bims-auttor 2026-04-12 papers

bims-auttor

Biomed News

on Autophagy and mTOR

Issue of 2026–04–12
forty-one papers selected by
Viktor Korolchuk, Newcastle University

STUB1-VCP/p97 limits PINK1 overaccumulation to safeguard mitophagy and memory.
Where and how do mammalian cells shape autophagosomes?
Two Routes for Removing Unhealthy Mitochondria: Degradation and Secretion.
The SWR1 complex prevents the vacuolar delivery of ATG proteins through a noncanonical pathway.
Dynamin-2 promotes Atg9A retrieval from phagophores during autophagy.
The Roles of Alix and VPS4A in Autophagy and Endosomal Pathways and Their Relation to HBV Replication.
Coronavirus NSP5 protease cleaves CCDC50 to evade antiviral autophagy.
Distinct autophagy impairment mechanisms of huntingtin aggregates with different polyQ lengths.
Phase separation of C19orf12 regulates BNIP3 protein quality control and maintains neuronal mitophagy.
Deciphering the role of SIRT6 in suppressing the AMPK-mTOR-TFEB axis: regulation of autophagy activation in HCC.
Cholesterol-dependent lysosomal docking of mTORC1 mediated by TM6SF1.
From Defence to Dysfunction: The Dual Role of Autophagy and Mitophagy in Cardiomyopathy.
Lysosomal Control of Aging through Transcriptional and Epigenetic Regulation.
Autophagic extracellular vesicles: a distinct secretory route linking autophagy to extracellular communication.
In situ architecture of developmentally programmed mitophagy reveals ER-phagophore membrane continuity.
DAPK1-Mediated Parkin Inactivation Enhances Neurotoxicity via MITOL-Dependent Degradation.
ATG14-Mediated SNARE Complex Activation Promotes ΔFosB Degradation to Ameliorate Levodopa-Induced Dyskinesia.
A lineage-specific autophagic mechanism of P-body turnover.
Rab12 is a regulator of mitophagy and mitochondrial homeostasis.
Disruption of the OPTN-TBK1 axis impairs autophagosome formation in prion disease.
SQSTM1/p62-mediated autophagy and antioxidation contribute to white spot syndrome virus pathogenesis in shrimp.
The integrated stress response suppresses PINK1-dependent mitophagy by preserving mitochondrial import efficiency.
Silicon rhodamine-based fluorescent probes for monitoring mitochondrial viscosity dynamics during mitophagy.
Translation in proximity to forming autophagosomes during sustained autophagy.
Fatty acid synthesis supports tumor progression through facilitating the activity of TORC1 signaling.
FAM134B isoform 2/RETREG1-2 defines a calnexin-TOLLIP-coupled ER-phagy pathway that restricts Ebola virus glycoprotein and is antagonized by VP40 through macro-autophagy.
Newcastle disease virus exploits Golgi stress and Golgiphagy to promote ferroptosis.
ADT-OH promotes mitophagy and suppresses the cytosolic mtDNA-cGAS-STING inflammatory cascade in microglia.
L-Leucine Upregulates Lysosomal Biogenesis and Autophagy to Lower Plaques in 5XFAD Mouse Model of Alzheimer's Disease.
Concept and connotation of the geroprotective and anti-aging effects of metformin: From AMPK activation to SASP suppression.
Lysosomal Expansion Compartments Mediate Zinc and Copper Homeostasis in Caenorhabditis elegans.
Genetic and environmental risk factors of Parkinsonism.
In vivo CRISPR/Cas9 Screening Reveals that UBE2L3 Modulates Autophagic Flux through TSC2 Ubiquitination and Potentiates PD-1 Blockade in Triple-Negative Breast Cancer.
Dietary restriction shapes intergenerational ribosome abundance and early growth of Caenorhabditis elegans offspring.
Wdfy3-dependent autophagy impairment recapitulates presymptomatic neurodegenerative signatures in mice.
NCOA4-mediated ferritinophagy: emerging role and novel therapeutic target in precision oncology.
Intracellular GRP78-Directed Delivery of Rapamycin by Biomolecular Condensates of Hydra-Elastin-like Polypeptides.
The Emerging Role of Novel PTMs in Autophagy: Implications for Diabetes and Its Complications.
Lysosomal Membrane Proteins: Key Regulators of Glucose Metabolism and Its Associated Diseases.
Species-specific cleavage of the autophagy adaptor p62 dictates responses to TNF.
Shifts in protein aggregate stability define proteostasis decline in the aging human brain.

Autophagy. 2026 Apr 11.

STUB1-VCP/p97 limits PINK1 overaccumulation to safeguard mitophagy and memory.

Jin-Yi Lin, Ze-Bo Huang, Evandro F Fang, Guang Lu.

  PINK1 serves as the central regulator of PINK1-PRKN-mediated mitophagy, and its precise regulation is critical for efficient mitochondrial clearance. Although the cleavage of PINK1 and its subsequent degradation via the N-end rule pathway under basal conditions are well understood, how full-length PINK1 stability is regulated following mitochondrial damage has remained elusive. In our recent study, we identified the STUB1-VCP/p97 axis as a mechanism that fine-tunes full-length PINK1 levels during mitophagy. We demonstrate that STUB1 functions as an E3 ubiquitin ligase that catalyzes K48-linked polyubiquitination of full-length PINK1, which is subsequently recognized and extracted by VCP/p97 for proteasomal degradation. Disruption of this axis results in excessive accumulation of full-length PINK1, accelerated turnover of PRKN, and impaired mitophagy. Moreover, we find that this regulatory mechanism is compromised in the brains of patients with Alzheimer disease (AD), and its disruption leads to neuronal mitophagy defects and impaired associated learning capability in C. elegans. These findings demonstrate that the STUB1-VCP/p97 complex fine-tunes PINK1 levels to ensure efficient mitophagy and preserve mitochondrial homeostasis.Abbreviations: AD, Alzheimer disease; CALCOCO2/NDP52, calcium binding and coiled-coil domain 2; MPP, mitochondrial processing peptidase; MQC, mitochondrial quality control; OMM, outer mitochondrial membrane; OPTN, optineurin; PARL, presenilin associated rhomboid like; PINK1, PTEN induced kinase 1; PRKN, parkin RBR E3 ubiquitin protein ligase; SILAC, stable isotope labeling by amino acids in cell culture; STUB1, STIP1 homology and U-box containing protein 1; TPR, tetratricopeptide repeat; VCP/p97, valosin containing protein; WIPI2, WD repeat domain, phosphoinositide interacting 2.

Keywords:  Alzheimer disease; PINK1; PRKN; STUB1; VCP/p97; memory; mitochondrial homeostasis; mitophagy; ubiquitin-proteasome system

DOI:  https://doi.org/10.1080/15548627.2026.2658848
J Biol Chem. 2026 Apr 07. pii: S0021-9258(26)00298-X. [Epub ahead of print] 111428

Where and how do mammalian cells shape autophagosomes?

Claudia Puri, David C Rubinsztein.

Autophagy is a fundamental cellular process responsible for degrading and recycling cytoplasmic components and regulates homeostasis, development, and survival under stress. Autophagy plays critical roles in diseases including neurodegeneration, cancers, and various infectious and inflammatory conditions. While the molecular machinery of autophagy has been well studied, increasing evidence highlights a complex interplay between autophagy and endocytosis. Traditionally, mammalian autophagosomes were believed to originate from compartments closely associated with the endoplasmic reticulum (ER), or the ER itself. However, more recent research has demonstrated that the recycling endosome serves as the main platform for autophagosome formation. The recruitment of WIPI2, an essential autophagy protein, to autophagosome initiation sites depends on its coincident detection of phosphatidylinositol 3-phosphate (PI(3)P) and RAB11A, a recycling endosome marker. This enables conjugation of LC3 (microtubule-associated protein light-chain 3) family members to the recycling endosome membranes to become nascent autophagosomes. These findings underscore the critical role of RAB11- compartment in autophagosome biogenesis. Contrary to the conventional model that has inferred that autophagosomes derive from spherical precursors with single apertures, structured illumination microscopy reveals these precursors are finger-like structures - much like a hand grasping an object. We will describe the experimental path that led to an understanding of how autophagosomes form from outgrowths of the recycling endosomes, then close after engulfing their contents. This step is a prerequisite for the final step of autophagosome formation, the release of autophagosomes from the recycling endosome membranes, a process that is perturbed by a major Alzheimer's disease gene.

DOI: https://doi.org/10.1016/j.jbc.2026.111428
Circ Res. 2026 Apr 10. 138(8): e326985

Two Routes for Removing Unhealthy Mitochondria: Degradation and Secretion.

Xi Fang, Åsa B Gustafsson.

  Mitochondria are highly dynamic, double-membraned organelles that generate the majority of ATP in cardiomyocytes while supporting cellular homeostasis and signal transduction. Accumulation of dysfunctional mitochondria can promote cardiomyocyte loss, impair contractile function, and ultimately lead to myocardial damage. To preserve mitochondrial integrity, cardiomyocytes rely on multilayered quality control mechanisms to remove defective mitochondria. Two major routes have emerged for this process: degradation, primarily via autophagy, and secretion via extracellular vesicles. This review summarizes the mechanisms of mitochondrial degradation and secretion in the heart and highlights their contributions to cardiac disease progression and potential as therapeutic targets.

Keywords:  extracellular vesicles; homeostasis; mitochondria; mitophagy; myocytes, cardiac

DOI:  https://doi.org/10.1161/CIRCRESAHA.125.326985
J Cell Biol. 2026 Jun 01. pii: e202511133. [Epub ahead of print]225(6):

The SWR1 complex prevents the vacuolar delivery of ATG proteins through a noncanonical pathway.

