bims-auttor 2026-08-23 papers

bims-auttor

Biomed News

on Autophagy and mTOR

Issue of 2026–08–23
twenty-two papers selected by
Viktor Korolchuk, Newcastle University

Substrate-specific regulation of the mTORC1 pathway by G protein-coupled receptors.
The methyltransferase Rrp8 is a positive regulator of autophagy flux in Saccharomyces cerevisiae.
Inhibiting Wnt/β-catenin-mTOR signaling enhances autophagy and porphyrin clearance in murine porphyrias with hepatic involvement.
Protein Homeostasis and Mitochondrial Quality Control in Neurodegeneration.
A longevity-associated ubiquitin E3 ligase UBE3C governs lamin B1 homeostasis through selective autophagy and delay senescence.
Sequalae and reversal of age-dependent alterations in mitochondrial dynamics via autophagy enhancement in reprogrammed human neurons.
Autophagy and mitophagy in pancreatic β-cell homeostasis and their involvement in diabetes pathophysiology.
Exercise as a Programmable Regulator of Mitophagy Sensitivity in Aging Muscle and Age-Related Disease.
You can't say you didn't get fair warning.
Comparative analysis of neuronal proteolytic pathways reveals neuron-specific and sub-compartmental-specific capacities with aging.
Non-cell autonomous control of presynaptic remodeling by the hypothalamic autophagy-NPY axis.
Canonical and noncanonical autophagy in immunity.
Nanotechnology for targeted modulation of mitophagy: molecular mechanisms, therapeutic applications, and translational perspectives.
Loss of BECN1 does not compromise autophagosome formation but alters cargo selection and HLA-restricted antigen presentation of B cells.
Bridging LysoPD and MitoPD: Lysosomal pH Links Two Hallmarks of Parkinson's Disease.
AI-augmented discovery of autophagy regulators through mechanistic interpretation of multiomics data.
Astrocytes mobilize a broader repertoire of lysosomal repair mechanisms than neurons.
BAG6-RNF115 Couples Protein Quality Control with Ribosome Assembly.
Autophagy as a mechanistic link between physical exercise and Alzheimer's disease.
ER-liquid condensate contacts sequester FAM134B/C and RhoA to govern cell morphology.
A combined artificial intelligence-wet lab approach identifies a pivotal role of the NAD+-mitophagy axis on aging and neurodegeneration.
Puerarin extends lifespan and enhances the resistance to oxidative stress through AMPK/TFEB mediated autophagy in Caenorhabditis elegans.

Biochem J. 2026 Aug 19. pii: BCJ20260165. [Epub ahead of print]

Substrate-specific regulation of the mTORC1 pathway by G protein-coupled receptors.

Samuel J Atkinson, Florentina Negoita, Yuichiro Ioi, William Vincent Ritchie, Kyle Thompson, Max Gardner, Peter T Ashdown, Kristina Hellberg, Terunao Takahara, Kei Sakamoto, Dawn Thompson, James N Hislop, Riko Hatakeyama.

  The mammalian/mechanistic Target of Rapamycin Complex 1 (mTORC1) orchestrates cell growth and metabolism in response to diverse extracellular and intracellular cues. mTORC1 phosphorylates a broad range of substrates, each of which plays important physiological roles. Emerging evidence suggests that mTORC1 can respond to upstream signals in a nuanced manner, enabling differential regulation of individual substrates and, consequently, specific downstream biological processes. Phosphorylation of non-canonical mTORC1 substrates, such as the lysosome biogenesis regulator transcription factor EB (TFEB), can be regulated independently of phosphorylation of canonical substrates. However, the nature of signals that determine the signaling selectivity of mTORC1 remains incompletely understood. Here, we studied mTORC1 regulation by G protein-coupled receptors (GPCRs). We found that phosphorylation of TFEB responds to GPCRs differently, compared to canonical mTORC1 substrates controlling protein synthesis such as S6K1 and 4EBP1. In particular, the muscarinic acetylcholine receptor M5 (M5R) promoted phosphorylation of S6K1 and 4EBP1, while triggering TFEB dephosphorylation. Consequently, M5R stimulated protein synthesis without inhibiting lysosome biogenesis. mTORC1 can thus separately regulate anabolic and catabolic processes under the control of M5R. This study highlights the importance of reassessing the effects of GPCRs on mTORC1 by concurrently monitoring individual substrates, a critical consideration to be made when evaluating GPCR ligands as therapeutic agents targeting the mTORC1 pathway.

Keywords:  G protein-coupled receptor (GPCR); mammalian/mechanistic Target of Rapamycin Complex 1 (mTORC1); muscarinic acetylcholine receptor M5 (M5R)

DOI:  https://doi.org/10.1042/BCJ20260165
MicroPubl Biol. 2026 ;2026

The methyltransferase Rrp8 is a positive regulator of autophagy flux in Saccharomyces cerevisiae.

Swaroopa Badenahalli Narasimhaiah, Elizabeth Delorme-Axford.

