bims-auttor 2026-10-11 papers

bims-auttor

Biomed News

on Autophagy and mTOR

Issue of 2026–10–11
thirty-two papers selected by
Viktor Korolchuk, Newcastle University

The R2TP Complex Couples mTORC1 Signaling to Vacuolar ATPase Assembly and Lysosomal Function.
SIRT1 Regulates Late Stage of Autophagy and Mitophagy via Autophagosome-Lysosome Fusion in Cardiomyocytes.
Emerging mechanisms of ATG8-independent non-canonical autophagy.
Chaperone-mediated autophagy in physiological homeostasis, disease and ageing.
Evolutionarily conserved selective autophagy pathways.
Structural basis for the selective inhibition of the PI3KC3-C2 complex by Rubicon in endolysosome maturation and mitophagy.
MOSPD3 mediates the ER recruitment of ATG2A to promote autophagy.
Caloric restriction mimetics rewire the AMPK-mTOR-ULK1 signaling nexus to restore autophagic proteostasis in the aging brain.
Inhibition of dipeptidyl peptidase 7 impairs lysophagy in LLOMe-treated HepG2 cells.
Inhibition of the Lysosomal Amino Acid Sensor SLC38A9 by the Membrane Microprotein SPAR.
TBK1-mediated phosphorylation of WIPI2 links bacteria recognition to autophagosome formation in xenophagy.
Dissipation of lysosome pH impairs formation and collapses existing LPS-induced lysosome tubules in macrophages.
Decline of chaperone-mediated autophagy in aging impairs macrophage clearance of senescent cells.
TBK1 eliminates aggregation-prone monomeric TDP-43 through an IFNβ-immunoproteasome pathway in ALS models.
OXR1 is a dual redox-mitochondrial checkpoint governing osteoclast differentiation and bone loss in an osteoporosis mouse model.
Mitophagy in pathogenesis and therapeutic implications for infection.
GlRac regulates an ATG8-independent autophagy-like pathway in Giardia lamblia.
The Autophagy-Epigenome Axis in Hypothalamic Neurons: A Unified Framework for Understanding Obesity Persistence and Therapeutic Resistance.
Nucleocytoplasmic shuttling of USP15 promotes pathological autophagy that disrupts neural stem cell homeostasis and neurodevelopment.
Autolysosomal enhancer GHF201 attenuates pathophysiology in a mucopolysaccharidosis type I mouse model.
Lysosomes as chemical and metabolic organizers of central nervous system injury and repair.
One organelle to rule them all: enhancement of lysosomal activity as a therapeutic modality for protein misfolding neurodegenerative diseases.
Nanotechnology meets neurodegeneration: restoring lysosomal function with nanovectors.
Directing mutant huntingtin towards degradation: Strategies and therapeutic opportunities.
Chromatin stability safeguards mitochondrial homeostasis and restrains TORC1 signaling.
Synaptic Proteostasis in Health and Disease.
Live visualization of dynamic autophagy processes in LC3 reporter mice using enhanced two-photon microscopy.
Differential autophagy cargo engagement in amyloid-β-induced neuronal toxicity.
From retina to brain: retinal dysfunction and dopaminergic neurodegeneration in Drosophila models of Parkinson's disease.
Lysosomal Expansion Compartments Mediate Zinc and Copper Homeostasis in Caenorhabditis elegans.
Mitochondrial transfer protects against cisplatin-induced hearing loss by fumarate-mediated activation of mitophagy.
Adding Tat-Beclin1 to an endurance training program promotes additive improvements in physical function in aged male mice.

J Cell Biochem. 2026 Oct;127(10): e70133

The R2TP Complex Couples mTORC1 Signaling to Vacuolar ATPase Assembly and Lysosomal Function.

Xiao-Wen Zhang, Ming-Yue Wu, Qi Zhu, Xu Zhuang, Yu Dong, Shuang Zhang, Jia-Hong Lu.

  The vacuolar ATPase (V-ATPase) is essential for lysosomal acidification and autophagy, and its activity is regulated by nutrient-sensitive reversible assembly of its V1 and Vo domains. While mTORC1 is known to inhibit V-ATPase assembly, the precise molecular mechanisms remain incompletely understood. Here, using TurboID-based proximity labeling and quantitative mass spectrometry, we identified the R2TP complex subunits RPAP3 and PIH1D1 as novel autophagy-responsive interactors of the V-ATPase V1A subunit (encoded by ATP6V1A). We found that mTORC1 inhibition disrupts the R2TP-V1A interaction, promoting the relocation of the V1 domain to lysosomes and its assembly with the Vo domain to form active proton pumps. Functionally, knockdown of RPAP3 or PIH1D1 enhanced autophagic flux, increased lysosomal proteolytic activity, and promoted the clearance of soluble α-synuclein in a cellular model of Parkinson's disease (PD). Our study reveals the R2TP complex as a critical molecular switch that couples mTORC1 signaling to V-ATPase assembly and lysosomal function, thereby identifying a new pathway for regulating lysosomal catabolism with significant therapeutic potential for neurodegenerative disorders.

Keywords:  R2TP complex; V‐ATPase; autophagy; lysosomal function; mTORC1

DOI:  https://doi.org/10.1002/jcb.70133
FASEB J. 2026 Oct 15. 40(19): e72361

SIRT1 Regulates Late Stage of Autophagy and Mitophagy via Autophagosome-Lysosome Fusion in Cardiomyocytes.

Atsushi Kuno, Yukika Saga, Ryusuke Hosoda, Hiroki Aida, Ayuka Kurihara, Yuki Tatekoshi, Koki Abe, Ryo Numazawa, Naotoshi Iwahara.

  Sirtuin-1 (SIRT1) is an NAD+-dependent deacetylase implicated in autophagosome formation; however, whether SIRT1 also regulates autophagosome clearance during late-stage autophagy remains unclear. Here, we investigated the role of SIRT1 in autophagosome clearance during autophagy and mitophagy in cardiomyocytes. Mitochondrial stress induced by carbonyl cyanide m-chlorophenyl hydrazone (CCCP) decreased mitochondrial protein levels and increased phosphorylation of ubiquitin, a PINK1 target, in H9c2 cardiomyocytes. These CCCP-induced decreases in mitochondrial proteins were prevented by co-treatment with chloroquine, an inhibitor of lysosomal degradation, supporting the induction of CCCP-triggered mitophagy. SIRT1 knockdown similarly prevented the CCCP-induced reduction in mitochondrial proteins and led to the accumulation of autophagosomes containing fragmented mitochondria without attenuating ubiquitin phosphorylation, suggesting that SIRT1 acts downstream of mitochondrial tagging. Tandem GFP-RFP LC3 assay and LC3-LAMP1 colocalization analysis demonstrated impaired autophagosome-lysosome fusion following SIRT1 knockdown. In vivo, cardiomyocyte-specific SIRT1 knockout mice exhibited elevated basal LC3-II levels and a blunted LC3-II response to chloroquine, consistent with impaired autophagic flux. In a doxorubicin (DOX)-treated model, SIRT1 deficiency attenuated autophagosome degradation during the early period after DOX administration. Mechanistically, SIRT1 interacted with Rab7, a key regulator of autophagosome-lysosome fusion, raising the possibility that SIRT1 might regulate fusion through post-translational modification of Rab7 or related components. Collectively, these findings identify SIRT1 as a regulator of autophagosome-lysosome fusion that promotes autophagosome degradation during autophagy and mitophagy in cardiomyocytes.

