bims-auttor 2025-11-30 papers

bims-auttor

Biomed News

on Autophagy and mTOR

Issue of 2025–11–30
forty-two papers selected by
Viktor Korolchuk, Newcastle University

pH-dependent regulation in SLC38A9.
Portioning organelles for autophagic clearance.
Disruption of the PIKfyve complex unveils an adaptive mechanism to promote lysosomal repair and mitochondrial homeostasis.
Bulk and selective autophagy cooperate to remodel a fungal proteome in response to changing nutrient availability.
Reconstitution of multistep recruitment of ULK1 to membranes in autophagy.
C9ORF72 Is Pivotal to Maintain a Proper Protein Homeostasis in Mouse Skeletal Muscle.
Tank-Binding Kinase 1 protects against MASH progression via mitochondrial quality control.
Exercise suppresses DEAF1 to normalize mTORC1 activity and reverse muscle aging.
The CTLH ubiquitin ligase substrates ZMYND19 and MKLN1 negatively regulate mTORC1 at the lysosomal membrane.
NAD+ restores proteostasis through splicing-dependent autophagy.
Autophagy and mitophagy at the synapse and beyond: implications for learning, memory and neurological disorders.
Mitochondrial Quality Control and Cell Death.
The RAB27A effector SYTL5 regulates mitophagy and mitochondrial metabolism.
The lysosomal carrier SLC29A3 supports antibacterial signaling, and promotes autophagy by activating TRPML1 in murine dendritic cells.
The ESCRT-0 protein HRS regulates hepatocellular lipid droplet catabolism.
Disruption of Rab9-dependent mitophagy contributes to menopause-induced sarcopenia.
Deleterious variants in the autophagy-related gene RB1CC1/FIP200 impair immunity to SARS-CoV-2.
Neurodegenerative Disease and Autophagy in iPSC models.
Autophagy Impairment in Retinal Ganglion Cells Following Hypoglycemia in Mice.
Autophagy and GLUT1 Trafficking: An Overview of Molecular Mechanisms.
Ventral hippocampal autophagy and mitophagy dynamics shape behavioral responses to chronic mild stress in adult male rats.
Proteome Landscapes Decode Organelle Vulnerabilities in cortical and dopaminergic-like induced neurons Across Lysosomal Storage Disorders.
CREG1 promotes autophagy and protects the heart against nutritional stress-induced injury and age-associated hypertrophy, fibrosis and diastolic dysfunction.
Loss of ARF5 impairs recovery after lysosomal damage.
Prolonged Survival with Dieting for Improved Autophagy.
The interplay between autophagy, p16INK4a, and senescence in tumor cells: a systematic review.
Screening for residues in Atg11, a central organizer of selective autophagy in yeast, important for binding with Atg9.
Smart Nanoparticles Disrupting Energy Supply through Triple Mechanisms to Kill Tumors via Dual Disruption of Mitochondria and Lysosomes.
Structural organization of p62 filaments and the cellular ultrastructure of calcium-rich p62-enwrapped lipid droplet cargo.
Regulation of mitochondrial dynamics and function by melatonin type 1 receptor in parkinson's disease.
APOE4 impairs Nrf2-PINK1/Parkin-dependent mitochondrial clearance through disrupted antioxidant and mitophagy signaling.
Inhibition of autophagy-lysosomal function exacerbates microglial and monocyte lipid metabolism reprograming and dysfunction after brain injury.
ER-to-Golgi Trafficking is a Nutrient-Sensitive Checkpoint Linking Glucose Starvation to Cell Surface Remodeling.
Visualizing PINK1 Activity Dynamics in Single Cells with a Phase Separation-Based Kinase Activity Reporter.
FGF9 alleviates diabetic cardiomyopathy by activating Nrf2 via SQSTM1/p62-Keap1 in mice.
Autophagy in Stress-Induced Neuropsychiatric Disorders and Depression.
Structural basis for the recruitment and selective phosphorylation of Akt by mTORC2.
Larp1 supports brain growth and spatial memory via post-transcriptional control of the translation machinery.
TFEB-nuclear translocation promotes BNIP3-mediated mitophagy and alleviates oxidative stress and ferroptosis in acute pancreatitis.
APP Induces AICD-Mediated Autophagy-Dependent Axon Degeneration.
ESCRT-III function in membrane fission and repair.
State-selective small molecule degraders that preferentially remove aggregates and oligomers.

bioRxiv. 2025 Oct 25. pii: 2025.10.24.684471. [Epub ahead of print]

pH-dependent regulation in SLC38A9.

Xuelang Mu, Ampon Sae Her, Tamir Gonen.

Cells rely on precise metabolic control to adapt to environmental cues. The mechanistic target of rapamycin complex 1 (mTORC1) senses nutrient availability, with amino acids serving as key signals. Lysosomes, which act as nutrient recycling centers, maintain amino acid homeostasis by breaking down macromolecules and releasing amino acids for cellular use. SLC38A9, a lysosomal amino acid transporter, functions as both a transporter and a sensor in the mTORC1 pathway. Here, we investigated whether SLC38A9 activity is regulated by pH. We show that arginine uptake by SLC38A9 is pH-dependent, and that the histidine residue His544 serves as the pH sensor. Mutating His544 abolishes the pH dependence of arginine uptake without impairing overall transport activity, indicating that His544 is not directly involved in substrate binding. Instead, protonation or deprotonation of His544 appears to influence transport through SLC38A9. To explore this mechanism, we compared two structures of SLC38A9 that we determined, one at high pH and one at low pH, and proposed a working model for pH-induced activation. These findings highlight the role of local ionic changes in modulating lysosomal transporters and underscore the intricate regulatory mechanisms that govern SLC38A9 function and, ultimately, mTORC1 signaling.

DOI: https://doi.org/10.1101/2025.10.24.684471
Autophagy. 2025 Nov 28.

Portioning organelles for autophagic clearance.

Mikhail Rudinskiy, Maurizio Molinari.

  The lysosomal/vacuolar clearance of portions of organelles including the endoplasmic reticulum (ER), mitochondria, the Golgi apparatus and the nucleus, organellophagy, is mediated by autophagy receptors anchored at the surface of their respective organelles. Organellophagy receptors are activated, induced or derepressed in response to stimuli such as nutrient or oxygen deprivation, accumulation of toxic or aged macromolecules, membrane depolarization, pathogen invasion, cell differentiation and many others. Their activation drives the portioning of the homing organelle, and the engagement of Atg8/LC3/GABARAP (LC3) proteins via LC3-interacting regions (LIRs) that results in autophagic clearance. In our latest work, we elaborate on the fact that all known mammalian and yeast organellophagy receptors expose their LIR embedded within intrinsically disordered regions (IDRs), i.e. cytoplasmic stretches of amino acids lacking a fixed three-dimensional structure. Our experiments reveal that the IDR modules of organellophagy receptors are interchangeable, required and sufficient to induce the fragmentation of the organelle that displays them at the limiting membrane, independent of LC3 engagement. LC3 engagement drives lysosomal delivery. Building on these findings, we propose harnessing practical and therapeutic potential of controlled organelle fragmentation and organellophagy through ORGAnelle TArgeting Chimeras (ORGATACs).

Keywords:  Endoplasmic reticulum (Er)phagy; ORGAnelle TArgeted chimeras (ORGATACs); intrinsically disordered regions (IDRs); mitophagy; organellophagy receptors; targeted organelle degradation

DOI:  https://doi.org/10.1080/15548627.2025.2597458
Nat Commun. 2025 Nov 28. 16(1): 10761

Disruption of the PIKfyve complex unveils an adaptive mechanism to promote lysosomal repair and mitochondrial homeostasis.

Candice Kutchukian, Maria Casas, Rose E Dixon, Eamonn J Dickson.

Lysosomes are essential organelles that regulate cellular homeostasis through complex membrane interactions. Phosphoinositide lipids play critical roles in orchestrating these functions by recruiting specific proteins to organelle membranes. The PIKfyve/Fig4/Vac14 complex regulates PI(3,5)P₂ metabolism, and intriguingly, while loss-of-function mutations cause neurodegeneration, acute PIKfyve inhibition shows therapeutic potential in neurodegenerative disorders. We demonstrate that PIKfyve/Fig4/Vac14 dysfunction triggers a compensatory response where reduced mTORC1 activity leads to ULK1-dependent trafficking of ATG9A and PI4KIIα from the TGN to lysosomes. This increases lysosomal PI(4)P, facilitating cholesterol and phosphatidylserine transport at ER-lysosome contacts to promote membrane repair. Concurrently, elevated lysosomal PI(4)P recruits ORP1L to ER-lysosome-mitochondria three-way contacts, enabling PI(4)P transfer to mitochondria that drives ULK1-dependent fragmentation and increased respiration. These findings reveal a role for PIKfyve/Fig4/Vac14 in coordinating lysosomal repair and mitochondrial homeostasis, offering insights into cellular stress responses.

DOI: https://doi.org/10.1038/s41467-025-65798-6
Cell Rep. 2025 Nov 25. pii: S2211-1247(25)01357-9. [Epub ahead of print]44(12): 116585

Bulk and selective autophagy cooperate to remodel a fungal proteome in response to changing nutrient availability.

Bertina Telusma, Jean-Claude Farré, Danica S Cui, Suresh Subramani, Joseph H Davis.