Siyu Fan, Huan Yang, Jianting Lei, Xinyue Gong, Yiyu Lin, Yuan Zhou, Yuhang Cui, Yuanyuan Ding, Mingzhu Fan, Shan Feng, Weijing Yao, Dong Fang, Kunrong Mei, Hongguang Xia, Cong Yi.

Autophagy is a conserved catabolic process that relies on vacuoles or lysosomes. While autophagosome formation is well characterized, the mechanisms that prevent autophagy-related proteins form being enclosed by the autophagosome and degraded in the vacuole remain unclear in yeast. Here, we show that the SWR1 chromatin remodeling complex plays an essential, noncanonical role in this process. Genome-wide screening identified the SWR1 complex as a critical regulator that prevents the vacuolar delivery of multiple autophagy proteins. This process depends on the structural integrity and ATPase activity of the SWR1 complex. Mechanistically, the SWR1 subunit Rvb1 interacts directly with Atg21, and this interaction is important for SWR1 localization to the phagophore assembly site and efficient protein retrieval. Disruption of the Atg21-Rvb1 interaction results in the vacuolar accumulation of autophagy proteins. These findings uncover an unexpected link between a chromatin remodeling complex and the autophagy machinery, highlighting the Atg21-Rvb1 module as a key regulator of autophagy dynamics in yeast.

DOI: https://doi.org/10.1083/jcb.202511133
bioRxiv. 2026 Mar 13. pii: 2026.03.11.711183. [Epub ahead of print]

Dynamin-2 promotes Atg9A retrieval from phagophores during autophagy.

Andrew Caliri, Alejandro Martorell Riera, Akash Saha, Panagiota Kolitsida, Cinta Iriondo Martinez, Samuel Itskanov, Janos Steffen, Carla M Koehler, Alexander M van der Bliek.

Autophagy involves the rapid growth of phagophores through membrane addition. This growth is triggered by vesicles containing the Atg9A protein. However, Atg9A is not incorporated into mature autophagosomes. We now demonstrate that Dynamin-2 (Dnm2) colocalizes with the BAR domain protein Endophilin-B1 (EndoB1/Bif-1/SH3GLB1) and other autophagy proteins when autophagy is induced. Our data suggest that Atg9A is retrieved from phagophores via fission, with Dnm2 acting as the membrane scission protein. Blocking Atg9A recycling, either by mutating Dnm2, using RNA interference, or applying chemical inhibitors, results in Atg9A remaining in autophagosomes and being degraded during autophagy. Overall, these findings provide new insights into the roles of membrane-scission proteins in autophagy.

DOI: https://doi.org/10.64898/2026.03.11.711183
FASEB J. 2026 Apr 15. 40(7): e71771

The Roles of Alix and VPS4A in Autophagy and Endosomal Pathways and Their Relation to HBV Replication.

Jia Li, Thekla Kemper, Shuping Tong, Xueyue Wang, Yong Lin, Mengji Lu.

  Autophagic and endosomal pathways coordinately contribute to hepatitis B virus (HBV) production, with the endosomal sorting complex required for transport (ESCRT) components ALG-2-interacting protein X (Alix) and the vacuolar protein sorting 4A (VPS4A) playing important but mechanistically elusive roles. This study investigates the roles of Alix and VPS4A in HBV biogenesis within the context of endosomal trafficking and autophagy. Using gene silencing and overexpression of wild-type (WT) or dominant-negative (DN) mutants of Alix and VPS4A in HBV replication cell models, we found that Alix silencing increased intracellular HBV DNA and HBV surface antigen (HBsAg), extracellular HBsAg, and virions, while decreasing secreted naked capsids. It promoted HBsAg secretion along the early endosomes but reduced its transport to late endosomes and autophagosomes. Furthermore, Alix silencing impaired autophagosome formation by activating the AKT/MTOR pathway. In contrast, VPS4A silencing had minimal effects, whereas DN VPS4A significantly blocked HBV secretion by disrupting endosomal trafficking, promoting autophagosome formation and lysosome activity, ultimately leading to HBV degradation. Our findings demonstrate that the endosomal pathway is critical for HBV secretion when lysosomal activity is suppressed. Conversely, increased lysosomal function drives HBV degradation through the autophagosome-lysosome pathway.

Keywords:  Alix; HBV; VPS4A; autophagosome; degradation; endosomal trafficking

DOI:  https://doi.org/10.1096/fj.202504742R
Autophagy. 2026 Apr 11.

Coronavirus NSP5 protease cleaves CCDC50 to evade antiviral autophagy.

Ke Li, Hongyun Wei, Wenqiu Yin, Peng Zhou, Hui Jin, Anan Jongkaewwattana, Sizhu Suolang, Hongbo Zhou, Rui Luo.

  Selective macroautophagy/autophagy is a critical component of innate antiviral defense, relying on selective autophagy receptors to recognize viral cargo and deliver it for lysosomal degradation. In our recent study, we demonstrated that porcine deltacoronavirus (PDCoV) evades this pathway through its NSP5 protease. We uncovered a previously unrecognized antiviral function of the selective autophagy receptor CCDC50, which recognizes K63-linked polyubiquitinated PDCoV envelope (E) protein at lysine 72 and mediates its autophagic degradation, thereby restricting viral replication. This antiviral mechanism operates independently of the canonical receptors SQSTM1/p62 and NBR1. We further demonstrate that PDCoV NSP5 cleaves CCDC50 at glutamine 171, a conserved cleavage site also targeted by NSP5 orthologs from porcine epidemic diarrhea virus/PEDV, transmissible gastroenteritis virus/TGEV, and SARS-CoV-2. This cleavage disrupts the interaction of CCDC50 with ubiquitin and MAP1LC3/LC3, thereby impairing autophagic degradation of the E protein. Collectively, these findings establish CCDC50 as a selective autophagy receptor with antiviral activity against coronaviruses and reveal that coronavirus NSP5 promotes infection by proteolytically dismantling receptor-mediated antiviral autophagy.

Keywords:  CCDC50; NSP5; PDCoV; cleavage; selective autophagy

DOI:  https://doi.org/10.1080/15548627.2026.2658847
Cell Chem Biol. 2026 Apr 06. pii: S2451-9456(26)00102-9. [Epub ahead of print]

Distinct autophagy impairment mechanisms of huntingtin aggregates with different polyQ lengths.

Heejung Kim, Hae Nim Lee, Suhyun Kim, Seung Jae Hyeon, Hyunmin Jo, Kyung-Soo Inn, Hoon Ryu, Jihye Seong.

  Huntington's disease (HD) is characterized by the aggregation of mutant huntingtin (mHTT) containing elongated polyglutamine (polyQ) tracts. mHTT aggregates that fail to be cleared by autophagy cause neurotoxicity. While the polyQ length in patients with HD ranges from 40 to over 90 repeats, how these varying polyQ lengths affect autophagy impairment remains unclear. Using polyQ aggregation sensors based on bimolecular fluorescence complementation (BiFC), we uncovered distinct autophagy impairment mechanisms: PolyQ103 aggregates evade recognition by autophagy receptor SQSTM1/p62, whereas polyQ43 condensates are recognized by SQSTM1/p62, but their bulky association prevents complete autophagosome formation. Interestingly, overexpression of optineurin (Optn), another autophagy receptor, preferentially binds to polyQ103 aggregates but not polyQ43 condensates, improving cell survival. K63-ubiquitination on polyQ103 aggregates serves as a critical determinant for Optn recruitment via its UBAN domain. These findings reveal polyQ length-dependent pathological mechanisms underlying autophagy impairment of mHTT aggregates, suggesting potential therapeutic strategies for patients with longer polyQ sequences.

Keywords:  BiFC; Huntington’s disease; SQSTM1/p62; autophagy; optineurin; polyQ lengths

DOI:  https://doi.org/10.1016/j.chembiol.2026.03.010
Autophagy. 2026 Apr 11. 1-15

Phase separation of C19orf12 regulates BNIP3 protein quality control and maintains neuronal mitophagy.

Changjuan Shao, Sabina Bhatta, Meena Kumari, Fengqin Wu, Sandra L Siedlak, Sandy Torres, Fanpeng Zhao, Xiongwei Zhu, Wenzhang Wang.

  Mutations in C19orf12, an orphan gene with elusive function, cause mitochondrial membrane protein-associated neurodegeneration (MPAN). Despite the intriguing mitochondrial deficits, the mechanisms underlying the loss of function of C19orf12 in MPAN pathogenesis remain unclear. In this study, we aim to explore the functional impacts of C19orf12 mutations on mitophagy in MPAN models in vitro and in vivo. Our findings suggest that C19orf12 regulates the turnover of mitophagy receptor BNIP3 proteins through the lysosomal degradation pathway. Disruption of this process leads to the accumulation of oxidized BNIP3 proteins on mitochondria that are ineffective in initiating mitophagy. Mechanistically, C19orf12 participates in protein condensate formation by liquid-liquid phase separation to facilitate BNIP3 protein turnover on the mitochondrial membrane. Along with mitophagy deficits, a rodent MPAN model exhibits motor deficits and core pathological features of MPAN, including iron accumulation, axonal spheroids, and neuroinflammation. This study underscores the pivotal role of C19orf12 in regulating the quality control of BNIP3 protein to control mitophagy, highlighting the significance of impaired mitophagy in the pathogenesis of MPAN.Abbreviations: ATP: adenosine triphosphate; BafA: bafilomycin A1; BNIP3: BCL2 interacting protein 3; BTZ: bortezomib; C19orf12: chromosome 19 open reading frame 12; CFP: cyan fluorescent protein; CHX: cycloheximide; DNP: dinitrophenyl; FCCP: carbonyl cyanide-p-trifluoromethoxyphenylhydrazone; FRAP: fluorescence recovery after photobleaching; GFP: green fluorescent protein; H&E stain: haematoxylin and eosin stain; LCD: low complexity domain; LC/MS: liquid chromatography-mass spectrometry; LLPS: liquid-liquid phase seperation; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; mito-SRAI: mitochondrial signal-retaining autophagy indicator; MG132: cbz-leu-leu-leucinal; MMP: mitochondrial membrane potential; MPAN: mitochondrial membrane protein-associated neurodegeneration; NBIA: neurodegeneration with brain iron accumulation;PLA: proximity ligation assay; RFP: red fluorescent protein; ROS: reactive oxygen species; STX17: syntaxin 17; TFAM: transcription factor A, mitochondrial; TOLLES: TOLerance of lysosomal EnvironmentS; YPet: YFP for energy transfer.