Keywords:  Sirtuin‐1; autophagosome–lysosome fusion; autophagy; doxorubicin; mitophagy

DOI:  https://doi.org/10.1096/fj.202601047R
J Physiol Biochem. 2026 Oct 07. pii: 102. [Epub ahead of print]82(1):

Emerging mechanisms of ATG8-independent non-canonical autophagy.

Suvam Saha, Debasish Kumar Ghosh.

  ATG8-independent autophagy represents an emerging field of cellular degradation that challenges the long-held view that LC3/GABARAP lipidation is universally required for autophagosome formation and autophagic flux. Over the past decade, studies across mammals, plants, and protozoa have revealed that cells can execute degradative mechanisms through alternative macroautophagy, microautophagy-like pathways, and autophagy-like systems that operate with reduced or absent reliance on ATG8 proteins. These discoveries have reshaped the conceptual framework of autophagy by separating membrane biogenesis, cargo sequestration, and lysosomal delivery into potentially ATG8-uncoupled modules. ATG8-independent pathways are now recognized as important for stress adaptation, organelle quality control, developmental remodeling, and selective cargo degradation. This review summarizes the historical development, mechanistic diversity, and biological relevance of ATG8-independent autophagy, and discusses its implications for disease biology and therapeutic targeting. Understanding these unconventional pathways will be essential for a complete view of autophagic regulation in health and disease.

Keywords:  ATG8-independent autophagy; Autophagy machinery diversity; Autophagy regulation; Non-canonical autophagy; Organelle quality control; Stress-induced cellular degradation

DOI:  https://doi.org/10.1007/s13105-026-01243-6
Nat Rev Mol Cell Biol. 2026 Oct 05.

Chaperone-mediated autophagy in physiological homeostasis, disease and ageing.

Susmita Kaushik, Ana Maria Cuervo.

Chaperone-mediated autophagy (CMA), the first-described selective lysosomal degradation pathway, is distinguished from other degradative pathways by the unique mechanism by which substrates reach the lysosomal lumen: CMA relies on a cytosolic targeting chaperone and a lysosomal membrane receptor that doubles as a translocation complex. In this Review, we highlight recent discoveries of additional molecular components involved in CMA and describe how genetic and pharmacological modulation of CMA in vivo, along with the identification of the subproteome degraded by CMA in different organs, has revealed an expanding range of physiological functions regulated by CMA in an organ-specific manner. CMA not only degrades damaged proteins but also targets fully functional proteins to terminate their physiological roles. Consequently, CMA dysfunction, as observed in ageing and age-related diseases, leads to cellular alterations beyond the mere accumulation of damaged proteins. We summarize recent findings linking CMA to common diseases and discuss efforts to therapeutically target CMA in these conditions.

DOI: https://doi.org/10.1038/s41580-026-01023-6
Autophagy. 2026 Oct 06. 1-26

Evolutionarily conserved selective autophagy pathways.

András Jipa, Virág Vincze, Daniela Evdokimova, Dániel Dénes, Lilla Beatrix Péter, Zsombor Esküdt, Bence Csaba Béres, Gábor Juhász.

  Selective autophagy is a regulated process that ensures the specific recognition and lysosomal degradation of defined intracellular substrates, including damaged organelles, protein aggregates, and invading pathogens. Despite intense research interest, several mechanistic aspects of selective autophagy remain incompletely understood. Comparative analysis across different models offers a valuable framework for identifying evolutionarily conserved molecular components and regulatory principles. In this review, we provide a detailed overview of seven major evolutionarily conserved selective autophagy pathways: mitophagy, xenophagy, pexophagy, lysophagy, ER-phagy, Golgiphagy, and ribophagy, building on data from four widely used model organisms (mammals, Drosophila melanogaster, Caenorhabditis elegans, and Saccharomyces cerevisiae). We focus on the core molecular machinery including the modes of cargo recognition via already characterized and predicted selective receptors, and orchestration of cargo capture into forming autophagosomes.

Keywords:  Er-phagy; Golgiphagy; lysophagy; mitophagy; pexophagy; xenophagy

DOI:  https://doi.org/10.1080/15548627.2026.2736925
bioRxiv. 2026 Aug 10. pii: 2026.08.07.743589. [Epub ahead of print]

Structural basis for the selective inhibition of the PI3KC3-C2 complex by Rubicon in endolysosome maturation and mitophagy.

Minghao Chen, Aniketh Bishnu, Yongjia Duan, Julia F Riley, Qingyang Ni, Aaron Joiner, Isaac J Allen, Erika L F Holzbaur, Ian G Ganley, James H Hurley.

Rubicon is a negative regulator of autophagy and the endolysosomal network (ELN) and an antagonist of the class III phosphatidylinositol 3-kinase complex II (PI3KC3-C2). Inhibition of Rubicon is considered a potential means to therapeutically upregulate autophagy and the ELN to treat Parkinson's disease and other conditions characterized by autophagic and ELN dysfunction. Rubicon is specific for the UVRAG-containing PI3KC3-C2 over the purely autophagic ATG14- containing PI3KC3-C1 complex. Here, we determined the high-resolution cryo-electron microscopy structure of PI3KC3-C2 in complex with the PI3KC3-binding domain (PIKBD) of Rubicon and compared it to cryo-EM structures of unbound PI3KC3-C2 and PI3KC3-C1. Rubicon binds directly to PI3KC3-C2 only via the BARA domain of the BECN1 subunit, which is common to both C1 and C2. The selectivity of Rubicon for the PI3KC3-C2 complex over the PI3KC3-C1 complex is attributed to a conformation of the BECN1 BARA domain induced by UVRAG, rather than to direct contact with UVRAG or direct antagonism by the ATG14 subunit of PI3KC3-C1. Targeted disruption of the Rubicon:PI3K3-C2 structural interface by site-directed mutations enhances mitophagic activity in human epithelial cells to levels comparable to those observed in Rubicon knockout (KO) cells. Similarly, disruption of the interaction in Rubicon-overexpressing hippocampal neurons restored lysosomal flux to wild-type levels. These data show that suppressing the function of PI3K3- C2 can fully account for the negative regulatory effects of Rubicon in the autophagy and ELN pathways.
Significance Statement: Endolysosome maturation and autophagosome-lysosome fusion require the production of phosphatidylinositol 3-phosphate (PI(3)P) by the class III phosphatidylinositol 3-kinase complex II (PI3KC3-C2). Rubicon is a key negative regulator of endolysosomes and autophagy that suppresses PI3KC3-C2 activity. Here, we reveal in atomistic detail how Rubicon selectively recognizes PI3KC3-C2. Disrupting the Rubicon-PI3KC3-C2 interaction restores mitophagy and enhances lysosomal activity to the same extent as Rubicon gene deletion, establishing that PI3KC3-C2 inhibition fully accounts for the biological regulatory effects of Rubicon in the autophagy and lysosome pathways.

DOI: https://doi.org/10.64898/2026.08.07.743589
J Cell Biol. 2026 Nov 02. pii: e202601047. [Epub ahead of print]225(11):

MOSPD3 mediates the ER recruitment of ATG2A to promote autophagy.

Yuanjiao Du, Tiantian Zhou, Yazhou Liu, Nanxin Ye, Bing Zou, Weiping Chang, Lin Deng, Wei-Ke Ji.

