bims-auttor Biomed News
on Autophagy and mTOR
Issue of 2025–01–19
fifty-nine papers selected by
Viktor Korolchuk, Newcastle University
  1. Mechanisms of autophagosome formation.
  2. Protocol for microinjection of rapamycin into the zebrafish habenula.
  3. mTORC1 regulates the pyrimidine salvage pathway by controlling UCK2 turnover via the CTLH-WDR26 E3 ligase.
  4. Dopamine degrades ferritin by chaperone-mediated autophagy to elevate mitochondrial iron level in astroglial cells.
  5. TBC1D15 Inhibits Autophagy of Microglia through Maintaining the Damaged Swelling Lysosome in Alzheimer's Disease.
  6. The interconnective role of the UPS and autophagy in the quality control of cancer mitochondria.
  7. The ER protein CANX (calnexin)-mediated autophagy protects against alzheimer disease.
  8. Tracking Chaperone-Mediated Autophagy Flux with a pH-Resistant Fluorescent Reporter.
  9. The Critical Role of Autophagy and Phagocytosis in the Aging Brain.
  10. NR1D1 Inhibition Enhances Autophagy and Mitophagy in Alzheimer's Disease Models.
  11. mTOR signalling controls protein aggregation during heat stress and cellular aging in a translation- and Hsf1-independent manner.
  12. TSC complex decrease the expression of mTOR by regulated miR-199b-3p.
  13. Fasting activates optineurin-mediated mitophagy in chondrocytes to protect against osteoarthritis.
  14. Activation of TFEB protects against diabetic vascular calcification by improving autophagic flux and activating Nrf2 antioxidant system.
  15. Presenilins as hub proteins controlling the endocytic and autophagic pathways and small extracellular vesicle secretion.
  16. Autophagy in brain tumors: molecular mechanisms, challenges, and therapeutic opportunities.
  17. Structure of the human autophagy factor EPG5 and the molecular basis of its conserved mode of interaction with Atg8-family proteins.
  18. Focus on the Forgotten Organelle: Regulation of Lysosomes in Skeletal Muscle.
  19. Mechanisms coupling the mTOR pathway to chronic obstructive pulmonary disease (COPD) pathogenesis.
  20. A STING-CASM-GABARAP pathway activates LRRK2 at lysosomes.
  21. TFEB activator protects against ethanol toxicity-induced cardiac injury by restoring mitophagy and autophagic flux.
  22. Pym-18a, a novel pyrimidine derivative ameliorates glucocorticoid induced osteoblast apoptosis and promotes osteogenesis via autophagy and PINK 1/Parkin mediated mitophagy induction.
  23. Histone demethylases in autophagy and inflammation.
  24. Survival strategies of cancer cells: the role of macropinocytosis in nutrient acquisition, metabolic reprogramming, and therapeutic targeting.
  25. The anti-senescence effect of D-β-hydroxybutyrate in Hutchinson-Gilford progeria syndrome involves progerin clearance by the activation of the AMPK-mTOR-autophagy pathway.
  26. V-ATPase Disassembly at the Yeast Lysosome-Like Vacuole Is a Phenotypic Driver of Lysosome Dysfunction in Replicative Aging.
  27. Non-Structural Protein V of Canine Distemper Virus Induces Autophagy via PI3K/AKT/mTOR Pathway to Facilitate Viral Replication.
  28. Alcohol dehydrogenase 1 acts as a scaffold protein in mitophagy essential for fungal pathogen adaptation to hypoxic niches within hosts.
  29. Deletion of BMP4 impairs trophoblast function and decidual macrophage polarization via autophagy leading to recurrent spontaneous abortion.
  30. Bipolar and schizophrenia risk gene AKAP11 encodes an autophagy receptor coupling the regulation of PKA kinase network homeostasis to synaptic transmission.
  31. Research Advances in Chaperone-Mediated Autophagy (CMA) and CMA-Based Protein Degraders.
  32. Engineered hypoxia-responsive albumin nanoparticles mediating mitophagy regulation for cancer therapy.
  33. Mechanistic Target of Rapamycin Signaling Activity in the Human Placenta Across Gestation and in Maternal Obesity.
  34. Targeting mitophagy in neurodegenerative diseases.
  35. Autophagy regulator ATG5 preserves cerebellar function by safeguarding its glycolytic activity.
  36. ZFAND6 promotes TRAF2-dependent mitophagy to restrain cGAS-STING signaling.
  37. Accumulation of autophagosomes in aging human photoreceptor cell synapses.
  38. A Small-Molecule Drug for the Self-Checking of Mitophagy.
  39. USP1 promotes pancreatic cancer progression and autophagy by deubiquitinating ATG14.
  40. Transcription factor EB (TFEB) activity increases resistance of TNBC stem cells to metabolic stress.
  41. Intercellular communication is crucial in the regulation of healthy aging via exosomes.
  42. Rapamycin protects glucocorticoid-induced glaucoma model mice against trabecular meshwork fibrosis by suppressing mTORC1/2 signaling.
  43. Apelin-13 inhibits ischemia-reperfusion mediated podocyte apoptosis by reducing m-TOR phosphorylation to enhance autophagy.
  44. FOXG1 promotes osteogenesis of bone marrow-derived mesenchymal stem cells by activating autophagy through regulating USP14.
  45. Beyond Redox Regulation: Novel Roles of TXNIP in the Pathogenesis and Therapeutic Targeting of Kidney Disease.
  46. Engineering Covalent Aptamer Chimeras for Enhanced Autophagic Degradation of Membrane Proteins.
  47. Unifying biology of neurodegeneration in lysosomal storage diseases.
  48. RNF128 deficiency in macrophages promotes colonic inflammation by suppressing the autophagic degradation of S100A8.
  49. Deciphering the role of TMEM164 in autophagy-mediated ferroptosis and immune modulation in non-small cell lung cancer.
  50. SIRT1/PGC-1α-mediated mitophagy participates the improvement roles of BMAL1 in podocytes injury in diabetic nephropathy: evidences from in vitro experiments.
  51. Noncanonical PI(4,5)P2 coordinates lysosome positioning through cholesterol trafficking.
  52. β-Catenin/c-Myc Axis Modulates Autophagy Response to Different Ammonia Concentrations.
  53. M6A Demethyltransferase FTO Attenuates Meniscus Degeneration and Osteoarthritis via Orchestrating Autophagy and Energetic Metabolism.
  54. Mitochondrial Electron Flow Dynamics Imaging for Assessing Mitochondrial Quality and Drug Screening.
  55. Circulating autophagy regulator Rubicon is linked to increased myocardial infarction risk.
  56. Vaccinia growth factor-dependent modulation of the mTORC1-CAD axis upon nutrient restriction.
  57. Autophagy-Mediated Downregulation of AXL and TIM-1 Promotes Sustained Zika Virus Infection.
  58. Autophagy related 7 (ATG7) regulates food intake and liver health during asparaginase exposure.
  59. Administration of AICAR, an AMPK Activator, Prevents and Reverses Diabetic Polyneuropathy (DPN) by Regulating Mitophagy.
  1. Proc Jpn Acad Ser B Phys Biol Sci. 2025 ;101(1): 32-40
    Mechanisms of autophagosome formation.
    Yuko Fujioka, Nobuo N Noda.
      The formation of autophagosomes is a pivotal step in autophagy, a lysosomal degradation system that plays a crucial role in maintaining cellular homeostasis. After autophagy induction, phase separation of the autophagy-related (Atg) 1 complex occurs, facilitating the gathering of Atg proteins and organizes the autophagosome formation site, where the initial isolation membrane (IM)/phagophore is generated. The IM then expands after receiving phospholipids from endomembranes such as the endoplasmic reticulum. This process is driven by the collaboration of lipid transfer (Atg2) and scrambling (Atg9) proteins. The IM assumes a cup shaped morphology and undergoes closure, resulting in the formation of a double membrane-bound autophagosome. The Atg8 lipidation system is hypothesized to be a pivotal factor in this process. This review presents an overview of the current understanding of these processes and discusses the basic mechanisms of autophagosome formation.
    Keywords:  autophagosome; autophagy; lipid scramblase; lipid transfer protein; phase separation; ubiquitin-like protein
    DOI:  https://doi.org/10.2183/pjab.101.005
  2. STAR Protoc. 2025 Jan 11. pii: S2666-1667(24)00731-7. [Epub ahead of print]6(1): 103566
    Protocol for microinjection of rapamycin into the zebrafish habenula.
    Olga Doszyn, Tomasz Dulski, Justyna Zmorzynska.
      Mechanistic target of rapamycin complex 1 (mTorC1) activity plays a crucial role in brain development. Here, we present an approach for rapamycin microinjection into the habenula of larval zebrafish to achieve localized inhibition of the mTorC1 pathway and explore the role of mTorC1 in habenula function. We describe steps for performing microinjections and maintaining zebrafish larvae before and after the procedure. For complete details on the use and execution of this protocol, please refer to Doszyn et al.1.
    Keywords:  Developmental biology; Model Organisms; Neuroscience
    DOI:  https://doi.org/10.1016/j.xpro.2024.103566
  3. Cell Rep. 2025 Jan 13. pii: S2211-1247(24)01530-4. [Epub ahead of print]44(1): 115179
    mTORC1 regulates the pyrimidine salvage pathway by controlling UCK2 turnover via the CTLH-WDR26 E3 ligase.
    Brittany Q Pham, Sang Ah Yi, Alban Ordureau, Heeseon An.
      One critical aspect of cell proliferation is increased nucleotide synthesis, including pyrimidines. Pyrimidines are synthesized through de novo and salvage pathways. Prior studies established that the mammalian target of rapamycin complex 1 (mTORC1) promotes pyrimidine synthesis by activating the de novo pathway for cell proliferation. However, the involvement of mTORC1 in regulating the salvage pathway remains unclear. Here, we report that mTORC1 controls the half-life of uridine cytidine kinase 2 (UCK2), the rate-limiting enzyme in the salvage pathway. Specifically, UCK2 is degraded via the CTLH-WDR26 E3 complex during mTORC1 inhibition, which is prevented when mTORC1 is active. We also find that UCK1, an isoform of UCK2, affects the turnover of UCK2 by influencing its cellular localization. Importantly, altered UCK2 levels through the mTORC1-CTLH E3 pathway affect pyrimidine salvage and the efficacy of pyrimidine analog prodrugs. Therefore, mTORC1-CTLH E3-mediated degradation of UCK2 adds another layer of complexity to mTORC1's role in regulating pyrimidine metabolism.
    Keywords:  CP: Metabolism; CP: Molecular biology; CTLH; UCK2; WDR26; YPEL5; degradomics; mTOR; mTORC1; pyrimidine; pyrimidine salvage; ubiquitin
    DOI:  https://doi.org/10.1016/j.celrep.2024.115179
  4. Free Radic Biol Med. 2025 Jan 14. pii: S0891-5849(25)00021-8. [Epub ahead of print]
    Dopamine degrades ferritin by chaperone-mediated autophagy to elevate mitochondrial iron level in astroglial cells.
    Som Dev, Somya Asthana, Pratibha Singh, Pankaj Seth, Chayanika Banerjee, Chinmay K Mukhopadhyay.
      Iron accumulation and mitochondrial dysfunction in astroglia are reported in Parkinson's disease (PD). Astroglia control iron availability in neurons in which dopamine (DA) synthesis is affected in PD. Despite their intimate relationship the role of DA in astroglial iron homeostasis is limited. Here we show that DA degrades iron storage protein ferritin in astroglial cells involving lysosomal proteolysis. Lysosomal ferritinophagy is mainly associated with macroautophagy; however, we revealed the involvement of chaperone-mediated autophagy (CMA) in DA-induced ferritin degradation. In CMA, cytosolic proteins containing a specific pentapeptide motif bind with HSC70 to be transported to lysosome mediated by LAMP2A. We identified the conserved pentapeptide motif in ferritin-H (Ft-H), mutations of which resulted loss of its interaction with HSC70. Pharmacological inhibitors of HSC70 or LAMP2/2A knockdown blocks DA-induced Ft-H degradation. DA also induces cytosolic cargo NCOA4 for ferritinophagy. We further reveal that DA promotes cathepsin B to lysis ferritin within the lysosome. Inhibitor of cathepsin B, knocking down of LAMP2, or HSC70 inhibitor attenuate DA-induced elevated mitochondrial iron level. Our results establish a direct role of DA on astroglial iron homeostasis and novel involvement of CMA in ferritin degradation in response to a biological stimulus. These results also may help in better understanding iron dyshomeostasis and mitochondrial dysfunction reported in PD.
    Keywords:  Dopamine; NCOA4; astroglia; cathepsin B; chaperone-mediated autophagy; ferritin; mitochondrial iron
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.01.021
  5. Aging Dis. 2025 Jan 09.
    TBC1D15 Inhibits Autophagy of Microglia through Maintaining the Damaged Swelling Lysosome in Alzheimer's Disease.
    You Wu, Yong-Ming Zhou, Wei Wu, Wan-Rong Jiang, Xin-Yuan Zhang, Si-Yuan Song, Zhao-Hui Yao.
      Autophagy in microglia is essential for the clearance of amyloid-beta (Aβ) and amyloid plaques in Alzheimer's disease. However, reports regarding the levels of autophagy in microglia have been inconsistent; some studies indicate an early enhancement followed by a subsequent reduction, while others describe a persistently weakened state. Notably, there is a lack of systematic studies documenting the temporal changes in microglial autophagy. TBC1D15, a Rab GTPase, plays a crucial role in lysosomal membrane repair, yet its function in regulating microglial autophagy in Alzheimer's disease remains unexplored. Current research suggests that microglial autophagy is activated in 3-month-old AD mice but gradually decreases by 12 months of age. Furthermore, TBC1D15 levels are significantly elevated in the lysosomes of microglia in Alzheimer's disease. Silencing TBC1D15 markedly inhibits swelling and Aβ phagocytosis in BV2 cells following Aβ treatment while simultaneously promoting autophagy and lysophagy. LIMP II/ATG8-TBC1D15-Dynamin2/RAB7 might participate in lysosome swelling of microglia in AD. These findings indicate that TBC1D15 in microglia is critical for the decline of autophagy in Alzheimer's disease. It is suggested that targeting microglial TBC1D15 may be an important strategy for enhancing autophagy, which facilitates the clearance of amyloid plaques as a therapeutic approach for Alzheimer's disease.