Keywords:  Iron accumulation; LLPS; NBIA; mitochondrial membrane; mitophagosome; protein degradation

DOI:  https://doi.org/10.1080/15548627.2026.2655834
Cancer Gene Ther. 2026 Apr 09.

Deciphering the role of SIRT6 in suppressing the AMPK-mTOR-TFEB axis: regulation of autophagy activation in HCC.

Cong Shan Li, Hua Jin, Ruoyu Meng, Seung-Woo Baek, Seong-Hun Kim, Ok Hee Chai, Byung Hyun Park, Ju-Seog Lee, Na Ri Lee, Soo Mi Kim.

Sirtuin 6 (SIRT6), belong to the NAD-dependent class III protein deacetylase family, is implicated in cancer development through a multifaceted role. While it has been identified with both tumor-suppressive and tumor-promoting roles in Hepatocellular carcinoma (HCC), there remains considerable debate regarding its exact function. The specific molecular mechanisms driving its tumor-suppressive effects in HCC remains poorly understood. In this study, we mechanistically identified a novel pathway involving AMP-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), and transcription factor EB (TFEB): upregulation of SIRT6 enhances AMPK activity and suppresses mTOR activation, leading to TFEB nuclear translocation and the subsequent induction of autophagy. Importantly, our study provides the first evidence that SIRT6 induces the translocation of TFEB into the nucleus, facilitating autophagy. Intriguingly, SIRT6 silencing counteracted the effects of mTOR inhibitors on TFEB and autophagy, suggesting that SIRT6 probably activates lysosome function via an AMPK-mTOR-TFEB axis in HCC. Our in vivo experiments bolster our findings, demonstrating that SIRT6 effectively suppressed HCC tumor growth and metastasis. Overall, our research provides compelling evidence that SIRT6 functions as a tumor suppressor in HCC, offering a valuable therapeutic mechanism for treating HCC and paving the way for a promising avenue in future HCC treatment. Schematic illustration of SIRT6's role in hepatocellular carcinoma. Proposing a model to elucidate the regulatory mechanism of SIRT6-AMPK-mTOR-TFEB signaling axis in orchestrating autophagy activation within hepatocellular carcinoma. Phosphorylation of AMPK by SIRT6 leads to the inhibition of mTOR and its downstream targets. This modulation influences TFEB, promoting its translocation into the nucleus and triggering autophagy activation. This intricate cascade is marked by a significant increase in substrate degradation and the formation of autophagic bilayers, ultimately culminating in the suppression of cell proliferation and the augmentation of cell death.

DOI: https://doi.org/10.1038/s41417-026-01023-w
bioRxiv. 2026 Apr 03. pii: 2026.04.01.715928. [Epub ahead of print]

Cholesterol-dependent lysosomal docking of mTORC1 mediated by TM6SF1.

Sen Hong, Liangjie Jia, Rong Wang, Nadia Elghobashi-Meinhardt, Helen H Hobbs, Xiaochun Li.

The Transmembrane 6 Superfamily (TM6SF) comprises two members: TM6SF1, a ubiquitously expressed lysosomal membrane protein of unknown function, and TM6SF2, an endoplasmic reticulum protein required for lipidation of Apolipoprotein B-containing lipoproteins. Here, we identify TM6SF1 as a cholesterol-bound lysosomal docking factor for mTORC1. Loss of TM6SF1 disrupts spatial organization of the lysosomal mTORC1 machinery and results in constitutive activation of Transcription Factor EB (TFEB) without altering lysosomal pH or interfering with cholesterol trafficking. Using cryo-electron microscopy, we determined the structure of human TM6SF1 at 2.9-Å resolution, revealing a cholesterol-bound polytopic homodimer. Biochemical analyses show that TM6SF1 directly engages LAMTOR1 to stabilize the Ragulator complex, and that disruption of cholesterol binding to TM6SF1 impairs this interaction, leading to mTORC1 mislocalization and sustained TFEB activation. These findings establish cholesterol-bound TM6SF1 as a structural determinant of mTORC1 docking, uncovering a direct mechanistic link between lysosomal cholesterol and growth control.

DOI: https://doi.org/10.64898/2026.04.01.715928
J Biochem Mol Toxicol. 2026 Apr;40(4): e70830

From Defence to Dysfunction: The Dual Role of Autophagy and Mitophagy in Cardiomyopathy.

Nandini Dubey, Gauri Chaturvedi, Pranav Panchbhai, Satnam Singh, Ahsas Goyal, Nirmal Singh, Vishal Kumar Vishwakarma, Neeraj Parakh, Lakshmy Ramakrishnan, Harlokesh Narayan Yadav.

  Cardiomyopathy is a disease unique to the heart muscle that increases a patient's risk of death due to heart failure, contrary to vascular conditions. Cellular powerhouses called mitochondria produce oxygen species that are reactive, that may damage both the mitochondria as well as the heart muscle if they are not managed. They also provide energy for contractions in the heart. Maintaining proper heart function both at base and in reaction to various stress and illness circumstances depends on autophagy as well as mitochondrial autophagy, which eliminates damaged mitochondria. Understanding the pathogenesis of heart diseases, which includes a wide spectrum of cardiovascular problems connected to related cardiomyopathies, is still hampered by autophagy and mitophagy. Additionally, heart failure continues to be a primary source of increased morbidity among people with cardiomyopathy, despite notable advances in lowering death rates from cardiovascular diseases (CVDs). Due to their role in the development of cardiovascular conditions, these cellular processes are appealing targets for diagnosis and therapy. They are crucial for preserving cellular equilibrium and eliminating damaged or malfunctioning components. Further, cardiomyopathies remain a major concern despite the availability of several traditional diagnostic and treatment approaches. Thus, we are going to explore the possible autophagy and mitophagy in the development and progression of cardiomyopathy and provide an overview of current research in this area in this review.

Keywords:  autophagy; cardiomyopathy; heart failure; mitochondria; mitophagy

DOI:  https://doi.org/10.1002/jbt.70830
Ageing Res Rev. 2026 Apr 08. pii: S1568-1637(26)00126-1. [Epub ahead of print] 103134

Lysosomal Control of Aging through Transcriptional and Epigenetic Regulation.

Yikai Bai, Yu Luo, Yuyuan Wang, Jiayi Qiu, Dan Li.

  Despite the well-known role as degradative organelles, lysosomes have been identified as a central signaling hub in maintaining cellular homeostasis. Lysosomal dysfunction is a well-established driver of cellular senescence and age-related pathologies. However, the precise molecular mechanisms through which lysosomes actively regulate aging remain unclear. Excitingly, latest studies show that lysosomes are not merely passive in aging but may actively govern longevity. In this review we summarize two significant discoveries about lysosome and senescence. Li et al. discovered the lysosomal surveillance response (LySR) and Zhang et al. uncovered transgenerational lysosomal signaling. These pathways substantially contribute to enhanced organismal longevity. We further discuss the transcription factor EB (TFEB) as a central regulator linking lysosomal activity to senescence and tissue homeostasis. Together, these findings reposition lysosomes as dynamic regulators that integrate stress and metabolic cues to modulate aging programs. Therefore, targeting lysosomal signaling emerges as a promising strategy for extending healthspan and mitigating age-related disorders.

Keywords:  Aging; Lysosome; Senescence; Transcription, TFEB

DOI:  https://doi.org/10.1016/j.arr.2026.103134
Autophagy. 2026 Apr 09.

Autophagic extracellular vesicles: a distinct secretory route linking autophagy to extracellular communication.

Hongqi Wei, Yuxuan Fu.

  Macroautophagy/autophagy is classically defined as a degradative pathway that delivers cytoplasmic material to lysosomes. However, accumulating evidence indicates that autophagy can also support unconventional secretion. A recent study identifies a previously unrecognized subtype of small extracellular vesicles termed autophagic extracellular vesicles (AEVs). These vesicles originate from amphisomes formed by the fusion of autophagosomes with multivesicular bodies and are characterized by a size below 100 nm together with the presence of autophagic cargos, ESCRT-III components and RAB13. Importantly, biogenesis of AEVs is distinct from that of classical exosomes, which requires specific components of the ESCRT III complex and the GTPase RAB27A. The further finding that enterovirus can exploit AEVs to infect receptor-negative cells, thereby expanding viral tropism, suggests that secretory autophagy serves as a pivotal mechanism driving pathogen dissemination. This work provides the conceptual framework of extracellular vesicle heterogeneity and positions secretory autophagy as an important contributor to intercellular communication.

Keywords:  Amphisomes; ESCRT-III; RAB13; autophagic extracellular vesicles (AEVs); enterovirus; secretory autophagy

DOI:  https://doi.org/10.1080/15548627.2026.2658229
Autophagy. 2026 Apr 08.

In situ architecture of developmentally programmed mitophagy reveals ER-phagophore membrane continuity.

Yufei Huang, Tianyu Zheng, Xiaofeng Sun, Ruoxi Wang, Shujun Cai.