Macroautophagy (hereafter referred to as autophagy) is a dynamic pathway of cellular degradation and recycling that is conserved from yeast to humans. The products of autophagic degradation may be used for anabolic reactions during nutrient-limited conditions. Thus, autophagy serves both metabolic and quality control functions. However, the role of nucleolar proteins in autophagy remains largely unexplored. Here we identify Ribosomal RNA processing 8 (Rrp8) as a positive regulator of autophagy flux in the yeast Saccharomyces cerevisiae. Our work provides insight into the role of the conserved nucleolar protein Rrp8 in regulating cellular responses to starvation.

DOI: https://doi.org/10.17912/micropub.biology.002252
Autophagy. 2026 Aug 19. 1-22

Inhibiting Wnt/β-catenin-mTOR signaling enhances autophagy and porphyrin clearance in murine porphyrias with hepatic involvement.

Oluwashanu Balogun, Pamela Cornuet, Elizabeth Lee, Garima Patel, Abdul-Shahid Raheem, Junjie Zhu, Amber Marie Vandevender, Anila P Ashokan, Raheleh Nasrollahi, Raymond E West, Octavia Peck Palmer, Jia-Jun Liu, Thomas D Nolin, Claudette St Croix, Xiaochao Ma, Grant Bullock, Silvia Liu, Satdarshan P Monga, Donna Beer Stolz, Michael Jurczak, M Bishr Omary, Kari Nejak-Bowen.

  Porphyrias are rare metabolic disorders arising from defects in heme biosynthesis, leading to accumulation of toxic porphyrin intermediates, mitochondrial dysfunction, and liver injury. Current therapies are limited in efficacy, emphasizing the need for novel treatments. Prior studies showed hepatocyte-specific β-catenin deletion attenuates porphyrin accumulation and liver injury in 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-induced porphyria. We hypothesized that inhibiting components of the Wnt-β-catenin-glutamine synthesis (GS) pathway reduces heme synthesis and also enhances porphyrin clearance by activating autophagy and improving mitochondrial quality control. We combined pharmacologic Wnt inhibition and hepatocyte-specific GS deletion in murine models of porphyria. Readouts included spatial transcriptomics, targeted metabolomics, immunohistochemistry, confocal mt-Keima imaging, high-resolution respirometry, and transmission electron microscopy. Human liver biopsies and explants from porphyria patients were also examined by dual-label immunohistochemistry. Wnt inhibition during DDC suppressed upregulation of heme biosynthesis genes, reduced porphyrin intermediate accumulation, and enhanced autophagic flux. GS deletion attenuated porphyrin biosynthesis by limiting intracellular glutamine. Wnt and GS deletion produced additive increases in autophagy, restored zonation, and further reduced porphyrin accumulation. Wnt inhibition restored mitophagy, whereas GS deletion primarily improved mitochondrial coupling efficiency. Wnt inhibition also decreased fibrosis in a genetic mouse model of porphyria. Patient samples mirrored murine findings, with heme enzymes and autophagy inversely correlated with β-catenin expression in porphyria cutanea tarda. By disrupting Wnt-GS signaling, we establish a link between increased autophagy, reduced porphyrin formation, and heme pathway regulation in mouse and human liver. These findings identify the Wnt signaling pathway as a potential therapeutic target in porphyria.Abbreviations: ALA: δ-Aminolevulinic acid; AIP: acute intermittent porphyria; ALAS: aminolevulinic acid synthase; ALAD: aminolevulinic acid dehydratase; ALP: alkaline phosphatase: AST: aspartate aminotransferase; ALT: alanine aminotransferase; DAB: 3,3'-diaminobenzidine; DDC: 3,5-diethoxycarbonyl-1,4-dihydrocollidine; EPP: erythropoietic protoporphyria; Fech: ferrochelatase; GAPDH: glyceraldehyde 3-phosphate dehydrogenase; GS: glutamine synthesis; H&E: hematoxylin and eosin: HO-1: heme oxygenase 1; IHC: immunohistochemistry; KO: knockout; LAMP1: lysosomal associated membrane protein 1; LC3: microtubule-associated protein 1 A/1B-light chain 3; mTOR: mechanistic target of rapamycin; PBG: porphobilinogen; PBS: phosphate-buffered saline; PP-IX: protoporphyrin-IX; PCT: porphyria cutanea tarda; RCR: respiratory control ratio; SQSTM1/p62: sequestosome 1; TEM: transmission electron microscopy; Wnt-I: Wnt-C59 (inhibitor).

Keywords:  Glutamine synthetase; heme biosynthesis; hepatic zonation; macroautophagy; mechanistic target of rapamycin (mTOR); mitophagy

DOI:  https://doi.org/10.1080/15548627.2026.2716960
WIREs Mech Dis. 2026 Jul-Aug;18(4):18(4): e70014

Protein Homeostasis and Mitochondrial Quality Control in Neurodegeneration.

Rosa Di Lorenzo, Rola S Zeidan, Riccardo Calvani, Vito Pesce, Emanuele Marzetti, Anna Picca.