    DOI:  https://doi.org/10.14336/AD.2024.1373
  6. Cell Mol Life Sci. 2025 Jan 12. 82(1): 42
    The interconnective role of the UPS and autophagy in the quality control of cancer mitochondria.
    Wanting Xu, Lei Dong, Ji Dai, Lu Zhong, Xiao Ouyang, Jiaqian Li, Gaoqing Feng, Huahua Wang, Xuan Liu, Liying Zhou, Qin Xia.
      Uncontrollable cancer cell growth is characterized by the maintenance of cellular homeostasis through the continuous accumulation of misfolded proteins and damaged organelles. This review delineates the roles of two complementary and synergistic degradation systems, the ubiquitin-proteasome system (UPS) and the autophagy-lysosome system, in the degradation of misfolded proteins and damaged organelles for intracellular recycling. We emphasize the interconnected decision-making processes of degradation systems in maintaining cellular homeostasis, such as the biophysical state of substrates, receptor oligomerization potentials (e.g., p62), and compartmentalization capacities (e.g., membrane structures). Mitochondria, the cellular hubs for respiration and metabolism, are implicated in tumorigenesis. In the subsequent sections, we thoroughly examine the mechanisms of mitochondrial quality control (MQC) in preserving mitochondrial homeostasis in human cells. Notably, we explored the relationships between mitochondrial dynamics (fusion and fission) and various MQC processes-including the UPS, mitochondrial proteases, and mitophagy-in the context of mitochondrial repair and degradation pathways. Finally, we assessed the potential of targeting MQC (including UPS, mitochondrial molecular chaperones, mitochondrial proteases, mitochondrial dynamics, mitophagy and mitochondrial biogenesis) as cancer therapeutic strategies. Understanding the mechanisms underlying mitochondrial homeostasis may offer novel insights for future cancer therapies.
    Keywords:  Autophagy-lysosome; Cancer therapy; Mitochondrial chaperones; Mitochondrial proteases; Mitophagy; Protein quality control; UPS
    DOI:  https://doi.org/10.1007/s00018-024-05556-x
  7. Autophagy. 2025 Jan 15. 1-20
    The ER protein CANX (calnexin)-mediated autophagy protects against alzheimer disease.
    Hongtao Shen, Yuying Xie, Yan Wang, Yusheng Xie, Yongxiang Wang, Zhenyan Su, Laixi Zhao, Shi Yao, Xiaoling Cao, Jinglan Liang, Junrui Long, Rimei Zhong, Jinfeng Tang, Sijie Wang, Liangqing Zhang, Xiaojing Wang, Björn Stork, Lili Cui, Wenxian Wu.
      Although the relationship between macroautophagy/autophagy and Alzheimer disease (AD) is widely studied, the underlying mechanisms are poorly understood, especially the regulatory role of the initiation signaling of autophagy on AD. Here, we find that the ER transmembrane protein CANX (calnexin) is a novel interaction partner of the autophagy-inducing kinase ULK1 and is required for ULK1 recruitment to the ER under basal or starved conditions. Loss of CANX results in the inactivity of ULK1 kinase and inhibits autophagy flux. In the brains of people with AD and APP-PSEN1 mice, the interaction of CANX and ULK1 declines. In mice, the lack of CANX in hippocampal neurons causes the accumulation of autophagy receptors and neuron damage, which affects the cognitive function of C57BL/6 mice. Conversely, overexpression of CANX in hippocampal neurons enhances autophagy flux and partially contributes to improving cognitive function of APP-PSEN1 mice, but not the CANX variant lacking the interaction domain with ULK1. These findings reveal a novel role of CANX in autophagy activity and cognitive function by cooperating with ULK1.Abbreviation: AD: Alzheimer disease; APEX: ascorbate peroxidase; APP: amyloid beta precursor protein; APP-PSEN1 mice: amyloid beta precursor protein-presenilin 1 transgenic mice; ATG: autophagy related; Aβ: amyloid-β; BiFC: bimolecular fluorescence complementation; CANX: calnexin; EBSS: Earle's balanced salt solution; EM: electron microscopy; IP: immunopurification; KO: knockout; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MWM: Morris water maze; PLA: proximity ligation assay; PtdIns3K: class III phosphatidylinositol 3-kinase; PtdIns3P: phosphatidylinositol-3-phosphate; SQSTM1/p62, sequestosome 1.
    Keywords:  Alzheimer disease; ER; ULK1; autophagy initiation; calnexin
    DOI:  https://doi.org/10.1080/15548627.2024.2447206
  8. Int J Mol Sci. 2024 Dec 24. pii: 17. [Epub ahead of print]26(1):
    Tracking Chaperone-Mediated Autophagy Flux with a pH-Resistant Fluorescent Reporter.
    Ruotong Qi, Xingyi Chen, Zihan Li, Zheng Wang, Zhuohui Xiao, Xinyue Li, Yuanyuan Han, Hongfei Zheng, Yanjun Wu, Yi Xu.
      Chaperone-mediated autophagy (CMA) is a selective autophagic pathway responsible for degrading cytoplasmic proteins within lysosomes. Monitoring CMA flux is essential for understanding its functions and molecular mechanisms but remains technically complex and challenging. In this study, we developed a pH-resistant probe, KFERQ-Gamillus, by screening various green fluorescent proteins. This probe is activated under conditions known to induce CMA, such as serum starvation, and relies on LAMP2A and the KFERQ motif for lysosomal localization and degradation, demonstrating its specificity for the CMA pathway. It enables the detection of CMA activity in living cells through both microscopy and image-based flow cytometry. Additionally, we created a dual-reporter system, KFERQ-Gamillus-Halo, by integrating KFERQ-Gamillus with the Halo-tag system. This probe not only distinguishes between protein synthesis and degradation but also facilitates the detection of intracellular CMA flux via immunoblotting and the rapid assessment of CMA activity using flow cytometry. Together, the KFERQ-Gamillus-Halo probe provides quantitative and time-resolved monitoring for CMA activity and flux in living cells. This tool holds promising potential for high-throughput screening and biomedical research related to CMA.
    Keywords:  Gamillus; chaperone-mediated autophagy; flux; halo
    DOI:  https://doi.org/10.3390/ijms26010017
  9. Int J Mol Sci. 2024 Dec 25. pii: 57. [Epub ahead of print]26(1):
    The Critical Role of Autophagy and Phagocytosis in the Aging Brain.
    Stephen C Bondy, Meixia Wu.
      As the organism ages, there is a decline in effective energy supply, and this retards the ability to elaborate new proteins. The consequences of this are especially marked in the gradual decline in brain function. The senescence of cells and their constituent organelles is ultimately the cause of aging of the entire nervous system. What is less immediately obvious is that brain aging is also accompanied by the failure of catabolic events that lead to the removal of non-functional cells and ineffective subcellular components. The removal of non-working cellular and subcellular elements within the brain is essential in order to allow the appearance of fresh cells and organelles with a full range of capacities. Thus, the maintenance of operative mechanisms for the dispersal of failed tissue components is important, and its diminished capacity with aging is a significant contributory factor to the onset and progression of age-related neurological disorder. This report discusses the mechanisms underlying autophagy and phagocytosis and how these can be adversely modulated as aging proceeds. The means by which the effective recycling of cellular components may be reinstated in the aged brain are considered.
    Keywords:  autophagy; brain aging; mitophagy; neurodegeneration; phagocytosis
    DOI:  https://doi.org/10.3390/ijms26010057
  10. Aging Dis. 2025 Jan 14.
    NR1D1 Inhibition Enhances Autophagy and Mitophagy in Alzheimer's Disease Models.
    Shi-Qi Zhang, Zhangming Niu, Alexander Anisimov, Fang Shi, Shenglong Deng, Xianglu Xiao, Shu-Qin Cao, Jun-Ping Pan, He-Ling Wang, Maria J Lagartos-Donate, Nihal Gullu Bozbas, Ping-Jie Wang, Ruixue Ai, Yan Li, Guang Yang, Sofie Lautrup, Evandro F Fang.
      Alzheimer's disease (AD) is marked by extracellular beta-amyloid (Aβ) plaques and intracellular Tau tangles, leading to progressive cognitive decline and neuronal dysfunction. Impaired autophagy, a process by which a cell breaks down and destroys damaged or abnormal proteins and other substances, contributes to AD progression. This study investigated Nuclear Receptor Subfamily 1 Group D Member 1 (NR1D1) as a potential therapeutic target for modulating autophagy. We show that NR1D1 depletion significantly enhances autophagic flux and mitophagy in human cell lines as well as wildtype and AD Caenorhabditis elegans (C. elegans) models. Our findings revealed that NR1D1 knockdown increased autophagy markers and activated the proteins Sirtuin 1 (SIRT1) and CTSB cathepsin B (Cathepsin B), both linked to autophagy function. In 5 familial AD mutations (5xFAD) mice, Nr1d1 knockdown restored the expression level of autophagy markers. C. elegans experiments revealed that depletion of the worm ortholog of NR1D1, nhr-85, improved neuronal mitophagy, enhanced associative memory in amyloid-β models, and extended lifespan. These findings suggest NR1D1 as a promising therapeutic target for improving cellular autophagy mechanisms in AD.
    DOI:  https://doi.org/10.14336/AD.2024.1654
  11. J Biol Chem. 2025 Jan 09. pii: S0021-9258(25)00019-5. [Epub ahead of print] 108172
    mTOR signalling controls protein aggregation during heat stress and cellular aging in a translation- and Hsf1-independent manner.
    Arthur Fischbach, Per O Widlund, Xinxin Hao, Thomas Nyström.
      The mTOR (mechanistic target of rapamycin) signaling pathway appears central to the aging process as genetic or pharmacological inhibition of mTOR extends lifespan in most eukaryotes tested. While the regulation of protein synthesis by mTOR has been studied in great detail, its impact on protein misfolding and aggregation during stress and aging is less explored. In this study, we identified the mTOR signaling pathway and the linked SEA complex as central nodes of protein aggregation during heat stress and cellular aging, using Saccharomyces cerevisiae as a model organism. Based on a synthetic genetic array (SGA) screen, we found that reduced mTOR activity, achieved through deletion of TCO89, an mTORC1 subunit, almost completely prevents protein aggregation during heat stress and aging without reducing global translation rates and independently of an Hsf1-dependent stress response. Conversely, increased mTOR activity, achieved through deletion of NPR3, a SEA complex subunit, exacerbates protein aggregation, but not by over-activating translation. In summary, our work demonstrates that mTOR signaling is a central contributor to age-associated and heat shock-induced protein aggregation and that this is unlinked to quantitatively discernable effects on translation and Hsf1.
    Keywords:  Aging; mTOR; protein aggregation; proteinopathy; proteostasis; spatial protein quality control
    DOI:  https://doi.org/10.1016/j.jbc.2025.108172
  12. Sci Rep. 2025 Jan 13. 15(1): 1892
    TSC complex decrease the expression of mTOR by regulated miR-199b-3p.
    Na Zhao, Qiuhong Xiong, Ping Li, Guangxin Chen, Han Xiao, Changxin Wu.
      The TSC complex formed by TSC1 and TSC2 is the most important upstream negative regulator of mTORC1. Genetic variations in either TSC1 or TSC2 cause tuberous sclerosis complex (TSC) disease which is a rare autosomal dominant disorder resulting in impairment of multiple organ systems. In this study, besides a reported variation, c.2509_2512del (p.Asn837Valfs*11, p.N837fs) in TSC1, we found a de novo TSC2 variation c.1113delG (p.Gln371Hisfs*18, p.Q371fs), which these two mutation influence the formation of TSC complex. We found that the decrease of TSC complex with the appearance of the decreased miR-199b-3p expression. At the same time, the reduction of miR-199b-3p increased the expression of mTOR and the activation of mTORC1 and mTORC2, the additional miR-199b-3p caused the decrease the expression of mTOR and the activation of mTORC1 and mTORC2. In brief, our results may illustrate a novel mechanism of TSC caused by variations in either TSC1 or TSC2, and a new mTOR expression regulator, miR-199b-3p.
    Keywords:  MTOR; MiR-199b-3p; TSC; TSC1; TSC2
    DOI:  https://doi.org/10.1038/s41598-025-85706-8
  13. Commun Biol. 2025 Jan 16. 8(1): 68
    Fasting activates optineurin-mediated mitophagy in chondrocytes to protect against osteoarthritis.
    Min-Na Zhang, Ran Duan, Gui-Hong Chen, Mei-Jun Chen, Chun-Gu Hong, Xin Wang, Zhi-Lin Pang, Chun-Yuan Chen, Hua-Feng Liu, Da Zhong, Hui Xie, Wen-Bao Hu, Zheng-Zhao Liu.
      Mitochondrial homeostasis plays a crucial role in the pathogenesis of osteoarthritis (OA), a chronic musculoskeletal disorder characterized by articular cartilage degeneration and chondrocyte apoptosis. However, molecular mechanisms underlying the association between mitophagy and OA remain unclear. Here, we aimed to investigate the role of the autophagy receptor protein optineurin (OPTN) in OA, and explore the effects of dietary intervention on OA symptoms and its relationship with OPTN-mediated mitophagy. Our findings showed the downregulation of OPTN in patients with OA. Using an Optn-knockout mouse model, we demonstrated that OPTN deficiency leads to impaired mitophagy, resulting in the accumulation of damaged mitochondria, increased production of reactive oxygen species, and chondrocyte apoptosis. Furthermore, fasting prevented OA progression by activating OPTN-mediated mitophagy and maintaining mitochondrial homeostasis in mice. The present study revealed a novel mechanism by which OPTN-mediated mitophagy influences chondrocytes and the OA phenotype in Optn-knockout mice, suggesting that OPTN-mediated mitophagy plays a crucial role in OA development and progression. This study provides new insights into the pathogenesis of OA and offers a potential avenue for the development of novel drugs targeting OPTN to mitigate OA progression.
    DOI:  https://doi.org/10.1038/s42003-025-07541-x
  14. Am J Physiol Endocrinol Metab. 2025 Jan 13.
    Activation of TFEB protects against diabetic vascular calcification by improving autophagic flux and activating Nrf2 antioxidant system.