  Selective mitochondrial clearance by autophagy (mitophagy) is essential for development and cellular homeostasis. However, how phagophores acquire sufficient membrane to engulf large mitochondria remains poorly understood. Here, we studied the in situ architecture of forming mitophagosomes in the developing Drosophila intestine by combining cryo-electron tomography (cryo-ET), serialized on-grid lift-in sectioning for tomography (SOLIST), cryo-focused ion beam (cryo-FIB) milling, and volume electron microscopy. Our data reveal that the endoplasmic reticulum (ER) forms continuous membrane connections with the phagophore during mitophagosome formation. In Vps13D mutant enterocytes, stalled mitochondrial phagophore membrane expansion is associated with an accumulation of persistent ER-phagophore membrane continuities. Together, our findings support a model in which the ER can establish direct membrane continuity with the phagophore to facilitate rapid mitophagosome formation. AbbreviationAPF: after puparium formation; BLTP: bridge-like lipid transfer protein; CCS: cleaning cross-section; cryo-ET: cryo-electron tomography; cryo-FIB: cryo-focused ion beam; CTF: contrast transfer function; ER: endoplasmic reticulum; HPF: high-pressure freezing; mitolysosome: autolysosome containing a mitochondrion; mitophagophore: mitochondrial phagophore; mitophagy: selective mitochondrial clearance by autophagy; NGS: normal goat serum; OMM: outer mitochondrial membrane; OsO4: osmium tetroxide; PB: phosphate buffer; PBSTx: PBS containing 0.3% (w:t) Triton X-100; RCS: regular cross-section; RT: room temperature; RT-FIB-SEM: room-temperature focused ion beam scanning electron microscopy; SOLIST: serialized on-grid lift-in sectioning for tomography; TLD: Through-the-Lens Detector.

Keywords:  Cryo-ET; Cryo-FIB; Drosophila; Vps13D; mitochondria; mitophagy; serial cryo-lift-out

DOI:  https://doi.org/10.1080/15548627.2026.2657543
J Cell Mol Med. 2026 Apr;30(7): e71132

DAPK1-Mediated Parkin Inactivation Enhances Neurotoxicity via MITOL-Dependent Degradation.

Chul Hong Park, Donghyuk Shin, Kwang Chul Chung.

  Parkinson's disease (PD) is characterised by progressive neurodegeneration and is marked by the formation of Lewy bodies, which are intracellular aggregates primarily composed of α-synuclein. Mitochondrial dysfunction and impaired protein degradation pathways are thought to play critical roles in PD progression, contributing to the loss of dopaminergic neurons in the substantia nigra. Phosphorylation of α-synuclein has been shown to promote its aggregation, underscoring its potential role in disease progression. Parkin, an E3 ubiquitin ligase, is widely regarded as a pleiotropic neuroprotective protein that modulates the mitochondrial quality control, as well as metabolic turnover and the accumulation of α-synuclein. Death-associated protein kinase 1 (DAPK1), which is involved in the regulation of apoptosis and autophagy, has recently emerged as an important factor in neurodegeneration. While DAPK1 has been implicated in Alzheimer's disease through its role in tau aggregation and amyloid-β production, our findings suggest that DAPK1 may also influence PD-related pathways by phosphorylating parkin at Ser136 and Ser198. This phosphorylation promotes the mitochondrial transport of parkin, enhancing interaction with mitochondria-localised E3 ubiquitin ligase MITOL and consequently leading to the degradation of parkin. Given the neuroprotective role of parkin, its reduction increases the vulnerability of neurons to 6-hydroxydopamine-induced toxicity, potentially contributing to decreased neuronal survival. Together, these findings suggest that DAPK1 functions as a previously unrecognised modulator of parkin and could potentially influence PD-related neurodegenerative processes. This pathway may provide a mechanistic link between mitochondrial dysfunction, α-synuclein pathology and neuronal cell death.

Keywords:  6‐OHDA; DAPK1; MITOL; neuronal toxicity; parkin; phosphorylation; ubiquitination

DOI:  https://doi.org/10.1111/jcmm.71132
J Neurochem. 2026 Apr;170(4): e70431

ATG14-Mediated SNARE Complex Activation Promotes ΔFosB Degradation to Ameliorate Levodopa-Induced Dyskinesia.

Yi Wu, Ke Liu, Zhaoyuan Zhang, Zhuoran Ma, Zhicheng Tang, An Chang, Haoxuan Ouyang, Heng Zhai, Xuebing Cao, Yan Xu.

  The chronic accumulation of ΔFosB in striatal medium spiny neurons has been implicated as a pivotal contributor to the pathogenesis of levodopa-induced dyskinesia (LID). While recent studies have implicated autophagy in the degradation of ΔFosB and the amelioration of LID, the precise mechanisms remain elusive. We induced LID in a unilateral 6-hydroxydopamine-lesioned parkinsonism rat model via chronic levodopa treatment. To modulate the autophagy pathway, we overexpressed ATG14 in the striatum of LID rats and administered chloroquine, an autophagy inhibitor, peripherally. We assessed LID severity using abnormal involuntary movements (AIMs) scores. Western blotting, real-time quantitative polymerase chain reaction, immunofluorescence, immunohistochemistry, transmission electron microscopy, and Golgi staining were employed to measure autophagy flux, synaptic alterations, and ΔFosB levels. Chronic levodopa treatment reduced ATG14 and SNARE complex (STX17, SNAP29, and VAMP8) levels, disrupted their interaction, impaired autophagy flux, affected synaptic function, and led to ΔFosB accumulation in the striatum of PD rats. Upregulating ATG14 in the striatum of LID rats improved AIMs scores, facilitated SNARE-mediated autophagosome-lysosome fusion, restored synaptic deficits, and promoted ΔFosB degradation. However, these beneficial effects of ATG14 upregulation were negated by chloroquine administration. Our findings suggest that upregulating ATG14 enhances SNARE formation, promoting autophagy flux and thereby reducing LID occurrence by facilitating ΔFosB degradation.

Keywords:  ATG14; SNARE; autophagy; levodopa‐induced dyskinesia; ΔFosB

DOI:  https://doi.org/10.1111/jnc.70431
Dev Cell. 2026 Apr 08. pii: S1534-5807(26)00084-5. [Epub ahead of print]61(4): 707-708

A lineage-specific autophagic mechanism of P-body turnover.

Oluwatoyosi M Adaramodu, Brian D Gregory.

Processing bodies (P-bodies) are cytoplasmic RNA granules that assemble and dissolve as cells adjust gene expression; however, mechanisms that control their turnover in eukaryotic organisms are unclear. In this issue of Developmental Cell, Abdrakhmanov et al. demonstrate that P-bodies are degraded in Marchantia polymorpha via the direct interaction of the decapping proteins EDC4 and DCP1 with the autophagy receptor ATG8.

DOI: https://doi.org/10.1016/j.devcel.2026.02.019
bioRxiv. 2026 Mar 31. pii: 2026.03.29.715103. [Epub ahead of print]

Rab12 is a regulator of mitophagy and mitochondrial homeostasis.

Tara Richbourg, Alex George, Anas Bitar, Ian T Ryde, Casey Farrell, Tuyana Malankhanova, Jennifer Liu, Silas A Buck, Ivana Barraza, So Young Kim, Xiaoyan Nie, Andrew B West, Joel N Meyer, Laurie H Sanders.

Rab GTPases orchestrate vesicular trafficking, but their contributions to mitochondrial quality control are not fully defined, despite links to multiple mitochondria-related human diseases. We conducted a family-wide siRNA-based screen using mt-mKeima/YFP-Parkin HeLa cells to identify regulators of depolarization-induced mitophagy. The screen identified several candidate Rabs, and follow-up studies validated Rab12 as a negative regulator of mitophagy. Rab12 knockdown or knockout augments clearance of damaged mitochondria basally and/or after FCCP-induced depolarization, with findings reproduced across distinct cell types. Rab12 depletion increased mitochondrial content, lowered mitochondrial membrane potential, and reduced mitochondrial DNA damage, without detectable changes in overall cellular bioenergetic capacity. Together, these results indicate that Rab12 restrains mitophagic engagement and its loss permits accumulation of lower-functioning mitochondria that are hypersensitive to mitophagy-inducing stress. Rab12 thus emerges as a novel effector linking vesicular trafficking machinery and mitochondrial homeostasis, with potential implications for neurodegenerative disorders and other Rab-associated diseases.

DOI: https://doi.org/10.64898/2026.03.29.715103
Life Sci. 2026 Apr 07. pii: S0024-3205(26)00190-6. [Epub ahead of print] 124381

Disruption of the OPTN-TBK1 axis impairs autophagosome formation in prion disease.

Jingjing Wang, Pei Wen, Zhixin Sun, Fengting Gou, Qing Fan, Yuheng He, Deming Zhao, Lifeng Yang.

  Prion diseases are chronic, transmissible, and neurodegenerative disorders that affect both humans and other mammals. Mitophagy is essential for maintaining mitochondrial homeostasis and normal neuronal function. Our previous research show that the PINK1-Parkin-dependent mitophagy pathway is impaired in the PrP106-126 induced prion disease model, yet the underlying downstream mechanisms remain elusive. We report that impaired phosphorylation of ubiquitin at Ser65 diminishes OPTN recruitment to mitochondria, thereby influence mitochondrial translocation of TBK1 and ATG9A, consequently suppresses TBK1 autophosphorylation that depends on the OPTN-ATG9A interaction. As a result, reduction of OPTN phosphorylation dependent on TBK1 inhibits autophagosome formation and ultimately leads to defective mitophagy. Importantly, overexpression of OPTN rescued the mitophagy impairment induced by PrP106-126 and partially restoring mitochondrial morphology and function. Our findings identify OPTN as a critical node, proposing its therapeutic targeting as a strategy to counteract prion disease progression.