Quality control (QC) processes include a network of cellular pathways that prevent the accumulation of toxic aggregates by repairing, recycling, and/or eliminating defective components, including mitochondria. Among these pathways are the proteostasis network, which regulates the proteome, and mitochondrial quality control (MQC) mechanisms, which maintain mitochondrial number and integrity. QC relies on a hierarchically and spatially integrated regulatory axis rather than individual parallel units. Such systems coordinate mitochondrial biogenesis, dynamics, and autophagic recycling with proteostasis to ensure the maintenance of high-quality mitochondria and bioenergetically efficient cells. Neurons, post-mitotic cells with high energy demands, depend heavily on these mechanisms and on the spatial coordination of MQC. Here, we discuss how failure of this integrated QC axis, rather than dysfunction of its individual components alone, can drive neuronal decline and contribute to the neurodegeneration.

DOI: https://doi.org/10.1002/wsbm.70014
bioRxiv. 2026 Aug 06. pii: 2026.08.05.741138. [Epub ahead of print]

A longevity-associated ubiquitin E3 ligase UBE3C governs lamin B1 homeostasis through selective autophagy and delay senescence.

Di Guan, Seungsoo Kim, Karim Omar, Ying Hao, Gordon Huang, HyeRim Han, Jiping Yang, Naftali Horwitz, Phuong-Anh Dinh, Jihyun Hwang, Haiyuan Yu, Yousin Suh.

Nuclear lamina integrity is fundamental to cellular homeostasis across the lifespan 1 , and its progressive deterioration is closely linked to human aging 2 . Yet, the regulatory mechanism that govern this decline and how they might be counteracted in long-lived individuals remain poorly defined. Here, by combining whole-exome sequencing of Ashkenazi Jewish centenarians with GTEx transcriptomes, we identify ubiquitin E3 ligase UBE3C strongly associated with exceptional longevity and progressively declines with age across human tissues. UBE3C knockdown triggers premature senescence and destabilizes key nuclear lamina components Lamin B1 (LMNB1) and Lamin B receptor (LBR), while the longevity-associated UBE3C variant delays senescence and preserves LMNB1/LBR expression. Mechanistically, UBE3C interacts directly with LMNB1/LBR and modulates their abundance via selective autophagy. Notably, we uncover the ER- resident autophagy trigger CKAP4 3 bridges UBE3C and LMNB1. UBE3C loss enhances LMNB1-CKAP4 binding, linking nuclear lamina turnover to autophagy. Together, our findings establish UBE3C as a central guardian of nuclear lamina maintenance during senescence and offering novel insights into interventions against age-related nuclear lamina deterioration.

DOI: https://doi.org/10.64898/2026.08.05.741138
Autophagy. 2026 Aug 16.

Sequalae and reversal of age-dependent alterations in mitochondrial dynamics via autophagy enhancement in reprogrammed human neurons.

Eva Klinman, Ji-Sun Kwon, Roland E Dolle, Stephen C Pak, Gary A Silverman, David H Perlmutter, Andrew S Yoo.

  How aging of human neurons affects dynamics of essential organelle such as mitochondria and autophagosomes remains largely unknown. MicroRNA-induced directly reprogrammed neurons (miNs) derived from adult fibroblasts retain age-associated signatures of the donor, enabling the study of age-dependent features in human neurons, including longitudinal isogenic samples. Transcriptomic analysis revealed that neurons derived from elderly individuals are characterized by gene expression changes associated with the regulation of autophagosomes, lysosomes, and mitochondria, compared to young counterparts. To clarify these changes at the cellular level, we performed live-cell imaging of cellular organelles in miNs from donors of different ages. Older donor miNs exhibit decreased mitochondrial membrane potential, which surprisingly co-occurs with a significant increase in mitochondrial fission and fusion events. We posit that the increased fission and fusion of mitochondria may reflect age-dependent compensation for impaired mitochondrial turnover, perhaps due to changes in macroautophagy/autophagy. We subsequently identified a significant decrease in autophagosome acidification in neurons derived from individuals > 65 years compared to younger donors, and a corresponding age-dependent reduction in neuritic lysosomes resulting in fewer lysosomes available to acidify autophagosomes. This age-dependent deficit in autolysosome flux was rescued by promoting autophagosome generation through TFEB, which also reversed the age-dependent increase in mitochondrial fission and fusion and improved mitochondrial health. Partial organelle recovery occurred after inducing mitophagy or inhibiting mitochondrial fission. Together, this work reveals a mechanism by which aging reduces autophagic flux secondary to a loss of neuritic lysosomes, resulting in mitochondria-intrinsic mechanisms to avoid loss of energy production.

Keywords:  Aging; TFEB; autolysosome; dynamics; live-cell; longitudinal; mitochondria; mitophagy; neuronal

DOI:  https://doi.org/10.1080/15548627.2026.2719435
FEBS Lett. 2026 Aug 19.

Autophagy and mitophagy in pancreatic β-cell homeostasis and their involvement in diabetes pathophysiology.

Yunkyeong Lee, Mingming Tong, Anna L Gloyn.