  Cells remodel their proteomes in response to changing environments by coordinating protein synthesis and degradation. In yeast, degradation occurs via proteasomes and vacuoles, with bulk and selective autophagy supplying vacuolar cargo. Although these pathways are known, their relative contributions to proteome-wide remodeling remain unreported. To assess this, we developed a method (nPL-qMS) to pulse-label the methylotrophic yeast Komagataella phaffii (Pichia pastoris) with isotopically labeled nutrients that, when coupled to quantitative proteomics, enables global monitoring of protein degradation following an environmental perturbation. Genetic ablations revealed that autophagy drives most proteome remodeling upon nitrogen starvation, with minimal non-autophagic contributions. Cytosolic protein complexes, including ribosomes, are degraded through bulk autophagy, whereas degradation of peroxisomes and mitochondria uses selective autophagy. Notably, these pathways are independently regulated by environmental cues. Our approach expands known autophagic substrates, highlights autophagy's major role in fungal proteome remodeling, and provides rich resources and methods for future proteome remodeling studies.

Keywords:  CP: Microbiology; CP: Molecular biology; autophagy; mitophagy; pexophagy; protein degradation; proteome quality control; quantitative mass spectrometry

DOI:  https://doi.org/10.1016/j.celrep.2025.116585
bioRxiv. 2025 Nov 09. pii: 2025.11.07.687251. [Epub ahead of print]

Reconstitution of multistep recruitment of ULK1 to membranes in autophagy.

Yongjia Duan, Ye Lu, Sanjoy Paul, Johannes Betz, Lea Wilhelm, Annan S I Cook, Xuefeng Ren, Elias Adriaenssens, Sascha Martens, Ian G Ganley, Gerhard Hummer, James H Hurley.

The ULK1 complex (ULK1C) and the class III phosphatidylinositol 3-kinase complex I (PI3KC3-C1) act together to initiate autophagy. Human ULK1C consists of ULK1 itself, FIP200, and the HORMA domain heterodimer ATG13:ATG101. PI3P generated by PI3KC3-C1 is essential to recruit and stabilize ULK1C on membranes for ULK1 to phosphorylate its membrane-associated substrates in autophagy induction, even though ULK1C subunits do not contain any PI3P-binding domains. Here we show that the ATG13:ATG101 dimer forms a tight complex with the PI3P-binding protein WIPI3, as well as with WIPI2. Bound to WIPI2-3, ATG13:ATG101 aligns with the membrane to insert its Trp-Phe (WF) finger into the membrane. Molecular dynamics simulations show that alignment of WIPIs and the ATG101 WF finger cooperatively stabilizes the complex on membranes, explaining the essential role of the WF residues in autophagy. Biochemical reconstitution and a cell-based assay show that WIPI3:ATG13 engagement is required for ATG16L1 phosphorylation by ULK1, ATG13 puncta formation, and bulk autophagic flux. We further showed that a kinase domain (KD)-proximal PVP motif within the ULK1 IDR docks onto the surface of the ATG13:ATG101 HORMA dimer and used molecular modeling to show how the ULK1 KD is brought close to the membrane surface. Biochemical reconstitution and cell-based assays show that the PVP motif is essential for in vitro ULK1 phosphorylation of ATG16L1 and important for BNIP3/NIX-dependent mitophagy. These data establish a stepwise pathway for recruitment of the ULK1 KD to the vicinity of the membrane surface downstream of PI3KC3-C1.

DOI: https://doi.org/10.1101/2025.11.07.687251
Cells. 2025 Nov 11. pii: 1765. [Epub ahead of print]14(22):

C9ORF72 Is Pivotal to Maintain a Proper Protein Homeostasis in Mouse Skeletal Muscle.

Francesca Sironi, Paola Parlanti, Cassandra Margotta, Jessica Cassarà, Valentina Bonetto, Caterina Bendotti, Massimo Tortarolo, Valentina Cappello.

  The C9ORF72 gene mutation is a major cause of amyotrophic lateral sclerosis (ALS). Disease mechanisms involve both loss of C9ORF72 protein function and toxic effects from hexanucleotide repeat expansions. Although its role in neurons and the immune system is well studied, the impact of C9ORF72 deficiency on skeletal muscle is not yet well understood, despite muscle involvement being a key feature in ALS pathology linked to this mutation. This study examined skeletal muscle from C9ORF72 knockout mice and found a 19.5% reduction in large muscle fibers and altered fiber composition. Ultrastructural analysis revealed mitochondrial abnormalities, including smaller size, pale matrix, and disorganized cristae. Molecular assessments showed increased expression of Atrogin-1, indicating elevated proteasomal degradation, and markers of enhanced autophagy, such as elevated LC3BII/LC3BI ratio, Beclin-1, and reduced p62. Mitochondrial quality control was impaired, with a 3.6-fold increase in PINK1, upregulation of TOM20, reduced Parkin, and decreased PGC-1α, suggesting disrupted mitophagy and mitochondrial biogenesis. These changes led to the accumulation of damaged mitochondria. Overall, the study demonstrates that C9ORF72 is critical for maintaining muscle protein and mitochondrial homeostasis. While C9orf72-haploinsufficiency does not directly compromise muscle strength in mice, it may increase the vulnerability of skeletal muscle in C9ORF72-associated ALS.

Keywords:  amyotrophic lateral sclerosis; atrogenes; autophagy; mitochondria; mitophagy; skeletal muscle

DOI:  https://doi.org/10.3390/cells14221765
Res Sq. 2025 Oct 09. pii: rs.3.rs-7476559. [Epub ahead of print]

Tank-Binding Kinase 1 protects against MASH progression via mitochondrial quality control.

Jin Young Huh, Sung-Min An, Jun Hee Jang, Jin Hyun Sung, Ji Won Myung, Yong Geun Jeon, Won Taek Lee, Jin Won Jeon, Kyung Min Yim, Jae-Ho Lee, Bichen Zhang, Jong Bae Seo, Seung Soon Im, Jae Bum Kim, Alan Saltiel.

Mitochondrial dysfunction is a critical driver of metabolic dysfunction-associated steatotic liver disease (MASLD) progression to steatohepatitis (MASH), yet the mechanisms governing mitochondrial quality control in hepatocytes remain poorly defined. Here, we identify TANK-binding kinase 1 (TBK1) as an essential regulator of hepatic mitophagy and lysosomal activity. Using TBK1-deficient hepatocytes and liver-specific TBK1 knockout (LTKO) mice, we show that TBK1 loss leads to the accumulation of depolarized, ROS-producing mitochondria due to impaired mitophagy flux, including defective lysosomal degradation. Mechanistically, TBK1 is required for p62 phosphorylation at Ser403 and partially modulates mTOR signaling to preserve lysosomal acidification. Therapeutic restoration of TBK1 expression via AAV8 delivery enhanced mitophagy, reduced mitochondrial burden, and ameliorated liver fibrosis. Notably, both human samples and murine steatohepatitis models exhibited a significant decline in TBK1 kinase activity. Collectively, these findings establish TBK1 as a critical guardian of mitochondrial and lysosomal homeostasis in MASH.

DOI: https://doi.org/10.21203/rs.3.rs-7476559/v1
Proc Natl Acad Sci U S A. 2025 Dec 02. 122(48): e2508893122

Exercise suppresses DEAF1 to normalize mTORC1 activity and reverse muscle aging.

Sze Mun Choy, Kah Yong Goh, Wen Xing Lee, Weiyi Jiang, Qian Gou, Priya D Gopal Krishnan, Shi Chee Ong, Kenon Chua, Nathan Harmston, Hong-Wen Tang.

  Skeletal muscle is essential for movement, respiration, and metabolism, with mTORC1 acting as a key regulator of protein synthesis and degradation. In aging muscle, mTORC1 becomes overactivated, contributing to sarcopenia, though the mechanisms remain unclear. Here, we identify DEAF1, a FOXO-regulated transcription factor, as a key upstream driver of mTORC1 in aged muscle. Elevated Deaf1 expression increases mTOR transcription, leading to heightened mTORC1 activity, impaired proteostasis, and muscle senescence. Remarkably, exercise suppresses Deaf1 expression via FOXO activation, restoring mTORC1 balance and alleviating muscle aging. Conversely, FOXO inhibition or Deaf1 overexpression blocks exercise benefits on muscle health. These findings highlight DEAF1 as a critical link between FOXO and mTORC1 and suggest that targeting the FOXO-DEAF1-mTORC1 axis may offer therapeutic potential to preserve muscle function during aging.

Keywords:  autophagy; mTORC1; muscle; proteostasis; sarcopenia

DOI:  https://doi.org/10.1073/pnas.2508893122
Nat Commun. 2025 Nov 28. 16(1): 10731

The CTLH ubiquitin ligase substrates ZMYND19 and MKLN1 negatively regulate mTORC1 at the lysosomal membrane.

Yin Wang, Yifei Liao, Yizhe Sun, Bidisha Mitra, Rui Guo, Brenda Iturbide Piedras, Shaowen White, Hsin-Yao Tang, John M Asara, Italo Tempera, Paul M Lieberman, Benjamin E Gewurz.

Most Epstein-Barr virus-associated gastric carcinoma (EBVaGC) harbor non-silent mutations that activate phosphoinositide 3 kinase (PI3K) to drive downstream metabolic signaling. To gain insights into PI3K/mTOR pathway dysregulation in this context, we perform a human genome-wide CRISPR/Cas9 screen for hits that synergistically blocked EBVaGC proliferation together with the PI3K antagonist alpelisib. Multiple subunits of carboxy terminal to LisH (CTLH) E3 ligase, including the catalytic MAEA subunit, are among top screen hits. CTLH negatively regulates gluconeogenesis in yeast, but not in higher organisms. The CTLH substrates MKLN1 and ZMYND19, which highly accumulated upon MAEA knockout, associate with one another and with lysosome outer membranes to inhibit mTORC1. Rather than perturbing mTORC1 lysosomal recruitment, ZMYND19 and MKLN1 block the interaction between mTORC1 and Rheb and also with mTORC1 substrates S6 and 4E-BP1. Thus, CTLH enables cells to rapidly tune mTORC1 activity at the lysosomal membrane via the ubiquitin/proteasome pathway.