Keywords:  Mitophagy; OPTN; Phosphorylation; Prion diseases; TBK1

DOI:  https://doi.org/10.1016/j.lfs.2026.124381
Autophagy. 2026 Apr 08.

SQSTM1/p62-mediated autophagy and antioxidation contribute to white spot syndrome virus pathogenesis in shrimp.

Suttipong Tungwaravut, Phattarunda Jaree, Han-Ching Wang, Kunlaya Somboonwiwat.

  Selective macroautophagy/autophagy, mediated by selective autophagy receptors (SARs), targets cellular cargo and pathogenic proteins for lysosomal degradation. While crucial in antiviral immunity, viruses have evolved strategies to evade or exploit selective autophagy. Despite extensive studies in vertebrates, the role of selective autophagy in crustaceans during viral infections remains largely unexplored. This study investigates the molecular mechanism of Penaeus vannamei selective autophagy receptor SQSTM1/p62 (PvSQSTM1) in the shrimp immune response to white spot syndrome virus (WSSV) infection. We demonstrated that WSSV infection activates PvSQSTM1-mediated selective autophagy in hemocytes. During infection, PvSQSTM1 was predominantly localized in the cytoplasm, with partial nuclear localization. PvSQSTM1 silencing reduced viral load and increased shrimp survival by suppressing autophagic activity. PvSQSTM1 dynamically interacted with the major WSSV envelope protein VP28 during early infection and facilitated WSSV encapsulation within autophagosomes. Apart from selective autophagy, PvSQSTM1 was involved in antioxidant resistance mechanisms, as shown by its direct binding to PvKEAP1, an adaptor of the SQSTM1-KEAP1-NFE2L2/Nrf2 pathway. The reduced expression of downstream genes in the SQSTM1-KEAP1-NFE2L2/Nrf2 pathway was observed in PvSQSTM1-silenced shrimp infected with WSSV, leading to increased H2O2 levels in hemocytes. Together, these findings suggest that PvSQSTM1-mediated autophagy facilitates viral encapsulation within autophagosomes and regulates the KEAP1-NFE2L2/Nrf2 antioxidant pathway to suppress ROS levels. This mechanism potentially allows the virus to evade the host's immune system and establish a successful infection. This work expands our understanding of host-virus interactions, highlighting the contribution of PvSQSTM1 to WSSV pathogenesis.

Keywords:  SQSTM1/p62; SQSTM1/p62-KEAP1-NFE2L2/Nrf2 pathway; Selective autophagy; shrimp agricultural sustainability; white spot syndrome virus

DOI:  https://doi.org/10.1080/15548627.2026.2657545
Nat Commun. 2026 Apr 09.

The integrated stress response suppresses PINK1-dependent mitophagy by preserving mitochondrial import efficiency.

Mingchong Yang, Zengshuo Mo, Kelly Walsh, Wen Liu, Imane Nait Irahal, Damien Arnoult, Xiaoyan Guo.

Mitophagy is crucial for maintaining mitochondrial health, but how its levels adjust to different stress conditions remains unclear. In this study, we investigated the role of the DELE1-HRI axis of the integrated stress response (ISR) in regulating mitophagy, a key mitochondrial quality control mechanism. Our findings show that the ISR suppresses PINK1-dependent mitophagy under many mitochondrial stress conditions by maintaining mitochondrial presequence protein import, independent of ATF4 activation. Mitochondrial presequence protein import efficiency is tightly linked to the rate of protein synthesis. Without the ISR, increased protein synthesis overwhelms the mitochondrial import machineries, reducing import efficiency. This impairment can be mitigated by pharmacological attenuation of protein synthesis, such as with mTOR or general translation inhibitors. Under severe depolarizing stress, mitochondrial import is heavily impaired even with an active ISR, leading to significant PINK1 accumulation. In contrast, mild mitochondrial stress allows more efficient protein import in the presence of the ISR, resulting in lower mitophagy. Without the ISR, mitochondrial protein import becomes significantly compromised, causing PINK1 accumulation to reach the threshold level necessary to trigger mitophagy. These findings reveal a link between ISR-regulated protein synthesis, mitochondrial protein import, and mitophagy, offering potential therapeutic targets for diseases associated with mitochondrial dysfunction.

DOI: https://doi.org/10.1038/s41467-026-71630-6
Chem Commun (Camb). 2026 Apr 07.

Silicon rhodamine-based fluorescent probes for monitoring mitochondrial viscosity dynamics during mitophagy.

Zixuan Zhao, Hongling Li, Lijun Li, Jinping Liu, Qi Ai, Xin Wen, Baoxiang Gao.

Mitochondrial autophagy (mitophagy) is pivotal for mitochondrial quality control and intracellular homeostasis. However, real-time visualization of mitochondrial inner membrane viscosity - a key biophysical parameter of mitophagy - remains challenging. To address this, a silicon rhodamine (SiR)-based dual-modal imaging probe was developed, enabling reliable real-time monitoring of mitophagic processes and providing novel insights into mitochondrial remodeling during autophagy.

DOI: https://doi.org/10.1039/d6cc00586a
Nat Commun. 2026 Apr 10.

Translation in proximity to forming autophagosomes during sustained autophagy.

Yunping Xue, Kaela O'Connor, Karsten Nalbach, Alexandre Savard, Karyn E King, Ryan C Russell, Christian Behrends, Derrick Gibbings.

Autophagy is an evolutionarily conserved catabolic process. In a process requiring a cascade of over 35 autophagy-related genes (Atg), a cupped phagophore membrane expands to surround cytoplasmic material, and seals itself to form an autophagosome, which finally fuses with lysosomes. Large numbers of autophagosomes form during stress responses, while simultaneously cells drastically reduce translation to conserve energy. Here, using proximity-labeling and Fluorescence in situ Hybridization we demonstrate that multiple mRNAs encoding proteins required for autophagy preferentially localize in proximity to forming autophagosomes. Polysome fractionation and proteomics of nascent proteins in proximity to forming autophagosomes provides evidence for the local translation of these mRNAs. Translation and the ribosome-binding protein RACK1 were required for the localization of these mRNAs to forming autophagosomes. Inhibition of translation or knockdown of RACK1 caused depletion of several proteins required for autophagy and a reduction in the number of autophagosomes. Local translation may enable a rapid, energy-efficient supply of proteins for autophagy to enable cells to massively induce autophagy while conserving energy during cell stress.

DOI: https://doi.org/10.1038/s41467-026-71551-4
Cell Death Dis. 2026 Apr 10.

Fatty acid synthesis supports tumor progression through facilitating the activity of TORC1 signaling.

Dorottya Károlyi, Sólyom Bálint Bótor, Natali Neuhauser, András Rubics, Janka Szinyákovics, Tibor Kovács, Mária Péter, Gábor Balogh, Fergal O'Farrell, Szabolcs Takáts.

Biosynthesis of lipids and fatty acids (FAs) is essential for the normal functioning of cellular processes, and lipid availability determines the progression of multiple malignant tumor types. To date, the roles of individual steps in lipid biosynthesis during tumor growth and their interaction with intracellular signaling pathways are not well understood. Our study demonstrates that upregulation of de novo FA and lipid synthesis is a conserved characteristic of malignant tumors. In vivo tumor cell-specific silencing of components of the neutral lipid biosynthetic apparatus revealed that loss of several enzymes involved in FA and diacylglycerol synthesis inhibited tumor growth. Specifically, acetyl-CoA carboxylase (ACC), which catalyzes the first step of FA synthesis, drives late-stage tumor growth. FA synthesis perturbation led to inactivation of TORC1 (mechanistic Target of Rapamycin Complex 1)-accompanied by activation of the catabolic process autophagy. Moreover, TORC1 activity cannot be fully restored by hyperactivation of upstream Insulin/PI3K signaling or inhibition of AMP-activated kinase (AMPK) in ACC-deficient tumor cells, but supplementation with ectopic oleic acid can partially increase TORC1 activity and tumor progression. In addition to their metabolic value, the role of FAs in promoting TORC1 gives us new insight into cancer cell dependence on de novo FA synthesis.

DOI: https://doi.org/10.1038/s41419-026-08738-6
bioRxiv. 2026 Apr 02. pii: 2026.04.01.715898. [Epub ahead of print]

FAM134B isoform 2/RETREG1-2 defines a calnexin-TOLLIP-coupled ER-phagy pathway that restricts Ebola virus glycoprotein and is antagonized by VP40 through macro-autophagy.

Jing Zhang, Tao Wang, Jiaxin Wen, Jing Lan, Sunan Li, Yong-Hui Zheng.

Selective autophagy of the endoplasmic reticulum (ER-phagy) is critical for ER proteostasis and host defense, yet how ER quality-control pathways interface with ER-phagy to restrict viral glycoproteins remains poorly defined. Previously, the 1st known ER-phagy receptor gene RETREG1 (RETR1)/FAM134B gene was reported to restrict Ebola virus (EBOV) replication in vivo by inhibiting the viral glycoprotein (GP) and viral protein 40 kDa (VP40) expression, but this mechanism remains unknown. Here, we identify the truncated RETR1/FAM134B isoform 2 (RETR1-2), but not its full-length protein RETR1, as an ER-phagy receptor that targets EBOV-GP for degradation. RETR1-2 broadly triggers GP degradation across ebolavirus species but not Marburg virus and inhibits EBOV replication. Mechanistically, RETR1-2 recognizes EBOV-GP via its luminal domain, undergoes GP-induced oligomerization, and directs GP-containing ER membranes to lysosomes through canonical macro-autophagy. Using unbiased mass spectrometry, we identified TOLLIP as the key cytoplasm adaptor for RETR1-2, which also requires cooperation with the ER chaperone calnexin for EBOV-GP degradation. Notably, the PI3P-binding C2 domain of TOLLIP mediates its interaction with RETR1-2, and the EBOV-GP degradation occurs independently of ubiquitination, revealing an unexpected role for TOLLIP in ER-phagy. Furthermore, EBOV-VP40 antagonizes this pathway by selectively targeting RETR1-2 for macroautophagic degradation independently of TOLLIP, thereby restoring GP expression and viral infectivity. Nevertheless, RETR1-2 reciprocally degrades VP40 via a similar mechanism. Together, these findings define a calnexin-TOLLIP-RETR1-2 axis that links ER quality control to ER-phagy-mediated antiviral restriction and uncover a reciprocal host-virus arms race centered on selective macro-autophagy.