    Xue-Jiao Sun, Sheng-Jue Xiao, Wen-Qi Ma, Hong Jin, Li-Qun Ren, Yu-Yu Yao, Zheng-Dong Chen, Xiao-Xue Li, Tian Chen, Nai-Feng Liu.
      Autophagic flux blockade and excessive oxidative stress play important roles in the pathogenesis of diabetic vascular calcification (VC). Transcription factor EB (TFEB) is an important regulator of many autophagy-lysosomal related components, which is mainly involved in promoting autophagy process in cells. Nuclear factor erythroid-2 related factor 2 (Nrf2) antioxidant system is considered as one of the key pathways in response to intracellular oxidative stress. Periostin (POSTN), a matrix protein, is widely involved in regulating the formation and maintenance of organs such as bones, teeth, heart valves, and tendons. We have previously reported that POSTN interfered with autophagic flux in an oxidative stress-dependent manner in vascular smooth muscle cells (VSMCs) to aggravate the development of diabetic VC. However, how POSTN interfered with autophagic flux by regulating oxidative stress has not been clarified. This study aims to further explore the roles of TFEB, POSTN, autophagy and Nrf2 antioxidant system in the development of diabetic VC. Our experimental results revealed that activation of TFEB attenuated diabetic VC by improving autophagic flux and activating Nrf2 antioxidant system, while POSTN reduced the autophagic degradation of KEAP1 by inhibiting lysosomal function, thus inhibiting the activation of the Nrf2 antioxidant system, and ultimately abolishing the protective effect of TFEB against diabetic VC. In conclusion, this study uncovers that TFEB play an important role in alleviating diabetic VC by improving autophagic flux and activating Nrf2 antioxidant system, suggesting that TFEB may be a new target for the prevention and treatment of diabetic VC.
    Keywords:  Nrf2; POSTN; TFEB; autophagy; diabetic vascular calcification
    DOI:  https://doi.org/10.1152/ajpendo.00161.2023
  15. J Extracell Vesicles. 2025 Jan;14(1): e70019
    Presenilins as hub proteins controlling the endocytic and autophagic pathways and small extracellular vesicle secretion.
    Inger Lauritzen, Anaïs Bini, Anaïs Bécot, Anne-Sophie Gay, Céline Badot, Sophie Pagnotta, Mounia Chami, Frédéric Checler.
      Emerging evidence indicates that autophagy is tightly connected to the endocytic pathway. Here, we questioned the role of presenilins (PSENs 1 and 2), previously shown to be involved in autophagy regulation, in the secretion of small endocytic-originating extracellular vesicles known as exosomes. Indeed, while wild-type cells responded to stimuli promoting both multivesicular endosome (MVE) formation and secretion of small extracellular vesicles (sEVs) enriched in canonical exosomal proteins, PSEN-deficient cells were almost unaffected to these stimuli. Moreover, in PSEN-deficient cells, the re-expression of either PSEN1 or the functional active PSEN1delta9 mutant led to a rescue of most sEV secretion, while the deletion of PSEN1 alone almost fully phenocopied total PSEN invalidation. We found that the lack of sEV secretion in PSEN-deficient cells was also due to overactivated autophagy promoting MVEs to degradation rather than to plasma membrane fusion. Hence, in these cells, the autophagic blocker bafilomycin A1 (BafA1) not only increased the intracellular levels of the MVE protein CD63, but also turned on sEV secretion by stimulating autophagy-dependent unconventional secretion. In that case, sEVs arised from amphisomes and were enriched in both canonical exosomal proteins and lysosomal-autophagy-associated cargo. Altogether, we here demonstrate that PSENs, and particularly PSEN1, act as hub proteins controlling the balance between endosomal/autophagic degradation and secretion. More generally, our findings strengthen the view of a strong interconnection between the endocytic and autophagic pathways and their complementary roles in sEV secretion.
    Keywords:  APP C‐terminal fragments; CD63; amphisomes; autophagy; multivesicular endosomes; presenilins; small extracellular vesicles
    DOI:  https://doi.org/10.1002/jev2.70019
  16. J Transl Med. 2025 Jan 13. 23(1): 52
    Autophagy in brain tumors: molecular mechanisms, challenges, and therapeutic opportunities.
    Jiarui Zhang, Jinan Zhang, Chen Yang.
      Autophagy is responsible for maintaining cellular balance and ensuring survival. Autophagy plays a crucial role in the development of diseases, particularly human cancers, with actions that can either promote survival or induce cell death. However, brain tumors contribute to high levels of both mortality and morbidity globally, with resistance to treatments being acquired due to genetic mutations and dysregulation of molecular mechanisms, among other factors. Hence, having knowledge of the role of molecular processes in the advancement of brain tumors is enlightening, and the current review specifically examines the role of autophagy. The discussion would focus on the molecular pathways that control autophagy in brain tumors, and its dual role as a tumor suppressor and a supporter of tumor survival. Autophagy can control the advancement of different types of brain tumors like glioblastoma, glioma, and ependymoma, demonstrating its potential for treatment. Autophagy mechanisms can influence metastasis and drug resistance in glioblastoma, and there is a complex interplay between autophagy and cellular responses to stress like hypoxia and starvation. Autophagy can inhibit the growth of brain tumors by promoting apoptosis. Hence, focusing on autophagy could offer fresh perspectives on creating successful treatments.
    Keywords:  Autophagy; Brain tumor; Cancer progression; Glioblastoma
    DOI:  https://doi.org/10.1186/s12967-024-06063-0
  17. Autophagy. 2025 Jan 14. 1-19
    Structure of the human autophagy factor EPG5 and the molecular basis of its conserved mode of interaction with Atg8-family proteins.
    Yiu Wing Sunny Cheung, Sung-Eun Nam, Gage M J Fairlie, Karlton Scheu, Jennifer M Bui, Hannah R Shariati, Jörg Gsponer, Calvin K Yip.
      The multi-step macroautophagy/autophagy process ends with the cargo-laden autophagosome fusing with the lysosome to deliver the materials to be degraded. The metazoan-specific autophagy factor EPG5 plays a crucial role in this step by enforcing fusion specificity and preventing mistargeting. How EPG5 exerts its critical function and how its deficiency leads to diverse phenotypes of the rare multi-system disorder Vici syndrome are not fully understood. Here, we report the first structure of human EPG5 (HsEPG5) determined by cryo-EM and AlphaFold2 modeling. Our structure revealed that HsEPG5 is constructed from helical bundles analogous to tethering factors in membrane trafficking pathways but contains a unique protruding thumb domain positioned adjacent to the atypical tandem LIR motifs involved in interaction with the GABARAP subfamily of Atg8-family proteins. Our NMR spectroscopic, molecular dynamics simulations and AlphaFold modeling studies showed that the HsEPG5 tandem LIR motifs only bind the canonical LIR docking site (LDS) on GABARAP without engaging in multivalent interaction. Our co-immunoprecipitation analysis further indicated that full-length HsEPG5-GABARAP interaction is mediated primarily by LIR1. Finally, our biochemical affinity isolation, X-ray crystallographic analysis, affinity measurement, and AlphaFold modeling demonstrated that this mode of binding is observed between Caenorhabditis elegans EPG-5 and its Atg8-family proteins LGG-1 and LGG-2. Collectively our work generated novel insights into the structural properties of EPG5 and how it potentially engages with the autophagosome to confer fusion specificity.ABBREVIATIONS: ATG: autophagy related; CSP: chemical shift perturbation; eGFP: enhanced green fluoresent protein; EM: electron microscopy; EPG5: ectopic P-granules 5 autophagy tethering factor; GST: glutathione S-transferase; HP: hydrophobic pocket; HSQC: heteronuclear single-quantum correlation; ITC: isothermal titration calorimetry; LDS: LC3 docking site; LIR: LC3-interacting region; MD: molecular dynamics; NMR: nuclear magnetic resonance; TEV: tobacco etch virus.
    Keywords:  Autophagy; EPG5; NMR spectroscopy; Vici syndrome; cryo-EM
    DOI:  https://doi.org/10.1080/15548627.2024.2447213
  18. Exerc Sport Sci Rev. 2025 Jan 13.
    Focus on the Forgotten Organelle: Regulation of Lysosomes in Skeletal Muscle.
    Neushaw Moradi, Anastasiya Kuznyetsova, Victoria C Sanfrancesco, Sabrina Champsi, David A Hood.
       ABSTRACT: Research on the role of the lysosome as the terminal organelle in autophagy and in communicating with other organelles in skeletal muscle is in its infancy. We hypothesize that the lysosome can adapt positively to exercise to improve the clearance of cargo, like dysfunctional mitochondria, within muscle, representing an important therapy for protein homeostasis in aging and muscle disuse.
    DOI:  https://doi.org/10.1249/JES.0000000000000358
  19. Cytokine Growth Factor Rev. 2025 Jan 03. pii: S1359-6101(24)00106-0. [Epub ahead of print]
    Mechanisms coupling the mTOR pathway to chronic obstructive pulmonary disease (COPD) pathogenesis.
    Ankita Goyal, Vishal Chopra, Kranti Garg, Siddharth Sharma.
      Chronic Obstructive Pulmonary Disease (COPD) is a poorly reversible respiratory disorder distinguished by dyspnea, cough, expectoration and exacerbations due to abnormality of airways or emphysema. In this review, we consider the therapeutic potential of targeting Mammalian target of Rapamycin (mTOR) for treating COPD. The mTOR is a highly conserved serine-threonine protein kinase that integrates signals from growth factors and nutrients to control protein synthesis, lipid biogenesis and metabolism. Dysregulated mTOR pathway signaling due to genetic factors or cigarette smoking impairs autophagy, driving the buildup of abnormal cells and damaged proteins, resulting in inflammation and oxidative stress. Persistent mTOR activation also contributes to pulmonary vascular cell proliferation, facilitating the development of pulmonary resistance in COPD. Rapamycin, an inhibitor of mTOR, prevents the buildup of senescent cells in the lungs of COPD patients and inhibits the release of lung tissue-damaging proteases. mTOR also impacts the corticosteroid sensitivity in COPD patients by regulating the levels of histone deacetylases. The emerging role of gut-lung axis dysbiosis in the progression of COPD and its influence on mTOR further highlights the relevance of the mTOR pathway in COPD pathophysiology.
    Keywords:  COPD; autophagy; corticosteroid resistance; growth factors; gut lung axis; mTOR; senescence
    DOI:  https://doi.org/10.1016/j.cytogfr.2024.12.005
  20. J Cell Biol. 2025 Feb 03. pii: e202310150. [Epub ahead of print]224(2):
    A STING-CASM-GABARAP pathway activates LRRK2 at lysosomes.
    Amanda Bentley-DeSousa, Agnes Roczniak-Ferguson, Shawn M Ferguson.
      Mutations that increase LRRK2 kinase activity have been linked to Parkinson's disease and Crohn's disease. LRRK2 is also activated by lysosome damage. However, the endogenous cellular mechanisms that control LRRK2 kinase activity are not well understood. In this study, we identify signaling through stimulator of interferon genes (STING) as an activator of LRRK2 via the conjugation of ATG8 to single membranes (CASM) pathway. We furthermore establish that multiple chemical stimuli that perturb lysosomal homeostasis also converge on CASM to activate LRRK2. Although CASM results in the lipidation of multiple ATG8 protein family members, we establish that LRRK2 lysosome recruitment and kinase activation are highly dependent on interactions with the GABARAP member of this family. Collectively, these results define a pathway that integrates multiple stimuli at lysosomes to control the kinase activity of LRRK2. Aberrant activation of LRRK2 via this pathway may be of relevance in both Parkinson's and Crohn's diseases.
    DOI:  https://doi.org/10.1083/jcb.202310150
  21. Biochim Biophys Acta Mol Basis Dis. 2025 Jan 11. pii: S0925-4439(25)00013-4. [Epub ahead of print]1871(3): 167668
    TFEB activator protects against ethanol toxicity-induced cardiac injury by restoring mitophagy and autophagic flux.
    Mengxue Zhao, Ruocheng Zhang, Xiuzhu Chen, Peixuan Li, Hui Yang, Bin Gao, Baoxin Li, Weina Zhou, Yuanyuan Wang, Yunliang Zhang, Li Zhong, Rui Guo.
      Excessive alcohol consumption is a major cause of alcoholic cardiomyopathy (ACM) and myocardial injury. This study aims to investigate the role of transcription factor EB (TFEB) in ethanol-induced cardiac anomalies using a murine model, AC16 human cardiomyocytes, and human plasma. Wild-type mice treated with a TFEB activator (Compound 1) or vehicle (25 mg/kg/d) were challenged with or without ethanol (3 g/kg/d, i.p.) for three consecutive days. Cardiac geometry and function were evaluated by echocardiography. The expressions of TFEB, molecules related to mitochondria, markers of apoptosis, mitophagy and lysosomes were examined in heart tissues and AC16 cardiomyocytes. Mitochondrial function, lysosome activity, and their localizations were measured in AC16 cardiomyocytes. Levels of TFEB and autophagic markers were also detected in human serum from healthy individuals and patients with ACM. Ethanol administration in mice induced severe cardiac dysfunction accompanied by upregulated P62 and LC3B, downregulated TFEB, lysosomal markers and mitophagy-associated receptors in heart tissues. Ethanol toxicity also led to reduced mitochondrial and lysosomal activity. Interestingly, TFEB activation mitigated the detrimental effects caused by ethanol. Inhibition of autophagy abolished the anti-apoptotic effect of TFEB in AC16 cells. In conclusion, TFEB is beneficial in ethanol-induced cardiac anomalies by reducing apoptosis, recovering lysosomal activity, and restoring proper mitophagy and autophagic flux.
    Keywords:  Alcoholic cardiomyopathy; Apoptosis; Autophagic flux; Ethanol toxicity; Mitophagy; TFEB
    DOI:  https://doi.org/10.1016/j.bbadis.2025.167668
  22. Biochem Pharmacol. 2025 Jan 10. pii: S0006-2952(25)00013-9. [Epub ahead of print] 116751
    Pym-18a, a novel pyrimidine derivative ameliorates glucocorticoid induced osteoblast apoptosis and promotes osteogenesis via autophagy and PINK 1/Parkin mediated mitophagy induction.