DOI: https://doi.org/10.1038/s41467-025-65760-6
Autophagy. 2025 Nov 28.

NAD+ restores proteostasis through splicing-dependent autophagy.

Ruixue Ai, Evandro F Fang.

  Autophagy preserves neuronal integrity by clearing damaged proteins and organelles, but its efficiency declines with aging and neurodegeneration. Depletion of the oxidized form of nicotinamide adenine dinucleotide (NAD+) is a hallmark of this decline, yet how metabolic restoration enhances autophagic control has remained obscure. Meanwhile, alternative RNA splicing errors accumulate in aging brains, compromising proteostasis. Here, we identify a metabolic - transcriptional mechanism linking NAD+ metabolism to autophagic proteostasis through the NAD+ -EVA1C axis. Cross-species analyses in C. elegans, mice, and human samples reveal that NAD+ supplementation corrects hundreds of age- or Alzheimer-associated splicing errors, notably restoring balanced expression of EVA1C isoforms. Loss of EVA1C impairs the memory and proteostatic benefits of NAD+, underscoring its essential role in neuronal resilience. Mechanistically, NAD+ rebalances EVA1C isoforms that interact with chaperones BAG1 and HSPA/HSP70, reinforcing their network to facilitate chaperone-assisted selective autophagy and proteasomal degradation of misfolded proteins such as MAPT/tau. Thus, NAD+ restoration coordinates RNA splicing fidelity with downstream proteostatic systems, establishing a metabolic - transcriptional checkpoint for neuronal quality control. This finding expands the paradigm of autophagy regulation, positioning metabolic splice-switching as a crucial mechanism to maintain proteostasis and suggesting new strategies to combat aging-related neurodegenerative diseases.

Keywords:  Aging; NAD+ precursors; alzheimer disease; machine learning; rna splicing; tauopathy

DOI:  https://doi.org/10.1080/15548627.2025.2596679
Autophagy. 2025 Nov 23. 1-43

Autophagy and mitophagy at the synapse and beyond: implications for learning, memory and neurological disorders.

Jiayi Lu, Damian N Di Florio, Patricia Boya, Sandra Maday, Wolfdieter Springer, Charleen T Chu.

  The human brain is one of the most metabolically active tissues in the body, due in large part to the activity of trillions of synaptic connections. Under normal conditions, macroautophagy/autophagy at the synapse plays a crucial role in synaptic pruning and plasticity, which occurs physiologically in the absence of disease- or aging-related stressors. Disruption of autophagy has profound effects on neuron development, structure, function, and survival. Neurons are dependent upon maintaining high-quality mitochondria, and alterations in selective mitochondrial autophagy (mitophagy) are heavily implicated in both genetic and environmental etiologies of neurodegenerative diseases. The unique spatial and functional demands of neurons result in differences in the regulation of metabolic, autophagic, mitophagic and biosynthetic processes compared to other cell types. Here, we review recent advances in autophagy and mitophagy research with an emphasis on studies involving primary neurons in vitro and in vivo, glial cells, and iPSC-differentiated neurons. The synaptic functions of genes whose mutations implicate autophagic or mitophagic dysfunction in hereditary neurodegenerative and neurodevelopmental diseases are summarized. Finally, we discuss the diagnostic and therapeutic potentials of autophagy-related pathways.Abbreviations: AD: Alzheimer disease; ALS: amyotrophic lateral sclerosis; APP: amyloid beta precursor protein; ASD: autism-spectrum disorder; BDNF: brain-derived neurotrophic factor; BPAN: β-propeller protein associated neurodegeneration; CR: caloric restriction; ΔN111: deleted N-terminal region 111 residues; DLG4/PSD95: discs large MAGUK scaffold protein 4; ER: endoplasmic reticulum; FTD: frontotemporal dementia; HD: Huntington disease; LIR: LC3-interacting region; LRRK2: leucine rich repeat kinase 2; LTD: long-term depression; LTP: long-term potentiation; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; OMM: outer mitochondrial membrane; PD: Parkinson spectrum diseases; PGRN: progranulin; PINK1: PTEN induced kinase 1; PRKA/PKA: protein kinase cAMP-activated; PtdIns3P: phosphatidylinositol-3-phosphate; p-S65-Ub: ubiquitin phosphorylated at serine 65; PTM: post-translational modification; TREM2: triggering receptor expressed on myeloid cells 2.

Keywords:  Biomarkers; Parkinson disease; dementia; dendritic spines; mitochondria; neurodegenerative diseases; neurodevelopmental disorders; synaptic plasticity

DOI:  https://doi.org/10.1080/15548627.2025.2581217
Int J Mol Sci. 2025 Nov 16. pii: 11084. [Epub ahead of print]26(22):

Mitochondrial Quality Control and Cell Death.

Zurui Zhang, Mengyuan Zhang, Hongchi Jin, Shuang Lv, Yilei Li, Yanru Li.

  Mitochondrial quality control includes mitochondrial biogenesis, fusion, fission (to maintain mitochondrial function), and mitochondrial autophagy (for removing damaged mitochondria). This is a highly delicate and complex process involving many molecules. Mitochondrial quality control is crucial for maintaining mitochondrial homeostasis and function, preserving energy supply, eliminating damaged mitochondria to prevent cytotoxicity, promoting mitochondrial regeneration and repair, protecting cells from oxidative stress and senescence, and facilitating cellular communication and material exchange. In this review, we introduce the structure and function of mitochondria, the mechanisms of quality control, and the relationship between mitochondrial quality control and cellular processes such as pyroptosis, apoptosis, and ferroptosis. We also summarize the proteins, enzymes, and their molecular mechanisms involved in these processes and propose a "spatiotemporal-threshold" model for the mitochondrial quality control-cell death axis.

Keywords:  apoptosis; ferroptosis; mitochondrial autophagy; mitochondrial dynamics; mitochondrial fission; mitochondrial fusion; mitochondrial quality control; pyroptosis

DOI:  https://doi.org/10.3390/ijms262211084
Elife. 2025 Nov 26. pii: RP105541. [Epub ahead of print]14

The RAB27A effector SYTL5 regulates mitophagy and mitochondrial metabolism.

Ana Lapão, Lauren Sophie Johnson, Laura Trachsel-Moncho, Samuel J Rodgers, Sakshi Singh, Matthew Y W Ng, Sigve Nakken, Eeva-Liisa Eskelinen, Anne Simonsen.

  SYTL5 is a member of the Synaptotagmin-Like (SYTL) protein family that differs from the Synaptotagmin family by having a unique N-terminal Synaptotagmin homology domain that directly interacts with the small GTPase RAB27A. Several SYTL protein family members have been implicated in plasma membrane transport and exocytosis, but the specific function of SYTL5 remains unknown. We here show that SYTL5 is a RAB27A effector and that both proteins localise to mitochondria and vesicles containing mitochondrial material. Mitochondrial recruitment of SYTL5 depends on its interaction with functional RAB27A. We demonstrate that SYTL5-RAB27A positive vesicles containing mitochondrial material, autophagy proteins and LAMP1 form during hypoxia and that depletion of SYTL5 and RAB27A reduces mitophagy under hypoxia mimicking conditions, indicating a role for these proteins in mitophagy. Indeed, we find that SYTL5 interacts with proteins involved in vesicle-mediated transport and cellular response to stress and that its depletion compromises mitochondrial respiration and increases glucose uptake. Intriguingly, SYTL5 expression is significantly reduced in tumours of the adrenal gland and correlates positively with survival for patients with adrenocortical carcinoma.

Keywords:  ACC; Mitochondria; RAB27A; SYTL5; cell biology; hypoxia; mitophagy; none

DOI:  https://doi.org/10.7554/eLife.105541
Proc Natl Acad Sci U S A. 2025 Dec 02. 122(48): e2511539122

The lysosomal carrier SLC29A3 supports antibacterial signaling, and promotes autophagy by activating TRPML1 in murine dendritic cells.

Daniel J Netting, Cynthia López-Haber, Zachary Hutchins, José A Martina, Rosa Puertollano, Adriana R Mantegazza.

  The solute carrier (SLC)29A3 exports nucleosides from lysosomes into the cytosol, maintaining solute homeostasis and providing metabolic intermediates for cellular processes. Loss-of-function mutations in SLC29A3 cause H syndrome, characterized by histiocytosis, hyperinflammation, and immunodeficiency. While dysfunctions in various cell types contribute to H syndrome and to SLC29A3 deficiency in mice, the mechanisms driving hyperinflammation and immunodeficiency are incompletely understood. Remarkably, the possible role played by dendritic cells (DCs), the most efficient antigen (Ag)-presenting cells and the main cellular link between innate and adaptive immunity, remains unknown. We show that, in murine DCs, SLC29A3 is recruited to phagosomes after bacterial capture, maintains phagosomal pH homeostasis, and ensures optimal antimicrobial phagosomal signaling to the production of IL-6, IL-12, pro-IL-1β, and CCL22. In addition, SLC29A3 promotes Ag presentation on MHC-II molecules to initiate adaptive immune responses. Notably, SLC29A3 supports the activity of the lysosomal calcium channel TRPML1, promoting the nuclear translocation of transcription factor TFEB and inducing autophagy, a major anti-inflammatory mechanism. Overexpression of human SLC29A3, but not the transport mutant G437R, in SLC29A3-deficient murine DCs restores cytokine production in response to bacterial phagocytosis, suggesting that SLC29A3 transport activity is required to drive phagosomal signaling. Our data suggest that SLC29A3 supports and controls immune function in DCs by promoting effective antimicrobial signaling and Ag presentation, and inducing autophagy. Our findings also uncover a TRPML1-dependent mechanism by which SLC29A3 activates TFEB and suggest that defects in phagosomal antibacterial signaling, TFEB activation, and autophagy may contribute to immunodeficiency and hyperinflammation in SLC29A3 disorders.