DOI: https://doi.org/10.64898/2026.04.01.715898
Autophagy. 2026 Apr 10. 1-17

Newcastle disease virus exploits Golgi stress and Golgiphagy to promote ferroptosis.

Xianjin Kan, Mengqing Yang, Guanglei Xie, Yuncong Yin, Hui Jiang, Yanmei Yuan, Yingjie Sun, Chan Ding.

  Ferroptosis, characterized by iron-dependent lipid peroxidation, has emerged as a pivotal cell death pathway in various diseases, yet its regulation during viral infection remains elusive. Here, we reveal that Newcastle disease virus (NDV) exploits the Golgi apparatus as a central hub to orchestrate ferroptotic cell death in tumor cells. NDV infection provokes robust Golgi stress and Golgiphagy, leading to the selective degradation of ARF1 (ARF GTPase 1), a GA-resident regulator of redox homeostasis, which in turn triggers a cascade of reactive oxygen species accumulation, lipid peroxidation, and ferroptosis. Mechanistically, we show that this process is dependent on the activation of the Golgi stress response and macroautophagy/autophagy-lysosome pathway. Importantly, inhibition of Golgi stress by exogenous spermine not only alleviates NDV-induced ferroptosis, but also demonstrates antiviral and cytoprotective effects, underscoring the translational potential of targeting the Golgi stress axis. Our findings uncover a previously unappreciated axis of virus-host interaction centering on Golgi stress and ferroptosis and suggest that modulation of organelle-specific stress responses represents a promising therapeutic strategy in both antiviral and cancer contexts.Abbreviations: AMPK: AMP-activated protein kinase; ARF1: ARF GTPase 1; ARF4: ARF GTPase 4; ATG7: autophagy related 7; BFA: brefeldin A; CGAS: cyclic GMP-AMP synthase; CHX: cycloheximide; CQ: chloroquine; CREB3: cAMP responsive element binding protein 3; DFO: deferoxamine; ER: endoplasmic reticulum; Fe2+: ferrous ions, GA: Golgi apparatus; GOLGA2/GM130: golgin A2; GPX4: glutathione peroxidase 4; GSH: glutathione; GSR: Golgi stress response; HCMV: human cytomegalovirus; HSV-1: herpes simplex virus 1; Lip-1: Liproxstatin-1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MDA: malondialdehyde; mtDNA: mitochondrial DNA; MTOR: mechanistic target of rapamycin kinase; NDV: Newcastle disease virus; NCOA4: nuclear receptor coactivator 4; PUFA: polyunsaturated fatty acid; ROS: reactive oxygen species; Rot: rotenone; SLC7A11: solute carrier family 7 member 11; SERPINH1/HSP47: serpin family H member 1; TFE3: transcription factor binding to IGHM enhancer 3; WT: wild-type.

Keywords:  ARF1; Golgi stress; Golgiphagy; Newcastle disease virus; ferroptosis; reactive oxygen species

DOI:  https://doi.org/10.1080/15548627.2026.2653010
Acta Pharmacol Sin. 2026 Apr 09.

ADT-OH promotes mitophagy and suppresses the cytosolic mtDNA-cGAS-STING inflammatory cascade in microglia.

Xiao-Ou Hou, Miao Wang, Rong Deng, Yi-Fan Lu, Jin-Ru Zhang, Li Ren, Jing Chen, Chun-Feng Liu, Ya-Ping Yang, Li-Fang Hu.

  Mitochondrial dysfunction, driven by genetic susceptibility or environmental insults, contributes to the pathogenesis of neurodegenerative disorders, including Parkinson's disease (PD). Mitophagy is a selective pathway that eliminates dysfunctional mitochondria, and mitophagy inducers hold therapeutic promise for neurodegeneration. However, the arsenal of specific, clinically viable inducers remains limited. ADT-OH, a slow-release H2S compound, was recently reported to induce mitochondrial uncoupling through sulfide-quinone oxidoreductase (SQR)-mediated oxidation of H2S. In this study, we report that ADT-OH elicits mitophagic flux in microglia. This is evidenced by the reduced steady-state levels of mitochondrial marker proteins (TOM20, COXIV, and HSP60), enhanced mitochondrial fission dynamics, and mitochondrial translocation into lysosomes, as visualized by the mt-Keima probe. Mechanistically, its mitophagy-promoting effect is dependent on SQR-mediated mitochondrial uncoupling and subsequent activation of PINK1-PARKIN signaling. Importantly, ADT-OH abrogates the accumulation of dysfunctional mitochondria and the subsequent cytosolic release of mitochondrial DNA in α-synuclein preformed fibrils (α-Syn PFF)-challenged microglia, thereby blunting the activation of the cGAS-STING pathway and the downstream production of inflammatory mediators. Furthermore, systemic administration of ADT-OH dampened microglial activation and cGAS expression in α-Syn-overexpressing PD mice, thereby mitigating the loss of midbrain dopaminergic neurons and ameliorating motor coordination deficits. Collectively, our findings demonstrate that ADT-OH exerts robust neuroprotective effects in PD models, both in vitro and in vivo, by enhancing mitophagy and inhibiting microglia-mediated neuroinflammation.

Keywords:  ADT-OH; Parkinson’s disease; cGAS-STING; microglia; mitochondrial DNA; mitophagy

DOI:  https://doi.org/10.1038/s41401-026-01789-7
J Neurochem. 2026 Apr;170(4): e70432

L-Leucine Upregulates Lysosomal Biogenesis and Autophagy to Lower Plaques in 5XFAD Mouse Model of Alzheimer's Disease.

Ramesh K Paidi, Sukhamoy Gorai, Susanta Mondal, Kalipada Pahan.

  Twenty different amino acids are required for the human body for proper functioning as amino acids serve as building blocks for proteins. We screened different essential and non-essential amino acids for the ability to stimulate lysosomal biogenesis and, interestingly, found an essential amino acid L-leucine as the most potent one in stimulating lysosomal biogenesis in astrocytes. However, D-leucine remained weaker than L-leucine in terms of stimulation of lysosomal biogenesis. Accordingly, L-leucine increased autophagy in cultured brain cells and in vivo in the brain of 5XFAD mice, one of the animal models of Alzheimer's disease (AD). L-Leucine also stimulated the uptake and degradation of amyloid-β in astrocytes and reduced the plaque load and improved cognitive functions in 5XFAD mice. Although L-leucine was discovered about 200 years back, until now, no receptor has been identified for L-leucine. Here, we noticed that L-leucine binds to the ligand-binding domain of peroxisome proliferator-activated receptor α (PPARα) to activate this nuclear hormone receptor. Accordingly, L-leucine remained ineffective in increasing lysosomal biogenesis and autophagy in PPARα-/- brain cells. Lentiviral establishment of full-length PPARα, but not Y314D-PPARα, reinstated the autophagy-stimulating effect of L-leucine in PPARα-/- astrocytes, emphasizing the importance of leucine's interaction with the Y314 residue. Moreover, oral L-leucine decreased the plaque load and improved spatial learning and memory in 5XFAD mice, but not in 5XFADΔPPARα mice (5XFAD lacking PPARα), highlighting the involvement of PPARα in the neuroprotective effects of L-leucine. These results may be beneficial for AD patients.

Keywords:  Alzheimer's disease; L‐leucine; autophagy; cognitive function; lysosomal biogenesis; plaque

DOI:  https://doi.org/10.1111/jnc.70432
Mol Cell Endocrinol. 2026 Apr 04. pii: S0303-7207(26)00079-1. [Epub ahead of print]618 112802

Concept and connotation of the geroprotective and anti-aging effects of metformin: From AMPK activation to SASP suppression.

Abdullah I Aedh, Hayder M Al-Kuraishy, Mustafa M Shokr, Mubarak Alruwaili, Gaber El-Saber Batiha.

  Biological aging is the risk factor underlying most of the chronic diseases of late life, such as cardiovascular disease, cancer, and neurodegeneration. Despite more than fifteen years of intensive research and the evaluation of hundreds of candidate compounds, no pharmacological therapy has yet been approved to target aging itself, leaving clinical medicine without an intervention that addresses the fundamental driver of multi-morbidity in older populations. It has been shown that the anti-diabetic metformin reduces mortality and the incidence of several age-related diseases in both diabetic and non-diabetic populations, independent of glycemic control. At standard therapeutic plasma concentrations achieved in aged human tissues, metformin engages multiple interconnected hallmarks of aging, such as activation of AMP-activated protein kinase (AMPK), inhibition of mechanistic target of rapamycin (mTOR) signaling, restoration of autophagy, modulation of other signaling pathways, improvement of mitochondrial function, and attenuation of senescence-associated inflammatory signaling. Large observational cohorts and meta-analyses further demonstrate that metformin use is associated with mechanistic plausibility, epidemiological consistency, and an unparalleled long-term safety record. Conversely, metformin may adversely affect the aging process when administered in aged animals, suggesting a controversial role of metformin effect on aging process. Nevertheless, the exact cellular and molecular mechanisms of the anti-aging role of metformin are not fully elucidated. Thus, this review integrates preclinical, epidemiological, and randomized clinical evidence supporting the role of metformin in aging to discuss and explain the possible anti-aging role of metformin.