    Sonu Khanka, Sumit K Rastogi, Krishna Bhan Singh, Kriti Sharma, Shahid Parwez, Mohammad Imran Siddiqi, Arun K Sinha, Ravindra Kumar, Divya Singh.
      Glucocorticoid-induced osteoporosis (GIOP) is the most common type of secondary osteoporosis, marked by reduced bone density and impaired osteoblast function. Current treatments have serious side effects, highlighting the need for new drug candidates. Pyrimidine derivatives have been noted for their potential in suppressing osteoclastogenesis, but their effects on osteogenesis and GIOP remain underexplored. Our recent study identified a novel pyrimidine derivative, Pym-18a, which enhances osteoblast functions. In this study, Pym-18a was found to mitigate the detrimental effects of Dexamethasone (Dex) in osteoblast cells and in GIOP in Balb/C mice. Pretreatment with Pym-18a followed by Dex (100 µM) for 24 h restored osteoblast alkaline phosphatase activity and viability. Pym-18a reduced Dex-induced apoptosis and reactive oxygen species (ROS) generation at cellular and mitochondrial levels and preserved mitochondrial membrane potential. Dex impaired autophagy and mitophagy, but Pym-18a pretreatment increased expression of autophagy markers (LC3II) and mitophagy markers (PINK1, Parkin, TOM20) while decreasing P62 expression. The osteogenic effects of Pym-18a were diminished in the presence of 3-MA (an autophagy inhibitor). In silico studies showed mTOR inhibition by Pym-18a, corroborated by its suppression of Dex-induced mTOR activation. In vivo, Pym-18a (10 mg/kg) significantly improved bone microarchitecture, trabecular connectivity, and strength, and corrected P1NP and CTX levels altered by Dex. Pym-18a also promoted autophagy, mitophagy, and suppressed mTOR activation in GIOP mice. Overall, Pym-18a mitigates detrimental effect of Dex by modulating autophagy and PINK/Parkin-mediated mitophagy through mTOR inhibition, suggesting it as a potential novel therapeutic option for GIOP.
    Keywords:  Autophagy; Glucocorticoid; Mitophagy; Osteoblast apoptosis; Oxidative stress; Pym-18a (N-(5-Bromo-4-(4-bromophenyl)-6-(2,4,5-trimethoxyphenyl) pyrimidin-2-yl) hexanamide)
    DOI:  https://doi.org/10.1016/j.bcp.2025.116751
  23. Cell Commun Signal. 2025 Jan 13. 23(1): 24
    Histone demethylases in autophagy and inflammation.
    Yaoyao Ma, Wenting Lv, Yi Guo, Tong Yin, Yujie Bai, Ziqi Liu, Chao Chen, WenjuanYang, Jiayi Feng, Wenbin Qian, Ruiling Tang, Yanting Su, Shigang Shan, Huifen Dong, Yongfen Bao, Lihua Qu.
      Autophagy dysfunction is associated with changes in autophagy-related genes. Various factors are connected to autophagy, and the mechanism regulating autophagy is highly complicated. Epigenetic changes, such as aberrant expression of histone demethylase, are actively associated not only with oncogenesis but also with inflammatory responses. Among post-translational modifications, histone lysine methylation holds significant importance. There are over 30 members of histone lysine demethylases (KDMs), which act as epigenetic regulators in physiological processes and diseases. Importantly, KDMs are abnormally expressed in the regulation of cellular autophagy and inflammation, representing a crucial mechanism affecting inflammation-related diseases. This article reviewed the function of KDMs proteins in autophagy and inflammation. Specifically, It focused on the specific regulatory mechanisms underlying the activation or inhibition of autophagy, as well as their abnormal expression in inflammatory responses. By analyzing each KDM in epigenetic modification, this review provides a reliable theoretical basis for clinical decision marking regarding autophagy abnormalities and inflammatory diseases.
    Keywords:  Autophagy; Histone demethylases; Inflammation
    DOI:  https://doi.org/10.1186/s12964-024-02006-w
  24. Autophagy. 2025 Jan 16.
    Survival strategies of cancer cells: the role of macropinocytosis in nutrient acquisition, metabolic reprogramming, and therapeutic targeting.
    Guoshuai Xu, Qinghong Zhang, Renjia Cheng, Jun Qu, Wenqiang Li.
      Macropinocytosis is a nonselective form of endocytosis that allows cancer cells to largely take up the extracellular fluid and its contents, including nutrients, growth factors, etc. We first elaborate meticulously on the process of macropinocytosis. Only by thoroughly understanding this entire process can we devise targeted strategies against it. We then focus on the central role of the MTOR (mechanistic target of rapamycin kinase) complex 1 (MTORC1) in regulating macropinocytosis, highlighting its significance as a key signaling hub where various pathways converge to control nutrient uptake and metabolic processes. The article covers a comprehensive analysis of the literature on the molecular mechanisms governing macropinocytosis, including the initiation, maturation, and recycling of macropinosomes, with an emphasis on how these processes are hijacked by cancer cells to sustain their growth. Key discussions include the potential therapeutic strategies targeting macropinocytosis, such as enhancing drug delivery via this pathway, inhibiting macropinocytosis to starve cancer cells, blocking the degradation and recycling of macropinosomes, and inducing methuosis - a form of cell death triggered by excessive macropinocytosis. Targeting macropinocytosis represents a novel and innovative approach that could significantly advance the treatment of cancers that rely on this pathway for survival. Through continuous research and innovation, we look forward to developing more effective and safer anti-cancer therapies that will bring new hope to patients.
    Keywords:  Anti-cancer therapies; MTORC1; MTORC2; macropinocytosis; metabolic reprogramming; methuosis
    DOI:  https://doi.org/10.1080/15548627.2025.2452149
  25. Geroscience. 2025 Jan 16.
    The anti-senescence effect of D-β-hydroxybutyrate in Hutchinson-Gilford progeria syndrome involves progerin clearance by the activation of the AMPK-mTOR-autophagy pathway.
    Feliciano Monterrubio-Ledezma, Ashley Salcido-Gómez, Tania Zavaleta-Vásquez, Fernando Navarro-García, Bulmaro Cisneros, Lourdes Massieu.
      D-β-hydroxybutyrate, BHB, has been previously proposed as an anti-senescent agent in vitro and in vivo in several tissues including vascular smooth muscle. Moreover, BHB derivatives as ketone esters alleviate heart failure. Here, we provide evidence of the potential therapeutic effect of BHB on Hutchinson-Gilford progeria syndrome (HGPS), a rare condition characterized by premature aging and heart failure, caused by the presence of progerin, the aberrant protein derived from LMNA/C gene c.1824C > T mutation. We have assessed several hallmarks of HGPS-senescent phenotype in vitro, such as progerin levels, nuclear morphometric aberrations, nucleolar expansion, cellular senescent morphology, SA-βGal-positive cells, H3K9me3 heterochromatin, γH2AX foci, Lamin B1, p21Waf1/Cip1 and p16CDKN2A abundance, and autophagy. Strikingly, BHB improved nuclear and nucleolar morphometrics, diminished the senescence-phenotype, and unstuck autophagy in HGPS as observed by an enhanced degradation of the cargo protein receptor SQSTM1/p62, suggesting the stimulation of the autophagic flux. Additionally, we observed a decrease in progerin abundance, the cause of senescence in HGPS. Furthermore, compound C, an inhibitor of AMPK, and SBI-0206965, an inhibitor of ULK1/2 and AMPK, which prevent autophagy activation, reversed BHB-induced progerin decline as well as its anti-senescent effect in an AMPK-mTORC1 dependent manner. Altogether, these results suggest that the anti-senescence effect of BHB involves progerin clearance by autophagy activation supporting the potential of BHB for HGPS therapeutics and further preclinical trials.
    Keywords:  AMPK; Autophagy; Hutchison-Gilford progeria syndrome; Ketone bodies; Progerin clearance; Senescence
    DOI:  https://doi.org/10.1007/s11357-024-01501-9
  26. Aging Cell. 2025 Jan 16. e14487
    V-ATPase Disassembly at the Yeast Lysosome-Like Vacuole Is a Phenotypic Driver of Lysosome Dysfunction in Replicative Aging.
    Fiza Hashmi, Patricia M Kane.
      Declines in lysosomal acidification and function with aging are observed in organisms ranging from yeast to humans. V-ATPases play a central role in organelle acidification, and V-ATPase activity is regulated by reversible disassembly in many different settings. Using the yeast Saccharomyces cerevisiae as a replicative aging model, we demonstrate that V-ATPases disassemble into their V1 and V0 subcomplexes in aging cells, with release of V1 subunit C (Vma5) from the lysosome-like vacuole into the cytosol. Disassembly is observed after > 5 cell divisions and results in overall vacuole alkalinization. Caloric restriction, an established mechanism for reversing many age-related outcomes, prevents V-ATPase disassembly in older cells and preserves vacuolar pH homeostasis. Reversible disassembly is controlled in part by the activity of two opposing and conserved factors: the Regulator of Acidification of Vacuoles and Endosomes (RAVE) complex and Oxr1. The RAVE complex promotes V-ATPase assembly and a rav1∆ mutant shortens replicative lifespan; Oxr1 promotes disassembly and an oxr1∆ mutation extends the lifespan. Importantly, the level of Rav2, a subunit of the RAVE complex, declines in aged cells, and Rav2 overexpression delays V-ATPase disassembly with age. These data indicate that reduced V-ATPase assembly contributes to the loss of lysosomal acidification with age, which affects replicative lifespan.
    Keywords:   Saccharomyces cerevisiae ; aging; caloric restriction; lysosomes; proton pumps
    DOI:  https://doi.org/10.1111/acel.14487
  27. Int J Mol Sci. 2024 Dec 25. pii: 84. [Epub ahead of print]26(1):
    Non-Structural Protein V of Canine Distemper Virus Induces Autophagy via PI3K/AKT/mTOR Pathway to Facilitate Viral Replication.
    Xin Tian, Rui Zhang, Shuang Yi, Yu Chen, Ying Jiang, Xianwen Zhang, Zhidong Zhang, Yanmin Li.
      Canine distemper (CD) is a highly infectious disease of dogs which is caused by canine distemper virus (CDV). Previous studies have demonstrated that CDV infection can induce autophagy in cells. However, the mechanism underlying CDV-induced autophagy remains not fully understood. The CDV non-structural protein V plays a vital role in viral replication and pathogenicity in the host. In this study, we investigated the relationship between the CDV-V protein and autophagy induction and further explored its impact on the viral replication and the mechanism behind this. Our results showed that the V protein induced autophagy via inhibiting the phosphorylation of PI3K, AKT, and mTOR to promote viral replication. The activation or inhibition of PI3K phosphorylation resulted in enhancing or reducing viral replication, respectively. Further studies revealed that the V protein interacted with PI3K to induce cellular autophagy. The present study demonstrated that the CDV-V protein can induce cellular autophagy by inhibiting the PI3K/AKT signaling pathway to enhance viral replication. The results improve the understanding of the molecular mechanism of CDV infection and offer new perspectives for the development of effective treatment and prevention strategies.
    Keywords:  CDV-V; PI3K; autophagy; canine distemper virus (CDV)
    DOI:  https://doi.org/10.3390/ijms26010084
  28. Int J Biol Macromol. 2025 Jan 08. pii: S0141-8130(25)00200-4. [Epub ahead of print] 139651
    Alcohol dehydrogenase 1 acts as a scaffold protein in mitophagy essential for fungal pathogen adaptation to hypoxic niches within hosts.
    Jin-Li Ding, Li Li, Kang Wei, Hao Zhang, Nemat O Keyhani, Ming-Guang Feng, Sheng-Hua Ying.
      Fungi have evolved diverse physiological adaptations to hypoxic environments. However, the mechanisms mediating such adaptations remain obscure for many filamentous pathogenic fungi. Here, we show that autophagy mediated mitophagy occurs in the insect pathogenic fungus Beauveria bassiana under hypoxic conditions induced by host cellular immune responses. Mitophagy was essential for fungal evasion from insect hemocyte encapsulation, allowing for fungal proliferation and colonization in the host hemocoel. Our data showed that B. bassiana autophagy-related protein 11 (Atg11) interacts with Atg8 as a scaffold mediating mitophagy. The mitochondrial protein Atg43 was demonstrated to act as a receptor for the selective mitophagy, directly interacting with Atg8 for the autophagosomal targeting. Alcohol dehydrogenase BbAdh1, as a novel scaffold protein, participates in mitophagy through interacting with Atg8 and Atg11 under hypoxic stress. BbAdh1 was critical for fungal intracellular redox homeostasis and energy metabolism under hypoxic conditions. These data provide a pathway for mitochondrial degradation via metabolism linked autophagosome- to-vacuole targeting during hypoxic stress. This mitophagy results in depletion of oxidative mitochondrial dependent functions as a cellular adaptation to the low oxygen levels.
    Keywords:  Fungal survival; Hypoxic stress; Mitophagy
    DOI:  https://doi.org/10.1016/j.ijbiomac.2025.139651
  29. Int Immunopharmacol. 2025 Jan 12. pii: S1567-5769(25)00004-9. [Epub ahead of print]147 114015
    Deletion of BMP4 impairs trophoblast function and decidual macrophage polarization via autophagy leading to recurrent spontaneous abortion.
    Lujia Tang, Fangfang Dai, Yuwei Zhang, Ruiqi Wang, Wei Tan, Ran Gu, Liping Chen, Linlin Wang, Hua Liu, Yanxiang Cheng, Liangbin Xia.
      Bone morphogenetic protein 4 (BMP4) is widely involved in the regulation of cell proliferation and differentiation, but its role in Recurrent Spontaneous Abortion (RSA) remains unclear. RSA is a disease that affects roughly 1-2% of partner pairs, but its pathogenesis is still unclear. In recent years, many studies have focused on the role of decidual macrophages in RSA. In this study, we found decreased expression levels of BMP4 in villous tissues of RSA patients and found that low expression of RUNX2 leads to down-regulation of BMP4, which impairs trophoblast function. More importantly, we found in both co-culture system and human recombinant BMP4 protein models that BMP4 overexpression polarizes THP-1-derived macrophages toward M2, and down-regulation of BMP4 leads to macrophage polarization toward M1. Mechanically, we found that BMP4 promotes macrophage polarization via regulating autophagy level. The recovery experiment was further confirmed that 3-MA (autophagy inhibitor) inhibit THP-1-derived macrophage polarization toward M2 induced by BMP4 overexpression and exogenous addition of rBMP4, and rapamycin (autophagy agonists) inhibit macrophages polarization toward M1 from down-regulation of BMP4. Our study further reveals the mechanism of maternal-fetal interface cell interactions in RSA, which can help in the diagnosis and treatment of RSA.
