and induced kidney aging using D-galactose (D-gal). The results showed that CAV1 expression increased in the renal cortex of the aging mice, which was accompanied by exacerbated renal interstitial fibrosis, elevated levels of senescence-associated proteins γH2AX and p16INK4a, and increased β-galactosidase activity. Moreover, autophagy and AMPK phosphorylation in PTECs were reduced. These phenotypes were partially reversed in D-gal-induced Cav1 knockout mice. Similar results were observed in D-gal-induced human proximal tubular epithelial (HK-2) cells, but these effects were blocked when AMPK activation was inhibited. Additionally, in CaMKK2 knockdown HK-2 cells, siCAV1 failed to promote AMPK phosphorylation, whereas this effect persisted when STK11 was knocked down. Besides, we examined the phosphorylation of CaMKK2 and found that siCAV1 increased its activity. Given that CaMKK2 activity is affected by intracellular Ca2+, we examined Ca2+ levels in HK-2 cells and found that D-gal treatment reduced intracellular Ca2+ concentration, but CAV1 knockdown did not alter these levels. Through GST pull-down assays, we demonstrated a direct interaction between CAV1 and CaMKK2. In conclusion, these findings suggest that CAV1 exacerbates renal tubular epithelial cell senescence by directly interacting with CaMKK2, suppressing its activity and AMPK-mediated autophagy via a Ca2+-independent pathway.
    Keywords:   AMPK ; CAV1 ; CaMKK2 ; Autophagy; Kidney Aging; Renal Tubular Epithelial Cell
    DOI:  https://doi.org/10.1111/acel.14501
  67. Clin Immunol. 2025 Jan 28. pii: S1521-6616(25)00017-8. [Epub ahead of print] 110442
    NLRX1 deficiency exacerbates skin inflammation in atopic dermatitis by disrupting mitophagy.
    Lixin Yue, Pei Qiao, Xia Li, Ke Xue, Bingyu Pang, Yaxing Bai, Pu Song, Huanhuan Qu, Hongjiang Qiao, Danni Sun, Xingan Wu, Rongrong Liu, Gang Wang, Erle Dang.
      NLRX1 is an important regulator of inflammatory signaling in innate immune cells. Recent studies indicate NLRX1 activation may be a novel mechanism for inflammatory diseases, however, it has not been explored in atopic dermatitis (AD). Our study aims to investigate the potential role of NLRX1 in the pathogenesis of AD. We observed a significant decrease in NLRX1 expression in AD skin lesions and MC903-indued AD dermatitis. NLRX1 deficiency exacerbated AD inflammation, characterized by increased skin thickness, exacerbated inflammatory infiltration, and compromised skin barrier function. Mechanistically, NLRX1 regulated TSLP expression through Parkin-PINK1-mediated mitophagy in keratinocytes. Furthermore, topical application of NLRX1 agonist alleviated AD progression, including reduced ear thickness, diminished redness, and improved skin barrier function. This study provides novel insights into the regulatory role of NLRX1 in skin inflammation in AD, highlighting the potential therapeutic implications of targeting NLRX1 and mitophagy in AD treatment.
    Keywords:  Atopic dermatitis; Inflammation; Keratinocytes; Mitophagy; NLRX1; Skin
    DOI:  https://doi.org/10.1016/j.clim.2025.110442
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