ATG2A transfers glycerophospholipids from the endoplasmic reticulum (ER) to the expanding phagophore during autophagy, but how it is anchored to the ER in mammalian cells has been unclear. Here, we identify MOSPD3, an atypical member of the VAP family, as the ER adaptor for ATG2A. Endogenous MOSPD3 occupies ER subdomains adjacent to nascent autophagic structures, and it captures ATG2A through a direct interaction between its major sperm protein (MSP) domain and an FFNT (two phenylalanines in a neutral tract) motif near the ATG2A N terminus. Disrupting either side of this interface abolishes ER recruitment and prevents ATG2A from supporting autophagy. Its paralog MOSPD1 acts redundantly on ATG2B, and cells lacking both adaptors are defective in autophagic flux. MSP-FFNT recognition therefore provides the ER-side anchor that positions the ATG2A lipid-transfer bridge for autophagosome biogenesis.

DOI: https://doi.org/10.1083/jcb.202601047
Mol Cell Neurosci. 2026 Oct 05. pii: S1044-7431(26)00058-8. [Epub ahead of print]139 104128

Caloric restriction mimetics rewire the AMPK-mTOR-ULK1 signaling nexus to restore autophagic proteostasis in the aging brain.

Hosam Al-Jehani, Hayder M Al-Kuraishy, Ahmed M Abdelaziz, Ahmed A Mohamed, Ahmed M Mamdoh, Arafa Musa, Omar Mohamed Abdu Mursy, Gaber El-Saber Batiha.

  Brain aging is driven by progressive failure of neuronal proteostasis, culminating in the accumulation of toxic protein aggregates characteristic of Alzheimer's, Parkinson's, and Huntington's diseases. The AMPK-mTOR-autophagy signaling hub integrates cellular energy status with protein clearance machinery, making it a critical therapeutic node. Caloric restriction mimetics (CRMs), including rapamycin, metformin, resveratrol, and spermidine, exploit this axis by activating AMPK via AMP/ATP modulation and simultaneously suppressing mTORC1 kinase activity. This dual action relieves mTORC1-mediated inhibition of the ULK1 complex, triggering autophagosome nucleation, while sustained mTORC1 suppression promotes TFEB-driven lysosomal biogenesis, collectively restoring autophagic flux. Preclinically, these molecular events enhance clearance of amyloid-β, tau, α-synuclein, and mutant huntingtin and improve mitochondrial quality control via mitophagy. Despite robust mechanistic evidence, clinical translation remains constrained by poor CNS bioavailability, context-dependent autophagic outcomes, and the absence of validated pharmacodynamic biomarkers (e.g., LC3-II turnover, p62 flux) to confirm neuronal target engagement in humans. This review integrates CRM action on the AMPK/mTOR/autophagy axis with both the hallmarks of neuronal aging and disease-specific pathology, providing a molecular framework to guide the rational design of CNS-penetrant formulations, combination strategies, and personalized approaches to modify neurodegeneration.

Keywords:  AMPK; Autophagy; Brain aging; CRMs; Neurodegeneration; Proteostasis; mTOR

DOI:  https://doi.org/10.1016/j.mcn.2026.104128
FEBS Lett. 2026 Oct 08.

Inhibition of dipeptidyl peptidase 7 impairs lysophagy in LLOMe-treated HepG2 cells.

Na Yeon Park, Inho Kwon, Yong Hwan Kim, Ji-Eun Bae, Joon Bum Kim, Seong Hyun Kim, Sungho Maeng, Doo Sin Jo, Dong-Hyung Cho.

  Lysophagy selectively eliminates damaged lysosomes to preserve lysosomal homeostasis, but its regulatory mechanisms remain incompletely understood. Here, we identify dipeptidyl peptidase 7 (DPP7), a lysosomal serine protease, as a regulator of lysophagy. Inhibition or depletion of DPP7 impaired clearance of LLOMe-damaged lysosomes in HepG2 cells, as evidenced by sustained galectin-3 puncta and reduced lysophagic flux. DPP7 inhibition did not block TFEB activation; however, it markedly reduced ubiquitin accumulation on damaged lysosomes and attenuated the recruitment of SQSTM1 and LC3. This defect was accompanied by impaired lysosomal re-acidification and reduced maturation of cathepsin D and L. Together, our findings identify DPP7 as a novel modulator of ubiquitin-dependent lysophagy and reveal an unexpected role for a lysosomal peptidase in lysosomal quality control.

Keywords:  DPP7; LLOMe; Lysophagy; Lysosomal integrity; UAMC00039

DOI:  https://doi.org/10.1002/1873-3468.70482
bioRxiv. 2026 Aug 10. pii: 2026.08.07.743590. [Epub ahead of print]

Inhibition of the Lysosomal Amino Acid Sensor SLC38A9 by the Membrane Microprotein SPAR.

Ampon Saeher, Xuelang Mu, Tamir Gonen.

Long noncoding RNAs encode for microproteins that regulate cellular functions. Small regulatory peptide of amino acid response (SPAR) is a microprotein in the lysosome that responds to amino acid availability of the cell. In this study, we investigated the interactions between SPAR and SLC38A9, a lysosomal amino acid transporter and receptor involved in the mechanistic target of rapamycin 1 (mTORC1) pathway. We found that SPAR binds SLC38A9 and inhibits arginine transport in SLC38A9. Moreover, the downstream recruitment of Rag GTPases is also inhibited when SPAR is present in SLC38A9 liposomes. Docking model shows potential interactions between SPAR and SLC38A9. Together, these findings reveal the mechanism of mTORC1 inhibition through microprotein SPAR and illustrates the power of non long coding RNAs in altering cellular functions.
Statement of Significance: Microproteins encoded from long noncoding RNAs are emerging as critical regulators of many pathways. This study investigates a novel mechanism of SPAR microprotein that directly regulates the mechanistic target of rapamycin complex1 (mTORC1) signaling pathway through the lysosomal amino acid transporter SLC38A9. SPAR blocks both arginine transport and the downstream recruitment of Rag GTPases. These findings provide critical results in how SPAR controls cellular amino acid availability, while broadly highlighting the powerful regulatory mechanism of microproteins in cellular processes.

DOI: https://doi.org/10.64898/2026.08.07.743590
Autophagy. 2026 Oct 09.

TBK1-mediated phosphorylation of WIPI2 links bacteria recognition to autophagosome formation in xenophagy.

Chuying Qian, Hongtao Zhang, Jin Li, Wei Wan, Wei Liu.

  Xenophagy, a selective autophagy pathway, is a critical innate immune defense mechanism that targets pathogens for lysosomal degradation. However, the molecular mechanisms enabling autophagosomes to specifically recognize and engulf bacteria remain incompletely understood. Here, we identify WIPI2, a core component that drives autophagosome biogenesis, as a novel phosphorylation substrate of TBK1 during Salmonella Typhimurium infection. We demonstrate that TBK1 phosphorylates WIPI2 at Ser96, which enhances its interaction with ATG16L1 and its binding to PtdIns3P. Crucially, the recruitment of WIPI2 to intracellular bacteria is dependent on its interaction with ATG16L1, which is localized to the Salmonella-containing vacuole. Furthermore, TBK1-mediated phosphorylation of WIPI2 is required for efficient bacterial clearance. Collectively, our findings reveal a molecular mechanism whereby TBK1-mediated phosphorylation of WIPI2 directs localized phagophore expansion around invading bacteria, thereby bridging bacterial recognition with autophagosome assembly.