    Keywords:  Autophagy; BMP4; Macrophage polarization; RSA; Trophoblast cell
    DOI:  https://doi.org/10.1016/j.intimp.2025.114015
  30. bioRxiv. 2024 Dec 31. pii: 2024.12.30.630813. [Epub ahead of print]
    Bipolar and schizophrenia risk gene AKAP11 encodes an autophagy receptor coupling the regulation of PKA kinase network homeostasis to synaptic transmission.
    You-Kyung Lee, Cong Xiao, Xiaoting Zhou, Le Wang, Meghan G McReynolds, Zhiping Wu, Eric Purisic, Henry Kim, Xianting Li, Zhiping Pang, Jinye Dai, Junmin Peng, Nan Yang, Zhenyu Yue.
      Human genomic studies have identified protein-truncating variants in AKAP11 associated with both bipolar disorder and schizophrenia, implicating a shared disease mechanism driven by loss-of-function. AKAP11, a protein kinase A (PKA) adaptor, plays a key role in degrading the PKA-RI complex through selective autophagy. However, the neuronal functions of AKAP11 and the impact of its loss-of-function remains largely uncharacterized. Through multi-omics approaches, cell biology, and electrophysiology analysis in mouse models and human induced neurons, we delineated a central role of AKAP11 in coupling PKA kinase network regulation to synaptic transmission. Loss of AKAP11 disrupted PKA activity and impaired cellular functions that significantly overlap with pathways associated with the psychiatric disease. Moreover, we identified interactions between AKAP11, the PKA-RI adaptor SPHKAP, and the ER-resident autophagy-related proteins VAPA/B, which co-adapt and mediate PKA-RI degradation. Notably, AKAP11 deficiency impaired neurotransmission and decreased presynaptic protein levels in neurons, providing key insights into the mechanism underlying AKAP11 -associated psychiatric diseases.
    DOI:  https://doi.org/10.1101/2024.12.30.630813
  31. J Med Chem. 2025 Jan 16.
    Research Advances in Chaperone-Mediated Autophagy (CMA) and CMA-Based Protein Degraders.
    Zhaoping Pan, Xiaowei Huang, Mingxia Liu, Xian Jiang, Gu He.
      Molecular mechanisms of chaperone-mediated autophagy (CMA) constitute essential regulatory elements in cellular homeostasis, encompassing protein quality control, metabolic regulation, cellular signaling cascades, and immunological functions. Perturbations in CMA functionality have been causally associated with various pathological conditions, including neurodegenerative pathologies and neoplastic diseases. Recent advances in targeted protein degradation (TPD) methodologies have demonstrated that engineered degraders incorporating KFERQ-like motifs can facilitate lysosomal translocation and subsequent proteolysis of noncanonical substrates, offering novel therapeutic interventions for both oncological and neurodegenerative disorders. This comprehensive review elucidates the molecular mechanisms, physiological significance, and pathological implications of CMA pathways. Additionally, it provides a critical analysis of contemporary developments in CMA-based degrader technologies, with particular emphasis on their structural determinants, mechanistic principles, and therapeutic applications. The discourse extends to current technical limitations in CMA investigation and identifies key obstacles that must be addressed to advance the development of CMA-targeting therapeutic agents.
    DOI:  https://doi.org/10.1021/acs.jmedchem.4c02681
  32. Nat Commun. 2025 Jan 11. 16(1): 596
    Engineered hypoxia-responsive albumin nanoparticles mediating mitophagy regulation for cancer therapy.
    Wenyan Wang, Shun-Yu Yao, Jingjing Luo, Chendi Ding, Qili Huang, Yao Yang, Zhaoqing Shi, Jiachan Lin, Yu-Chen Pan, Xiaowei Zeng, Dong-Sheng Guo, Hongzhong Chen.
      Hypoxic tumors present a significant challenge in cancer therapy due to their ability to adaptation in low-oxygen environments, which supports tumor survival and resistance to treatment. Enhanced mitophagy, the selective degradation of mitochondria by autophagy, is a crucial mechanism that helps sustain cellular homeostasis in hypoxic tumors. In this study, we develop an azocalix[4]arene-modified supramolecular albumin nanoparticle, that co-delivers hydroxychloroquine and a mitochondria-targeting photosensitizer, designed to induce cascaded oxidative stress by regulating mitophagy for the treatment of hypoxic tumors. These nanoparticles are hypoxia-responsive and release loaded guest molecules in hypoxic tumor cells. The released hydroxychloroquine disrupts the mitophagy process, thereby increasing oxidative stress and further weakening the tumor cells. Additionally, upon laser irradiation, the photosensitizer generates reactive oxygen species independent of oxygen, inducing mitochondria damage and mitophagy activation. The dual action of simultaneous spatiotemporal mitophagy activation and mitophagy flux blockade results in enhanced autophagic and oxidative stress, ultimately driving tumor cell death. Our work highlights the effectiveness of hydroxychloroquine-mediated mitophagy blockade combined with mitochondria-targeted photosensitizer for cascade-amplified oxidative stress against hypoxic tumors.
    DOI:  https://doi.org/10.1038/s41467-025-55905-y
  33. Biol Reprod. 2025 Jan 13. pii: ioaf007. [Epub ahead of print]
    Mechanistic Target of Rapamycin Signaling Activity in the Human Placenta Across Gestation and in Maternal Obesity.
    Katie L Bidne, Kathryn E Erickson, Theresa L Powell, Thomas Jansson.
      The mechanistic target of rapamycin (mTOR) system is vital to placental development, formation, and function. Alterations in this system in the placenta have been associated with altered fetal growth. However, changes in placental mTOR signaling across gestation are poorly understood. We collected 81 human placental samples from 4-40 weeks' gestation to test the hypothesis that placental mTOR signaling activity increases over gestation and is activated in maternal obesity in early gestation. Proteins involved in upstream mTOR regulation and mTORC1/2 downstream signaling were quantified using immunoblotting in placentas of male or female fetuses. Readouts of mTORC1 activation, phospho-rpS6 and phospho-4EBP1 were highest in first trimester and decreased across gestation. Phosphorylation of AKT (308 and 473) increased over gestation. Interestingly, abundance of cytochrome c oxidase I and mitochondrial ATP synthase, key subunits of mitochondrial complexes III/IV and V, respectively, were elevated in first trimester obese placentas compared to control, but only in placenta from female fetuses. We suggest that the high placental mTOR signaling activity in early pregnancy may be related to the high anabolism and active trophoblast proliferation and invasion in the second half of the first trimester. In addition, we conclude that maternal obesity has only limited impact on this key placental signaling pathway across gestation in women.
    Keywords:  first trimester; maternal-fetal exchange; pregnancy; signal transduction; trophoblast
    DOI:  https://doi.org/10.1093/biolre/ioaf007
  34. Nat Rev Drug Discov. 2025 Jan 14.
    Targeting mitophagy in neurodegenerative diseases.
    Odetta Antico, Paul W Thompson, Nicholas T Hertz, Miratul M K Muqit, Laura E Parton.
      Mitochondrial dysfunction is a hallmark of idiopathic neurodegenerative diseases, including Parkinson disease, amyotrophic lateral sclerosis, Alzheimer disease and Huntington disease. Familial forms of Parkinson disease and amyotrophic lateral sclerosis are often characterized by mutations in genes associated with mitophagy deficits. Therefore, enhancing the mitophagy pathway may represent a novel therapeutic approach to targeting an underlying pathogenic cause of neurodegenerative diseases, with the potential to deliver neuroprotection and disease modification, which is an important unmet need. Accumulating genetic, molecular and preclinical model-based evidence now supports targeting mitophagy in neurodegenerative diseases. Despite clinical development challenges, small-molecule-based approaches for selective mitophagy enhancement - namely, USP30 inhibitors and PINK1 activators - are entering phase I clinical trials for the first time.
    DOI:  https://doi.org/10.1038/s41573-024-01105-0
  35. Nat Metab. 2025 Jan 15.
    Autophagy regulator ATG5 preserves cerebellar function by safeguarding its glycolytic activity.
    Janine Tutas, Marianna Tolve, Ebru Özer-Yildiz, Lotte Ickert, Ines Klein, Quinn Silverman, Filip Liebsch, Frederik Dethloff, Patrick Giavalisco, Heike Endepols, Theodoros Georgomanolis, Bernd Neumaier, Alexander Drzezga, Guenter Schwarz, Bernard Thorens, Graziana Gatto, Christian Frezza, Natalia L Kononenko.
      Dysfunctions in autophagy, a cellular mechanism for breaking down components within lysosomes, often lead to neurodegeneration. The specific mechanisms underlying neuronal vulnerability due to autophagy dysfunction remain elusive. Here we show that autophagy contributes to cerebellar Purkinje cell (PC) survival by safeguarding their glycolytic activity. Outside the conventional housekeeping role, autophagy is also involved in the ATG5-mediated regulation of glucose transporter 2 (GLUT2) levels during cerebellar maturation. Autophagy-deficient PCs exhibit GLUT2 accumulation on the plasma membrane, along with increased glucose uptake and alterations in glycolysis. We identify lysophosphatidic acid and serine as glycolytic intermediates that trigger PC death and demonstrate that the deletion of GLUT2 in ATG5-deficient mice mitigates PC neurodegeneration and rescues their ataxic gait. Taken together, this work reveals a mechanism for regulating GLUT2 levels in neurons and provides insights into the neuroprotective role of autophagy by controlling glucose homeostasis in the brain.
    DOI:  https://doi.org/10.1038/s42255-024-01196-4
  36. iScience. 2025 Jan 17. 28(1): 111544
    ZFAND6 promotes TRAF2-dependent mitophagy to restrain cGAS-STING signaling.
    Kashif Shaikh, Melissa Bowman, Sarah M McCormick, Linlin Gao, Jiawen Zhang, Jesse White, John Tawil, Arun Kapoor, Ravit Arav-Boger, Christopher C Norbury, Edward W Harhaj.
      ZFAND6 is a zinc finger protein that interacts with TNF receptor-associated factor 2 (TRAF2) and polyubiquitin chains and has been linked to tumor necrosis factor (TNF) signaling. Here, we report a previously undescribed function of ZFAND6 in maintaining mitochondrial homeostasis by promoting mitophagy. Deletion of ZFAND6 in bone marrow-derived macrophages (BMDMs) upregulates reactive oxygen species (ROS) and the accumulation of damaged mitochondria due to impaired mitophagy. Consequently, mitochondrial DNA (mtDNA) is released into the cytoplasm, triggering the spontaneous expression of interferon-stimulated genes (ISGs) in a stimulator of interferon genes (STING) dependent manner, which leads to enhanced viral resistance. Mechanistically, ZFAND6 bridges a TRAF2-cIAP1 interaction and mediates the recruitment of TRAF2 to damaged mitochondria, which is required for the initiation of ubiquitin-dependent mitophagy. Our results suggest that ZFAND6 promotes the interactions of TRAF2 and cIAP1 and the clearance of damaged mitochondria by mitophagy to maintain mitochondrial homeostasis.
    Keywords:  Cell biology; Omics; Transcriptomics
    DOI:  https://doi.org/10.1016/j.isci.2024.111544
  37. Exp Eye Res. 2025 Jan 10. pii: S0014-4835(25)00011-9. [Epub ahead of print] 110240
    Accumulation of autophagosomes in aging human photoreceptor cell synapses.
    Tapas C Nag.
      Autophagy is common in the aging retinal pigment epithelium (RPE). A dysfunctional autophagy in aged RPE is implicated in the pathogenesis of age-related macular degeneration. Aging human retina accompanies degenerative changes in photoreceptor mitochondria. It is not known how the damaged mitochondria are handled by photoreceptor cells with aging. This study examined donor human retinas (age: 56-94 years; N=12) by transmission electron microscopy to find mitochondrial dynamics and status of autophagy in macular photoreceptor cells. Observations were compared between the relatively lower age (56-78 years) and aged retinas (80-94 years). Mitochondrial fusion was predominant in photoreceptor inner segments (ellipsoids), but rarely seen in the synaptic terminals. Also, fusion became widespread with progressive aging in ellipsoids (12% and 21% between rods and cones at tenth decade, respectively). More importantly, it was found that the photoreceptor synaptic mitochondria altered significantly with aging (swelling and loss of cristae), compared to those in ellipsoids that became dark and condensed. The damaged synaptic mitochondria were sequestered inside autophagosomes, whose frequency was higher in aged photoreceptors, being 34% in cone and 24% in rod terminals, at tenth decade. However, autolysosomes/residual bodies were rare, and thus the aged photoreceptor synaptic terminals harboured many autophagosomes, the possible reasons for which are discussed. Such age-related altered mitochondrial population and defective autophagy in synaptic terminals may influence photoreceptor survival in late aging.
    Keywords:  Retina; aging; autophagy; mitochondria; photoreceptor cells; synapses
    DOI:  https://doi.org/10.1016/j.exer.2025.110240
  38. Angew Chem Int Ed Engl. 2025 Jan 12. e202421269
    A Small-Molecule Drug for the Self-Checking of Mitophagy.
    Yanan Gao, Qingjie Bai, Youxiao Ren, Xintian Shao, Mengrui Zhang, Luling Wu, Simon Lewis, Tony James, Xiaoyuan Chen, Qixin Chen.
