bims-auttor 2026-01-04 papers

bims-auttor

Biomed News

on Autophagy and mTOR

Issue of 2026–01–04
twenty-two papers selected by
Viktor Korolchuk, Newcastle University

TFEB coordinates autophagosome biogenesis and ribophagy during starvation via SQSTM1.
Autophagy and selective autophagy receptors: Key players against Alzheimer's disease.
PEX14 powers OPTN (optineurin) to drive peroxisome turnover.
Growth factor-independent mTORC1 signaling promotes primary cilia length via suppression of autophagy.
A novel mechanism of lysosome-dependent microautophagy of er exit sites.
Phosphorylation of Atg12 for optimal autophagy in yeast Komagataella phaffii.
Host-Microbe Interactions: Understanding the Mechanism of Autophagy in Viral Replication and Immune Evasion.
Methods for Measuring TNFα-Induced Autophagy in Cancer Cells.
Autophagy-Related Proteins Influence Mouse Epididymal Sperm Motility.
p62 sorts Lupus La and selected microRNAs into breast cancer-derived exosomes.
DEAF1 - a transcriptional brake on muscle autophagy.
mTOR signaling networks: mechanistic insights and translational frontiers in disease therapeutics.
A dwdr45 knock-out drosophila model to decipher the role of autophagy in BPAN.
Hsp70-Bim interaction mediated mitophagy as a potential therapeutic target for CML stem cells.
Senecavirus a VP2 protein orchestrates PRDX1 degradation through dual autophagy pathways: macroautophagy and chaperone-mediated autophagy.
circFKBP8(5S,6)-encoded protein promotes stress susceptibility in mice by down-regulating dopamine D3 receptor expression and its downstream AMPK/mTOR/ULK1 autophagy signaling.
Unraveling Lysosomal Exocytosis: From Molecular Mechanisms to Physiological Functions.
Novel Roles of GDF15 in Alleviating Renal Fibrosis: Promoting Autophagy and Lysosome Biogenesis via Inhibition of the PI3K/Akt/mTOR Pathway.
KLHL8-mediated ubiquitination and TAX1BP1-dependent autophagic degradation of GPX4 drive neuronal ferroptosis.
Pexophagy meets physiology.
Linking Cell Architecture to Mitochondrial Signaling in Neurodegeneration: The Role of Intermediate Filaments.
Interplay of GBA1 with lysosomal dysfunction and inflammation in Parkinson's disease.

Sci Adv. 2026 Jan 02. 12(1): eaea9302

TFEB coordinates autophagosome biogenesis and ribophagy during starvation via SQSTM1.

Maria Iavazzo, Laura Cinque, Sophie Levantovsky, Castrese Morrone, Jlenia Monfregola, Andrea Raimondi, Elena Polishchuk, Rossella De Cegli, Diego Carrella, Edoardo Nusco, Luigi Ferrante, Francesca Sacco, Lisa B Frankel, Christian Behrends, Carmine Settembre.

(Macro)autophagy is a conserved cellular degradation pathway that delivers substrates to lysosomes via autophagosomes. Among various physiological stimuli, nutrient starvation is the most potent inducer of autophagy. In response to starvation, transcription factor EB (TFEB) is activated and up-regulates a broad set of autophagy-related genes. However, the mechanisms by which TFEB promotes autophagosome biogenesis remain incompletely understood. Here, we demonstrate that TFEB-mediated transcriptional induction of sequestosome 1 (SQSTM1; p62) triggers the formation of SQSTM1-positive bodies that recruit essential autophagy factors, thereby initiating autophagosome biogenesis. Genetic disruption of TFEB-dependent SQSTM1 regulation markedly impairs starvation-induced autophagy, underscoring the critical role of the TFEB-SQSTM1 axis in the autophagic response to nutrient stress. Furthermore, we show that these SQSTM1 bodies contain ubiquitinated ribosomal proteins and that TFEB promotes ribosomal protein ubiquitination by inducing the E3 ubiquitin ligase ZNF598. Collectively, our findings uncover a transcriptionally coordinated mechanism that regulates both autophagosome biogenesis and substrate ubiquitination, facilitating efficient cargo clearance during starvation-induced autophagy.

DOI: https://doi.org/10.1126/sciadv.aea9302
Neural Regen Res. 2025 Dec 30.

Autophagy and selective autophagy receptors: Key players against Alzheimer's disease.

Krenare Bruqi, Flavie Strappazzon.

  The devastating neurodegenerative disorder of Alzheimer's disease hallmarks the presence of protein aggregates known as amyloid-β plaques and neurofibrillary tangles, composed of amyloid-β peptides and aberrantly phosphorylated Tau protein, respectively. The accumulation of these inclusions leads to significant alterations in neuronal homeostasis and overall brain function, resulting in a progressive and rapid cognitive decline. Autophagy, the molecular mechanism of cellular waste removal through the lysosomal pathway, accounts for the degradation of both amyloid-β plaques and neurofibrillary tangles in the brain, conferring therefore protection against the pathology. In addition to general autophagy, several lines of evidence have reported the implication of selective autophagy receptors, including sequestosome1/p62, the neighbor of BRCA1 gene, the nuclear-dot protein 52, and optineurin, in mediating the autophagic clearance of amyloid-β, phosphorylated Tau, or both. Herein, we have highlighted autophagy and selective autophagy as pivotal mechanisms in Alzheimer's disease, underlining selective autophagy receptors as a potential target for treatments in the future.