Keywords:  TFEB; antigen MHC-II presentation; autophagy; dendritic cells; lysosomal solute carriers

DOI:  https://doi.org/10.1073/pnas.2511539122
bioRxiv. 2025 Nov 13. pii: 2025.11.13.686840. [Epub ahead of print]

The ESCRT-0 protein HRS regulates hepatocellular lipid droplet catabolism.

Mathilda M Willoughby, Ankit Shroff, Bridget E Crossman, Micah B Schott.

Lipid droplets (LDs) are dynamic organelles that regulate lipid storage and metabolism pathways central to metabolic liver disease. LD turnover occurs in part through lysosomal catabolism (i.e. lipophagy) whereby LDs are thought to follow two distinct trafficking pathways: autophagosome-dependent macro lipophagy and the autophagosome-independent micro lipophagy. However, the molecular machinery that regulates these two distinct pathways, especially that of microlipophagy in mammalian cells, is poorly understood. In yeast, microlipophagy has been shown to rely on a protein family known as the endosomal sorting complex required for transport (ESCRT). Here, we used an ESCRT-specific RNAi library in hepatocytes which identified the ESCRT-0 protein hepatocyte growth factor receptor substrate (HRS) as a critical regulator of LD homeostasis. HRS depletion leads to significant LD accumulation which is not due to increased LD formation but from impaired LD catabolism. HRS-deficient cells retain lipolysis activity; however, they exhibit decreased LD targeting via microlipophagy, accompanied by compensatory increases in autophagosome targeting to LDs. In agreement with these findings, HRS knockdown suppressed mTOR signaling, boosted autophagosome formation, and reduced the degradation of autophagic cargo. Despite maintaining lysosome numbers, HRS knockdown raised lysosomal pH causing decreased autophagic degradative capacity and contributing to LD accumulation. Overall, these findings identify HRS as a modulator of LD turnover in mammalian cells, regulating lipophagy through lysosomal function.
Significance Statement: The regulatory molecular mechanisms of lipophagy are not clearly defined. This study identifies novel ESCRT proteins as regulators of LD homeostasis in several cell lines.In hepatocytes, we identified HRS specifically regulates LD catabolism, whereby HRS-dependent regulation of LDs is dual-faceted, affecting LD-lysosomal targeting and lysosomal function.Our findings are significant because they provide mechanistic insights into the role of ESCRT proteins in LD metabolism. Elucidating ESCRT-mediated lipophagy can potentially aid in developing novel targets to prevent aberrant lipid trafficking and utilization, particularly in the liver where LDs can accumulate and cause irreversible liver damage.

DOI: https://doi.org/10.1101/2025.11.13.686840
Exp Gerontol. 2025 Nov 20. pii: S0531-5565(25)00299-2. [Epub ahead of print] 112970

Disruption of Rab9-dependent mitophagy contributes to menopause-induced sarcopenia.

Shota Uebo, Yoshiyuki Ikeda, Yoshihiro Uchikado, Yuichi Sasaki, Yuichi Akasaki, Takuro Kubozono, Mitsuru Ohishi.

  Aim Sarcopenia, a major cause of frailty in postmenopausal women, is linked to mitochondrial dysfunction, but the underlying mechanisms remain unclear. This study aimed to clarify whether mitophagy, a mitochondrial quality control mechanism, contributes to postmenopausal sarcopenia, to elucidate its underlying mechanism, and to assess whether it can be rescued.
METHODS: C57BL/6 mice (12-week-old females) underwent ovariectomy to establish a menopause mouse model, or sham surgery, and the therapeutic effects of nicotinamide mononucleotide (NMN) were assessed. Human skeletal muscle myoblasts (HSMMs) differentiated under postmenopausal conditions with or without 17β-estradiol (E2), and Rab9 expression was modulated using CRISPR activation.
RESULTS: Ovariectomized mice exhibited decreased muscle mass and strength. E2 deficiency in HSMMs inhibited skeletal muscle cell differentiation, promoted senescence, impaired mitochondrial function, and reduced mitophagy. However, E2 deficiency did not modulate light chain 3 and autophagy-related 7 but reduced Rab9 expression and the colocalization of Rab9 with lysosomal-associated membrane protein 2, suggesting that E2 mediates mitophagy through Rab9-dependent alternative autophagy. Furthermore, overexpression of Rab9 in E2-deficient HSMMs enhanced mitophagy, improved mitochondrial function, suppressed cellular senescence, and promoted skeletal muscle cell differentiation. The administration of NMN to ovariectomized mice increased Rab9 expression and improved sarcopenia through increased mitophagy.
CONCLUSION: This study demonstrates that estrogen deficiency impairs mitophagy originated from Rab9-dependent alternative autophagy, leading to mitochondrial dysfunction and sarcopenia, while enhancement of Rab9 restores mitochondrial quality control and muscle function. These results identify Rab9-dependent mitophagy as a potential therapeutic target for postmenopausal sarcopenia.

Keywords:  Alternative autophagy; Estrogen; Menopause-induced sarcopenia; Mitochondria; Mitophagy; Nicotinamide mononucleotide; Rab9

DOI:  https://doi.org/10.1016/j.exger.2025.112970
Nat Commun. 2025 Nov 27. 16(1): 10618

Deleterious variants in the autophagy-related gene RB1CC1/FIP200 impair immunity to SARS-CoV-2.

COVID Human Genetic Effort

The clinical outcome of SARS-CoV-2 infection spans from asymptomatic viral elimination to lethal COVID-19 pneumonia, which is due to type I interferon (IFN) deficiency in at least 15-20% of cases. We report two unrelated male patients with critical COVID-19 who are heterozygous for rare deleterious variants in RB1CC1, encoding the autophagy-related FIP200 protein. Airway epithelial cells genetically deprived of FIP200 or cell lines expressing the RB1CC1/FIP200 patient variants exhibit elevated SARS-CoV-2 replication and impaired autophagic flux. The antiviral function of FIP200 is independent of canonical autophagy and type I IFN, but involves the selective autophagy receptor NDP52. We identify a non-canonical function of FIP200 in a novel lysosomal degradation pathway, in which SARS-CoV-2 virions are targeted to single-membrane compartments for degradation of viral RNA in LC3B-positive acidified vesicles. This pathway is impaired in FIP200-deficient cells and in cells expressing FIP200 patient haplotypes. Collectively, we describe a cell-autonomous anti-SARS-CoV-2 restriction pathway, dependent on FIP200 and NDP52, and independent of canonical autophagy and type I IFN, which can underlie critical COVID-19 pneumonia.

DOI: https://doi.org/10.1038/s41467-025-65308-8
Neurosci Res. 2025 Nov 26. pii: S0168-0102(25)00174-9. [Epub ahead of print] 104991

Neurodegenerative Disease and Autophagy in iPSC models.

Sodbileg Odonchimed, Keiko Imamura, Haruhisa Inoue.

  Neurodegenerative diseases are characterized by the gradual deterioration of specific neuronal populations, ultimately resulting in motor, cognitive, or behavioral impairments. Despite the worldwide increase in disease incidence, effective therapies remain unavailable. A common pathological hallmark of neurodegenerative diseases is the accumulation of misfolded protein aggregates, which impair normal cellular function. Accordingly, numerous studies and therapeutic strategies have focused on targeting these toxic aggregates and protein quality control via autophagy, a vital cellular recycling mechanism. Autophagy dysregulation has been implicated in the pathogenesis of several neurodegenerative diseases. Induced pluripotent stem cell (iPSC) technology has emerged as a powerful platform for modeling neurodegenerative diseases, and iPSC-derived models provide human-relevant systems for studying autophagic dysfunction in vitro. In this review, we discuss the key findings of recent studies investigating autophagy in iPSC-based models of neurodegenerative diseases, including Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal dementia, and other diseases.

Keywords:  autophagy; disease model; iPSCs; neurodegenerative disease

DOI:  https://doi.org/10.1016/j.neures.2025.104991
Cells. 2025 Nov 12. pii: 1774. [Epub ahead of print]14(22):

Autophagy Impairment in Retinal Ganglion Cells Following Hypoglycemia in Mice.

Daria Fresia, Enrica Cannizzaro, Angelica Borgo, Marc Schwab, Raphaël Roduit.

  (1) Background: Diabetic retinopathy (DR), caused by hypo- and hyperglycaemia, is the leading cause of blindness. Hypoglycemia induces endoplasmic reticulum stress and retinal cell death in mice, and low-glucose conditions induce macroautophagy/autophagy defects in 661W photoreceptor cells and retinal explants. Very few studies have analyzed the effect of hypoglycemia on retinal autophagy, so we decided to fill this gap. (2) Methods: We use C57BL/6 and GFP-LC3 mice and isolated retinal ganglion cells (RGCs) from both mouse models to study the autophagy process. (3) Results: Intraocular injection of rapamycin and 5 h hypoglycemia showed an increase in autophagosomes formation, specifically in the RGCs. Isolated GFP-LC3 RGCs showed an increase in autophagosome formation under low-glucose conditions. In contrast, infection of isolated C57BL/6 RGCs with the RFP-GFP-LC3 lentivirus revealed a defect in autophagosome/lysosome fusion under these conditions. (4) Conclusions: This study showed that 5 h hypoglycemia induces autophagosomes formation in mouse RGCs; however, a defect in the fusion process inhibits the protective effect of autophagy. Therefore, modulating both autophagic and apoptotic pathways might be important to avoid complications associated with DR.