  Autophagy is an evolutionarily conserved cellular quality control pathway that responds to the metabolic state of the cell, and its dysregulation has been broadly associated with metabolic disorders like diabetes mellitus. Among different types of autophagy, mitophagy or the selective autophagic clearance of dysfunctional mitochondria has emerged as particularly relevant in pancreatic β-cell biology and its pathophysiology. Recent advances in functional genomics and animal studies implicate the autophagy/mitophagy pathway components as effector transcripts at diabetes risk loci, providing a new rationale for investigation of genetic determinants of autophagy/mitophagy in β cells. In this review, we take a β-cell centric perspective to examine the evidence for autophagy/mitophagy across four clinically relevant diabetes categories (type 1, type 2, gestational, and monogenic diabetes) and discuss the functional significance and complexity of these pathways in β-cell failure.

Keywords:  autophagy; diabetes; genetics; mitophagy; β‐cell

DOI:  https://doi.org/10.1002/1873-3468.70436
IUBMB Life. 2026 Aug;78(8): e70127

Exercise as a Programmable Regulator of Mitophagy Sensitivity in Aging Muscle and Age-Related Disease.

Peng Ran, Lifang Yang.

  Aging is increasingly recognized as a systems-level process marked by progressive deterioration of mitochondrial performance in tissues with high energetic demand, placing skeletal muscle at the center of systemic metabolic and functional decline. Beyond its mechanical role, skeletal muscle acts as a regulatory hub for energy homeostasis, redox balance, and inter-organ signaling, functions that depend critically on effective mitochondrial quality control. Emerging evidence indicates that age-related mitochondrial dysfunction arises not only from impaired biogenesis but also from dysregulated mitophagy, the selective autophagic removal of damaged mitochondria. Mitophagy is now understood as a dynamic, context-sensitive process integrating metabolic state, mechanical loading, and cellular stress, rather than a binary response to severe mitochondrial damage. Exercise represents a uniquely potent, non-pharmacological modulator of this process. By transiently perturbing cellular energy balance, calcium flux, and redox signaling, physical activity activates coordinated mitophagic and biogenic programs that promote mitochondrial renewal without precipitating energetic collapse. In contrast to chronic pathological stressors, exercise induces pulsatile, recoverable mitochondrial challenges that recalibrate quality-control thresholds. Importantly, mitophagic responses to exercise are heterogeneous and nonlinear. Exercise modality, intensity, frequency, and temporal organization generate distinct mitochondrial signals, producing fiber-type-specific and age-dependent adaptations. In aging muscle, elevated activation thresholds, delayed clearance kinetics, and lysosomal constraints frequently blunt adaptive mitophagy, indicating remodeling rather than a simple suppression of quality-control logic. This review integrates molecular, physiological, and translational evidence to redefine exercise as a precision regulator of mitophagy in aging skeletal muscle. This review proposes that tailored exercise strategies targeting mitophagy may provide a scalable, non-pharmacological approach to preserve mitochondrial quality and functional resilience during aging.

Keywords:  aging; exercise; healthspan; mitochondrial quality control; mitophagy; skeletal muscle

DOI:  https://doi.org/10.1002/iub.70127
Autophagy. 2026 Sep;22(9): 2057-2058

You can't say you didn't get fair warning.

Daniel J Klionsky, Nicholas Ktistakis.

The journal Autophagy is now in its twenty-second year. Unlike many, perhaps most, other journals we have instituted various requirements to help ensure scientific clarity and reproducibility. Two of the most important requirements are the use of standardized nomenclature and the inclusion of specific ordering information for reagents. These are not arbitrary formatting issues - there are specific reasons they are required, which we will remind you of below. The point of this editor's corner is to explain that these requirements are now going to be enforced upon manuscript submission.

DOI: https://doi.org/10.1080/15548627.2026.2692832
Cell Mol Life Sci. 2026 Aug 13. pii: 308. [Epub ahead of print]83(1):

Comparative analysis of neuronal proteolytic pathways reveals neuron-specific and sub-compartmental-specific capacities with aging.

Mira Sleiman, Dimitra Ranti, Sudarson Baskaran, Patricia Kreis, Saskia Muth, Christian Gallrein, Agnieszka Münster-Wandowski, Norman Rahnis, Emilio Cirri, Britta J Eickholt, Janine Kirstein.

  Proteostasis is essential for maintaining neuronal function, and its dysregulation is a hallmark of aging and neurodegeneration. The ubiquitin-proteasome system (UPS) and macroautophagy are the two major proteolytic pathways responsible for protein degradation. However, their capacity and regulation differ between cell types and across aging. To elucidate the activity of both proteolytic pathways with aging, we performed a comparative analysis of the activity of UPS and macroautophagy in distinct neuronal subcellular compartments, in the soma and at synaptic terminals, across aging in neurons of Mus musculus (mouse) and Caenorhabditis elegans (nematode). In mice, our results identified differences between brain areas. While the cortical proteasomal activity declined with aging in both the somatic as well as synaptic-enriched neuronal subcompartments, the cerebellar proteasomal activity decreased only in the somatic-enriched compartments with aging. In C. elegans, we detected a decrease of proteasomal activity in both somatic and synaptic compartments of neurons. Interestingly, we observed an age-dependent change in several markers of autophagy in different fractions and brain areas of mice and a reduction of autophagosomes and autolysosomes with aging in C. elegans. Thus, we uncovered neuron-specific and subcompartmental-specific proteolytic capacities with aging that could manifest in different neuronal vulnerabilities for proteotoxic challenges with aging.