      Mitophagy that disrupt mitochondrial membrane potential (MMP), represents a critical focus in pharmacology. However, the discovery and evaluation of MMP-disrupting drugs are often hampered using commercially available marker molecules that target similar or identical zones. These markers can significantly interfere with, obscure, or amplify the functional effects of MMP-targeting drugs, frequently leading to clinical failures. In response to this challenge, we propose a "one-two punch" drug design strategy that integrates both target-zone drug functionality and non-target zone biological reporting within a single small-molecule drug. We have developed a novel mitophagy self-check drug (MitoSC) that exhibits dual-color and dual-localization properties. The functional component of this system is a variable MitoSC that disrupts MMP homeostasis, thereby inducing mitophagy. Upon activation, this component transforms into a blue-fluorescent monomer (MitoSC-fun) specifically within the mitochondrial target zone. The biological reporting component is represented by a red-fluorescent monomer (MitoSC-rep) that localizes to lysosomes, the non-target zone. As mitophagy progresses, the fluorescent signals from MitoSC-rep (lysosomes) and MitoSC-fun (mitochondria) converge, enabling real-time monitoring of the mitophagy process. Our findings underscore the potential of a single-molecule drug to exert target-zone specific actions while simultaneously providing non-target zone self-checking, offering a new perspective for drug design.
    Keywords:  Dual localization; Lysosomes; Mitochondria; Self-checking; Subcelluar
    DOI:  https://doi.org/10.1002/anie.202421269
  39. J Biol Chem. 2025 Jan 13. pii: S0021-9258(25)00037-7. [Epub ahead of print] 108190
    USP1 promotes pancreatic cancer progression and autophagy by deubiquitinating ATG14.
    Leilei Li, Zhili Fan, Mengfei Liu, Hao Dong, Jing Li, Yu Li, Zan Song, Ying Liu, Zhicheng Zhang, Xinyu Gu, Tao Zhang.
      Pancreatic ductal adenocarcinoma (PDAC) is characterized by extremely poor prognosis, high mortality and limited therapeutic strategy. Autophagy is hyperactivated in PDAC and targeting autophagy are emerging as promising therapeutic strategies. The dysfunction of deubiquitinase USP1 results in tumorigenesis and chemotherapy resistance. However, little is known about how USP1 regulates autophagy and its mechanism in tumor progression and drug sensitivity in PDAC. In this study, we found USP1 elevated in pancreatic cancer and USP1 expression inversely correlated with overall survival. USP1 depletion inhibited cell proliferation, epithelial-mesenchymal transition (EMT) and migration in PDAC cells. Interestingly, USP1 knockdown or inhibition reduced autophagy initiation and autophagy flux. By screening of interacting protein using co-Immunoprecipitation, we identified that USP1 interacted with ATG14 protein, acting as a core component in autophagy initiation. Furthermore, USP1 overexpression deubiquitinated and enhanced ATG14 protein stability by reduced binding ubiquitin levels, whereas USP1 inhibition promoted its proteasome-dependent degradation. Notably, USP1 depletion or a novel USP1 inhibitor I-138 dramatically delayed tumor growth in xenograft model. USP1 inhibitor synergistically enhanced the anti-cancer efficiency of cisplatin in PDAC cells. Collectively, our study identifies USP1 as the first deubiquitinase in the modulation of ATG14 deubiquitination and unveils a regulatory role for USP1 in autophagy and PDAC progression. Targeting USP1 using a selective inhibitor I-138 may provide an effective strategy for chemotherapy treatment and combating drug resistance in autophagy-activated pancreatic cancer.
    Keywords:  ATG14; USP1; autophagy; cisplatin sensitivity; pancreatic ductal adenocarcinoma
    DOI:  https://doi.org/10.1016/j.jbc.2025.108190
  40. Life Sci Alliance. 2025 Mar;pii: e202302259. [Epub ahead of print]8(3):
    Transcription factor EB (TFEB) activity increases resistance of TNBC stem cells to metabolic stress.
    Milad Soleimani, Mark Duchow, Ria Goyal, Alexander Somma, Tamer S Kaoud, Kevin N Dalby, Jeanne Kowalski, S Gail Eckhardt, Carla Van Den Berg.
      Breast cancer stem cells (CSCs) are difficult to therapeutically target, but continued efforts are critical given their contribution to tumor heterogeneity and treatment resistance in triple-negative breast cancer. CSC properties are influenced by metabolic stress, but specific mechanisms are lacking for effective drug intervention. Our previous work on TFEB suggested a key function in CSC metabolism. Indeed, TFEB knockdown (KD) inhibited mammosphere formation in vitro and tumor initiation/growth in vivo. These phenotypic effects were accompanied by a decline in CD44high/CD24low cells. Glycolysis inhibitor 2-deoxy-D-glucose (2-DG) induced TFEB nuclear translocation, indicative of TFEB transcriptional activity. TFEB KD blunted, whereas TFEB (S142A) augmented 2-DG-driven unfolded protein response (UPR) mediators, notably BiP/HSPA5 and CHOP. Like TFEB KD, silencing BiP/HSPA5 inhibited CSC self-renewal, suggesting that TFEB augments UPR-related survival. Further studies showed that TFEB KD attenuated 2-DG-directed autophagy, suggesting a mechanism whereby TFEB protects CSCs against 2-DG-induced stress. Our data indicate that TFEB modulates CSC metabolic stress response via autophagy and UPR. These findings reveal the novel role of TFEB in regulating CSCs during metabolic stress in triple-negative breast cancer.
    DOI:  https://doi.org/10.26508/lsa.202302259
  41. Pharmacol Res. 2025 Jan 10. pii: S1043-6618(25)00016-7. [Epub ahead of print]212 107591
    Intercellular communication is crucial in the regulation of healthy aging via exosomes.
    Huifang Sun, Tengyuan Xia, Shuting Ma, Tao Lv, Yuhong Li.
      The hallmarks of aging encompass a variety of molecular categories (genomic, telomeric, and epigenetic), organelles (proteostasis, autophagy, and mitochondria), cellular components (including stem cells), systems (such as intercellular communication and chronic inflammation), and environmental factors (dysbiosis and nutrient sensing). These hallmarks play a crucial role in the aging process. Despite their intricate interconnections, the relationships among the hallmarks of aging remain unclear. Although the boundaries between these hallmarks may be indistinct, they exhibit interdependence, with the influence of one hallmark extending to others. Building on this foundation, we investigated the interrelations among the various hallmarks of aging and provided a systematic overview of their logical relationships, proposing that cellular communication plays a crucial role in the aging process. Exosomes function as a primary mode of cellular communication and significantly impact the aging process. Therefore, we propose utilizing exosomes as valuable tools for understanding the mechanisms of aging and addressing age-related concerns. Exosomes may represent a novel approach for the treatment and diagnosis of aging-related conditions in animals. Furthermore, our research reveals that exocytosis in young nematodes slows the aging process, while exocytosis in aged nematodes has the opposite effect, accelerating aging. In conclusion, exosomes act as intercellular messengers that influence the maintenance of a healthy aging process and link the hallmarks of aging with indicators of well-being.
    Keywords:  Aging; Cellular communication; Exosomes; Lifestyle
    DOI:  https://doi.org/10.1016/j.phrs.2025.107591
  42. Eur J Pharmacol. 2025 Jan 11. pii: S0014-2999(25)00022-6. [Epub ahead of print] 177269
    Rapamycin protects glucocorticoid-induced glaucoma model mice against trabecular meshwork fibrosis by suppressing mTORC1/2 signaling.
    Yuning Song, Feifei Wang, Hongdou Luo, Haijian Hu, Yulian Pang, Ke Xu, Xu Zhang.
      Systemic or local use of glucocorticoids (GCs) can induce pathological elevation of intraocular pressure (IOP), potentially leading to permanent visual loss. Previous studies have demonstrated that rapamycin (Rapa) inhibits the activation of retinal glial cells and the production of neuroinflammation, achieving neuroprotective goals. However, there has been little research on the effect of Rapa on the trabecular meshwork (TM). This study aimed to investigate the protective effect and potential mechanism of Rapa in a glucocorticoid-induced glaucoma (GIG) model. Our findings indicate that Rapa significantly inhibited the IOP increase induced by dexamethasone acetate (Dex-Ac) and improved TM fibrosis and retinal ganglion cell (RGC) damage. In cultured human trabecular meshwork cells (HTMCs) treated with dexamethasone (Dex) and Rapa under different conditions revealed that Rapa inhibits Dex-induced HTMC fibrosis and cytoskeletal changes. This effect may result from the specific suppression of the mechanistic target of rapamycin complex 1 (mTORC1) pathway by Rapa, which reduces abnormal extracellular matrix (ECM) deposition. Alternatively, the improvement in cytoskeleton entanglement might be due to the inhibition of the mechanistic target of rapamycin complex2 (mTORC2) pathway. These two potential mechanisms may collectively contribute to the protective effects of Rapa in GIG. This study provides a new theoretical basis for using of Rapa in the treatment of GIG.
    Keywords:  Rapamycin; dexamethasone; fibrosis; glaucoma; mTOR; trabecular meshwork
    DOI:  https://doi.org/10.1016/j.ejphar.2025.177269
  43. FASEB J. 2025 Jan 31. 39(2): e70319
    Apelin-13 inhibits ischemia-reperfusion mediated podocyte apoptosis by reducing m-TOR phosphorylation to enhance autophagy.
    Xiang Zheng, Dongshan Chen, Jiyue Wu, Zihao Gao, Mingcong Huang, Chunmeng Fan, Jing Chang, Yu Liu, Xiangjun Zeng, Wei Wang.
      Podocytes are essential to maintain the normal filtration function of glomerular basement membrane, which could be injured by ischemia-reperfusion. As complicated function of autophagy in terminal differentiated podocytes, autophagy dysfunction might contribute to I/R induced renal dysfunction following glomerular filtration membrane (GFM) injuries. Meanwhile, apelin-13, an endogenous polypeptide, has been proved to be effective in regulating autophagy and apoptosis in podocytes. Therefore, it is hypothesized that apelin-13 may protect podocytes from IRI by inhibiting podocyte apoptosis through regulation of podocyte autophagy. Our study demonstrates for that podocytes are also involved in renal ischemia-reperfusion (I/R) injury and shows in detail the morphological and functional changes in podocytes during renal I/R. Because podocytes are terminally differentiated cells whose homeostasis require high levels of autophagy, we investigate the cellular mechanisms underlying the effects of apelin-13 on I/R-mediated podocyte injury in terms of autophagy. In addition, our study demonstrates that apelin-13 ameliorates renal I/R injury in podocyte injury, by increasing podocyte autophagy through inhibition of m-TOR phosphorylation, which in turn inhibits apoptosis.
    Keywords:  apelin‐13; apoptosis; autophagy; ischemia–reperfusion injury; podocyte
    DOI:  https://doi.org/10.1096/fj.202402850R
  44. Commun Biol. 2025 Jan 15. 8(1): 59
    FOXG1 promotes osteogenesis of bone marrow-derived mesenchymal stem cells by activating autophagy through regulating USP14.
    Yiqi Zhang, Long Zhou, Qin Fu, Ziyun Liu.
      The osteogenic differentiation of bone marrow-derived mesenchymal stem cells (BMSCs) is key for bone formation, and its imbalance leads to osteoporosis. Forkhead Box Protein G1 (FOXG1) is associated with osteogenesis, however, the effect of FOXG1 on osteogenesis of BMSCs and ovariectomy (OVX)-induced bone loss is unknown. In our study, FOXG1 expression in BMSCs increases after osteogenic induction. FOXG1 overexpression significantly increases osteoblast marker expression ALP activity, and calcium deposition, while the opposite results are observed in FOXG1 knockdown BMSCs, suggesting that FOXG1 promotes osteogenic differentiation. Additionally, autophagy promotes the differentiation process in BMSCs. We find that FOXG1 induces autophagy, and osteogenic differentiation is blocked via inhibiting FOXG1-caused autophagy, indicating that FOXG1 accelerates osteogenic differentiation via inducing autophagy. Eight-week-old female C57BL/6J mice are used in OVX models, FOXG1 overexpression decreases bone loss by increasing bone formation. Moreover, FOXG1 overexpression suppresses osteoclast differentiation. Mechanically, FOXG1 transcriptionally represses ubiquitin-specific protease14 (USP14) via binding to the USP14 promoter. USP14 overexpression prevents the promoting effect of FOXG1 on osteogenic differentiation in BMSCs. Therefore, our findings suggest that FOXG1 promotes BMSC osteogenic differentiation and inhibits osteoclast differentiation, eventually blocking OVX-induced bone loss, which may provide a promising approach for osteoporosis treatment.
    DOI:  https://doi.org/10.1038/s42003-024-07429-2
  45. Am J Pathol. 2025 Jan 13. pii: S0002-9440(25)00001-X. [Epub ahead of print]
    Beyond Redox Regulation: Novel Roles of TXNIP in the Pathogenesis and Therapeutic Targeting of Kidney Disease.
    Chuang Li, Yili Fang, Ying Maggie Chen.
      Cellular stress conditions, such as oxidative and endoplasmic reticulum (ER) stresses contribute to development of various kidney diseases. Oxidative stress is prompted by reactive oxygen species (ROS) accumulation and delicately mitigated by glutathione and thioredoxin (Trx) antioxidant systems. Initially identified as a Trx-binding partner, thioredoxin interacting protein (TXNIP) is significantly upregulated and activated by oxidative and ER stresses. The function of TXNIP is closely linked to its subcellular localizations. Under normal physiological conditions, TXNIP primarily localizes to the nucleus. When exposed to ROS or ER stress, TXNIP relocates to mitochondria and binds to mitochondrial Trx2, which releases Trx-tethered apoptosis signal-regulating kinase 1 (ASK1) and activates ASK1-mediated apoptosis. Oxidative and ER stresses are also closely associated with autophagy. TXNIP can promote or inhibit autophagy depending on different contexts. Although recent studies have highlighted the indispensable role of TXNIP in the etiology and progression of kidney disease, TXNIP-targeted therapy is still missing. This review will focus on the following aspects: (1) Oxidative and ER stresses; (2) Regulation and function of TXNIP during cellular stress; (3) TXNIP in stress-regulated autophagy; (4) TXNIP in kidney diseases, including nephrotic syndrome, diabetic nephropathy and chronic kidney disease, acute kidney injury and kidney aging; (5) Novel treatment agents targeting TXNIP in kidney disease, where we will review the current advances in chemical compounds and RNA-based therapy suppressing TXNIP.