Keywords:  Alzheimer's diseases; amyloid-β pathology; amyloid-β plaques; autophagy; neurodegeneration; neurofibrillary tangles; selective autophagy; selective autophagy receptors; tauopathy

DOI:  https://doi.org/10.4103/NRR.NRR-D-25-00976
Autophagy. 2025 Dec 31. 1-3

PEX14 powers OPTN (optineurin) to drive peroxisome turnover.

Hongli Li, Jorge E Azevedo, Marc Fransen.

  Cells maintain organelle integrity and metabolic balance through tightly coordinated quality control systems. Autophagy plays a central role by recycling damaged and unnecessary cellular components, with selective pathways providing specificity through dedicated receptors. Although OPTN is well-established as a receptor for mitophagy, aggrephagy, and xenophagy, its role in pexophagy, the selective autophagic degradation of peroxisomes, has only recently been recognized. Our recent work identifies the peroxisomal membrane protein PEX14 as a critical docking platform for OPTN, enabling recruitment of autophagic machinery and initiation of pexophagy. How PEX14 engages OPTN, what triggers this interaction, and how it drives the autophagic engulfment of peroxisomes remain unclear. In this punctum, we contextualize our findings and highlight unresolved questions that must be addressed to understand the physiological and pathological relevance of this process.

Keywords:  Autophagy receptors; TBK1; organelle quality control; peroxisome biogenesis; pexophagy; phosphorylation; ubiquitination

DOI:  https://doi.org/10.1080/15548627.2025.2610452
iScience. 2025 Dec 19. 28(12): 114204

Growth factor-independent mTORC1 signaling promotes primary cilia length via suppression of autophagy.

Jong Shin, Khaled Tighanimine, Yann Cormerais, Dean M Rosenthal, Pratima Niroula, Samuel C Lapp, Krystle C Kalafut, Madi Y Cisse, Sandra Schrötter, Brendan D Manning.

  The mechanistic target of rapamycin (mTOR) complex 1 (mTORC1), a sensor of growth signals that control cell growth, has been studied mainly in proliferating cells. Primary cilia are sensory organelles present on most quiescent cells and are essential for receiving environmental and developmental signals. Given that ciliated cells are non-proliferative, we investigated whether mTORC1 signaling influences primary cilia growth. Here, we show that mTORC1 promotes cilia elongation without affecting ciliogenesis by suppressing autophagy. Inhibiting mTORC1 through pharmacological, nutritional, or genetic interventions shortened primary cilia, whereas activation of the pathway elongated them. Furthermore, pharmacological or genetic inhibition of autophagy-a key downstream process blocked by mTORC1-elongated primary cilia and rendered them resistant to mTORC1 inhibition. These mTORC1-mediated effects extend to mouse neurons ex vivo and in vivo. Thus, the mTORC1-mediated regulation of autophagy controls primary cilia length and may contribute to diseases in which ciliary function is altered, referred to as ciliopathies.

Keywords:  Cell biology; Molecular physiology

DOI:  https://doi.org/10.1016/j.isci.2025.114204
Autophagy. 2025 Dec 31.

A novel mechanism of lysosome-dependent microautophagy of er exit sites.

Dibyendu Bhattacharyya, Daniel J Klionsky.

  Endoplasmic reticulum (ER) exit sites (ERES) serve as essential hubs for the packaging and export of secretory proteins into the COPII vesicular pathway. Previous studies have shown that ERES are dynamic and capable of adapting to stress, but the molecular details controlling their degradation under nutrient stress conditions were largely unknown. The study by Liao et al. (2024) introduces a new mechanism in which ERES are degraded through lysosome-dependent microautophagy in response to nutrient stress. This process is uniquely facilitated by COPII components, the calcium-binding adaptor ALG2, and the ESCRT machinery. The authors demonstrate that inhibiting MTOR triggers calcium release from lysosomes, which then recruits ALG2, leading to SEC31 ubiquitination and subsequently promoting PDCD6IP/ALIX-ESCRT-dependent lysosomal engulfment of ERES. This research reveals an unexplored pathway for the quality control and recycling of secretory machinery, thereby improving our understanding of ER turnover and establishing a mechanistic link between nutrient sensing, autophagy, and remodeling of the secretory pathway.

Keywords:  Autophagy; COPII; ESCRT; er exit sites; microautophagy

DOI:  https://doi.org/10.1080/15548627.2025.2608387
J Biochem. 2025 Dec 29. pii: mvaf085. [Epub ahead of print]

Phosphorylation of Atg12 for optimal autophagy in yeast Komagataella phaffii.

Masatoshi Kobe, Kosuke Shiraishi, Takumi Nakatsuji, Hiroya Yurimoto, Kei Saito, Masahide Oku, Yasuyoshi Sakai.