Keywords:  Aging; Autophagy; Neuron; Proteasome; Protein turnover; Synaptosome

DOI:  https://doi.org/10.1007/s00018-026-06383-y
Autophagy. 2026 Aug 17.

Non-cell autonomous control of presynaptic remodeling by the hypothalamic autophagy-NPY axis.

Giovanna Cazzolla, David Toppe, Gina Krause, Gaga Kochlamazashvili, Janine Lützkendorf, Ina M Schedina, Heike Stephanowitz, Anna Maria Reisenbichler, Xingxiang Chen, Yannic Kerkhoff, Eric Reifenstein, Helen M Ernst, Max von Kleist, Andreas Zimmermann, Tobias Eisenberg, Frank Madeo, Fan Liu, Herbert Herzog, Anne Albrecht, Dietmar Schmitz, Volker Haucke, Stephan J Sigrist, Marta Maglione.

  Macroautophagy/autophagy is a critical cellular degradation pathway essential for neuronal proteostasis and synaptic function. Its decline with aging is associated with synaptic dysfunction and reduced circuit resilience. NPY (neuropeptide Y), a highly abundant brain neuropeptide, has emerged as an important regulator of autophagy and aging-related processes. In Drosophila, the NPY-family peptide sNPF modulates age-related changes in presynaptic architecture via non-cell autonomous mechanisms. Here, we examined whether autophagy and NPY interact within hypothalamic NPY+ AGRP+ neurons to regulate presynaptic organization in distant brain regions. We show that autophagy in these neurons non-cell autonomously controls hippocampal presynaptic active zone architecture and proteostasis, while maintaining NPY peptide levels. Importantly, dietary supplementation of the natural polyamine spermidine restored NPY expression in the aged hippocampus, highlighting its potential to rejuvenate neuropeptide signaling. Together, these findings reveal a pathway by which hypothalamic autophagy and NPY signaling regulate hippocampal synaptic architecture, linking metabolic state to synaptic resilience.

Keywords:  AGRP; ATG5; Active zone; aging; hippocampus; mossy fiber; presynapse

DOI:  https://doi.org/10.1080/15548627.2026.2719429
Immunity. 2026 Aug 17. pii: S1074-7613(26)00316-X. [Epub ahead of print]

Canonical and noncanonical autophagy in immunity.

Vojo Deretic.

  Canonical and noncanonical autophagic processes are integrated with innate and adaptive immunity and sterile or pathogen-induced inflammation. In canonical autophagy, double-membrane autophagosomes modified by ubiquitin-like ATG8 proteins in a process termed membrane atg8ylation sequester and eliminate intracellular targets such as invading microbes, defunct organelles, aggregates, and inflammatory molecules. Recently, a plethora of noncanonical processes that entail membrane atg8ylation of various intracellular organelles other than autophagosomes have been linked to immunity. This has led to confounding interpretations and conflation of diverse processes as autophagy. Here, we posit that these are divergent manifestations of a common ancestral homeostatic process of membrane atg8ylation and provide an overview of how they affect immunity and inflammation. These relationships are evident in model organisms and are reflected in human genetic predispositions to diseases with immune components. The membrane atg8ylation pathways affect acute and chronic inflammation, infections, autoimmunity, cancer, neurodegeneration, metabolic syndrome, diabetes, and other disorders.

Keywords:  autophagy; immunity; infection; membrane atg8ylation

DOI:  https://doi.org/10.1016/j.immuni.2026.07.017
Biomed Mater. 2026 Aug 18. 21(4):

Nanotechnology for targeted modulation of mitophagy: molecular mechanisms, therapeutic applications, and translational perspectives.

Jiaenli Bolati, Junjie Yang, Yueqi Yan, Donghua Yu, Chunmiao Yu.

  Mitophagy is a selective autophagic process responsible for the elimination of damaged or dysfunctional mitochondria, playing a critical role in maintaining mitochondrial quality control and cellular homeostasis. Dysregulated mitophagy has been implicated in the pathogenesis of numerous diseases, including neurodegenerative diseases, cancer, cardiovascular diseases, metabolic disorders, inflammatory and immune diseases, and musculoskeletal diseases. In recent years, nanotechnology-based approaches for the targeted modulation of mitophagy have emerged as promising therapeutic strategies due to their ability to achieve precise regulation, enhanced subcellular targeting, and reduced off-target effects. Building upon advances in the understanding of mitophagy mechanisms, a variety of nano-delivery systems have been developed, incorporating strategies such as mitochondria-targeting, stimuli-responsive activation, ligand-mediated targeting, and combination therapies. However, a comprehensive review integrating the molecular mechanisms of mitophagy, disease-specific therapeutic applications, nanoplatform design strategies, and translational challenges remains lacking. The present review provides an integrated overview of the molecular regulatory mechanisms of mitophagy, summarizes recent advances in nanotechnology-based therapeutic interventions across multiple disease types, and critically discusses current nanoplatform design strategies. Furthermore, key challenges associated with mitophagy evaluation, biosafety, pharmacokinetics, clinical translation, and regulatory considerations are highlighted, together with emerging technologies that may accelerate the development of next-generation mitophagy-targeting nanomedicines.