    Keywords:  TXNIP; autophagy; cellular stress; kidney disease
    DOI:  https://doi.org/10.1016/j.ajpath.2024.12.011
  46. Angew Chem Int Ed Engl. 2025 Jan 17. e202425123
    Engineering Covalent Aptamer Chimeras for Enhanced Autophagic Degradation of Membrane Proteins.
    Yang Shi, Yangfang Yun, Rong Wang, Zheng Liu, Zhenkun Wu, Yu Xiang, Jingjing Zhang.
      Targeted degradation of membrane proteins represents an attractive strategy for eliminating pathogenesis-related proteins. Aptamer-based chimeras hold great promise as membrane protein degraders, however, their degradation efficacy is often hindered by the limited structural stability and the risk of off-target effects due to the non-covalent interaction with target proteins. We here report the first design of a covalent aptamer-based autophagosome-tethering chimera (CApTEC) for the enhanced autophagic degradation of cell-surface proteins, including transferrin receptor 1 (TfR1) and nucleolin (NCL). This strategy relies on the site-specific incorporation of sulfonyl fluoride groups onto aptamers to enable the cross-linking with target proteins, coupled with the conjugation of an LC3 ligand to hijack the autophagy-lysosomal pathway for targeted protein degradation. The chemically engineered CApTECs exhibit enhanced on-target retention and improved structural stability. Our results also demonstrate that CApTECs achieve remarkably enhanced and prolonged degradation of membrane proteins compared to the non-covalent designs. Furthermore, the CApTEC targeting TfR1 is combined with 5-fluorouracil (5-FU) for synergistic tumor therapy in a mouse model, leading to substantial suppression of tumor growth. Our strategy may provide deep insights into the LC3-mdiated autophagic degradation, affording a modular and effective strategy for membrane protein degradation and precise therapeutic applications.
    Keywords:  Functional nucleic acid, Covalent conjugation, Protein degradation, Aptamer, Tumor therapy
    DOI:  https://doi.org/10.1002/anie.202425123
  47. J Inherit Metab Dis. 2025 Jan;48(1): e12833
    Unifying biology of neurodegeneration in lysosomal storage diseases.
    Anna M Ludlaim, Simon N Waddington, Tristan R McKay.
      There are currently at least 70 characterised lysosomal storage diseases (LSD) resultant from inherited single-gene defects. Of these, at least 30 present with central nervous system (CNS) neurodegeneration and overlapping aetiology. Substrate accumulation and dysfunctional neuronal lysosomes are common denominator, but how variants in 30 different genes converge on this central cellular phenotype is unclear. Equally unresolved is how the accumulation of a diverse spectrum of substrates in the neuronal lysosomes results in remarkably similar neurodegenerative outcomes. Conversely, how is it that many other monogenic LSDs cause only visceral disease? Lysosomal substance accumulation in LSDs with CNS neurodegeneration (nLSD) includes lipofuscinoses, mucopolysaccharidoses, sphingolipidoses and glycoproteinoses. Here, we review the latest discoveries in the fundamental biology of four classes of nLSDs, comparing and contrasting new insights into disease mechanism with emerging evidence of unifying convergence.
    Keywords:  Fabry disease; Gaucher disease; Krabbe disease; Nieman‐Pick; Sandhoff; Tay‐Sachs; lysosomal storage disease; metachromatic leukodystrophy; mucopolysaccharidosis; neuronal ceroid lipofuscinosis
    DOI:  https://doi.org/10.1002/jimd.12833
  48. Cell Death Dis. 2025 Jan 15. 16(1): 20
    RNF128 deficiency in macrophages promotes colonic inflammation by suppressing the autophagic degradation of S100A8.
    Xianwen Ran, Yue Li, Yahui Ren, Weilong Chang, Rui Deng, Huifen Wang, Weiwei Zhu, Yize Zhang, Yudie Cai, Jia Hu, Di Wang, Zhibo Liu.
      Macrophages play important roles in maintaining intestinal homeostasis and in the pathogenesis of inflammatory bowel diseases (IBDs). However, the underlying mechanisms that govern macrophage-mediated inflammation are still largely unknown. In this study, we report that RNF128 is downregulated in proinflammatory macrophages. RNF128 deficiency leads to elevated levels of effector cytokines in vitro and accelerates the progression of IBD in mouse models. Bone marrow transplantation experiments revealed that RNF128 deficiency in bone marrow cells contributes to the worsening of DSS-induced colitis. Mechanistically, RNF128 interacts with and destabilizes S100A8 by promoting its autophagic degradation, which is mediated by the cargo receptor Tollip. Moreover, the administration of an S100A8 neutralizing antibody mitigated the development of colitis and improved survival in DSS-treated Rnf128-/- mice. Overall, our study underscores the anti-inflammatory role of RNF128 in macrophages during the progression of colitis and highlights the potential of targeting the RNF128-Tollip-S100A8 axis to attenuate intestinal inflammation for the treatment of colitis.
    DOI:  https://doi.org/10.1038/s41419-025-07338-0
  49. Cell Immunol. 2025 Jan 10. pii: S0008-8749(24)00118-7. [Epub ahead of print]409-410 104915
    Deciphering the role of TMEM164 in autophagy-mediated ferroptosis and immune modulation in non-small cell lung cancer.
    Tahani Ahmad ALMatrafi.
       BACKGROUND: Non-small cell lung cancer (NSCLC) remains one of the most prevalent and deadly malignancies. Despite advancements in molecular therapies and diagnostic methods, the 5-year survival rate for lung adenocarcinoma patients remains unacceptably low, highlighting the urgent need for novel therapeutic strategies. Ferroptosis, a distinct form of regulated cell death, has emerged as a promising target in cancer treatment. This study investigates the role of TMEM164, a membrane protein, in promoting ferroptosis and modulating anti-tumor immunity in NSCLC, aiming to elucidate its therapeutic potential.
    METHODS: Using publicly available datasets, we performed bioinformatics analyses to identify TMEM164-regulated genes involved in ferroptosis. In addition, in vitro and in vivo assays were conducted to assess the impact of TMEM164 on cellular functions in NSCLC.
    RESULTS: Functional assays demonstrated that TMEM164 overexpression significantly inhibited invasion, migration, and cell proliferation in both in vitro and in vivo models. TMEM164 was also found to induce ferroptosis in NSCLC cells by promoting autophagy. Specifically, we identified a mechanism whereby TMEM164 mediates ATG5-dependent autophagosome formation, leading to the degradation of ferritin, GPX4, and lipid droplets. This degradation facilitated iron accumulation and lipid peroxidation, which triggered iron-dependent cell death. Notably, co-administration of TMEM164 upregulation and anti-PD-1 antibodies exhibited synergistic anti-tumor effects in a mouse model.
    CONCLUSION: These findings suggest that targeting TMEM164 to enhance ferroptosis and stimulate anti-tumor immunity may inhibit NSCLC progression. Consequently, TMEM164 holds promise as a new therapeutic target for NSCLC treatment.
    Keywords:  Autophagy; Ferroptosis; Immune checkpoint inhibitors (ICBs); Non-small cell lung cancer (NSCLC); Prognosis; TMEM164
    DOI:  https://doi.org/10.1016/j.cellimm.2024.104915
  50. Eur J Med Res. 2025 Jan 15. 30(1): 29
    SIRT1/PGC-1α-mediated mitophagy participates the improvement roles of BMAL1 in podocytes injury in diabetic nephropathy: evidences from in vitro experiments.
    Yanxia Rui, Yinfeng Guo, Linying He, Min-Er Wang, Henglan Wu.
       BACKGROUND: Dysfunction in podocyte mitophagy has been identified as a contributing factor to the onset and progression of diabetic nephropathy (DN), and BMAL1 plays an important role in the regulation of mitophagy. Thus, this study intended to examine the impact of BMAL1 on podocyte mitophagy in DN and elucidate its underlying mechanisms.
    MATERIALS AND METHODS: High D-glucose (HG)-treated MPC5 cells was used as a podocyte injury model for investigating the potential roles of BMAL1 in DN. Mitophagy was examined by detecting autophagosomes using transmission electron microscopy, and detecting the colocalization of LC3 and Tom20 using immunofluorescence staining. The interaction between BMAL1 and SIRT1 was conducted by immunoprecipitation (Co-IP) assay.
    RESULTS: In HG-induced podocyte injury model, we found that BMAL1 and SIRT1 mRNA level was significantly decreased, and positively correlated with mitophagy dysfunction. BMAL1 overexpression could ameliorate HG-induced podocyte injury, evidenced by improved cell viability, decreased cell apoptosis and inflammatory cytokines expression (TNF-α, IL-1β, and IL-6). BMAL1 overexpression could promote podocyte mitophagy coupled with increased expression of mitophagy markers PINK1 and Parkin. In terms of mechanism, Co-IP suggested that BMAL1 could interact with SIRT1. SIRT1 inhibitor Ex-527 addition obviously inhibit the effect of BMAL1 overexpression on the mitophagy, demonstrating that BMAL1 may act on mitophagy by SIRT1//PGC-1α axis.
    CONCLUSIONS: Our in vitro experiments demonstrate that BMAL1/SIRT1/PGC-1α pathway may protect podocytes against HG-induced DN through promoting mitophagy.
    Keywords:  BMAL1; Diabetic nephropathy; Mitophagy; Podocyte injury; SIRT1/PGC-1α
    DOI:  https://doi.org/10.1186/s40001-025-02280-5
  51. bioRxiv. 2025 Jan 03. pii: 2025.01.02.629779. [Epub ahead of print]
    Noncanonical PI(4,5)P2 coordinates lysosome positioning through cholesterol trafficking.
    Ryan M Loughran, Gurpreet K Arora, Jiachen Sun, Alicia Llorente, Sophia Crabtree, Kyanh Ly, Ren-Li Huynh, Wonhwa Cho, Brooke M Emerling.
      In p53-deficient cancers, targeting cholesterol metabolism has emerged as a promising therapeutic approach, given that p53 loss dysregulates sterol regulatory element-binding protein 2 (SREBP-2) pathways, thereby enhancing cholesterol biosynthesis. While cholesterol synthesis inhibitors such as statins have shown initial success, their efficacy is often compromised by the development of acquired resistance. Consequently, new strategies are being explored to disrupt cholesterol homeostasis more comprehensively by inhibiting its synthesis and intracellular transport. In this study, we investigate a previously underexplored function of PI5P4Ks, which catalyzes the conversion of PI(5)P to PI(4,5)P 2 at intracellular membranes. Our findings reveal that PI5P4Ks play a key role in facilitating lysosomal cholesterol transport, regulating lysosome positioning, and sustaining growth signaling via the mTOR pathway. While PI5P4Ks have previously been implicated in mTOR signaling and tumor proliferation in p53-deficient contexts, this work elucidates an upstream mechanism that unifies these earlier observations.
    DOI:  https://doi.org/10.1101/2025.01.02.629779
  52. Adv Biol (Weinh). 2025 Jan 11. e2400408
    β-Catenin/c-Myc Axis Modulates Autophagy Response to Different Ammonia Concentrations.
    S Sergio, B Spedicato, G Corallo, A Inguscio, M Greco, D Musarò, D Vergara, A F Muro, G De Sabbata, L R Soria, N Brunetti Pierri, M Maffia.
      Ammonia a by-product of nitrogen containing molecules is detoxified by liver into non-toxic urea and glutamine. Impaired ammonia detoxification leads to hyperammonemia. Ammonia has a dual role on autophagy, it acts as inducer at low concentrations and as inhibitor at high concentrations. However, little is known about the mechanisms responsible for this switch. Wnt/β-catenin signalling is emerging for its role in the regulation of ammonia metabolizing enzymes and autophagosome synthesis through c-Myc. Here, using Huh7 cell line, we show a modulation in c-Myc expression under different ammonia concentrations. An increase in c-Myc expression and in its transcriptional regulator β-catenin was detected at low concentrations of ammonia, when autophagy is active, whereas these modifications were lost under high ammonia concentrations. These observations were also recapitulated in the livers of spf-ash mice, a model of constitutive hyperammonaemia due to deficiency in ornithine transcarbamylase enzyme. Moreover, c-Myc-mediated activation of autophagy plays a cytoprotective role in cells under ammonia stress conditions as confirmed through the pharmacological inhibition of c-Myc in Huh7 cells treated with low ammonia concentrations. In conclusion, the unravelled role of c-Myc in modulating ammonia induced autophagy opens new landscapes for the development of novel strategies for the treatment of hyperammonemia.
    Keywords:  autophagy; c‐Myc; hyperammonemia; liver
    DOI:  https://doi.org/10.1002/adbi.202400408
  53. Adv Sci (Weinh). 2025 Jan 13. e2412379
    M6A Demethyltransferase FTO Attenuates Meniscus Degeneration and Osteoarthritis via Orchestrating Autophagy and Energetic Metabolism.
    Zongrui Jiang, Chengyun Zhang, Ruonan Liu, Zijing Zhu, Dianbo Long, Xingzhao Wen, Zhijian Yang, Dong Jiang, Guping Mao, Weiming Liao, Zhiqi Zhang.
      Impaired autophagy is reported to promote osteoarthritis (OA). However, the mechanism by which autophagy in regulating meniscus degeneration and OA remains unclear. Here, unconvered aberrant energetic metabolism pattern in meniscus cells with OA is uncovered first, which results in lower adenosine triphosphate (ATP) production. And these phenomena are induced by impaired autophagy in meniscus cells with OA. It is further revealed that the suppression of m6A demethylase fat mass and obesity-associated protein (FTO) inhibits autophagy and causing lower ATP production by reducing oxidative phosphorylation. Specific deletion of FTO in meniscus cells by generating FTOflox/flox; COL1A1-CreERT2 (FTOcko) mice impair autophagy and promote meniscus degeneration and OA, while intra-articular injection of adeno-associated virus of FTO (AAV-FTO) restores autophagy and alleviates meniscus degeneration and OA. Mechanistically, FTO regulates the mRNA stability of ATG16L1 by targeting the m6A methylation sites on ATG16L1 in a YTHDF2-dependent manner, thereby inhibiting the formation of autophagosomes and causing an imbalance in energetic metabolism. Intra-articular injection of AAV-FTO reverses the catabolic phenotype of meniscus degeneration and OA in FTOcko mice. In summary, these findings reveal FTO orchestrates autophagy and energetic metabolism by regulating ATG16L1 in a m6A-dependent manner. Therefore, targeting FTO might be a potential therapeutic strategy for meniscus degeneration and early-stage OA.