Keywords:  RNA-Seq; apoptosis; diabetic retinopathy; hypoglycemia; laser capture microdissection; lysosomal fusion defect

DOI:  https://doi.org/10.3390/cells14221774
Am J Physiol Cell Physiol. 2025 Nov 27.

Autophagy and GLUT1 Trafficking: An Overview of Molecular Mechanisms.

Sara Petrosino, Paolo Grumati.

  Autophagy is a catabolic process that enables cellular metabolic adaptation in response to nutrient deprivation. It facilitates the degradation of proteins and cellular components within lysosomes to generate essential metabolites. The glucose transporter 1 (GLUT1) is among the proteins that can undergo autophagy-mediated degradation in response to metabolic stimuli. GLUT1 is essential for cellular glucose supply in several tissues. Notably, GLUT1 facilitates glucose transport across the blood-brain barrier, creating a concentration gradient from the bloodstream into the brain's interstitial fluid. The presence of GLUT1, at the plasma membrane, is the first step in initiating glucose uptake and driving glycolysis inside the cell. Glycolysis can be initiated in response to several stimuli, including glucose availability, autophagy inhibition and growth factor accessibility. In this review, we highlight recently described mechanisms that govern the subcellular distribution of GLUT1 with a focus on autophagy-mediated trafficking. Understanding how autophagy coordinates GLUT1 sorting in response to metabolic demands may uncover novel therapeutic targets for metabolic disorders characterized by dysregulated GLUT1 trafficking.

Keywords:  Autophagy; GLUT1; Metabolism; Signalling; Trafficking

DOI:  https://doi.org/10.1152/ajpcell.00551.2025
Neurobiol Stress. 2025 Nov;39 100769

Ventral hippocampal autophagy and mitophagy dynamics shape behavioral responses to chronic mild stress in adult male rats.

Paola Brivio, Maria Teresa Gallo, Elena Volpari, Piotr Gruca, Magdalena Lason, Ewa Litwa, Fabio Fumagalli, Mariusz Papp, Francesca Calabrese.

  Major depressive disorder (MDD) is a highly prevalent psychiatric condition characterized by a range of symptoms that often lead to reduced quality of life. Although chronic stress is a major risk factor for the development of MDD, only a subset of individuals exposed to stress develop depressive symptoms, while others remain resilient. Emerging evidence suggests that autophagy and mitophagy, key cellular processes involved in maintaining homeostasis and energy balance, may play a critical role in the response to stress. In this study, we investigated the impact of 6 weeks of chronic mild stress (CMS) on autophagy and mitophagy pathways in adult male rats, aiming to explore their potential association with vulnerability or resilience to stress-induced anhedonic-like behavior. By analyzing key autophagy and mitophagy markers in the dorsal (dHip) and ventral hippocampus (vHip), we describe region- and phenotype-specific alterations that may reflect distinct neurobiological adaptations to stress. In particular, we observed enhanced mitophagy alongside an overall impairment of autophagy in the vHip of vulnerable rats, while resilient animals showed preserved activity. These findings provide new insights into the molecular mechanisms associated with stress susceptibility and may inform future studies aimed at identifying novel therapeutic targets for MDD.

Keywords:  Lysosomes; PINK1; Resilience; TFEB; Vulnerability

DOI:  https://doi.org/10.1016/j.ynstr.2025.100769
bioRxiv. 2025 Oct 08. pii: 2025.10.08.681047. [Epub ahead of print]

Proteome Landscapes Decode Organelle Vulnerabilities in cortical and dopaminergic-like induced neurons Across Lysosomal Storage Disorders.

Felix Kraus, Yuchen He, Yizhi Jiang, Delong Li, Yohannes A Ambaw, Federico M Gasparoli, Joao A Paulo, Tobias C Walther, Robert Farese, Steven P Gygi, Florian Wilfling, J Wade Harper.

Lysosomes maintain cellular homeostasis by degrading proteins delivered via endocytosis and autophagy and recycling building blocks for organelle biogenesis. Lysosomal Storage Disorders (LSDs) comprise a broad group of diseases affecting lysosomal degradation, ion flux, and lipid catabolism. Within this group, sphingolipidoses genes involved in glycosphingolipid breakdown are known (GBA1) or candidate (SMPD1, ASAH1) risk factors for Parkinsons Disease, though disease mechanisms remain unclear. Using our previously reported LSD mutant proteomic landscape in HeLa cells, we observed pronounced variability in endolysosomal proteome signatures among sphingolipid pathway mutants, with ASAH1 knockout cells showing altered lysosomal lipid composition, impaired endocytic trafficking, and disrupted ultrastructure by cryo-electron tomography. To extend these findings in a more physiologic context, we generated a human embryonic stem (ES) cell library comprising 23 LSD gene knockouts and profiled proteomic changes during differentiation into cortical and midbrain dopaminergic neurons over a 7 to 10 week period. LSD mutants exhibited lineage-specific alterations in organellar proteomes, revealing diverse vulnerabilities. Notably, GBA1 knockout and ASAH1knockout dopaminergic neurons showed disruptions in synaptic and mitochondrial compartments, correlating with impaired dopaminergic neuronal firing and disrupted presynaptic protein localization. This LSD mutant toolkit and associated proteomic landscape provides a resource for defining molecular signatures of LSD gene loss and highlights convergence of lysosomal dysfunction, synaptic integrity, and mitochondrial health as potential links between sphingolipidoses and PD risk.

DOI: https://doi.org/10.1101/2025.10.08.681047
bioRxiv. 2025 Nov 13. pii: 2025.11.11.687936. [Epub ahead of print]

CREG1 promotes autophagy and protects the heart against nutritional stress-induced injury and age-associated hypertrophy, fibrosis and diastolic dysfunction.

Yanmei Qi, Russel J Pepe, Glenn Tejeda, Yechaan Joo, NaYoung K Yang, Kevin B Hayes, Saum Rahimi, Zhongren Zhou, Shaohua Li, Leonard Y Lee.

Background: Cellular repressor of E1A-stimulated genes 1 (CREG1) is an evolutionarily conserved endolysosomal glycoprotein that enhances lysosomal biogenesis and autophagy, suppresses proliferation, and promotes differentiation. A prior gene targeting strategy that produced truncated N-terminal fragments resulted in embryonic lethality, limiting the ability to assess the physiological role of complete CREG1 loss. We hypothesized that CREG1 regulates cardiac autophagy, thereby maintaining cardiac structure and function under both physiological and stress conditions.
Methods: We generated true Creg1 knockout (KO) mice by deleting the entire open reading frame and established a gain-of-function model by inserting human CREG1 into the Rosa26 locus. Cardiac structure and function were assessed in global and cardiomyocyte-specific Creg1 knockout (cm Creg1 KO) and knock-in (cm CREG1 KI) mice. Autophagy was evaluated using biochemical assays, immunofluorescence, electron microscopy, and the CAG-EGFP-RFP-LC3 reporter analysis.
Results: Global Creg1 knockout mice developed progressive cardiac hypertrophy, fibrosis, and diastolic dysfunction at ∼80 weeks of age. At younger ages, CREG1 deficiency increased susceptibility to nutritional stress, resulting in mitochondrial damage and myofiber disruption in cardiomyocytes. cm Creg1 KO mice exhibited dilated cardiomyopathy, left atrial thrombosis, and lethality around 50 weeks of age; however, interpretation of disease severity is confounded by Myh6-Cre -associated cardiotoxicity, which may mask additional pathogenic effects attributable to CREG1 loss. In contrast, cm CREG1 KI mice demonstrated enhanced exercise capacity under nutritional stress. Mechanistically, CREG1 was localized to endolysosomal and autophagosomal compartments. Loss of CREG1 impaired autophagy flux and mitophagy, likely due to defective autophagosome membrane expansion and degradation. In contrast, CREG1 overexpression enhanced autophagy in cardiomyocytes.
Conclusions: CREG1 is a key regulator of cardiac autophagy, protecting the heart against nutritional stress-induced injury and age-associated cardiac hypertrophy, fibrosis, and diastolic dysfunction.
Graphic Abstract:

DOI: https://doi.org/10.1101/2025.11.11.687936
Front Mol Biosci. 2025 ;12 1699266

Loss of ARF5 impairs recovery after lysosomal damage.

Martyna O Iwaniec, Christopher J Bott, James E Casanova.

  Lysosomal dysfunction is a defining feature of aging and neurodegenerative diseases, where lysosomal membrane permeabilization and release of its contents can trigger cellular death pathways. To counteract this, cells rely on lysosomal quality control mechanisms, many of which depend on lipid delivery to repair damaged membranes. However, the regulatory pathways governing this process remain unclear. In this study, we investigated whether canonical ARF GTPases, best known for their roles in Golgi and endosomal vesicular trafficking, are recruited to damaged lysosomes and contribute to their repair. Using LysoIP-based lysosome isolation, super-resolution immunofluorescence imaging, and functional assays in HeLa and HEK293 cells, we found that ARF1, ARF5, and ARF6 localize to lysosomal membranes following L-leucyl-L-leucine methyl ester (LLOME)-induced permeabilization. While loss of ARF6 did not impair recovery, ARF5 depletion resulted in a nearly complete block of lysosomal repair. These findings identify ARF proteins as early responders to lysosomal damage and suggest isoform-specific roles in coordinating the pathways of lysosomal quality control.