  Macroautophagy is an evolutionarily conserved degradation pathway in eukaryotes that mediates the turnover of cytoplasmic components. The formation of autophagosomes, a hallmark of autophagy, involves autophagy-related (Atg) proteins, including two ubiquitin-like conjugation systems, Atg12 system and Atg8 system. In most species, Atg12 covalently binds Atg5, forming the Atg12-Atg5-Atg16 complex that functions as an E3-like enzyme to promote Atg8 conjugation with phosphatidylethanolamine (PE), a step essential for autophagosomal maturation. By contrast, certain species such as yeast Komagataella phaffii lack Atg10 and/or the C-terminal glycine of Atg12, relying instead on a non-covalent Atg12-Atg5 complex. However, the physiological significance of this reductively evolved non-covalent system and its divergence in molecular mechanisms from species harboring the canonical covalent Atg12 system remain undiscussed. In this study, we demonstrate that under nitrogen starvation, KpAtg12 is phosphorylated, and lipidation of KpAtg8 is enhanced. Our results with a phosphorylation-deficient mutant of KpAtg12 suggest that KpAtg12 phosphorylation modulates the activity of nitrogen starvation-induced macroautophagy through KpAtg8 lipidation reaction.

Keywords:   Komagataella phaffii ; Atg12; autophagy; non-covalent Atg12-Atg5 complex; phosphorylation

DOI:  https://doi.org/10.1093/jb/mvaf085
Vet Sci. 2025 Dec 15. pii: 1200. [Epub ahead of print]12(12):

Host-Microbe Interactions: Understanding the Mechanism of Autophagy in Viral Replication and Immune Evasion.

Ziyuan Fu, Xiaowen Li, A M Abd El-Aty, Ridvan Yagan, Xianghong Ju, Yanhong Yong.

  Autophagy is a highly conserved catabolic process in eukaryotic cells that maintains cellular homeostasis by degrading damaged or superfluous intracellular components. Autophagy plays a dual, paradoxical role during viral infection. However, for most viruses, the induction of autophagy provides a favorable intracellular environment for the full completion of their life cycles. Most viruses that benefit from autophagy adopt a "regulate but not destroy" strategy, i.e., they initiate the autophagic process while suppressing their immune system through mechanisms such as blocking autophagosome-lysosome fusion. This allows them to avoid self-elimination while redirecting other functions of the autophagic machinery-for instance, utilizing autophagy-derived structures such as autophagosomes and double-membrane vesicles (DMVs) as specialized sites for viral genome replication, particle assembly, and maturation. The maintenance of cellular homeostasis by autophagy is crucial for the establishment of viral infection, as it provides a viable cellular microenvironment for viral replication; after infection occurs, inhibiting the degradative function of autophagy becomes a key strategy for viruses. Although canonical degradative autophagy exerts a negative effect on most viruses, redirected nondegradative autophagic structures and repurposed autophagic mechanisms are essential for the efficient replication of various viruses. In-depth analysis of this dynamic virus-autophagy interplay will provide important insights for elucidating virus-host interactions and developing autophagy-targeted antiviral strategies.

Keywords:  antiviral therapy; autophagy; immune regulation; selective autophagy; viral escape; viral infection

DOI:  https://doi.org/10.3390/vetsci12121200
Methods Mol Biol. 2026 ;2983 143-158

Methods for Measuring TNFα-Induced Autophagy in Cancer Cells.

Sheyda Najafi, Ehab M Abo-Ali, Vikas V Dukhande.

  Autophagy is an evolutionarily conserved cellular mechanism in eukaryotes that plays an important role in the maintenance of cellular homeostasis. The autophagy process maintains protein homeostasis by recycling damaged organelles and degrading many long-lived or damaged proteins through lysosomes in coordination with the ubiquitin-proteasome system. Cytokines are low molecular weight secreted proteins that regulate a broad range of biological activities. For instance, pro-inflammatory cytokines such as tumor necrosis factor-α (TNFα) induce inflammation, autophagy, and apoptotic cell death. In this chapter, we discuss experimental techniques such as immunoblotting and fluorescence microscopy that can be utilized to measure autophagy in response to TNFα treatment.

Keywords:  Apoptosis; Autophagy; Bafilomycin A1; Chloroquine; Fluorescence microscopy; Immunoblotting; LC3; TNFα; p62

DOI:  https://doi.org/10.1007/978-1-0716-4901-5_14
Int J Mol Sci. 2025 Dec 10. pii: 11895. [Epub ahead of print]26(24):

Autophagy-Related Proteins Influence Mouse Epididymal Sperm Motility.

Lorena Rodríguez-Páez, Jonathan J Magaña, Charmina Aguirre-Alvarado, Verónica Alcántara-Farfán, Germán Chamorro-Cevallos, José Melesio Cristóbal-Luna, Erika Rosales-Cruz, Elba Reyes-Maldonado, Guadalupe Elizabeth Jiménez-Gutiérrez, Joaquín Cordero-Martínez.