Keywords:  ATG16L1; PtdIns3P; Salmonella; TBK1; V-ATPase; WIPI2; phosphorylation; xenophagy

DOI:  https://doi.org/10.1080/15548627.2026.2746965
Mol Biol Cell. 2026 Oct 08. mbcE25090457

Dissipation of lysosome pH impairs formation and collapses existing LPS-induced lysosome tubules in macrophages.

Shiraz Anwar, Solmaz Ebrahimi-Iranpour, Maria R Narciso, Jennifer Li, Saaimatul Huq, Tracy Lackraj, Tamara Beriia, Nazia Chowdhury, Mojca Mattiazzi Usaj, Roberto J Botelho.

While lysosomes are typically globular in morphology, lipopolysaccharide-activated macrophages reorganize lysosomes into an expanded tubular network. Here, we sought to determine if the V-ATPase and the lysosomal pH contribute to LPS-mediated lysosome tubulation in macrophages. We found that inhibition of the V-ATPase prevented lysosome tubulation and collapsed preformed tubules. However, the V-ATPase also controls mTORC1 activity, which itself is needed for tubulation. To distinguish between lysosomal pH and mTORC1, we turned to NH4Cl, which alkalinized lysosomal pH but did not interfere with mTORC1; yet NH4Cl blocked tubulation showing that an acidic lysosomal pH is needed for lysosome remodelling. Moreover, clamping the pH to either acidic or alkaline pH caused tubules to collapse, indicating that the pH gradient promotes tubulation, rather than a specific pH. These effects were not due to altered microtubule organization or impaired lysosome motility, suggesting that motors remained associated with lysosomes. On the other hand, while LPS did not alter the average pH of spherical or tubular lysosomes, growing tubules displayed a more acidic peripheral end relative to the pericentral end. Based on this observation, we propose that a localized pH gradient along the tubule may enable tubulation by modulating factors that catalyse tubule growth. [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text].

DOI: https://doi.org/10.1091/mbc.E25-09-0457
Nat Aging. 2026 Oct 05.

Decline of chaperone-mediated autophagy in aging impairs macrophage clearance of senescent cells.

Rebecca Sereda, Kristen Lindenau, Antonio Diaz, Zhaohui Liu, Olaya Santiago-Fernández, Rabia R Khawaja, Ronald Cutler, Jazmin Calyeca, Mericka McCabe, Sylvére Durand, Fanny Aprahamian, Natalia Del Pilar Vanegas, Hu Chen, Felipe Vilicich, Bhakti Chavda, Yair Botbol, Guido Kroemer, Toren Finkel, Evripidis Gavathiotis, Simone Sidoli, Ana L Mora, Mauricio Rojas, Susmita Kaushik, Ana Maria Cuervo.

Autophagy dysfunction and senescence are established drivers of aging, but their potential interaction remains poorly understood. Here we show that age-related decline of chaperone-mediated autophagy (CMA), a pathway for selective lysosomal protein degradation, changes senescent cell properties and impairs their immune clearance. CMA-deficient cells undergo senescence but acquire proteomic, metabolic and secretory features resembling those in aged senescent cells. Their senescence-associated secretory phenotype exhibits enhanced pro-senescence effects on neighboring cells and inhibits macrophage CMA, which impairs their ability to engulf senescent cells. Accordingly, blockage of CMA specifically in macrophages increases senescent cell accumulation in mice and delays senescence resolution during wound healing. Conversely, pharmacological CMA activation reduces senescent cell burden in aged mice and disease severity in a pulmonary fibrosis mouse model. Our findings identify CMA decline as a driver of senescent cell persistence and highlight CMA upregulation as a promising strategy to promote senescence resolution in aged organisms.

DOI: https://doi.org/10.1038/s43587-026-01240-w
EMBO Rep. 2026 Oct 05.

TBK1 eliminates aggregation-prone monomeric TDP-43 through an IFNβ-immunoproteasome pathway in ALS models.

Shohei Sakai, Kotaro Oiwa, Yohei Iguchi, Izzet Mehmet Akcay, Seiji Watanabe, Okiru Komine, Noriko Nagata, Mai Horiuchi, Jemeen Sreedharan, Masahisa Katsuno, Koji Yamanaka.

Loss-of-function mutations in TANK-binding kinase 1 (TBK1) cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), characterized by cytoplasmic aggregation of TAR DNA-binding protein 43 (TDP-43), known as TDP-43 pathology, but the mechanisms beyond impaired autophagy remain undefined. Here, we identify a TBK1-IFNβ-immunoproteasome axis as a novel autophagy-independent proteostatic pathway regulating TDP-43 clearance. TBK1 is activated by aggregation-prone monomeric TDP-43 via physical association, and this activation alleviates TDP-43 pathology in neuronal cells. TBK1 subsequently induces IFNβ expression, which upregulates the immunoproteasome to promote degradation of monomeric TDP-43 in neurons, including human iPSC-derived lower motor neurons. Importantly, IFNβ receptor expression is downregulated in spinal motor neurons from ALS patients with TDP-43 pathology. Furthermore, heterozygous Tbk1 deletion in SOD1G93A mice impairs immunoproteasome induction and increases polyubiquitinated protein accumulation in spinal cords, supporting the in vivo relevance of this pathway. Collectively, our findings reveal that impairment of the TBK1-IFNβ-immunoproteasome axis represents an autophagy-independent mechanism contributing to the development of TDP-43 pathology in ALS and FTD.

DOI: https://doi.org/10.1038/s44319-026-00953-8
Nat Commun. 2026 09 05. pii: 10553. [Epub ahead of print]17(1):

OXR1 is a dual redox-mitochondrial checkpoint governing osteoclast differentiation and bone loss in an osteoporosis mouse model.

Xiaojun Chen, Chengyu Zhou, Xiangyun Jin, Qiongxiang Lin, Lizhen Li, Zhongxiang Wang, Buran Chen, Qiu Dong, Jianbo He, Kavishadhi Chandrasekaran, Chau Bui, Alysia Hubbard, Qunwei Dong, Lei Chen, K Swaminathan Iyer, Jiandong Yuan, Nathan J Pavlos, Haibo Jiang, Kai Chen.

Osteoclasts are mitochondria-rich cells that rely on oxidative phosphorylation to fuel differentiation and bone resorption. Oxidative phosphorylation generates reactive oxygen species (ROS), which support signaling but can also threaten mitochondrial integrity. Oxidation Resistance 1 (OXR1) is a redox-responsive regulator involved in antioxidant defense, but its role in osteoclasts remains unclear. Here, we show that OXR1 is upregulated during mouse osteoclastogenesis and OXR1 mRNA is enriched in human osteoclasts. Knockdown of Oxr1 in mouse osteoclast precursors causes excessive ROS accumulation, mitochondrial damage, and impaired autophagic flux. Accordingly, myeloid-specific loss of Oxr1 results in defective osteoclast formation and increased bone mass in mice. Mechanistically, OXR1 binds the antioxidant response regulator KEAP1 and promotes KEAP1 association with the autophagy adaptor P62/SQSTM1, thereby supporting mitochondrial ubiquitination and mitophagic clearance. In an ovariectomy-induced osteoporosis mouse model, intraosseous AAV9-shRNA-mediated Oxr1 silencing or pharmacological OXR1 inhibition suppresses osteoclast activity and attenuates bone loss. Thus, our findings suggest OXR1 to be a dual-function regulator that buffers ROS and simultaneously orchestrates the autophagic clearance of damaged mitochondria during osteoclastogenesis, hinting at OXR1 as a potential target for preventing osteoclast‑driven bone loss.