Keywords:  mitochrial dysfunction; mitophagy; nanotechnology; targeted delivery; therapeutic strategies

DOI:  https://doi.org/10.1088/1748-605X/ae95c8
Autophagy. 2026 Aug 21.

Loss of BECN1 does not compromise autophagosome formation but alters cargo selection and HLA-restricted antigen presentation of B cells.

Svenja L Walter, Felix Baur Lermer, Sophie Buchser, Sibilla Sander, Kennith Brian Castelino, Marcel Wacker, Eanna Fennell, Lisa Rieble, Saskia von Boxberg, Sandra Schmid, Christopher A Hess, Laure-Anne Ligeon, Juliane Walz, Muriel Mari, Fulvio Reggiori, Jörn Dengjel, Christian Münz.

  BECN1 (beclin 1) is a member of the nucleation complex and considered crucial for induction of macroautophagy/autophagy, leading to the formation and ultimate degradation of autophagosomes. We found that in human B lymphoblastoid cell lines (LCLs) deficient of BECN1 (BECN1-KO), autophagosome formation was intact and autophagic flux could be induced upon nutrient starvation or MTOR inhibition. Remarkably, autophagosomal cargo differed significantly between BECN1-KO and control (CTRL) LCLs, revealing a preferred formation of autophagosomes at the endoplasmic reticulum (ER) and not at endosomes/lysosomes in BECN1-KO LCLs. Endosomal TLR3 (toll like receptor 3) was less frequently incorporated within autophagosomes in BECN1-KO LCLs. Additionally, several proteins of the ER-resident peptide loading complex for MHC class I antigen presentation were found enriched in autophagosomes from BECN1-KO LCLs, resulting in a diminished detection of BECN1-KO LCLs by T cells. Hence, BECN1 seems to be dispensable for autophagosome formation but rather contributes to cargo selection of phagophores and immunosurveillance.

Keywords:  B cells; Beclin-1; CD8+ T cells; MHC class I; peptide loading complex

DOI:  https://doi.org/10.1080/15548627.2026.2719432
Mov Disord. 2026 Aug 18.

Bridging LysoPD and MitoPD: Lysosomal pH Links Two Hallmarks of Parkinson's Disease.

Hari Prasad.



Keywords:  GBA1; Parkinson's disease; lysosomal pH; mitochondrial dysfunction; mitophagy

DOI:  https://doi.org/10.1002/mds.70492
Autophagy. 2026 Aug 21.

AI-augmented discovery of autophagy regulators through mechanistic interpretation of multiomics data.

Dachao Tang, Weiduo Xia, Chi Zhang, Yu Xue, Di Peng.

  Yu Xue: xueyu@hust.edu.cn Large-scale multiomics profiling has delineated dynamic molecular landscapes during autophagy, yet translating these complex datasets into mechanistic regulatory insights remains a major challenge. In our recent work, we developed LyMOI, a hybrid artificial intelligence workflow that combines graph-based deep learning and a large language model (LLM) for mechanistic interpretation of autophagy-related omics. The graph model integrates 1.3 TB of autophagy-associated multiomics datasets and prioritizes molecules of interest (MOIs) across 34 autophagy-specific conditions, and then LLM-based chain-of-thought (CoT) reasoning generates mechanistic hypotheses to interpret their potential roles in biological contexts. Using LyMOI, we identified essential regulators, including GIN4, ELM1, RVS167 and STE50, involved in yeast autophagy induced by nutrient deprivation. Furthermore, LyMOI revealed that two cancer-associated proteins, CTSL and FAM98A, are required for maintaining autophagy activity upon disulfiram (DSF) treatment. Silencing either CTSL or FAM98A attenuated DSF-induced autophagy and inhibited cancer cell proliferation. Notably, combination treatment with DSF and Z-FY-CHO, a CTSL-specific inhibitor previously developed against SARS-CoV-2 infection, potently suppressed tumor growth. Collectively, our work presents an LLM-powered platform with biologist-like reasoning for uncovering autophagy regulatory mechanisms.

Keywords:  Autophagy; CTSL; chain-of-thought reasoning; deep learning; large language model; multiomics

DOI:  https://doi.org/10.1080/15548627.2026.2719421
iScience. 2026 Aug 21. 29(8): 116866

Astrocytes mobilize a broader repertoire of lysosomal repair mechanisms than neurons.

Erin M Smith, Natali L Chanaday, Sandra Maday.