Keywords:  ARF; ORP; OSBP; lysosome; repair

DOI:  https://doi.org/10.3389/fmolb.2025.1699266
Noncoding RNA. 2025 Nov 04. pii: 77. [Epub ahead of print]11(6):

Prolonged Survival with Dieting for Improved Autophagy.

Akari Fukumoto, Moeka Nakashima, Satoru Matsuda.

  Food is a crucial component affecting the health of individuals, which may have the potential to expand lifespan. It has been shown that a long lifespan may be related to fine-tuned autophagy. In general, suitable autophagy could play a significant role in the anti-aging biological exertion of the host. AMPK, a member of serine and threonine kinases, could play vital roles within the autophagy signaling pathway in various cells. In addition, alterations in the kinase activity of AMPK have been shown to be connected to several pathologies of aging-related diseases. Therefore, autophagy could control the lifespan-related homeostasis within the host from cells to a body via the modification of AMPK. The design of the diet and/or nutrition targeting the AMPK would be a possibility to expand the lifespan. Some analyses of the molecular biology underlying the autophagy suggest that supplementation of accurate nutraceuticals, as well as dietary restriction, mild fasting, and/or appropriate physical exercise, could modulate AMPK signaling, which may be advantageous for life extension with the alteration of autophagy. Remarkably, it has been revealed that several non-coding RNAs (ncRNAs) might also play significant roles in the regulation of autophagy. In addition, the production of some ncRNAs may be associated with the alteration of gut microbiota with certain diets. Therefore, the modulation of AMPK action with ncRNAs through choosing the relevant diet could be a therapeutic tactic for promoting longevity, which is also accompanied by a reduced risk for several aging-related diseases.

Keywords:  AMPK; aging; aging-related diseases; autophagy; longevity; miRNA; ncRNA

DOI:  https://doi.org/10.3390/ncrna11060077
Cell Cycle. 2025 Nov 29. 1-11

The interplay between autophagy, p16INK4a, and senescence in tumor cells: a systematic review.

Ahmet Alperen Palabiyik, Esra Palabiyik.

  Autophagy and cellular senescence are fundamental determinants of tumor cell fate. p16INK4a has emerged as a key regulator at the intersection of these processes, yet its mechanistic role in the autophagy - senescence axis remains incompletely defined. Understanding this interaction is essential for identifying novel therapeutic opportunities in oncology. A systematic literature search was conducted across PubMed, Web of Science, and Scopus for studies published between January 2000 and April 2025, yielding 10 eligible studies after the application of predefined criteria. Evidence shows a dual role of autophagy in tumor biology. In some models, autophagy increased p16INK4a and senescence-associated β-gal activity, leading to stable growth arrest. Under stress conditions, however, it supported tumor cell survival despite senescence signals. Mechanistically, p16INK4a acted both upstream, modulating autophagic flux, and downstream, as an effector of autophagy-induced senescence. Study heterogeneity limited direct comparisons. Autophagy and p16INK4a interact bidirectionally to regulate senescence, representing a critical axis that can shift tumor cells between suppression and survival. Future research should prioritize standardized protocols, longitudinal models, and therapeutic evaluations to clarify whether targeting this pathway can be translated into effective cancer interventions.

Keywords:  Autophagy; cancer therapeutics; cellular senescence; p16INK4a; tumor suppression

DOI:  https://doi.org/10.1080/15384101.2025.2597989
bioRxiv. 2025 Nov 14. pii: 2025.11.14.688473. [Epub ahead of print]

Screening for residues in Atg11, a central organizer of selective autophagy in yeast, important for binding with Atg9.

Chimi Dolker Sherpa, Patricia Woghiren, Erin Leonello, Mina Abdel-Khalek, Benjamin J Schuessler, Josh V Vermaas, Steven K Backues.

The yeast protein Atg11, whose structure is unknown, is a central organizer of autophagosome formation that recruits Atg9 during selective autophagy. Although the residues in Atg9 responsible for this interaction are known, those in Atg11 are not. In an attempt to discover the binding site of Atg9 on Atg11, we screened a number of mutants within amino acid residues 455-627 of Atg11, guided in part by an AlphaFold2-generated model of the Atg11 dimer. However, we were not able to identify specific residues essential for the interaction with Atg9, suggesting that the binding region may lie elsewhere on Atg11.

DOI: https://doi.org/10.1101/2025.11.14.688473
Adv Sci (Weinh). 2025 Nov 26. e17373

Smart Nanoparticles Disrupting Energy Supply through Triple Mechanisms to Kill Tumors via Dual Disruption of Mitochondria and Lysosomes.

Xiao Xu, Qiqing Huang, Yang Liu, Jinzhuo Liu, Deyi Yang, Yanni Song, Xin Han.

  Targeting mitochondrial disruption as a strategy for inhibiting cancer cell proliferation presents a promising therapeutic approach. However, the process of mitophagy plays a protective role in cancer cells by aiding in damage repair, regulating energy metabolism, and promoting the development of drug resistance. Therefore, designing precise therapies that selectively damage mitochondria while inhibiting mitophagy remains a challenge. This study develops a biomimetic nanoplatform (MTCA@C) with hollow MnO2 as the core, loaded with tetrandrine and mitochondrial-targeted photosensitizer (Ce6-Apt), and coated with a cell membrane. Under the targeting of the ligand and irradiation of external near-infrared light, Ce6-Apt reaches the mitochondria to induce photodynamic reactions causing mitochondrial dysfunction, while also activating mitophagy. Tetrandrine induces lysosomal alkalinization, effectively disrupting the mitophagic flow, and Tet also causes macropinocytosis, characterized by excessive intracellular vacuole accumulation and expansion, leading to cell rupture and ultimately inducing methuosis. Notably, the synergistic effect of these three mechanisms cuts off the energy supply of tumor cells, achieving spatiotemporally controlled precision therapy. In summary, a biomimetic nanoplatform is designed that precisely disrupts the interaction between mitochondria and lysosomes to impair the compensatory energy supply of tumors, addressing the challenge of drug resistance in cancer treatment.

Keywords:  autophagy inhibition; cancer metabolism; lysosomal disruption; macropinocytosis; methuosis; mitochondrial targeting

DOI:  https://doi.org/10.1002/advs.202517373
Nat Commun. 2025 Nov 28.

Structural organization of p62 filaments and the cellular ultrastructure of calcium-rich p62-enwrapped lipid droplet cargo.

Sabrina Berkamp, Lisa Jungbluth, Alexandros Katranidis, Siavash Mostafavi, Olivera Korculanin, Peng-Han Lu, Lotte Ickert, Maya M Dierig, Lokesh Sharma, Lipi Thukral, Pitter F Huesgen, Natalia L Kononenko, Jörg Fitter, Rafal E Dunin-Borkowski, Carsten Sachse.

The selective autophagy receptor p62/SQSTM1 is known to form higher-order filaments in vitro and to undergo liquid-liquid phase separation when mixed with poly-ubiquitin. Here, we determine the full-length cryo-EM structure of p62 and elucidate a structured double helical filament scaffold composed of the PB1-domain associated with the flexible C-terminal part and the solvent-accessible major groove. At different pH values and upon binding to soluble LC3, LC3-conjugated membranes and poly-ubiquitin, we observe p62 filament re-arrangements in the form of structural unwinding, disassembly, lateral association and bundling, respectively. In the cellular environment, under conditions of ATG5 knockdown leading to stalled autophagy, we imaged high-contrast layers consisting of p62 oligomers enwrapping lipid droplets by cryogenic electron tomography in situ, which we identified as calcium as well as phosphorus by compositional spectroscopy analysis. Together, we visualize the cellular ultrastructure of p62 oligomers with high calcium content as a potential early stage of autophagy.

DOI: https://doi.org/10.1038/s41467-025-66785-7
Cell Mol Life Sci. 2025 Nov 25.

Regulation of mitochondrial dynamics and function by melatonin type 1 receptor in parkinson's disease.

Xiao-Bo Wang, Li-Li Qi, Jian-Min Wang, Yan-Rui Sun, Qian-Kun Lv, Bing-Er Cao, Shu-Min Jiang, Quan-Hong Ma, Chun-Feng Liu, Jun-Yi Liu, Fen Wang.

  Parkinson's disease (PD) is a neurodegenerative disease characterized by dopaminergic neuron loss and Lewy bodies in the substantia nigra. Abnormal mitochondrial function and accumulated α-synuclein (α-syn) are key etiological factors of PD. Melatonin type 1 receptor (MT1) regulates sleep upon activation by melatonin and may be reduced in PD patients. However, the role of MT1 in PD pathogenesis remains elusive. In this study, we found knockdown of MT1 caused mitochondrial dysfunction, mitochondrial fission and mitophagy in SH-SY5Y cells. Expression of mitochondrial fission protein dynamin-related protein 1 (DRP1) was increased and expression of fusion proteins optic atrophy 1 (OPA1), mitofusin 1 (MFN1) and mitofusin 2 (MFN2) were decreased. This was probably attributed to decreased phosphorylation of DRP1 at S637 by protein kinase A (PKA) and increased phosphorylation at S616 by extracellular-regulated kinase 1/2 (ERK1/2). Loss of MT1 exacerbated mitochondrial fission without influencing mitophagy, TH expression and movement in an MPTP-induced mouse model. Neuronal MT1 deficiency aggravated preformed fibrils induced autophagy inhibition and α-syn aggregation. Overexpression of MT1 reduced mitochondrial fission, increased LC3II expression and decreased P62 accumulation to promote autophagy in HEK293T cells, thus mitigating aggregation of α-syn. This study demonstrates the function of MT1 in mitochondria and autophagy, which sheds further light on PD prevention targeting MT1.