DOI: https://doi.org/10.1038/s41467-026-77379-2
Exp Mol Med. 2026 Oct 05.

Mitophagy in pathogenesis and therapeutic implications for infection.

Bokeum Jung, Bomi Lee, Asmita Sapkota, Taylor Roh, Wonhyoung Seo, Jin Kyung Kim, Eun-Kyeong Jo.

Mitophagy, a critical selective autophagy pathway targeting dysfunctional mitochondria, is involved in cellular homeostasis and quality control under various stressors. During infection, invading pathogens cause mitochondrial abnormalities that trigger mitophagy. Most bacteria and viruses can exploit mitophagy as a pro-pathogenic process to escape host antiviral responses during infection. Emerging evidence suggests that restoring mitophagy is beneficial for mitigating excessive inflammation, such as in sepsis, whereas mitophagy blockade can activate host defense during bacterial and viral infections. Here we review current knowledge on the role of mitophagy in bacterial and viral infections and sepsis, focusing on the mechanisms by which pathogens evade mitophagy or influence pathogenesis through mitophagy during different types of infection. We also highlight the potential beneficial effects of mitophagy modulators, reagents and small molecules against sepsis-induced pathologies and infections. Progress in these areas will expand our knowledge on alleviating pathology, promoting antimicrobial immune responses and maintaining cellular homeostasis, ultimately providing potential preventive and therapeutic strategies against pathogenic infections and inflammation associated with dysregulated mitophagy.

DOI: https://doi.org/10.1038/s12276-026-01852-7
PLoS Pathog. 2026 Oct 06. 22(10): e1014624

GlRac regulates an ATG8-independent autophagy-like pathway in Giardia lamblia.

Angélica Hollunder Klippel, Corryn Newman-Boulle, Grant Reed, Dule Dule, Saanya Kedia, Martin T Kelty, Wai Pang Chan, Han-Wei Shih, Alexander R Paredez.

Autophagy is a conserved catabolic process essential for cellular homeostasis and adaptation to nutrient stress. The protozoan parasite Giardia lamblia lacks most canonical autophagy-related (ATG) genes, including the hallmark ATG8, raising longstanding questions about whether this deeply divergent parasite can perform autophagy. Here, we identify an ATG8-independent autophagy-like pathway in Giardia regulated by GlRac, the parasite's sole Rho family GTPase. GlRac-positive double-membrane compartments are induced by encystation and nutrient depletion, and their abundance rapidly declines following amino acid replenishment but is unaffected by glucose, indicating amino acid-specific regulation. Giardia Target of Rapamycin (GTOR) levels decrease during nutrient depletion, and GTOR knockdown increases compartment abundance, identifying GTOR as a negative regulator of compartment formation and linking this pathway to nutrient sensing. Time-lapse microscopy revealed that these compartments form through linear and cup-shaped intermediates before becoming spherical and are subsequently cleared upon nutrient replenishment. Of nine putative ATG orthologs examined, none localized as specifically as GlRac to these structures, supporting the existence of a highly divergent pathway. Nevertheless, the compartments exhibit multiple conserved autophagy-associated features, including double-membrane morphology, actin recruitment, acidification, and cysteine protease activity. Pharmacological inhibition of cysteine proteases with E-64d or blocking V-ATPase-mediated acidification with concanamycin A promotes compartment accumulation, consistent with continuous degradative turnover. GlRac regulates compartment biogenesis bidirectionally: constitutive activation increases compartment abundance and size, whereas knockdown reduces them. Finally, quinacrine, an FDA-approved antigiardial drug that accumulates in acidic organelles, perturbs GlRac-positive compartments, consistent with its reported effects on autophagy in other eukaryotes, raising the possibility that this pathway contributes to parasite fitness. Together, these findings establish GlRac as a central regulator of an ATG8-independent autophagy-like pathway in Giardia and demonstrate that this parasite retains key structural, regulatory, and degradation-associated features of autophagy despite the apparent absence of most canonical ATG machinery.

DOI: https://doi.org/10.1371/journal.ppat.1014624
Exp Clin Endocrinol Diabetes. 2026 Oct 05.

The Autophagy-Epigenome Axis in Hypothalamic Neurons: A Unified Framework for Understanding Obesity Persistence and Therapeutic Resistance.

Amin Roshdy Soliman.

Abstract: Diet-induced obesity is increasingly understood as a disorder of central regulatory failure rather than simple energy imbalance. Two mechanisms-impaired hypothalamic autophagy and epigenetic reprogramming of feeding-regulatory genes-have been independently implicated in perpetuating obesity, yet their mechanistic intersection remains poorly defined. This perspective proposes that these processes are not parallel phenomena but components of a single self-reinforcing autophagy-epigenome axis (presented here as a working hypothesis) governed by shared nutrient-sensing hubs (mechanistic target of rapamycin complex 1, AMP-activated protein kinase, and sirtuin 1). In this model, chronic caloric excess simultaneously suppresses autophagic flux and induces epigenetic silencing of autophagy regulators, potentially creating a feed-forward loop that locks hypothalamic neurons into a pro-inflammatory, orexigenic state resistant to dietary normalization. The frequent weight regain observed after glucagon-like peptide-1 receptor agonist discontinuation-despite these agents' demonstrated capacity to enhance central autophagy and suppress neuroinflammation-raises the possibility that current pharmacotherapies may suppress downstream consequences without erasing the underlying epigenetic code. This perspective synthesizes preclinical and emerging translational evidence to argue that durable obesity treatment will require interventions capable of simultaneously restoring autophagic flux and reversing epigenetic modifications within hypothalamic feeding circuits, and identifies critical knowledge gaps that must be addressed to advance this paradigm from a bench to a bedside.

DOI: https://doi.org/10.1055/a-2961-3522
J Clin Invest. 2026 Oct 06. pii: e196452. [Epub ahead of print]

Nucleocytoplasmic shuttling of USP15 promotes pathological autophagy that disrupts neural stem cell homeostasis and neurodevelopment.

Kaylan Ml Burns, Mashiat Zaman, Daniel Young, Michelle Hua, Yu-Yun Gao, Yvonne Yan Yan Or, Farzaneh Nobakht, Bryn D Webb, Julie A Jurgens, Francis Ramond, Xing-Chang Wei, Caroline D Robson, Alistair T Pagnamenta, Marvel Megaly, Belal Tafech, Antoine Dufour, Timothy E Shutt, Ping Yee Billie Au, Guang Yang.

  During organogenesis, stem cells undergo cellular and metabolic remodelling, facilitated by autophagy-mediated turnover of organelles. Autophagy impairment has been linked to human diseases, including neurodevelopmental disorders associated with disrupted neural stem/precursor cell (NPC) homeostasis, but the underlying mechanisms and pathogenic processes governing these connections remain poorly understood. Here, we report three de novo variants of uncertain significance (p.Gly223Asp, p.Gly889Glu, p.Met978Val) in the deubiquitinase USP15 in human probands with diverse clinical features, including a spectrum of brain malformations and metabolic phenotypes. Proband variants differentially altered USP15 activity and nucleocytoplasmic localization. USP15 showed dynamic localization in NPCs of embryonic mouse cerebral cortex. Using a knock-in mouse model carrying the p.Met978Val variant, we showed that aberrant cytoplasmic accumulation of USP15, but not its loss-of-function, impaired NPC self-renewal and differentiation, leading to reduced neuronal output and enlarged lateral ventricles. Mechanistically, USP15 deubiquitinated autophagy regulator ATG16L1, impeded its normal turnover, and impaired autophagy. Concurrently, lipid droplet mobilization and mitochondrial dynamics were attenuated. Reestablishing the ubiquitination-deubiquitination balance restored autophagy activity and normal neurogenesis. Our findings suggest that nucleocytoplasmic shuttling of USP15 creates a switch-like autophagy signal controlling NPC homeostasis, and its disruption may contribute to the pathogenesis of complex neurodevelopmental conditions.