  Lysosomal damage impairs proteostasis and contributes to neurodegenerative diseases, yet cell-type-specific differences in lysosomal repair remain unclear. Using a neuron-astrocyte coculture system, we compared responses to lysosomal injury induced by a lysosomotropic methyl ester. Both neurons and astrocytes showed lysosomal damage, marked by Galectin-3 recruitment to lumenal lysosomal β-galactosides, disrupted lysosomal pH, and engagement of lysophagy receptors TAX1BP1 and p62. However, astrocytes showed a preferential recruitment of ESCRT (endosomal sorting complex required for transport) repair machinery to damaged lysosomes. Additionally, the lysosomal membrane reformation pathway regulated by the RAB7-GTPase-activating protein (GAP), TBC1D15, was more robustly activated in astrocytes. By contrast, the phosphoinositide-initiated membrane tethering and lipid transport (PITT) pathway, mediating lipid transfer between the endoplasmic reticulum (ER) and damaged lysosomes, was engaged in both cell types. Our data reveal a divergence in how neurons and astrocytes mobilize repair pathways to manage lysosomal damage. These data may reflect differences in lysosomal resilience between astrocytes and neurons and inform therapeutic strategies to correct lysosomal dysfunction in neurodegenerative diseases.

Keywords:  ESCRT; LLOMe; ORP9; PI4K2A; TBC1D15; astrocyte; lysosomal damage; neuron

DOI:  https://doi.org/10.1016/j.isci.2026.116866
bioRxiv. 2026 Aug 07. pii: 2026.08.06.742952. [Epub ahead of print]

BAG6-RNF115 Couples Protein Quality Control with Ribosome Assembly.

Anat Raiff, Colin Zenge, Alban Ordureau, Itay Koren.

Protein homeostasis relies on protein quality control (PQC) pathways that survey the proteome to eliminate aberrant polypeptides. The BAG6 complex is a central PQC factor that recognizes exposed hydrophobic regions, a feature commonly associated with misfolded, mislocalized, and mistranslated proteins. Whether this surveillance machinery also regulates intact, functional proteins as part of physiological proteostasis has remained unclear. Using unbiased quantitative proteomics, we identify the ribosomal protein RPL22L1 as an endogenous BAG6 substrate whose abundance is controlled by continuous proteasomal degradation. This turnover requires the RNF115 E3 ligase activity but not the canonical BAG6 partner RNF126, defining RPL22L1 as a selective RNF115-dependent substrate. Mechanistically, we map a bipartite hydrophobic degron that distinguishes RPL22L1 from its stable paralog RPL22, and show that BAG6-RNF115-mediated degradation is governed by substrate assembly state. Accordingly, RPL22L1 is protected from degradation upon incorporation into the 60S ribosome, where it substitutes for RPL22. When RPL22 is lost, either genetically or through recurrent inactivating mutations in microsatellite-unstable cancers, the vacant ribosomal binding site permits RPL22L1 incorporation, protecting it from BAG6-mediated degradation. These findings establish unassembly-coupled degradation as a mechanism by which BAG6 regulates the abundance of functional protein components, ensuring that they accumulate only when incorporated into their native macromolecular complexes.

DOI: https://doi.org/10.64898/2026.08.06.742952
Neuroscience. 2026 Aug 18. pii: S0306-4522(26)00561-0. [Epub ahead of print]614 307-317

Autophagy as a mechanistic link between physical exercise and Alzheimer's disease.

Zhouye Yu, Yanfang Wang, Yi Yang.

  Alzheimer's Disease (AD), the most prevalent cause of dementia worldwide, is a neurodegenerative disorder that currently has no cure. A growing body of evidence suggests that physical exercise is a potential non-pharmacological strategy in the treatment of AD. Recent findings highlight the involvement of autophagy in the modulatory actions of physical exercise for AD. Here, we present a narrative review of the current knowledge on how exercise impacts AD, specifically focusing on its regulation of autophagic activity in animal models of AD. Evidence from rodent studies further demonstrates that exercise may influence AD-related pathology through autophagy-lysosomal regulation, lysosomal homeostasis, and mitochondrial quality control, but direct human evidence remains limited. This review uniquely positions exercise-induced autophagy regulation as a central mechanistic hub, offering a novel paradigm for developing lifestyle-based interventions for AD.

Keywords:  Alzheimer’s disease; Autophagy; Cognition; Exercise

DOI:  https://doi.org/10.1016/j.neuroscience.2026.08.026
Mol Cell. 2026 Aug 17. pii: S1097-2765(26)00513-7. [Epub ahead of print]

ER-liquid condensate contacts sequester FAM134B/C and RhoA to govern cell morphology.

Natalia Jimenez-Moreno, Arianna Karageorgiou, Katie Winnington-Ingram, Jimi Wills, Chinmayi Pednekar, Melina Overhoff, Katherine Paine, Matthew Pearson, Lukas Gerasimavicius, Ann Wheeler, Natalia L Kononenko, Joseph A Marsh, Paul Verkade, Alex von Kriegsheim, Jon D Lane, Simon Wilkinson.