Keywords:  Autophagy; MPTP; Melatonin receptor MT1; Mitochondria dynamics; Parkinson’s disease; Α-synuclein

DOI:  https://doi.org/10.1007/s00018-025-05995-0
Free Radic Biol Med. 2025 Nov 21. pii: S0891-5849(25)01385-1. [Epub ahead of print]243 245-259

APOE4 impairs Nrf2-PINK1/Parkin-dependent mitochondrial clearance through disrupted antioxidant and mitophagy signaling.

Firoz Akhter, Asma Akhter, Donghui Zhu.

  APOE4, the strongest genetic risk factor for sporadic Alzheimer's disease (AD), is closely associated with mitochondrial dysfunction, yet the mechanisms remain poorly defined. We identify a previously unrecognized failure of the Nrf2-PINK1/Parkin axis in APOE4 neurons that compromises mitochondrial quality control. Unlike APOE3, APOE4 neurons fail to activate PINK1/Parkin-dependent mitophagy under stress, a defect compounded by impaired Nrf2 signaling and weakened antioxidant defenses. In vivo, APOE4 mice show age-dependent collapse of this pathway, correlating with progressive mitochondrial dysfunction and disrupted mito-nuclear communication. Pharmacological activation of Nrf2 or PINK1 restores mitochondrial clearance, highlighting the axis as a druggable node. These findings provide a mechanistic link between APOE4 and mitochondrial failure, establishing the Nrf2-PINK1/Parkin pathway as a critical driver of neurodegeneration and a promising target for therapeutic intervention in AD.

Keywords:  APOE4; Alzheimer's disease (AD); Mito-nuclear communication; Mitochondrial stress; Mitophagy; Nrf2-PINK/Parkin

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.11.040
Res Sq. 2025 Oct 21. pii: rs.3.rs-7682363. [Epub ahead of print]

Inhibition of autophagy-lysosomal function exacerbates microglial and monocyte lipid metabolism reprograming and dysfunction after brain injury.

Marta Lipinski, Amir Mehrabani-Tabari, Nivedita Hegdekar, Brian R Herb, Sazia Arefin Kachi, Chinmoy Sarkar, Sagarina Thapa, Dexter Nguyen, Yulemni Morel, Mehari Weldemariam, Ludovic Muller, W Andrews, Marcia Cortes-Gutierrez, Xiaoxuan Fan, Natarajan Ayithan, Olivia Pettyjohn-Robin, Sabrina Bustos, Lacey Greer, Jessica Gore, Maureen Kane, Seth Ament, Jace Jones.

CNS has an overall higher level of lipids than all tissues except adipose and contains up to 25% of total body cholesterol. Recent data demonstrate a complex crosstalk between lipid metabolism and inflammation, suggesting potential contribution of the lipid-rich brain environment to neuroinflammation. While recent data support the importance of brain lipid environment to inflammatory changes observed in age related chronic neurodegenerative diseases, in vivo interactions between lipid environment, lipid metabolism and neuroinflammation in acute brain disease and injury remain poorly understood. Here we utilize a mouse model of traumatic brain injury (TBI) to demonstrate that acute neurotrauma leads to widespread lipid metabolism reprograming in all microglial and brain associated and infiltrating monocyte populations. Additionally, we identify unique microglial and monocyte populations with higher degree of lipid metabolism reprograming and pronounced accumulation of neutral storage lipids, including cholesteryl esters and triglycerides. These lipids accumulate not only in lipid droplets but also in the microglial and monocyte lysosomes and are associated with lysosomal dysfunction and inhibition of autophagy after TBI. Our data indicate that lipid accumulation in these cells is the result of altered lipid handling rather than lipid synthesis and is triggered by phagocytosis of lipid-rich myelin debris generated after TBI. Finally, we use mice with autophagy defects in microglia and monocytes to demonstrate that further inhibition of autophagy leads to more pronounced lipid metabolism reprograming and exacerbated cellular lipid accumulation. Our data suggest a pathological feedback loop, where lipid phagocytosis causes inhibition of autophagy-lysosomal function, which in turn exacerbates cellular lipid retention, reprograming and inflammation.

DOI: https://doi.org/10.21203/rs.3.rs-7682363/v1
bioRxiv. 2025 Nov 01. pii: 2025.10.31.685804. [Epub ahead of print]

ER-to-Golgi Trafficking is a Nutrient-Sensitive Checkpoint Linking Glucose Starvation to Cell Surface Remodeling.

Joung Hyuck Joo, William Kasberg, Spencer Douglas, Uwemedimo Udoh, Alexandre Carisey, James Messing, Yong-Dong Wang, Shilpa Narina, Shondra M Pruett-Miller, Myriam Labelle, Jennifer Lippincott-Schwartz, Chi-Lun Chang, Mondira Kundu.

Cancer cells adapt to nutrient stress by remodeling the repertoire of proteins on their surface, enabling survival and progression under starvation conditions. However, the molecular mechanisms by which nutrient cues reshape the cell surface proteome to influence cell behavior remain largely unresolved. Here, we show that acute glucose starvation, but not amino acid deprivation or mTOR inhibition, selectively impairs ER-to-Golgi export of specific cargoes, such as E-cadherin, in a SEC24C-dependent manner. Quantitative cell surface proteomics reveal that glucose deprivation remodels the cell surface proteome, notably reducing surface expression of key adhesion molecules. This nutrient-sensitive reprogramming enhances cell migration in vitro and promotes metastasis in vivo . Mechanistically, we show that AMPK and ULK1 signaling orchestrate this process independent of autophagy, with ULK1-mediated phosphorylation of SEC31A driving SEC24C-dependent COPII reorganization. These findings establish ER-to-Golgi trafficking as a nutrient-sensitive regulatory node that links metabolic stress to cell surface remodeling and metastatic potential.

DOI: https://doi.org/10.1101/2025.10.31.685804
bioRxiv. 2025 Oct 16. pii: 2025.10.08.681260. [Epub ahead of print]

Visualizing PINK1 Activity Dynamics in Single Cells with a Phase Separation-Based Kinase Activity Reporter.

Katie G Vineall, Alexia Andrikopoulos, Michael J Sun, Anna Yan, Ethan R Hartanto, Danielle L Schmitt.

Phosphatase and tensin homologue-induced kinase 1 (PINK1) is a serine/threonine kinase that plays roles in mitophagy, cell death, and regulation of cellular bioenergetics. Current approaches for studying PINK1 function depend on bulk techniques that can only provide snapshots of activity and could miss the dynamics and cell-to-cell heterogeneity of PINK1 activity. Therefore, we sought to develop a novel PINK1 kinase activity reporter to characterize PINK1 activity. Taking advantage of the separation of phases-based activity reporter of kinase (SPARK) design, we developed a phase separation-based PINK1 biosensor (PINK1-SPARK). With PINK1-SPARK, we observe real-time PINK1 activity in single cells treated with mitochondria depolarizing agents or pharmacological activators. We then developed a Halo Tag-based PINK1-SPARK for multiplexed imaging of PINK1 activity with live-cell markers of mitochondrial damage. Thus, PINK1-SPARK is a new tool that enables temporal measurement of PINK1 activity in single live cells, allowing for further elucidation of the role of PINK1 in mitophagy and cell function.

DOI: https://doi.org/10.1101/2025.10.08.681260
Commun Biol. 2025 Nov 25. 8(1): 1681

FGF9 alleviates diabetic cardiomyopathy by activating Nrf2 via SQSTM1/p62-Keap1 in mice.

Ning An, Yunjie Chen, Lin Li, Bingyu Wang, Xuan Zhou, Gen Chen.

Fibroblast growth factor 9 (FGF9) plays a key role in development and cardioprotection, yet its function in diabetic cardiomyopathy (DCM) remains unclear. In a high-fat diet/streptozotocin (HFD/STZ)-induced DCM model, FGF9 attenuated cardiac hypertrophy, fibrosis, and systolic dysfunction, effects abolished in cardiomyocyte-specific Nrf2 knockout mice. Mechanistically, FGF9 restored AMPK activity and promoted autophagy, enhancing p62-mediated degradation of Keap1 and nuclear translocation of Nrf2. In neonatal rat cardiomyocytes (NRCMs), FGF9 reversed high glucose and palmitate (HG + PA)-induced suppression of AMPK phosphorylation, autophagic flux, and Nrf2 signaling. AAV9-mediated expression of wild-type AMPK (AMPKWT) or a dominant-negative AMPK mutant (AMPKT172A) confirmed that AMPK activation was essential for FGF9-induced Nrf2 activation. Functionally, FGF9 reduced lipid accumulation, preserved mitochondrial integrity, and alleviated oxidative stress. FGF9 ameliorates DCM via non-canonical autophagy-dependent activation of Nrf2, mediated by AMPK. These findings position FGF9 as a potential therapeutic target for diabetic myocardial injury.

DOI: https://doi.org/10.1038/s42003-025-09077-6
JAMA Psychiatry. 2025 Nov 26.

Autophagy in Stress-Induced Neuropsychiatric Disorders and Depression.

Akira Sawa, Kun Yang, Nicola G Cascella, Toshifumi Tomoda.