Keywords:  Autophagy; Cell biology; Development; Neurodevelopment; Neuroscience; Ubiquitin-proteosome system

DOI:  https://doi.org/10.1172/JCI196452
Life Sci Alliance. 2026 Dec;pii: e202603750. [Epub ahead of print]9(12):

Autolysosomal enhancer GHF201 attenuates pathophysiology in a mucopolysaccharidosis type I mouse model.

Pradeep Kumar, Emmanuelle Merquiol, Talya Avraham, Reut Sinai-Turyanski, Pankaj K Singh, Roberto A Ribas, Sahar Sweetat, Uri Sprecher, Noam Muchtar, Manjeet Gupta, Kumudesh Mishra, Shashank Kumar Ojha, Zhanna Yekhtin, Hava Glickstein, Ori Shalev, Alexandra Eliassaf, Anna Morshina, Hadas Segev-Yekutiel, Sharon Garti, Nissim Garti, Hannah Rosenmann, Miguel Weil, Matthew S Gentry, Galia Blum, Or Kakhlon.

Mucopolysaccharidosis type I (MPS-I) is a hereditary lysosomal storage disorder caused by deficiency in the lysosomal enzyme α-L-iduronidase (IDUA) leading to pathogenic over-accumulation of glycosaminoglycans (GAGs), major constituent of connective tissue and mediators of cell signaling. We tested the therapeutic efficacy of the autolysosomal activator GHF201 in the Idua -/- mouse model of MPS-I. We show that GHF201 reduced GAGs and increased cathepsin activity in Idua -/- mouse embryonic fibroblasts (MEFs) and brain cells. In vivo GHF201 improved aberrant locomotion and behavior, reduced interstitial cathepsins in joints and liver, increased systemic catabolism, corrected bone dysplasia, increased autophagic flux, and ameliorated CNS neurodegeneration and neuroinflammation. GHF201 also reduced brain N-glycans, which are degraded in lysosomes. In conclusion, the lysosomal and autophagic activator GHF201 was demonstrated to improve various pathophysiological parameters in MPS-I-modeling Idua -/- female mice. Our results suggest that GHF201 can complement the inadequate Aldurazyme enzyme replacement therapy as an add-on therapy.

DOI: https://doi.org/10.26508/lsa.202603750
Front Chem. 2026 ;14 1891677

Lysosomes as chemical and metabolic organizers of central nervous system injury and repair.

Tengfei Zhao, Hanxu Huang, Yifan Wang, Yuliang Zhong, Zhiwei Zhong, Deting Xue, Wei Zhu, Kan Xu.

  Lysosomes are degradative, metabolic and signaling organelles in central nervous system (CNS) cells and play essential roles in neural homeostasis, injury responses and disease progression. Changes in lysosomal function are required for neurons, microglia, astrocytes and oligodendrocyte-lineage cells to adapt to proteotoxic stress, lipid overload, mitochondrial damage and inflammatory stimulation. Therefore, lysosomal activity in the CNS is regulated by diverse chemical and cellular cues, including luminal acidification, hydrolase maturation, ion transport, membrane integrity, lipid handling and transcriptional lysosome biogenesis. Here, we summarize current knowledge of lysosomal organization and function in neural cells, including lysosomal membrane signaling, vacuolar H+-ATPase (V-ATPase)-dependent acidification, ion and redox regulation, lysosomal membrane quality control, and metabolic recycling of proteins, lipids, glycans and damaged organelles. We then survey pathological lysosomal remodeling in spinal cord injury, traumatic brain injury, Alzheimer's disease, Parkinson's disease and related neurological disorders. Across these conditions, lysosomal remodeling may initially support cargo clearance and stress adaptation, but becomes maladaptive when degradative capacity, membrane repair or lipid-processing ability fails to meet cellular demand. Finally, we discuss lysosome-oriented therapeutic strategies for neural repair, including restoration of lysosomal acidification and hydrolase activity, transcription factor EB/transcription factor E3 (TFEB/TFE3)-mediated lysosomal biogenesis, regulation of lysosomal ion channels, enhancement of myelin lipid turnover, and lysosome-responsive nanomedicine. This Review highlights lysosomes as active organizers of CNS injury and repair rather than passive endpoints of degradation.

Keywords:  central nervous system; lysosome; metabolism; neural repair; neuroinflammation

DOI:  https://doi.org/10.3389/fchem.2026.1891677
Front Neurosci. 2026 ;20 1941231

One organelle to rule them all: enhancement of lysosomal activity as a therapeutic modality for protein misfolding neurodegenerative diseases.

Robert C C Mercer.

  Protein misfolding neurodegenerative diseases are invariably fatal conditions with a paucity of available and universally embraced disease modifying therapies. It is crucial, therefore, to identify additional potential candidate molecules and/or targets with which to work toward human trials. In this mini-review, I will highlight the recent discoveries of compounds that physically associate with the lysosome to enhance or restore its activity. One potential target for the development of additional therapeutics that emerges from the consideration of these molecules is the proton pump responsible for acidification of the lysosomal lumen, the vacuolar H+-ATPase. While the approach of directly targeting lysosomal activity remains experimental at present, the wealth of evidence pointing to the involvement of the endolysosomal-autophagic system across protein misfolding neurodegenerative diseases raises the tantalizing possibility that this therapeutic modality could have broad applicability.

Keywords:  Aβ; TDP-43; lysosome; neurodegeneration; prion; tau; therapeutics; α-synuclein

DOI:  https://doi.org/10.3389/fnins.2026.1941231
Expert Opin Drug Deliv. 2026 Oct 09.

Nanotechnology meets neurodegeneration: restoring lysosomal function with nanovectors.

Clara Haristoy, Rémi Kinet, Benjamin Dehay.

   INTRODUCTION: Neurodegenerative diseases (NDs) remain a growing burden worldwide. Characterized primarily by degeneration of neurons in the central nervous system (CNS), driven in part by pathological protein aggregates and by alterations of the autophagy-lysosomal pathway (ALP), current therapeutic strategies only mitigate the outcomes of NDs rather than their origin, highlighting the need for the development of new targeted therapies.
AREAS COVERED: CNS-targeted nanoparticles (NPs) to tackle ALP have offered promising avenues by bypassing biological barriers, reducing pathological protein aggregates, restoring lysosomal pH and activity, upregulating autophagic flux, and contributing to neuroprotection. This report summarizes recent advances in the development of CNS-Targeted nanocarriers for autophagy as a treatment for ND.
EXPERT OPINION: Restoring ALP function is a promising disease-modifying strategy for NDs, as it helps clear toxic protein aggregates. Nanotechnology offers an effective way to deliver such therapies to the brain by overcoming the blood-brain barrier, enabling targeted, multimodal, and potentially cell-specific interventions. However, key challenges remain, including late diagnosis, the need for precise cell targeting, and concerns about long-term safety and bioaccumulation. Despite these limitations, growing research interest is expected to accelerate the development and clinical translation of these approaches.