  Autophagy is an intracellular process that recycles and degrades cytoplasmic components, including organelles and macromolecules, to provide energy and basic components for cell survival, maintain cellular homeostasis, and avoid self-damage. It is currently not fully known if mouse sperm undergoes the autophagy process, nor is the subcellular distribution, protein levels of autophagy-related proteins, and the biological role of autophagy in epididymal mouse sperm physiology fully understood. We aimed to investigate key autophagy markers, including LC3 (microtubule-associated protein 1A/1B-light chain 3), p62/SQSTM1 (Sequestosome 1), and mTOR (mechanistic Target of Rapamycin), in epididymal mouse sperm under capacitation (Cap) or non-capacitation (NC) conditions. Furthermore, we evaluated the possible role of these autophagy-related proteins on sperm viability, motility, intracellular pH (pHi), intracellular calcium concentrations [Ca2+]i, mitochondrial membrane potential, and acrosome reaction (AR) induction in the presence or absence of chloroquine (CQ), K67, and rapamycin. Our results suggest a dynamic re-localization of the autophagy-related proteins LC3, p62/SQSTM1, and mTOR under capacitation conditions. Moreover, treatment with specific autophagy inhibitors, such as CQ and K67, resulted in decreased LC3-II and p62/SQSTM1 protein levels. Additionally, rapamycin did not increase mTOR levels. Interestingly, treatment with these inhibitors also resulted in decreased motility, reduced mitochondrial membrane potential and hindered AR induction without affecting sperm viability. Overall, the presence and dynamic re-localization of LC3, p62/SQSTM1, and mTOR suggest that mouse epididymal sperm could perform initial steps of autophagy under capacitation conditions, and results of the pharmacological treatment could be associated with an important role of these autophagy-related proteins in sperm motility and AR induction.

Keywords:  LC3; acrosome reaction; mTOR; motility; p62/SQSTM1; spermatozoa

DOI:  https://doi.org/10.3390/ijms262411895
J Cell Biol. 2026 Mar 02. pii: e202503087. [Epub ahead of print]225(3):

p62 sorts Lupus La and selected microRNAs into breast cancer-derived exosomes.

Jordan Matthew Ngo, Justin Krish Williams, Morayma Mercedes Temoche-Diaz, Abinayaa Murugupandiyan, Randy Schekman.

Exosomes are multivesicular body-derived extracellular vesicles that are secreted by metazoan cells. Exosomes have utility as disease biomarkers, and exosome-mediated miRNA secretion has been proposed to facilitate tumor growth and metastasis. Previously, we demonstrated that the Lupus La protein (La) mediates the selective incorporation of miR-122 into metastatic breast cancer-derived exosomes; however, the mechanism by which La itself is sorted into exosomes remains unknown. Using unbiased proximity labeling proteomics, biochemical fractionation, superresolution microscopy, and genetic tools, we establish that the selective autophagy receptor p62 sorts La and miR-122 into exosomes. We then performed small RNA sequencing and found that p62 depletion reduces the exosomal secretion of tumor suppressor miRNAs and results in their accumulation within cells. Our data indicate that p62 is a quality control factor that modulates the miRNA composition of exosomes. Cancer cells may exploit p62-dependent exosome cargo sorting to eliminate tumor suppressor miRNAs and thus to promote cell proliferation.

DOI: https://doi.org/10.1083/jcb.202503087
Autophagy. 2025 Dec 31. 1-2

DEAF1 - a transcriptional brake on muscle autophagy.

Wen Xing Lee, Kah Yong Goh, Sze Mun Choy, Hong-Wen Tang.

  Macroautophagy/autophagy protects muscle from proteotoxic stress and maintains tissue homeostasis, yet skeletal muscle relies on it more than most organs. Adult fibers endure constant mechanical strain and require continuous turnover of long-lived proteins, while muscle stem cells (MuSCs) depend on autophagy to remain quiescent, activate after injury, and regenerate effectively. How autophagy is transcriptionally regulated in muscle has been unclear. We identified DEAF1 as a transcriptional brake on autophagy. In MuSCs, DEAF1 controls activation and regeneration and becomes aberrantly elevated with age, promoting protein aggregate formation and cell death. In muscle fibers, DEAF1 is chronically induced during aging, suppressing autophagy and driving functional decline. Exercise reverses DEAF1 induction, restoring autophagy and muscle function. These findings reveal DEAF1 as a key regulator linking autophagy to regeneration and aging, highlighting a therapeutically tractable axis for preserving muscle health.

Keywords:  Autophagy; DEAF1; muscle; muscle stem cell; regeneration

DOI:  https://doi.org/10.1080/15548627.2025.2610451
Signal Transduct Target Ther. 2025 Dec 30. 10(1): 428

mTOR signaling networks: mechanistic insights and translational frontiers in disease therapeutics.

Hanxiao Zhang, Xia Xiao, Zhenrui Pan, Svetlana Dokudovskaya.