  Endoplasmic reticulum (ER)-phagy receptors have elusive physiological functions beyond ER remodeling. To gain insight into these, we screen for cytoplasmic interactors of well-known receptors in mouse pancreatic ductal adenocarcinoma cells. Our data subsequently reveal a non-canonical action of PRKAR1A, a subunit of protein kinase A (PKA), in binding and activating FAM134B/C. At a molecular level, an amphipathic helix in the otherwise-disordered C terminus of FAM134B directly binds PRKAR1A dimers. Multimodal imaging reveals that this interaction occurs at interorganellar contact sites between the ER and liquid-like condensates of PRKAR1A. Mechanistically, ER-condensate contacts promote clustering of FAM134B/C with LC3B and recruit lysosomes, forming degradation hubs. Unexpectedly, these structures are found to control cytoplasmic signaling through FAM134B/C-mediated lysosomal sequestration of RhoA. Underscoring the physiologic relevance of this, these cytoplasmic-facing actions of FAM134B/C result in RhoA-dependent cell morphologic and migratory control in response to cyclic AMP (cAMP) stimuli. Thus, interorganellar contacts expand the roles of FAM134B/C ER-phagy receptors beyond ER degradation.

Keywords:  ER-phagy; LLPS; RHO GTPase; autophagy; cAMP; cancer; cell invasion; cytoskeleton; liquid-like condensate; lysosome

DOI:  https://doi.org/10.1016/j.molcel.2026.07.027
Alzheimers Dement. 2026 Aug;22(8): e71680

A combined artificial intelligence-wet lab approach identifies a pivotal role of the NAD+-mitophagy axis on aging and neurodegeneration.

Sofie Lautrup, Shu-Qin Cao, Xi Long, Bonnie Hei Man Liu, Beatriz Escobar-Doncel, Aristide Ferrante, Johannes Frank, Tomas Schmauck-Medina, Geoffrey Ho Duen Leung, Kristina Xiao Liang, Ning Lu, Katerina Veverova, Martin Vyhnalek, Frank W Pun, Alex Zhavoronkov, Evandro Fei Fang.

   INTRODUCTION: Emerging evidence points to a role of nicotinamide mononucleotide (NAD+) depletion and compromised mitophagy in aging and neurodegenerative diseases. We hypothesize that age-dependent impairment of the NAD+-mitophagy axis contributes to brain aging and neurodegeneration.
METHODS: We analyzed transcriptomic data from 12 human brain regions across 77 integrated public datasets spanning major neurodegenerative diseases and controls to assess NAD+-mitophagy axis alterations, focusing on Alzheimer's disease (AD). Key targets were validated in Caenorhabditis elegans, a human Tau cell model, and induced pluripotent stem cell (iPSC)-derived cortical neurons.
RESULTS: The NAD+-mitophagy axis is more severely dysregulated in neurodegeneration than in brain aging. Integrating computational and experimental approaches, we identified five AD-protective genes (ULK1, OPA1, LAMP2, MFN1, and ATP6V0E1) linked to synaptic resilience and/or reduced Tau pathology.
DISCUSSION: Our study combines artificial intelligence-driven and experimental approaches to identify novel targets for neurodegeneration, revealing disruption of the NAD+-mitophagy axis as a central player in brain aging and AD.

Keywords:  AD; ALS; HD; NAD+; PD; PandaOmics; aging; artificial intelligence; machine learning; mitophagy

DOI:  https://doi.org/10.1002/alz.71680
Mech Ageing Dev. 2026 Aug 21. pii: S0047-6374(26)00090-4. [Epub ahead of print] 112238

Puerarin extends lifespan and enhances the resistance to oxidative stress through AMPK/TFEB mediated autophagy in Caenorhabditis elegans.

Lingjie Meng, Yang Liu, Xiaocong Li, Xin Xiao, Xinyi Du, Fang Liu, Yi Xiao.

  As the aging population increases, exploring effective strategies to delay aging and promote healthy longevity has become a crucial topic in the life sciences. Puerarin (PUE) is a natural isoflavone derivative derived from Pueraria lobata, a plant widely recognized for its dual role as both a food and a medicinal herb. While PUE is known for its diverse pharmacological properties, its role in aging regulation and the associated molecular mechanisms are not yet fully elucidated. In this study, we found that PUE markedly extends the healthy lifespan of Caenorhabditis elegans and mitigates aging-related phenotypes, including lipofuscin accumulation and decreased locomotor capacity. Through genetic screening and functional validation, we demonstrated that PUE facilitates the nuclear translocation of the transcription factor HLH-30 (the mammalian homolog of TFEB) in an AMPK-dependent manner, thereby regulating autophagy. Importantly, this autophagic response was essential for the lifespan-extending effects of PUE. Additionally, PUE enhanced the oxidative stress resistance of C. elegans via the AMPK-TFEB signaling pathway, an effect characterized by reduced reactive oxygen species (ROS) accumulation and increased activities of antioxidant enzymes such as superoxide dismutase (SOD) and glutathione (GSH). The findings establish a mechanistic rationale for applying PUE in aging delay and age-related disease prevention and underscore the potential significance of medicinal food plants in developing anti-aging strategies.

Keywords:  AMPK/TFEB signaling pathway; Autophagy; Lifespan; Oxidative stress; Puerarin

DOI:  https://doi.org/10.1016/j.mad.2026.112238