    Keywords:  ATG16L1; FTO; N6‐methyladenosine; autophagy; energetic metabolism; meniscus degeneration
    DOI:  https://doi.org/10.1002/advs.202412379
  54. Adv Sci (Weinh). 2025 Jan 13. e2410561
    Mitochondrial Electron Flow Dynamics Imaging for Assessing Mitochondrial Quality and Drug Screening.
    Youxiao Ren, Ling-Ling Wu, Wenjing Song, Yanan Gao, Litao Shao, Zhiyuan Lu, Songsong Wang, Xintian Shao, Zhenjie Yu, Mengrui Zhang, Jing Wu, Liwen Han, Kewu Zeng, Qixin Chen.
      Mitochondrial quality control is paramount for cellular development, with mitochondrial electron flow (Mito-EF) playing a central role in maintaining mitochondrial homeostasis. However, unlike visible protein entities, which can be monitored through chemical biotechnology, regulating mitochondrial quality control by invisible entities such as Mito-EF has remained elusive. Here, a Mito-EF tracker (Mito-EFT) with a four-pronged probe design is presented to elucidate the dynamic mechanisms of Mito-EF's involvement in mitochondrial quality control. Heightened aggregation of Mito-EF in fiber-like healthy mitochondria compared to round-like damaged mitochondria is demonstrated, revealed Mito-EF aggregation correlated with mitochondrial morphological remodeling, particularly in regions undergoing mitochondrial fission and fusion, and show the Mito-EF signal associated with mitochondrial cristae maintained by Dynamin-Related Protein 1 (DRP1). This underscores the importance of considering Mito-EF in assessing mitochondrial quality control parameters. A novel drug screening evaluation parameter, Mito-EF is also introduced to screen and discover mitochondrial-targeted therapeutic modulators. This tracker provides new avenues for investigating the role of Mito-EF in maintaining mitochondrial homeostasis and quality control, offering a potent tool for assessing mitochondrial quality and drug screening.
    Keywords:  drug screening; imaging; mitochondria; mitochondrial electron flow; morphology
    DOI:  https://doi.org/10.1002/advs.202410561
  55. J Mol Cell Cardiol Plus. 2025 Mar;11 100279
    Circulating autophagy regulator Rubicon is linked to increased myocardial infarction risk.
    Marie-Hélène Grazide, Jean-Bernard Ruidavets, Wim Martinet, Meyer Elbaz, Cécile Vindis.
       Background: The identification of new biomarkers that improve existing cardiovascular risk prediction models for acute coronary syndrome is essential for accurately identifying high-risk patients and refining treatment strategies. Autophagy, a vital cellular degradation mechanism, is important for maintaining cardiac health. Dysregulation of autophagy has been described in cardiovascular conditions such as myocardial ischemia-reperfusion injury, a key factor in myocardial infarction (MI). Recently, Rubicon (Run domain Beclin-1-interacting and cysteine-rich domain-containing protein), a key negative regulator of autophagy, has been identified in the modulation of cardiac stress response.
    Objectives: This study aimed to explore the relationship between circulating Rubicon levels and MI, and to evaluate the incremental predictive value of Rubicon when integrated into a clinical risk prediction model for MI.
    Results: We analyzed plasma Rubicon concentrations in 177 participants, comprising type I MI patients and high-risk control subjects. Our results revealed significantly elevated plasma Rubicon levels in MI patients compared to the control group (126.5 pg/mL vs. 53 pg/mL, p < 0.001). Furthermore, Rubicon levels showed a positive correlation with cardiovascular risk factors such as total cholesterol and LDL cholesterol. Multivariate analysis confirmed that Rubicon levels were independently associated with an increased risk of MI. The inclusion of Rubicon in traditional cardiovascular risk models notably enhanced predictive accuracy for MI, with the area under the curve (AUC) rising from 0.868 to 0.905 (p < 0.001).
    Conclusions: These findings suggest that Rubicon is a valuable biomarker associated with MI risk, providing additional predictive value beyond standard cardiovascular risk factors. This highlights the importance of Rubicon's critical role in the pathophysiology of CVD.
    Keywords:  Autophagy; Biomarker; Myocardial infarction; Risk prediction; Rubicon
    DOI:  https://doi.org/10.1016/j.jmccpl.2024.100279
  56. J Virol. 2025 Jan 16. e0211024
    Vaccinia growth factor-dependent modulation of the mTORC1-CAD axis upon nutrient restriction.
    Lara Dsouza, Anil Pant, Blake Pope, Zhilong Yang.
      The molecular mechanisms by which vaccinia virus (VACV), the prototypical member of the poxviridae family, reprograms host cell metabolism remain largely unexplored. Additionally, cells sense and respond to fluctuating nutrient availability, thereby modulating metabolic pathways to ensure cellular homeostasis. Understanding how VACV modulates metabolic pathways in response to nutrient signals is crucial for understanding viral replication mechanisms, with the potential for developing antiviral therapies. In this study, we establish the importance of de novo pyrimidine synthesis during VACV infection. We report the significance of vaccinia growth factor (VGF), a viral early protein and a homolog of cellular epidermal growth factor (EGF), in enabling VACV to phosphorylate the key enzyme CAD of the de novo pyrimidine pathway at serine 1859, a site known to positively regulate CAD activity. Although nutrient-poor conditions typically inhibit mTORC1 activation, VACV activates CAD via the mTORC1-S6K1 signaling axis in a VGF-dependent manner, especially upon glutamine and asparagine limitation. However, unlike its cellular homolog EGF, the VGF peptide alone, in the absence of VACV infection, has minimal ability to activate CAD. This suggests the involvement of other viral factors yet to be identified. Our research provides a foundation for understanding the regulation of a significant metabolic pathway, de novo pyrimidine synthesis during VACV infection, shedding new light on viral regulation under distinct nutritional environments. This study not only has the potential to contribute to the advancement of antiviral treatments but also improve the development of VACV as an oncolytic agent and vaccine vector.IMPORTANCEViruses often reprogram host cell metabolism to facilitate replication. How poxviruses, such as the prototype member, vaccinia virus (VACV), modulate host cell metabolism is not well understood. Understanding how VACV affects these metabolic pathways is key to learning about viral replication and developing antiviral treatments. This study highlights the importance of de novo pyrimidine synthesis during VACV infection. We found that the vaccinia growth factor (VGF), a viral protein similar to the cellular epidermal growth factor (EGF), helps VACV activate the enzyme CAD of the de novo pyrimidine pathway. Upon nutrient limitation, VGF is needed for the activation of CAD through mTORC1-S6K signaling. VGF peptide alone is unable to activate this pathway independent of infection, suggesting the involvement of other viral factor(s). Our research not only sheds light on how VACV regulates metabolism but also holds promise for improving VACV as a cancer treatment and vaccine.
    Keywords:  CAD; asparagine; glutamine; mTORC1; metabolism; nutrient stress; nutrition; poxvirus; pyrimidine; vaccinia virus
    DOI:  https://doi.org/10.1128/jvi.02110-24
  57. bioRxiv. 2025 Jan 02. pii: 2024.12.31.630961. [Epub ahead of print]
    Autophagy-Mediated Downregulation of AXL and TIM-1 Promotes Sustained Zika Virus Infection.
    Jingyou Yu, Yi-Min Zheng, Megan A Sheridan, Toshihiko Ezashi, R Michael Roberts, Shan-Lu Liu.
      Zika virus (ZIKV) infection can lead to a variety of clinical outcomes, including severe congenital abnormalities. The phosphatidylserine (PS) receptors AXL and TIM-1 are recognized as critical entry factors for ZIKV in vitro . However, it remains unclear if and how ZIKV regulates these receptors during infection. In this study, we investigated AXL and TIM-1 expression in human alveolar basal epithelial A549 cells, glioblastoma U87 cells, and embryonic stem cells-derived trophoblast following ZIKV infection. We found that both the Asian strain FSS13025 and the African strain MR766 of ZIKV downregulate AXL, with a milder effect on TIM-1. We identified several ZIKV proteins, notably envelope (E), NS2A, NS3, and NS4B, that contribute to this downregulation. Notably, treatment with lysosomal inhibitor NH 4 Cl or the autophagy inhibitor 3-Methyladenine (3-MA) mitigated the AXL/TIM-1 downregulation, indicating autophagy's involvement in the process. Importantly, this downregulation facilitates sustained viral replication and promotes viral spread by preventing superinfection and limiting cell death, which is also associated with impaired innate immune signaling. Our findings uncover a mechanism by which ZIKV downregulates entry factors to enhance prolonged viral replication and spread.
    AUTHOR SUMMARY: Zika virus (ZIKV) infection has been associated with severe birth defects, yet the mechanisms underlying its pathogenesis remain poorly understood. In this study, we investigated phosphatidylserine (PS) receptors AXL and TIM-1 and discovered that they promote ZIKV entry but are downregulated by the virus infection. We identified several ZIKV proteins involved in AXL and TIM-1 down-regulation through an autophagy-mediated process. Mechanistically, this loss of surface receptors protects host cells from superinfection and cell death, while dampening the innate immune response, ultimately promoting viral spread. Our results contribute to a better understanding of ZIKV's interactions with host cells and offer insight into viral entry, innate signaling, and pathogenesis.
    DOI:  https://doi.org/10.1101/2024.12.31.630961
  58. J Biol Chem. 2025 Jan 09. pii: S0021-9258(25)00018-3. [Epub ahead of print] 108171
    Autophagy related 7 (ATG7) regulates food intake and liver health during asparaginase exposure.
    Brian A Zalma, Maria Ibrahim, Flavio C Rodriguez-Polanco, Chintan T Bhavsar, Esther M Rodriguez, Eduardo Cararo-Lopes, Saad A Farooq, Jordan L Levy, Ronald C Wek, Eileen White, Tracy G Anthony.
      Amino acid starvation by the chemotherapy agent asparaginase is a potent activator of the integrated stress response (ISR) in liver and can upregulate autophagy in some cell types. We hypothesized that autophagy related 7 (ATG7), a protein that is essential for autophagy and an ISR target gene, was necessary during exposure to asparaginase to maintain liver health. We knocked down Atg7 systemically (Atg7Δ/Δ) or in hepatocytes only (ls-Atg7KO) in mice before exposure to pegylated asparaginase for 5 d. Intact mice injected with asparaginase lost body weight due to reduced food intake and increased energy expenditure. Systemic Atg7 ablation reduced liver protein synthesis and increased liver injury in vehicle-injected mice, but did not further reduce liver protein synthesis, exacerbate steatosis or liver injury, or alter energy expenditure following 5 d asparaginase exposure. Atg7Δ/Δ mice were unexpectantly protected from asparaginase-induced anorexia and weight loss. This protection corresponded with reduced phosphorylation of hepatic GCN2 and blunted increases in ISR gene targets including growth differentiation factor 15 (GDF15), a negative regulator of food intake. Interestingly, asparaginase elevated serum GDF15 and reduced food intake in ls-Atg7KO mice, similar to intact mice. Liver triglycerides and production of the hepatokine fibroblast growth factor 21, another ISR gene target, were suppressed in asparaginase-exposed Atg7Δ/Δ and ls-Atg7KO mice. This work identifies a bidirectional relationship between autophagy and the ISR in the liver during asparaginase, affecting food intake and liver health.
    Keywords:  FGF21; GDF15; amino acid; body composition; eukaryotic initiation factor 2 (eIF2); gene expression; polysome profiling; protein synthesis; translation
    DOI:  https://doi.org/10.1016/j.jbc.2025.108171
  59. Int J Mol Sci. 2024 Dec 25. pii: 80. [Epub ahead of print]26(1):
    Administration of AICAR, an AMPK Activator, Prevents and Reverses Diabetic Polyneuropathy (DPN) by Regulating Mitophagy.
    Krish Chandrasekaran, Joungil Choi, Mohammad Salimian, Ahmad F Hedayat, James W Russell.
      Diabetic peripheral neuropathy (DPN) is a common complication of diabetes in both Type 1 (T1D) and Type 2 (T2D). While there are no specific medications to prevent or treat DPN, certain strategies can help halt its progression. In T1D, maintaining tight glycemic control through insulin therapy can effectively prevent or delay the onset of DPN. However, in T2D, overall glucose control may only have a moderate impact on DPN, although exercise is clearly beneficial. Unfortunately, optimal exercise may not be feasible for many patients with DPN because of neuropathic foot pain and poor balance. Exercise has several favorable effects on health parameters, including body weight, glycemic control, lipid profile, and blood pressure. We investigated the impact of an exercise mimetic, 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), on DPN. AICAR treatment prevented or reversed experimental DPN in mouse models of both T2D and T1D. AICAR in high-fat diet (HFD-fed) mice increased the phosphorylation of AMPK in DRG neuronal extracts, and the ratio of phosphorylated AMPK to total AMPK increased by 3-fold (HFD vs. HFD+AICAR; p < 0.001). Phospho AMP increased the levels of dynamin-related protein 1 (DRP1, a mitochondrial fission marker), increased phosphorylated autophagy activating kinase 1 (ULK1) at Serine-555, and increased microtubule-associated protein light chain 3-II (LC3-II, a marker for autophagosome assembly) by 2-fold. Mitochondria isolated from DRG neurons of HFD-fed had a decrease in ADP-stimulated state 3 respiration (120 ± 20 nmol O2/min in HFD vs. 220 ± 20 nmol O2/min in control diet (CD); p < 0.001. Mitochondria isolated from HFD+AICAR-treated mice had increased state 3 respiration (240 ± 30 nmol O2/min in HFD+AICAR). However, AICAR's protection in DPN in T2D mice was also mediated by its effects on insulin sensitivity, glucose metabolism, and lipid metabolism. Drugs that enhance AMPK phosphorylation may be beneficial in the treatment of DPN.
    Keywords:  AICAR; AMPK; diabetic neuropathy; exercise mimetics; glucose metabolism; intraepidermal nerve fiber density; lipid metabolism; mitochondrial biogenesis; mitochondrial fission; nerve conduction
    DOI:  https://doi.org/10.3390/ijms26010080
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