The mammalian target of rapamycin (mTOR) pathway is a central regulator of cellular growth, metabolism, and homeostasis, integrating a wide array of intracellular and extracellular cues, including nutrient availability, growth factors, and cellular stress, to coordinate anabolic and catabolic processes such as protein, lipid, and nucleotide synthesis; autophagy; and proteasomal degradation. The dysregulation of this signaling hub has broad implications for health and disease. To commemorate the 50th anniversary of the discovery of rapamycin, we provide a comprehensive synthesis of five decades of mTOR research. This review traces the historical trajectory from the early characterization of the biological effects of rapamycin to the elucidation of its molecular target and downstream pathways. We integrate fundamental and emerging insights into the roles of mTOR across nearly all domains of cell biology and development, with a particular focus on the expanding landscape of therapeutic interventions targeting this pathway. Special emphasis is placed on the crosstalk between mTOR signaling and mitochondrial regulation, highlighting the mechanisms by which these two metabolic hubs co-regulate cellular adaptation, survival, and disease progression. The dynamic interplay between mTOR and mitochondrial networks governs key aspects of bioenergetics, redox balance, and cell fate decisions and is increasingly implicated in pathophysiological contexts ranging from cancer and aging to neurodegenerative and immune disorders.

DOI: https://doi.org/10.1038/s41392-025-02493-4
Hum Mol Genet. 2025 Dec 29. pii: ddaf198. [Epub ahead of print]

A dwdr45 knock-out drosophila model to decipher the role of autophagy in BPAN.

Marion Celle, Sahra Aniorte, Abdul-Raouf Issa, Marion Falabregue, Haixiu Jin, Irene Sanchez-Mirasierra, Shuzhe Ding, Sandra-Fausia Soukup, Laurent Seugnet, Lujian Liao, Gaetan Lesca, Ludivine Walter, Bertrand Mollereau.

  Beta-propeller protein-associated neurodegeneration (BPAN) is a rare neurological disorder characterized by severe cognitive and motor impairments. BPAN is caused by de novo pathogenic variants in the WDR45 gene on the X chromosome. WDR45 gene encodes the protein WDR45/WIPI4, a known regulator of autophagy. A defective autophagy has been observed in cellular models of BPAN disease and is associated with neurological dysfunctions in wdr45 knockout (KO) mice. However, it remains unclear whether the autophagic defect directly contributes to all WDR45 loss-induced phenotypes or whether other WDR45-dependent cellular functions are involved. To investigate this, we generated a CRISPR/Cas9-mediated KO of CG11975 (dwdr45 KO), the Drosophila homolog of WDR45. Our analysis revealed that dwdr45 KO flies display BPAN-like phenotypes, including impaired locomotor function, seizure-like behavior, autophagy dysregulation and iron dyshomeostasis. Additionally, dwdr45 KO flies exhibit shortened lifespan compared to control flies. These findings demonstrate that dwdr45 KO fly is a relevant in-vivo model for investigating the key cellular and molecular mechanisms underlying BPAN-associated phenotypes. Here we showed that induction of autophagy in dwdr45 KO flies improved both the shortened lifespan and the seizure-like behavior, but did not restore locomotor function. This suggests that defective autophagy contributes to some, but not all, aspects of the phenotypes resulting from loss of dWdr45 function.

Keywords:  Drosophila; WDR45; autophagy; neurological disease; rare disease

DOI:  https://doi.org/10.1093/hmg/ddaf198
Stem Cell Reports. 2025 Dec 26. pii: S2213-6711(25)00355-8. [Epub ahead of print] 102751

Hsp70-Bim interaction mediated mitophagy as a potential therapeutic target for CML stem cells.

Ting Song, Yang Song, Hong Zhang, Zhiyuan Hu, Fangkui Yin, Maojun Jiang, Yanxin Zhang, Ziqian Wang, Zhichao Zhang.

  In chronic myeloid leukemia (CML), disease persistence in patients is maintained by leukemic stem cells (LSCs), which drive tyrosine kinase inhibitor (TKI) resistance. Autophagy has been proposed as a potential therapy to eradicate CML LSCs. Here, using a small-molecule inhibitor of Hsp70 (heat shock protein 70)-Bim (Bcl-2-interacting mediator of cell death) interaction, S1-10, we demonstrate that Hsp70-Bim is a target for CML stemness maintenance. Hsp70-Bim is driven by Bcr-Abl and mediates particularly stronger mitophagy in CML LSCs than differentiated CML cells and HSCs. The more selective mitophagy regulation of Hsp70-Bim than ULK1 (unc-51-like autophagy activating kinase 1) is illustrated. Pharmacological inhibition of Hsp70-Bim blocks mitophagy, leading to the differentiation of CML LSCs, loss of quiescence, and loss of LSC self-renewal potential. In the patient-derived xenograft (PDX) CML models, S1g-10 reduces the number of LSCs by more than 80% after two weeks of injection, without obvious toxicity on normal red blood cells.

Keywords:  Hsp70-Bim; chronic myeloid leukemia; leukemia stem cells; mitophagy; tyrosine kinase inhibitor

DOI:  https://doi.org/10.1016/j.stemcr.2025.102751
Autophagy. 2026 Jan 01. 1-19

Senecavirus a VP2 protein orchestrates PRDX1 degradation through dual autophagy pathways: macroautophagy and chaperone-mediated autophagy.