Keywords:  Autophagy; CNS; lysosomes; nanoparticles; neurodegenerative diseases; therapeutics

DOI:  https://doi.org/10.1080/17425247.2026.2748109
J Huntingtons Dis. 2026 Oct 09. 18796397261494078

Directing mutant huntingtin towards degradation: Strategies and therapeutic opportunities.

Florence Dm Wavreil, Sabine Schipper-Krom, Eric Aj Reits.

  Huntington's Disease (HD) is a progressive neurodegenerative disease that is caused by a CAG-repeat expansion in the exon 1 of the huntingtin (HTT) gene, which results in the formation of toxic mutant HTT (mHTT) exon 1 fragments with expanded polyglutamine (polyQ) stretch. These mHTT fragments are prone to misfolding and aggregation, causing cytotoxicity, particularly in the striatal neurons. The lack of disease-modifying treatments for HD emphasizes the need to develop new therapeutic strategies to prevent or reverse HD pathology. The reduction of the mHTT exon 1 fragment by facilitating its selective degradation may be a promising approach to prevent aggregation, thereby delaying or preventing the onset of HD. Since the ubiquitin-proteasome system (UPS) is not impaired in HD, enabling strategies to selectively target mHTT towards the UPS or autophagy would improve mHTT clearance. In this review, we describe three main strategies to modulate mHTT levels. First, we discuss different ubiquitin-modifying enzymes that have been associated with HTT and may act as possible therapeutic targets. Next, we focus on more targeted approaches for the selective degradation of mHTT with engineered small molecule compounds such as PROTACs and AUTOTACs. Finally, we summarize the current knowledge of HTT-specific intracellular antibodies (intrabodies) as potential candidates for gene therapy. Together, this review aims to assess different possible avenues for the treatment of HD.

Keywords:  autophagy; huntingtin; intrabodies; proteasome; proteostasis; small molecule compounds

DOI:  https://doi.org/10.1177/18796397261494078
PLoS Genet. 2026 Oct 08. 22(10): e1012330

Chromatin stability safeguards mitochondrial homeostasis and restrains TORC1 signaling.

Vinoth Sigamani, Mohd Yousuf, Daniel L Johnson, Brian D Strahl, R Nicholas Laribee.

Chromatin is dynamically regulated in response to nutrient flux to promote the transcriptional changes needed for adaptation. The mechanistic target of rapamycin complex 1 (yeast TORC1) kinase integrates nutrient signaling with chromatin regulation, yet whether chromatin signals back to regulate TORC1 remains unclear. We find that a histone H3 lysine 37 to alanine (H3K37A) mutant predicted to disrupt a histone-DNA contact promotes histone degradation, hyperactivates TORC1, and causes cytotoxicity upon TORC1 inhibition. This cytotoxicity is specific to H3K37A, since chromatin instability in wild-type histone H3 (H3WT) cells reduces histone abundance and hyperactivates TORC1 without cytotoxicity upon TORC1 inhibition. Combining H3K37A with these chromatin stability mutants exacerbates histone loss, TORC1 hyperactivity, and lethality during TORC1 inhibition. Transcriptome analysis indicates H3K37A deregulates mitochondrial retrograde signaling, which is exacerbated upon TORC1 inhibition and becomes cytotoxic due in part to defective mitochondrial import of an OXPHOS subunit. Retrograde inactivation, or neutralization of reactive oxygen species (ROS) prevents this toxicity. These findings identify chromatin stability as an upstream restraint on TORC1 signaling, revealing bidirectional communication between chromatin and a major nutrient-responsive pathway. They further show H3K37 has an additional functionality that prevents mitochondrial dysregulation during metabolic stress adaptation.

DOI: https://doi.org/10.1371/journal.pgen.1012330
J Neurochem. 2026 Oct;170(10): e70565

Synaptic Proteostasis in Health and Disease.

Paul G Donlin-Asp, Emma L Clayton.

  Neurons rely on tightly coordinated mechanisms of protein synthesis and degradation to maintain cellular homeostasis, a process known as proteostasis. Given their highly polarised and compartmentalised nature, regulation of proteostasis is especially important at neuronal synapses, which are spatially distant from the soma yet require rapid on-demand adaptation of the synaptic proteome. Neurons meet their demand for synaptic proteostasis through localised mRNA transport and translation, alongside specialised pathways for protein degradation. Recent advances reveal that thousands of transcripts localise to distal neuronal compartments and that their distribution may be shaped by RNA stability, RNA dynamics, and organelle-hitchhiking transport mechanisms. In parallel, processes such as synaptic autophagy and endolysosomal trafficking are crucial for maintaining synaptic structure and neurotransmission. Disruptions in these finely balanced mechanisms are a common underlying feature of various neurological disorders, including fragile X syndrome, amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease. This overview highlights key milestones and remaining questions in synaptic proteostasis, focusing on how local protein synthesis and degradation work together to preserve synaptic integrity and how their dysregulation can lead to disease.

Keywords:  autophagy; local translation; neurodegenerative disease; neurodevelopmental disease; proteostasis; synapse

DOI:  https://doi.org/10.1111/jnc.70565
Autophagy. 2026 Oct 09.

Live visualization of dynamic autophagy processes in LC3 reporter mice using enhanced two-photon microscopy.

Saeed Bohlooli Darian, Jeongmin Oh, Chan-Gi Pack, Jun Ki Kim.

  We developed a computationally enhanced intravital imaging framework for high-resolution analysis of macroautophagy/autophagy dynamics in vivo. By integrating two-photon microscopy with an optimized tissue stabilization method, motion artifacts were minimized, enabling real-time imaging of LC3-positive structures in the liver and skeletal muscle under physiological stress conditions, including starvation, ischemia, and ethanol exposure. Image quality was further improved using a trained denoising model and enhanced Super-Resolution Radial Fluctuations (eSRRF), enabling nanoscale visualization of autophagy-related compartments. To differentiate increased autophagosome formation from impaired degradation, autophagic flux was assessed via chloroquine-mediated lysosomal inhibition, enabling functional interpretation beyond static structural measurements. Together, this pipeline overcomes major technical limitations of intravital imaging and provides a robust framework for integrated structural and functional investigation of autophagy and related intracellular processes in vivo.

Keywords:  Chloroquine; GFP-LC3; denoising; eSRRF; intravital microscopy; super-resolution

DOI:  https://doi.org/10.1080/15548627.2026.2746966
Front Neurosci. 2026 ;20 1913175

Differential autophagy cargo engagement in amyloid-β-induced neuronal toxicity.

Danielle Brink, Rensu Theart, Benjamin Loos.