Keywords:  AMP-activated protein kinase; Autophagy; Biological aging; Cellular senescence; Mechanistic target of rapamycin; Metformin

DOI:  https://doi.org/10.1016/j.mce.2026.112802
bioRxiv. 2026 Mar 09. pii: 2026.03.05.709934. [Epub ahead of print]

Lysosomal Expansion Compartments Mediate Zinc and Copper Homeostasis in Caenorhabditis elegans.

Joy R Armendariz, Sean Teng, Camdyn Rakow, Raquel Herrera, Samuel Herrera, Moshe T Gordon, Si Chen, Stefan Vogt, Hanwenheng Liu, Makena Jarvis, Katryna Reese, Aidan T Pezacki, Christopher J Chang, Byung-Eun Kim, Daniel L Schneider, Adelita D Mendoza, Kerry Kornfeld.

Zinc is an essential transition metal that participates in many biological processes. In C. elegans , excess zinc is stored in lysosomes in intestinal cells; this process involves increasing the expression of the zinc transporter CDF-2 and remodeling of lysosomes characterized by an increase in the volume of the expansion compartment. To determine if this is a more general property, we investigated other metals. Here we report that lysosomes are remodeled in response to excess copper, manganese, and cadmium, with each metal causing an increase in the volume of the expansion compartment. Mutants with a reduced number of lysosomes were hypersensitive to growth retardation caused by excess copper and manganese, suggesting metal toxicity is prevented by metal sequestration in lysosomes. Using a novel method to analyze isolated lysosomes by X-ray Fluorescence Microscopy we demonstrated that zinc, copper and manganese are detectable in the lumen of lysosomes. To further analyze copper, we examined localization of CUA-1.1, a copper transporter that moves copper into the lumen of lysosomes. Like the zinc transporter CDF-2, CUA-1.1 localizes to both the acidified and expansion compartments in excess copper. These results indicate that the same intestinal lysosomes store zinc, copper and manganese. Lysosome remodeling characterized by an increase in volume of the expansion compartment is not specific to zinc but is a more general phenomenon during metal storage in lysosomes.

DOI: https://doi.org/10.64898/2026.03.05.709934
J Neural Transm (Vienna). 2026 Apr 06.

Genetic and environmental risk factors of Parkinsonism.

Petr Kanovsky, Katerina Mensikova, Pavel Cupr, Radek Vodicka, Kristyna Kolarikova, Tereza Strnadova, Sarah Elizabeth Victoria Cook, Dorota Sebelova-Konickova, Jana Klanova, Carlo Colosimo, Raymond Rosales.

  Parkinsonian disorders comprise a broad spectrum of neurodegenerative diseases with a wide variety of pathogenetic processes. These processes lead to the formation of pathological proteins, resulting in the brain diseases called synucleinopathies, tauopathies or TDP-43 proteinopathies. There is currently growing support for the hypothesis that genetic variants explain a significant fraction of the etiology of apparently sporadic parkinsonian disorders. Genetic risk factors can be stratified according to the metabolic or structural processes that can lead to cellular disturbance; these processes involve protein aggregation, protein and membrane trafficking, stabilization of the neurite structure, prion-like transmission of pathological proteins, ubiquitin-proteasome system balance, mitophagy, lysosome autophagy, synaptic functions, and dopamine transmission. Regarding the environmental risk factors, there are several substances that have been supposed of being a risk for the development of neurodegenerative proteinopathy and Parkinsonism, mainly the agents used in agriculture and the textile industry. The most important and most frequently studied are pesticides and trichlorethylene. Beside the globally ubiquitous substances which are supposedly neurotoxic and exposure to which can cause manifestations of Parkinsonism, there are more geographically (regionally) specific substances, which cause (or quite recently caused) the manifestation of endemically present Parkinsonism. Among ten types of endemic Parkinsonism, three of them are thought to have an environmental cause: Western Pacific Parkinsonism, Caribbean Parkinsonism, and North France cluster of atypical Parkinsonism.

Keywords:  Parkinson´ disease - alpha-synuclein - genetics - environment - risk factors

DOI:  https://doi.org/10.1007/s00702-025-03058-z
Int J Biol Sci. 2026 ;22(6): 2950-2969

In vivo CRISPR/Cas9 Screening Reveals that UBE2L3 Modulates Autophagic Flux through TSC2 Ubiquitination and Potentiates PD-1 Blockade in Triple-Negative Breast Cancer.

Jian Xu, Ling Cheng, Sien Ma, Chen Gan, Jiaying Chai, Xinyi Zheng, Longyu Hu, Meiwen Ling, Mingjun Zhang, Bao Zhao, Huaidong Cheng.

  Triple-negative breast cancer (TNBC), a distinct breast cancer subtype, poses significant challenges to conventional therapeutic approaches, and effective targeted therapies are limited. CRISPR/Cas9 library screening has demonstrated unprecedented efficiency and revolutionary potential in the identification of therapeutic targets. In this study, we performed In vivo CRISPR/Cas9 library screening and identified the E2 ubiquitin-conjugating enzyme UBE2L3 as a critical regulatory factor in the progression of TNBC. Loss of UBE2L3 restricted tumor cell growth by modulating autophagy in TNBC cells. Mechanistically, UBE2L3 downregulation led to increased tuberous sclerosis complex 2 (TSC2) expression, suppressing mTOR activity and altering autophagic processes in tumor cells. This regulation was mediated through the interaction between UBE2L3 and the E3 ubiquitin ligase SMURF2, which together control TSC2 protein ubiquitination and degradation. Autophagy and the tumor microenvironment are closely associated, and we observed that UBE2L3 knockdown in TNBC tumors significantly increased CD8+ T lymphocyte infiltration and enhanced tumor sensitivity to anti-PD-1 therapy. Collectively, our findings provide a theoretical foundation for considering UBE2L3 as a potential therapeutic target in TNBC.

Keywords:  CRISPR/Cas9; PD-1; TNBC; autophagy; ubiquitination

DOI:  https://doi.org/10.7150/ijbs.124937
PLoS Biol. 2026 Apr;24(4): e3003692

Dietary restriction shapes intergenerational ribosome abundance and early growth of Caenorhabditis elegans offspring.

Sigma Pradhan, Klement Stojanovski, Ferdinand Dellemann, Sacha Psalmon, Joel Tuomaala, Nicholas E Stroustrup, Benjamin D Towbin.

Cells adjust their proteome to their environment. Most prominently, ribosome expression often scales near linearly with the cellular growth rate to provide sufficient translational capacity while preventing metabolically wasteful ribosomal excess. In microbes, such proteome adjustments can passively perpetuate through symmetric cell division. However, in animals, a passive propagation is hindered by the separation between soma and germline. This separation raises the question whether the proteome of animals is reset at every generation or can be propagated from parent to offspring across this barrier. We addressed this question for the intergenerational effects of dietary restriction in Caenorhabditis elegans, combining proteomics and live imaging. Under ad libitum feeding, the offspring of dietarily restricted mothers grew more slowly than progeny of well-fed mothers. However, this growth disparity was attenuated when mTORC1 signaling in the progeny was inhibited, creating conditions in which the protein-synthesis capacity at hatching is less limiting. Maternal inhibition of mTORC1 signaling, either ubiquitously or specifically in the pharynx, similarly reduced growth and ribosomal protein levels in offspring, whereas other growth-reducing perturbations, such as reduced insulin signaling or mTORC1 inhibition in the epidermis, did not reduce progeny ribosomal protein levels. We conclude that maternal physiology shapes ribosomal protein provisioning across the soma-germline boundary, thereby modulating early offspring growth in accordance with post-hatching ribosome demand.

DOI: https://doi.org/10.1371/journal.pbio.3003692
Sci Rep. 2026 Apr 04.

Wdfy3-dependent autophagy impairment recapitulates presymptomatic neurodegenerative signatures in mice.

Aldo Vorkapich, Arshi Mustafa, Amanda L Flores-Torres, Konstantinos S Zarbalis, Cecilia Giulivi.

  WDFY3/ALFY is an adaptor protein involved in selective autophagy. Loss of Wdfy3 in mice causes severe deficits in neuronal health, and pathogenic mutations in WDFY3 are associated with neurodevelopmental disorders in humans. As impaired autophagy is increasingly implicated in Parkinson's disease (PD) and other neurodegenerative disorders, we investigated whether Wdfy3 haploinsufficiency produces early molecular and cellular signatures of neurodegeneration in Wdfy3+/lacZ mice, given that these diseases often exhibit presymptomatic alterations preceding overt clinical manifestations. Cortical tissue from 3-month-old presymptomatic mice showed significant proteomic overlap with both patient-derived PD cell lines and human brain proteomic datasets, particularly from the substantia nigra, underscoring the translational relevance of this model. Consistent with disease progression, immunofluorescence analyses of the cortex and substantia nigra from 14-month-old mice revealed significant dysregulation of multiple markers associated with neurodegeneration. Together, these findings demonstrate that impaired autophagy resulting from reduced Wdfy3 expression recapitulates key features of neurodegenerative disease at both early and later stages. By providing a platform to investigate presymptomatic pathogenic mechanisms, this model may inform the development and testing of future diagnostic and therapeutic strategies aimed at preserving neuronal health.

Keywords:  Autophagy; Biomarkers; Mitochondrial dysfunction; Mouse model; Neurodegeneration; Parkinson’s disease; Proteomics

DOI:  https://doi.org/10.1038/s41598-026-43314-0
Autophagy. 2026 Apr 11. 1-17

NCOA4-mediated ferritinophagy: emerging role and novel therapeutic target in precision oncology.

Dengwang Chen, Xinyue Jiang, Tao Duan, Ying Tian, Jidong Zhang, Xin Wang, Jun Tan.