Zhaoyang Li, Xiaoyu Yang, Jingyu Mao, Penghui Zeng, Yuxiang Qi, Yongyan Shi, Jinshuo Guo, Jianwei Zhou, Dedong Wang, Jue Liu, Lei Hou.

  Co-adaptation between viruses and autophagy has equipped viruses with diverse strategies to regulate host redox homeostasis, thereby facilitating viral replication. However, the mechanisms by which viruses manipulate PRDX1 (peroxiredoxin 1), a key antioxidative enzyme, via autophagy remain poorly understood. Here, we demonstrate that infection by Senecavirus A (SVA), an emerging picornavirus, induces PRDX1 degradation, and that PRDX1 negatively regulates viral replication. Decreased PRDX1 expression impairs cellular antioxidant defenses, leading to enhanced reactive oxygen species generation that facilitates SVA replication. Screening of viral proteins revealed that SVA VP1, VP2, and 3A induce PRDX1 degradation through vesicle formation-dependent macroautophagy. Notably, viral VP2 can also recruit HSPA8/HSC70 to specifically target PRDX1, directing it for degradation via LAMP2A-mediated chaperone-mediated autophagy (CMA). Collectively, these findings demonstrate that the SVA VP2 protein plays a central role in orchestrating both macroautophagy- and CMA-mediated PRDX1 degradation, establishing PRDX1 as a potential intervention target for countering SVA infection.Abbreviations: AKT/protein kinase B: AKT serine/threonine kinase; ATP: adenosine triphosphate; BHK-21: baby hamster kidney-21; CAT: catalase; CCCP: BMDMs: bone marrow-derived macrophages; CMA: chaperone-mediated autophagy; co-IP: co-immunoprecipitation; CCCP: carbonyl cyanide 3-chlorophenylhydrazone; CQ: chloroquine; DCFH-DA: 2',7'-dichlorodihydrofluorescein diacetate; DMSO: dimethyl sulfoxide; GFP: green fluorescent protein; GPX: glutathione peroxidase; GSH: glutathione; HEK-293T: human embryonic kidney 293T; hpi: hours post-infection; HSPA8/HSC70: heat shock protein family A (Hsp70) member 8; KO: knockout; LAMP2A: lysosomal associated membrane protein 2A; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; Mdivi-1: mitochondrial division inhibitor-1; mM: millimole; MMP: mitochondrial membrane potential; mPTP: mitochondrial permeability transition pore; MTOR: mechanistic target of rapamycin kinase; NAC: N-acetylcysteine; PI3K: phosphoinositide 3-kinase; PRDX1: peroxiredoxin 1; RT-qPCR: real-time quantitative reverse transcription polymerase chain reaction; ROS: reactive oxygen species; SD: standard deviation; SOD: superoxide dismutase; SQSTM1: sequestosome 1; SVA: Senecavirus A; TIMM23: translocase of inner mitochondrial membrane 23; TOMM20: translocase of outer mitochondrial membrane 20; WT: wild-type; μg: microgram; μm: micrometer; μM: micromolar.

Keywords:  Degradation; PRDX1; SVA VP2 protein; macroautophagy and chaperone-mediated autophagy; reactive oxygen species; viral replication

DOI:  https://doi.org/10.1080/15548627.2025.2610449
Genes Dis. 2026 Mar;13(2): 101718

circFKBP8(5S,6)-encoded protein promotes stress susceptibility in mice by down-regulating dopamine D3 receptor expression and its downstream AMPK/mTOR/ULK1 autophagy signaling.

Dandan Xu, Zihan Huang, Gaojia Zhang, Jiao Jiao, Yujia Cao, Mengyu Liu, Yan Kong, Zhijun Zhang.

  Major depressive disorder (MDD) is a serious mental disorder, yet the mechanism by which circular RNAs (circRNAs) are involved in the pathogenesis of MDD by encoding proteins is unknown. Our previous study has shown that circFKBP8(5S,6) relies on its encoded protein, namely cFKBP8, to promote susceptibility to chronic unpredictable mild stress (CUMS) in mice, but the precise molecular mechanisms are unknown. Here we found that overexpression of circFKBP8(5S,6) or cFKBP8 in neurons of the prelimbic cortex (PrL) of CUMS mice down-regulated the expression levels of DRD3 and its downstream AMPK/ULK1 (Ser555) and AMPK/mTOR/ULK1 (Ser757) pathways, which resulted in down-regulation of neuronal autophagy levels. Interestingly, both the activation and overexpression of DRD3 ameliorated the exacerbation of depressive-like behaviors induced by circFKBP8(5S,6) or cFKBP8, activated both the AMPK/ULK1 (Ser555) pathway and the AMPK/mTOR/ULK1 (Ser757) pathway, and up-regulated neuronal autophagy levels. In conclusion, circFKBP8(5S,6) or cFKBP8 promotes susceptibility to CUMS in mice, at least in part, by down-regulating DRD3 expression and its downstream AMPK/mTOR/ULK1 signaling pathway-mediated neuronal autophagy.