DOI: https://doi.org/10.1001/jamapsychiatry.2025.3580
Science. 2025 Nov 27. eadv7111

Structural basis for the recruitment and selective phosphorylation of Akt by mTORC2.

Martin S Taylor, Maggie Chen, Matthew Hancock, Maximilian Wranik, Bryant D Miller, Timothy R O'Meara, Brad A Palanski, Scott B Ficarro, Brian J Groendyke, Yufei Xiang, Kazuma T Kondo, Karen Y Linde-Garelli, Michelle J Lee, Dibyendu Mondal, Daniel Freund, Samantha Congreve, Kaay Matas, Maximiliaan Hennink, Kera Xibinaku, Max L Valenstein, Trevor van Eeuwen, Jarrod A Marto, Andrej Sali, Yi Shi, Nathanael S Gray, David M Sabatini, Nam Chu, Kacper B Rogala, Philip A Cole.

The mTOR protein kinase forms two multiprotein complexes, mTORC1 and mTORC2, that function in distinct signaling pathways. mTORC1 is regulated by nutrients, and mTORC2 is a central node in phosphoinositide-3 kinase (PI3K) and small guanosine triphosphate Ras signaling networks commonly deregulated in cancer and diabetes. Although mTOR phosphorylates many substrates in vitro, in cells, mTORC1 and mTORC2 have high specificity: mTORC2 phosphorylates the protein kinases Akt and PKC, but not closely related kinases that are mTORC1 substrates. To understand how mTORC2 recognizes substrates, we created semisynthetic probes to trap the mTORC2-Akt complex and determine its structure. Whereas most protein kinases recognize amino acids adjacent to the phosphorylation site, local sequence contributes little to substrate recognition by mTORC2. Instead, the specificity determinants were secondary and tertiary structural elements of Akt that bound the mTORC2 component mSin1 distal to the mTOR active site and were conserved amongst at least 18 related substrates. These results reveal how mTORC2 recognizes its canonical substrates and may enable the design of mTORC2-specific inhibitors.

DOI: https://doi.org/10.1126/science.adv7111
bioRxiv. 2025 Oct 10. pii: 2025.10.09.681478. [Epub ahead of print]

Larp1 supports brain growth and spatial memory via post-transcriptional control of the translation machinery.

Mark S Williams, Maegan J Watson, Carson C Thoreen.

In the brain, tight regulation of the translation of mRNAs is essential for development and plasticity. The translation machinery itself is largely encoded by mRNAs with terminal oligopyrimidine (TOP) motifs, which can be post-transcriptionally controlled by the mTOR signaling pathway. In neurons, these mRNAs are selectively enriched in axons, dendrites and synapses, suggesting local functions for their regulation. Here, we use a brain-specific knockout of the mTOR effector and TOP mRNA binding protein, Larp1, to uncover its role in brain development and behavior. Loss of Larp1 significantly decreases brain mass and reduces the density of neurons. We find that TOP mRNAs levels are depleted by more than 50% and selectively lost from synapses, reversing the enrichment that occurs when Larp1 is present. In behavior tests, Larp1-deficient mice are severely impaired in spatial learning and memory. These results demonstrate a critical role for Larp1 in maintaining the levels of essential mRNAs necessary for brain growth and highlight the importance of post-transcriptional regulation by mTOR for normal learning and memory.

DOI: https://doi.org/10.1101/2025.10.09.681478
Free Radic Biol Med. 2025 Nov 23. pii: S0891-5849(25)01390-5. [Epub ahead of print]243 398-413

TFEB-nuclear translocation promotes BNIP3-mediated mitophagy and alleviates oxidative stress and ferroptosis in acute pancreatitis.

Haoyu Zhang, Yuchen Jia, Zheng Wang, Jie Li, Xiaozhou Xie, Yixuan Ding, Feng Cao, Fei Li.

  Mitophagy, oxidative stress, and ferroptosis are critical processes in the development of acute pancreatitis (AP). Transcription factor EB (TFEB), a key regulator of autophagy and lysosomal biogenesis, plays a central role in the pathogenesis of AP. However, its specific regulatory mechanisms within the mitophagy-oxidative stress-ferroptosis network remain incompletely understood. This study investigated the therapeutic potential of ginkgetin (GK), a natural TFEB activator, in AP. The results demonstrated that GK activated TFEB and subsequently significantly alleviated pathological damage in AP in vivo and effectively inhibited acinar cell death in vitro. Further mechanistic studies revealed that TFEB activation markedly improved impaired autophagic flux in AP, enhanced mitophagy, and simultaneously suppressed ferroptosis and oxidative stress. Specifically, TFEB upregulated the expression of the lysosomal marker LAMP1 to restore autophagy-lysosome function and induced the expression of BNIP3, a key mitophagy receptor, thereby enhancing mitochondrial quality control, restoring mitochondrial function, and ultimately mitigating oxidative stress and ferroptosis. Functional experiments confirmed that TFEB exerts its protective effects through nuclear translocation. When nuclear translocation was blocked by a C270S mutation-a mutation that disrupts TFEB dissociation from 14-3-3 proteins and subsequent nuclear localization-TFEB's regulatory roles in autophagy, mitophagy, ferroptosis, and oxidative stress were significantly inhibited. This study elucidates that TFEB, through nuclear translocation, not only restores basal autophagy but also enhances mitophagy, thereby collectively inhibiting oxidative stress and ferroptosis and alleviating the progression of AP. These findings provide a novel therapeutic strategy for AP.

Keywords:  Acute pancreatitis; Ferroptosis; Ginkgetin; Mitophagy; Oxidative stress; TFEB

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.11.045
Aging Cell. 2025 Nov 23. e70301

APP Induces AICD-Mediated Autophagy-Dependent Axon Degeneration.

Jingjing Luo, Yu Qiu, Yu Pan, Ruihong Xu, Yi Sun, Yihao Sun, Luming Zhuang, Elleen Xue, Wenzhe Li, Qian Zhou, Zhongwei Lv, Chenglin Li, Lei Xue.

  The amyloid precursor protein (APP) plays a pivotal role in the pathogenesis of Alzheimer's disease (AD). While the production of Amyloid beta (Aβ) has traditionally been considered the primary cause of AD, the role of the APP intracellular domain (AICD) remains largely elusive. In this study, we established a novel model in the adult fly wing by expressing human APP, recapitulating AD-associated axon degeneration. Using this model, we discovered that ectopic APP expression in Drosophila wing margin neurons led to age-dependent axon degeneration. APP's effect depended on AICD production, and AICD overexpression alone was sufficient to induce axon degeneration in adult wings. Further investigations indicated that APP- or AICD-induced axon degeneration could be alleviated by blocking autophagy, but not apoptosis. Additionally, we identified a FoxO/Snail-Atg1 axis as an essential mediator of APP/AICD-induced autophagy-dependent axon degeneration. Finally, we demonstrated that administration of chloroquine, an autophagy inhibitor, effectively ameliorates APP- or AICD-induced axon degeneration. Our findings provide crucial insights into how APP induces autophagy-dependent axon degeneration through AICD production, laying a foundation for future investigations into AD pathogenesis.

Keywords:  AICD; APP; Alzheimer's disease; autophagy; axon degeneration

DOI:  https://doi.org/10.1111/acel.70301
Nat Rev Mol Cell Biol. 2025 Nov 26.

ESCRT-III function in membrane fission and repair.

M Burigotto, J G Carlton.

The endosomal sorting complex required for transport (ESCRT) machinery is an evolutionarily conserved multisubunit protein complex that remodels cellular membranes. Beyond its classical role in endosomal sorting, the ESCRT machinery has been implicated in an ever-growing number of functions, including viral budding, cytokinesis, autophagy, extracellular vesicle release, pruning of synaptic processes and the repair and closure of holes in cellular membranes. Membrane remodelling functions are typically ascribed to the ESCRT-III subcomplex. In this Review, we discuss recent mechanistic and structural insights into how these proteins assemble and are remodelled to achieve membrane severing. We focus particularly on how ESCRT-III is engaged at different subcellular compartments during both interphase and mitosis to repair and remodel membranes.

DOI: https://doi.org/10.1038/s41580-025-00909-1
Nat Commun. 2025 Nov 25. 16(1): 10486

State-selective small molecule degraders that preferentially remove aggregates and oligomers.

Jakub Luptak, Dean Clift, Aamir Mukadam, Jonathan Benn, Tyler Rhinesmith, Stephen H McLaughlin, Amy C Dodds, Jerson E Lapetaje, Matylda Sczaniecka-Clift, David J France, William A McEwan, Leo C James.

TRIM21 is a unique E3 ligase that uses a clustering-based activation mechanism to degrade complex multimeric substrates. This activity underpins the targeted protein degradation technology Trim-Away and genetically encoded degraders that selectively target aggregated tau protein and prevent tauopathy. Here we describe small molecules that mimic TRIM21's natural epitope and function as either effective inhibitors or potent and selective degraders called TRIMTACs. TRIMTACs mediate degradation as rapidly as PROTACs but can also selectively degrade specific protein pools depending on assembly state. We demonstrate the utility of this state-specific degradation by selectively removing the pro-inflammatory signalling protein Myd88 when assembled into the Myddosome and the cell-death protein RIPK3 when polymerised into the Necrosome. We further show that TRIMTACs can inhibit seeded tau aggregation under conditions where a PROTAC is ineffective. These results highlight that TRIM21's clustering-based activation can be exploited by small molecule degraders to carry out state-selective degradation of therapeutic targets.

DOI: https://doi.org/10.1038/s41467-025-65454-z