  Neurodegenerative diseases are characterized by progressive neuronal loss and the accumulation of misfolded proteins. In Alzheimer's disease, several pathogenic protein species, including amyloid precursor protein, amyloid beta, tau, phosphorylated tau, and alpha-synuclein, are known substrates of macroautophagy. However, the extent to which macroautophagy selectively engages these proteins for degradation under conditions of proteotoxic stress remains poorly understood. Here, the contribution of specifically macroautophagy to the degradation of amyloid precursor protein, amyloid beta, tau, phosphorylated tau, and alpha-synuclein was investigated using an amyloid precursor protein overexpression model. Mouse neuroblastoma N2A cells stably expressing the human Swedish amyloid precursor protein mutation were treated with butyric acid for 24 and 48 h to produce increasing proteotoxicity and molecular pathology. Autophagic flux was assessed using bafilomycin A1 and protein abundance quantified by western blotting. Confocal microscopy and colocalization analysis was performed to examine intracellular protein localization and recruitment to the autophagy compartment. Amyloid precursor protein overexpression and autophagosome/lysosome fusion inhibition elicited distinct protein-specific responses, with phosphorylated tau showing highest accumulation and autophagic recruitment. In contrast, tau and amyloid precursor protein exhibited moderate increases, while alpha-synuclein and amyloid beta showed differential and limited responses upon macroautophagy inhibition. Collectively, these findings suggest that the autophagy molecular machinery does not engage uniformly with Alzheimer's disease-associated proteins but may be characterized by a highly differential cargo engagement under amyloid precursor protein-driven proteotoxic stress. Phosphorylated tau emerged as the earliest and most prominent protein to be target to the autophagy compartment, highlighting its potential importance in disease progression and therapeutic intervention.

Keywords:  Alzheimer's disease; amyloid; autophagy; fluorescence; neurodegenerative disease

DOI:  https://doi.org/10.3389/fnins.2026.1913175
Front Cell Dev Biol. 2026 ;14 1929128

From retina to brain: retinal dysfunction and dopaminergic neurodegeneration in Drosophila models of Parkinson's disease.

Justyna Kadłuczka, Jakub Dymek, Elżbieta Pyza, Milena Damulewicz.

  Parkinson's disease (PD) is characterized by the progressive loss of dopaminergic neurons within the substantia nigra pars compacta. Although PD is primarily defined as a motor disorder, prodromal non-motor symptoms - such as circadian clock desynchronization and sleep disturbances - can emerge years before clinical diagnosis. Increasing evidence suggests that these non-motor manifestations, particularly circadian disruption, may contribute to disease progression. However, it remains unclear whether circadian dysfunction actively drives neurodegeneration or arises as a consequence of ongoing neuronal loss. In this study, we employed genetic models of PD in Drosophila melanogaster to investigate these relationships. Specifically, we examined the effects of parkin (park) silencing and neuronal expression of human α-Synuclein on photoreceptor morphology and function. Furthermore, we assessed whether mitophagy impairment or synucleinopathy confined to the visual system can influence the onset and progression of PD-related phenotypes. Given that sleep fragmentation is a common feature in PD patients, we also analyzed sleep patterns in flies, focusing on sleep duration. In parallel, we evaluated dopaminergic neuron degeneration, with particular emphasis on the protocerebral anterior medial (PAM) cluster, which plays a critical role in the regulation of sleep and locomotor activity. Taken together, our findings highlight the importance of elucidating the interplay between retinal cells disruption and neurodegeneration in deeper parts of the brain in Parkinson's disease.

Keywords:  Drosophila melanogaster; dopaminergic (DA) neuron; parkin; retina; synuclein alpha (SNCA)

DOI:  https://doi.org/10.3389/fcell.2026.1929128
Metallomics. 2026 Oct 07. pii: mfag030. [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. We developed a method to analyze isolated lysosomes by X-ray Fluorescence Microscopy; zinc, copper, and manganese are detectable in the lumen of lysosomes, and the concentration of zinc in the lysosomes increased substantially in worms exposed to excess dietary zinc. 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 both zinc and copper. Furthermore, lysosome remodeling characterized by an increase in volume of the expansion compartment is not specific to excess zinc but is a more general phenomenon during metal storage in lysosomes.

DOI: https://doi.org/10.1093/mtomcs/mfag030
Cell Rep. 2026 Oct 07. pii: S2211-1247(26)01186-1. [Epub ahead of print]45(10): 118107

Mitochondrial transfer protects against cisplatin-induced hearing loss by fumarate-mediated activation of mitophagy.

Yunhao Wu, Yunhui Gu, Yukai Wang, Rui Li, Weiwei Shi, Jiaxin Liu, Changjie Lai, Xinyu Wang, Jie Tang, Donghui Pan, Yi Zhang, Ning Wei, Yiwen Zheng, Jing Wang, Min Yang, Xiaolong Fu, Renjie Chai, Guangji Wang, Yunlong Shan.

  Sensorineural hearing loss (SNHL) affects millions of individuals worldwide, with platinum-based chemotherapeutics identified as a significant cause. In this study, we elucidate the mechanism by which mitochondrial transfer from mesenchymal stem/stromal cells (MSCs) protects against cisplatin-induced cochlear injury in a mouse model. Systemically administered MSCs home to the cochlea and transfer mitochondria to damaged spiral ganglion neurons (SGNs) via tunneling nanotubes, leading to elevated intracellular levels of the Krebs cycle intermediate fumarate, which activates mitophagy to eliminate dysfunctional mitochondria. Mechanistically, dimethyl fumarate (DMF)-a clinically available fumarate derivative-covalently modifies the phosphatase PPP1CB at cysteine 126, thereby blocking PPP1CB-mediated dephosphorylation of mitofusin 2 (MFN2), which in turn enhances mitophagy and ultimately preserves auditory function. These findings reveal that MSCs orchestrate mitochondrial replacement in damaged SGNs by delivering healthy mitochondria and facilitating the removal of impaired ones, underscoring the therapeutic potential of this strategy for treating SNHL related to mitochondrial dysfunction.

Keywords:  CP: cell biology; PPP1CB; dimethyl fumarate; mesenchymal stem/stromal cells; sensorineural hearing loss; spiral ganglion neurons

DOI:  https://doi.org/10.1016/j.celrep.2026.118107
Physiol Rep. 2026 Oct;14(19): e71128

Adding Tat-Beclin1 to an endurance training program promotes additive improvements in physical function in aged male mice.

Thuan Thien Tchen, Shakibur Rahman, Thaysa Ghiarone, Lynn A Spruce, Hossein Fazelinia, Elizabeth M Brown, Charalampos Papachristou, Sue C Bodine, Vitor A Lira, Kleiton A S Silva.

  Autophagy is a hallmark of aging, but it has not been exclusively targeted to attenuate aging-related physical dysfunction. Here, we combined Tat-Beclin1 and endurance training to determine its effect on physical function domains in aged male mice. Mice were randomly divided into Control (N = 5), Tat-Beclin1 (TB, 15 mg/kg, 2×/week, N = 9), Exercise (Exe, 70%-maximal-running-speed, 3×/week, N = 9), and TB+Exe (N = 8) for 1 month in 23-month-old male C57BL/6J mice. Animals were assessed for grip strength (GS), endurance capacity (EC) on a treadmill, and balance and coordination on a rotarod. Gastrocnemius/plantaris (G/P) and tibialis anterior muscles were harvested for western blotting, myofiber typing, and proteomic profiling (G/P only). Although no significant interaction was observed, the TB+Exe group showed improvements in GS, EC, and balance and coordination performance, an outcome comparable with additive effects of both therapies. Limited changes were observed in myofiber typing and autophagy markers among groups. A proteomic analysis revealed that TB upregulated biological processes involved in muscle contraction, whereas TB+Exe surprisingly upregulated acute inflammatory responses, including proteins such as haptoglobin and orosomucoid-1. Altogether, combining TB and endurance training elicits additive effects on physical functions of aged male mice and may represent a new approach to attenuate aging-related physical dysfunction.

Keywords:  Tat‐Beclin1; autophagy; exercise; physical function; proteomics

DOI:  https://doi.org/10.14814/phy2.71128