Keywords:  Autophagy; Dopamine D3 receptor; Major depressive disorder; circRNA-encoded protein; circRNAs

DOI:  https://doi.org/10.1016/j.gendis.2025.101718
Traffic. 2026 Mar;27(1): e70026

Unraveling Lysosomal Exocytosis: From Molecular Mechanisms to Physiological Functions.

Shanshan Jiang, Jingyi Fu, Shan Li, Zehui Li, Qirui Zhao, Yuqi Yin, Mei Yang, Yonghua Wang.

Lysosomal exocytosis is a fundamental cellular process that involves the fusion of lysosomes with the plasma membrane and the release of lysosomal contents into the extracellular space. This review provides an in-depth analysis of the molecular mechanisms, physiological functions, and disease implications of lysosomal exocytosis, highlighting recent advances and novel aspects. We discuss the intricate molecular machinery that orchestrates lysosomal trafficking, docking, and fusion, as well as the critical roles of lysosomal exocytosis in maintaining cellular homeostasis, facilitating intercellular communication, and contributing to specialized cellular functions. Additionally, the review explores the complex involvement of lysosomal exocytosis in various disease states, including lysosomal storage disorders, neurodegenerative diseases, cancers, and immune system disorders, underlining its potential as a therapeutic target. By identifying current knowledge gaps and providing future research directions, this review aims to stimulate further investigation into the multifaceted nature of lysosomal exocytosis and its implications for human health and disease.

DOI: https://doi.org/10.1111/tra.70026
J Cell Mol Med. 2026 Jan;30(1): e70951

Novel Roles of GDF15 in Alleviating Renal Fibrosis: Promoting Autophagy and Lysosome Biogenesis via Inhibition of the PI3K/Akt/mTOR Pathway.

Youqi Li, Jinge Gu, Danping Tao, Haoyang Wu, Chen Yang, Yongjun Shi, Chengwen Huang, Boxun Luo, Jun Zhang.

  Tubulointerstitial fibrosis (TIF) significantly contributes to the development of end-stage renal disease (ESRD) in chronic kidney disease (CKD). However, the underlying mechanisms driving its development remain poorly understood, thereby impeding the development of effective prevention and treatment strategies. Although growth differentiation factor 15 (GDF15) has been implicated in kidney diseases, its specific relationship and mechanisms in the context of renal TIF remain unclear. In this study, we investigated the role and mechanisms of GDF15 in TIF using a mouse model of unilateral ureteral obstruction (UUO) and human tubular epithelial cells (HK2) stimulated by transforming growth factor-β1 (TGF-β1). Our findings demonstrated a downregulation of GDF15 expression in TIF. The upregulation of GDF15 mitigates renal TIF and reduces macrophage infiltration, whereas its downregulation exacerbates these conditions. Further analysis revealed that GDF15 promotes autophagy and lysosome biogenesis via the PI3K/Akt/mTOR signalling pathway, conferring a protective effect against TIF. In summary, our study demonstrated a negative correlation between GDF15 expression and renal TIF, highlighting its protective role in TIF. Moreover, GDF15 was found to promote autophagy and resolution of TIF through the PI3K/Akt/mTOR signalling pathway.

Keywords:  GDF15; PI3K/Akt/mTOR pathway; autophagy; macrophage infiltration; tubulointerstitial fibrosis

DOI:  https://doi.org/10.1111/jcmm.70951
Free Radic Biol Med. 2025 Dec 30. pii: S0891-5849(25)01469-8. [Epub ahead of print]

KLHL8-mediated ubiquitination and TAX1BP1-dependent autophagic degradation of GPX4 drive neuronal ferroptosis.

Jingjing Zhao, Yanfei Liu, Wenhua Sun, Weiwei Li, Zheng Xu.

  Ferroptosis, characterized by iron-dependent lipid peroxidation, is considered a key cell death pathway activated during ischemic stroke. GPX4, a negative regulator of ferroptosis, exacerbates brain damage. However, the precise regulatory mechanisms governing this process remain poorly understood. Here, we determined that oxygen-glucose deprivation/reoxygenation (OGD/R)-induced GPX4 degradation is primarily dependent on autophagy activation. Mechanistically, the E3 ubiquitin ligase KLHL8 tags GPX4 through ubiquitination and promotes its binding to the selective autophagy receptor TAX1BP1, thereby synergistically mediating GPX4's autophagic-lysosomal degradation. Clinical database analysis also confirmed that KLHL8 and TAX1BP1 expression are significantly upregulated in brain tissue from patients with ischemic stroke and positively correlated with ferroptosis scores. Therapeutic approaches have shown that AAV-mediated GPX4 overexpression or the use of autophagy inhibitors can effectively stabilize GPX4 levels, inhibit neuronal ferroptosis, and significantly improve cerebral infarction and neurological function in mice undergoing middle cerebral artery occlusion (MCAO). In particular, the combination of GPX4 overexpression and artesunate demonstrated a potent synergistic neuroprotective effect. These findings suggest that a cascade consisting of KLHL8-mediated ubiquitination and TAX1BP1-mediated selective autophagy is a key pathway for GPX4 degradation, and that the KLHL8-TAX1BP1-GPX4 regulatory axis provides a potential therapeutic target for ischemic stroke.