  Iron is vital for life but can be toxic in excess by forming reactive oxygen species. Ferroptosis, a type of regulated cell death, relies on iron-dependent lipid peroxidation and requires a labile iron pool (LIP) in cells. Ferritin stores iron safely, and its degradation increases the LIP. Ferritinophagy, the autophagic breakdown of ferritin, is crucial for releasing stored iron to trigger ferroptosis. This review examines ferritinophagy's molecular mechanisms, highlighting NCOA4 (nuclear receptor coactivator 4) as the main receptor targeting ferritin for lysosomal degradation. It also discusses the regulatory network controlling NCOA4, including transcriptional factors like TP53/p53 and MYC/c-Myc, RNA-binding proteins, and post-translational modifications such as ubiquitination. We explore ferritinophagy-induced ferroptosis as a promising anti-cancer approach. Research shows that various natural compounds, repurposed drugs, and new metal complexes can induce tumor cell death by activating the NCOA4-ferritinophagy pathway, which is crucial for overcoming therapeutic resistance in many cancers. Understanding this pathway highlights the relationship between iron metabolism, macroautophagy/autophagy, and cell death, offering a foundation for new treatments for cancer and iron-related diseases.Abbreviation: FTH1: ferritin heavy chain 1; GPX4: glutathione peroxidase 4; GSH: glutathione; HIF: hypoxia-inducible factor; LIP: labile iron pool; MAPK/JNK: mitogen-activated protein kinase; NCOA4: nuclear receptor coactivator 4; PUFAs: polyunsaturated fatty acids; SLC7A11: solute carrier family 7 member 11; TFRC: transferrin receptor; TFEB: transcription factor EB.

Keywords:  Cancer therapy; NCOA4; ferritinophagy; ferroptosis; iron metabolism; therapeutic resistance

DOI:  https://doi.org/10.1080/15548627.2026.2656779
Biomacromolecules. 2026 Apr 09.

Intracellular GRP78-Directed Delivery of Rapamycin by Biomolecular Condensates of Hydra-Elastin-like Polypeptides.

Sara Aly Attia, Sambid Adhikari, Amy S Lee, John Andrew MacKay.

Rapamycin (Rapa) is a potent inhibitor of the mammalian target of rapamycin complex 1 (mTORC1) with possible applications in multiple diseases; however, it and its analogues exhibit low solubility, variable bioavailability, and dose-limiting side effects. To engineer a long-release carrier, we employ Rapa's cognate receptor (FKBP12) to modulate its solubility, rate of release, and cellular uptake. To target its internalization into cancer cells under stress with an unfolded protein response (UPR), we use an L-peptide that binds cell-surface glucose-regulated protein 78 (GRP78). Herein, the L-peptide was fused to five FKBP domains linked by an elastin-like polypeptide (ELP) selected to form a biomolecular condensate depot at body temperature. This novel GRP78-targeted carrier (L-5FV) was characterized by UV-vis spectrophotometry, dynamic light scattering (DLS), surface plasmon resonance (SPR), and dialysis under sink conditions to assess its thermosensitivity, particle assembly, binding kinetics to both Rapa and GRP78, and drug release, respectively. Functional delivery of cellular internalization and mTORC1 inhibition were confirmed using fluorescence microscopy and Western blot in dose- and time-dependent manners in a breast cancer cell line, BT-474. Both targeted and untargeted formulations are phase-separated at physiological temperatures and exhibit nanomolar affinity for FKBP12 and Rapa. Notably, L-5FV demonstrated a more significant cellular association and inhibition of p-rpS6, a mechanistic target of mTORC1 activity. This report provides insight into how to construct long-release, molecularly targeted drug carriers with applications in UPR-active cancers.

DOI: https://doi.org/10.1021/acs.biomac.5c02348
Free Radic Biol Med. 2026 Apr 03. pii: S0891-5849(26)00288-1. [Epub ahead of print]

The Emerging Role of Novel PTMs in Autophagy: Implications for Diabetes and Its Complications.

Ke Xu, Ge Yang, Jinjie Li, Wei Liu, Xin Jiang, Ying Xin.

  Diabetes mellitus is a metabolic disease with the highest prevalence and the fastest growth rate worldwide. The pathogenesis of diabetes mellitus and its complications is markedly complex, involving cell apoptosis, oxidative stress, inflammation, microangiopathy, and autophagy disorders. As an evolutionarily conserved process involving intracellular material turnover and organelle homeostasis, the role of autophagy is multifaceted. Autophagy contributes to the clearance of misfolded proteins and abnormal amyloid aggregates within islet beta cells to maintain beta cell function. However, overactivation or dysregulation of autophagy may lead to the degradation of essential components within beta cells, including insulin particles, thereby resulting in cell dysfunction. Protein post-translational modifications (PTMs) are central to epigenetics, and histone methylation and acetylation modifications-key pathophysiological processes in diabetes, including "metabolic memory," endothelial cell dysfunction, and inflammation, have been intensively investigated. In recent years, a growing number of novel PTMs have been discovered and confirmed in diabetes and its associated complications. In this review, we summarize disorders and regulatory mechanisms of autophagy, introduce several novel PTMs, and discuss their relationship with diabetes and its complications, providing a novel perspective on the pathogenesis and treatment of diabetes from an epigenetic perspective.

Keywords:  autophagy; diabetes; malonylation; post-translation modification; β-hydroxybutyrylation

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.04.004
FASEB J. 2026 Apr 30. 40(8): e71717

Lysosomal Membrane Proteins: Key Regulators of Glucose Metabolism and Its Associated Diseases.

Jiahao Xu, Yujie Jin, Shiqiang Liu, Song Dong, Chaoqun Xiong, Ruixi Zhang, Wenjun Pei, Xu Wu, Lizhuo Wang, Jialin Gao.

  Glucose homeostasis, which is critical for maintaining energy supply and health, involves glycogen metabolism, glycolysis, and gluconeogenesis. Lysosomal membrane proteins (LMPs) play core roles in regulating these processes. However, no focused systematic review of the topic has been reported. This review provides an in-depth analysis of the central roles of LMPs in glucose metabolism, focusing on the regulation of glucose homeostasis and their potential effects on metabolic diseases through the regulation of autophagy, signaling networks, specialized transporter functions, and other relevant mechanisms. In general, LMPs play core roles in lysosomal biosynthesis, and an in-depth study of their relationship with glucose metabolism could significantly highlight the important contribution of lysosomes in the development of related diseases.

Keywords:  gene regulation; glucose metabolism; lysosomal membrane protein; metabolism; molecular mechanisms

DOI:  https://doi.org/10.1096/fj.202501587R
Mol Cell. 2026 Apr 07. pii: S1097-2765(26)00189-9. [Epub ahead of print]

Species-specific cleavage of the autophagy adaptor p62 dictates responses to TNF.

Christoph Nössing, Olga Troitskaya, Jaclyn S Long, Andrew Craxton, Martina Brucoli, Eve Anderson, Sergio Lilla, David G McEwan, Annabel R Minton, Valentin J A Barthet, Jim O'Prey, Gemma Thomson, Colin Nixon, Sara Zanivan, Douglas Strathdee, Marion MacFarlane, Kevin M Ryan.

  Inflammation can affect many diseases. We report here that inflammatory cytokines invoke caspase-8-mediated cleavage of the autophagy adaptor p62/SQSTM1 at aspartic acid 329 in human cells, producing a previously described truncated form, which we term tr-p62. We show that TNF-driven cell death is tr-p62 dependent and that autophagy inhibition promotes death via tr-p62 accumulation. Mechanistically, p62 cleavage is receptor-interacting serine/threonine-protein kinase 1 (RIPK1) dependent, and tr-p62 stabilizes caspase-8 activating complex-IIb. tr-p62-driven cell death downstream of TNF is also RIPK1 and caspase dependent, promoting feedforward caspase-8 activation. p62 cleavage does not, however, affect necroptosis. Surprisingly, this caspase-8 cleavage site in p62 is absent in mice, and introduction of cleavable forms of p62 into mouse cells causes sensitization to TNF-induced death. Moreover, mice with CRISPR-Cas9-generated cleavable p62 exhibit TNF hypersensitivity and intestinal inflammation in vivo. These findings provide significant insights into TNF-induced cell death and introduce a mouse model that may provide better clarity for human-related studies of inflammatory disease.

Keywords:  TNF; autophagy; caspase; cell death; mice; p62

DOI:  https://doi.org/10.1016/j.molcel.2026.03.013
bioRxiv. 2026 Mar 30. pii: 2026.03.27.714902. [Epub ahead of print]

Shifts in protein aggregate stability define proteostasis decline in the aging human brain.

Edward Anderton, Jordan B Burton, Christina D King, Anna C Foulger, Dipa Bhaumik, Daria Timonina, Zachary Mayeri, Manish Chamoli, Julie K Andersen, Birgit Schilling, Gordon J Lithgow.

Loss of proteostasis and the accumulation of insoluble protein aggregates are features of aging across model organisms and occur in all major age-related neurodegenerative diseases; yet how aggregation proceeds during normal human brain aging remains unknown. Here, using detergent-fractionation proteomics, we show that brain aging does not involve uniform aggregate accumulation; rather, the insoluble proteome undergoes asymmetric remodeling beginning in midlife, with maximum-stability aggregates declining sharply by old age and intermediate-stability aggregates accumulating progressively before accelerating after age 80. Intermediate-stability aggregates are prone to liquid-liquid phase separation and are enriched among Alzheimer's disease plaque and tangle constituents. Proteasome and cytosolic chaperone capacity predict individual differences in aggregate burden as strongly as chronological age, offering human-level evidence in support of therapies targeting these pathways. These findings establish aggregate remodeling as a feature of normal brain aging and position intermediate-stability aggregate accumulation as a molecular event on the path to neurodegenerative disease.

DOI: https://doi.org/10.64898/2026.03.27.714902