Keywords:  Autophagic degradation; GPX4; Ischemic stroke; KLHL8; Neuronal ferroptosis; TAX1BP1

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.12.052
J Cell Biol. 2026 Feb 02. pii: e202511183. [Epub ahead of print]225(2):

Pexophagy meets physiology.

Michael J Clague.

In this issue, Xiong et al. (https://doi.org/10.1083/jcb.202503169) introduce mouse models that enable tissue-resolved mapping of peroxisome turnover and pexophagy across development, metabolism, and disease. This study reveals striking cell type-specific differences in peroxisome dynamics and establishes a versatile platform for dissecting how pexophagy integrates with mitochondrial quality control and whole-body metabolic homeostasis.

DOI: https://doi.org/10.1083/jcb.202511183
Int J Mol Sci. 2025 Dec 08. pii: 11852. [Epub ahead of print]26(24):

Linking Cell Architecture to Mitochondrial Signaling in Neurodegeneration: The Role of Intermediate Filaments.

Emanuele Marzetti, Rosa Di Lorenzo, Riccardo Calvani, Hélio José Coelho-Júnior, Francesco Landi, Vito Pesce, Anna Picca.

  Mitochondrial dysfunction is a pivotal contributor to neurodegeneration. Neurons heavily rely on mitochondrial oxidative metabolism and therefore need highly efficient quality control mechanisms, including proteostasis, mitochondrial biogenesis, fusion-fission dynamics, and mitophagy, to sustain bioenergetics and synaptic function. With aging, deterioration of mitochondrial quality control pathways leads to impaired oxidative phosphorylation, excessive reactive oxygen species generation, calcium imbalance, and defective clearance of damaged organelles, ultimately compromising neuronal viability. Pathological protein aggregates, such as α-synuclein in Parkinson's disease, β-amyloid and tau in Alzheimer's disease, and misfolded superoxide dismutase 1 and transactive response DNA-binding protein 43 in amyotrophic lateral sclerosis, further aggravate mitochondrial stress, establishing self-perpetuating cycles of neurotoxicity. Such mitochondrial defects underscore mitochondria as a convergent pathogenic hub and a promising therapeutic target for neuroprotection. Intermediate filaments (IFs), traditionally viewed as passive structural elements, have recently gained attention for their roles in cytoplasmic organization, mitochondrial positioning, and energy regulation. Emerging evidence indicates that IF-mitochondria interactions critically influence organelle morphology and function in neurons. This review highlights the multifaceted involvement of mitochondrial dysfunction and IF dynamics in neurodegeneration, emphasizing their potential as targets for novel therapeutic strategies.

Keywords:  axonal transport; cell architecture; cell quality; cytoskeleton; mitochondrial dynamics; mitochondrial quality; mitophagy; neurofilaments; neuron; reactive oxygen species

DOI:  https://doi.org/10.3390/ijms262411852
Neural Regen Res. 2025 Dec 30.

Interplay of GBA1 with lysosomal dysfunction and inflammation in Parkinson's disease.

Ruochen Wang, Taku Hatano, Nobutaka Hattori, Davide Cossu.

  Mutations in the glucocerebrosidase (GBA1) gene, encoding the lysosomal enzyme glucocerebrosidase, represent the most significant genetic risk factor for Parkinson's disease. These variants define a distinct clinical subtype characterized by earlier onset, accelerated motor decline, and pronounced cognitive impairment. This review synthesizes current insights into the molecular mechanisms linking GBA1 dysfunction to lysosomal failure, α-synuclein aggregation, and neuroinflammation. Pathogenic alleles such as N370S and L444P disrupt sphingolipid metabolism, resulting in toxic accumulations of glucosylceramide and glucosylsphingosine, endoplasmic reticulum stress, and impaired clearance of misfolded proteins. This initiates a self-reinforcing cycle in which glucocerebrosidase deficiency promotes α-synuclein aggregation, which subsequently impairs glucocerebrosidase trafficking. We explore the convergence of GBA1 mutations on the lysosomal-mitochondrial-autophagy axis, where impaired autophagic flux and disrupted organelle crosstalk amplify oxidative stress and activate the NLR family pyrin domain containing 3 inflammasome. The contribution of microglia, astrocytes, and oligodendrocytes to the neuroinflammatory cascade is eamined, along with the emerging influence of the microbiome-gut-brain axis in disease progression. Finally, we evaluate emerging therapeutic strategies, including pharmacological chaperones, NLRP3 inhibitors, adeno-associated virus-based gene therapy, and microbiome modulation, highlighting both promises and translational challenges such as blood-brain barrier penetration and mutation-specific efficacy. We conclude by advocating for precision medicine approaches, supported by robust biomarker development and advanced disease models, to guide tailored interventions for this aggressive Parkinson's disease subtype.

Keywords:  ; Parkinson's disease; autophagy-lysosome pathway; lysosomal dysfunction; microbiome- gut-brain axis; mitochondrial; neurodegeneration; neuroinflammation; precision medicine; α-synuclein

DOI:  https://doi.org/10.4103/NRR.NRR-D-25-01082