bims-auttor 2025-11-02 papers

bims-auttor

Biomed News

on Autophagy and mTOR

Issue of 2025–11–02
33 papers selected by
Viktor Korolchuk, Newcastle University

Mechanism of autophagy initiation by transmembrane selective autophagy receptors.
VPS35 mutation inhibits PINK1/parkin-mediated mitophagy via increased LRRK2 kinase activity.
Developing Endogenous Autophagy Reporters in Caenorhabditis elegans to Monitor Basal and Starvation-Induced Autophagy.
Lysosome heterogeneity and diversity mapped through its distinct cellular functions.
Recent progress regarding the role of autophagy in cardiac disease.
The Rab7-Epg5 and Rab39-ema modules cooperatively position autophagosomes for efficient lysosomal fusions.
Trans-synaptic signaling through GRID1/glutamate receptor delta-1 and CBLN1/cerebellin-1 facilitates autophagic flux in central amygdala and prevents chronic pain.
Impairment of lysosomal quality control in Huntington disease.
Defective chaperone-mediated autophagy in the retinal pigment epithelium of age-related macular degeneration patients.
Characterization of Corneal Defects in ATG7-Deficient Mice.
Autophagy: The Last Antioxidant to Unravel.
NRBF2 homodimerization by its coiled-coil domain strengthens association with the PtdIns3K complex mediated by the mit domain to promote autophagy.
Phospho-proteome profiling in human neurons reveals targets of TBK1 in ALS/FTD-associated autophagy networks.
Intrinsically accelerated cellular degradation is amplified by TDP-43 loss in ALS-vulnerable motor neurons in a zebrafish model.
Huntingtin knockdown dysregulates autophagic degradation of Apolipoprotein E.
CircAASS alleviates renal injury and fibrosis by regulating mitochondrial homeostasis in tubular epithelial cells.
Improved efficiency of protein aggregate removal using ubiquitin with a signal peptide.
GABARAP proteins regulate the packaging of HIV-1 genomic RNA into virions.
Roles of Autophagy and Oxidative Stress in Cardiovascular Disease.
XIAP-ULK1-Mediated mitophagy modulates carnitine metabolism to mitigate diabetic kidney disease.
microRNA-22 Inhibition Stimulates Mitochondrial Homeostasis and Intracellular Degradation Pathways to Prevent Muscle Wasting.
Mitophagy in Alzheimer's disease and its potential as a therapeutic target.
MITF regulates autophagy and extracellular vesicle cargo in gastrointestinal stromal tumors.
Sertad1 is elevated and plays a necessary role in neuron loss and cognitive impairment in a mouse model of Alzheimer's disease.
Chaperone-mediated autophagy controls brown adipose tissue thermogenic activity.
Autophagy-senescence interplay in kidney disease: mechanistic insights and therapeutic potential.
The senescent synapse: A look at autophagy, calcium handling, and mitochondrial bioenergetics at the synapse in ageing and Parkinson's disease.
Disrupted proteostasis and ionic imbalance in TDP-43 and tauopathies: Dual drivers of neurodegeneration.
Substrate recognition by the human mitochondrial processing peptidase and its processing of PINK1.
Potential Role of Membrane Contact Sites in the Dysregulation of the Crosstalk Between Mitochondria and Lysosomes in Alzheimer's Disease.
CLN7 protein functions at the interface between endolysosomes and stress granules to promote cell survival.
Oral Exposure to Food-Grade Nanoparticles Poses a Risk of Alzheimer's Disease-Like Symptoms by Triggering Autophagy Defects in Neurons.
The role of the SIRT1 and mTOR pathways in exercise-induced β-cell senescence reduction in type 2 diabetes mellitus.

EMBO J. 2025 Oct 30.

Mechanism of autophagy initiation by transmembrane selective autophagy receptors.

Elias Adriaenssens, Sascha Martens.

  Selective autophagy ensures the targeted degradation of damaged or surplus cellular components, including organelles, thereby safeguarding cellular homeostasis. This process relies on selective autophagy receptors (SARs) that link specific cargo to the autophagy machinery. These receptors exist in two distinct forms: soluble SARs that are recruited to the cargo on demand, and transmembrane SARs that are stably embedded in the membranes of organelles they target. While both receptor types converge on the same autophagy core machinery, they differ in how they recognize cargo, are regulated, and recruit this machinery to the site of degradation. In this review, we explore the unique challenges and strategies associated with transmembrane SARs, including how their activity is suppressed under basal conditions and activated in response to stress. We compare their mode of action with that of soluble SARs, highlight key differences in kinase regulation, including the roles of TBK1, ULK1, CK2, and Src, and discuss emerging models of autophagy initiation. We further highlight fundamental principles of organelle-selective autophagy and identify open questions that will guide future research.

Keywords:  Autophagosome; ER-phagy; Mitophagy; Quality Control; Selective Autophagy

DOI:  https://doi.org/10.1038/s44318-025-00615-w
Brain. 2025 Oct 30. pii: awaf414. [Epub ahead of print]

VPS35 mutation inhibits PINK1/parkin-mediated mitophagy via increased LRRK2 kinase activity.

Liselot Manders, Thibaut Heyninck, Dorien Imberechts, Bjørn Holst, Rejko Krüger, Wim Vandenberghe.

  The p.D620N mutation in VPS35 causes an autosomal dominant form of Parkinson's disease via mechanisms that are poorly understood. PINK1 and parkin, two proteins whose loss of function underlies autosomal recessive Parkinson's disease, cooperate to mediate mitophagy, a quality control pathway for selective elimination of damaged mitochondria. PINK1/parkin-mediated mitophagy is disrupted by LRRK2 mutations, which are the most prevalent cause of autosomal dominant Parkinson's disease. Here, we investigated whether the p.D620N VPS35 mutation has an effect on PINK1/parkin-mediated mitophagy. We identified a novel family with autosomal dominant Parkinson's disease caused by a p.D620N VPS35 mutation. We cultured skin fibroblasts and iPSC-derived dopaminergic neurons from the proband and from a second, unrelated Parkinson's disease patient with the p.D620N VPS35 mutation, and compared them with isogenic and non-isogenic control cells. PINK1/parkin-mediated mitophagy was severely impaired in VPS35 mutant fibroblasts and neurons, while non-selective, starvation-induced autophagy and lysosomal degradative capacity were preserved. siRNA-mediated VPS35 knockdown rescued the mitophagy defect in VPS35 mutant cells, whereas overexpression of wild-type VPS35 did not, suggesting a gain-of-function mechanism of the mutation. The VPS35 mutation did not interfere with activation of PINK1 or parkin after mitochondrial depolarization, but impaired mitochondrial recruitment of the autophagy receptor optineurin. LRRK2 kinase activity was increased in the VPS35 mutant cells, as shown by enhanced levels of the T73-phosphorylated form of the LRRK2 substrate RAB10. The enhanced level of phosphorylated RAB10 in VPS35 mutant cells was decreased by treatment with LRRK2 kinase inhibitors and by VPS35 knockdown. Importantly, the mitophagy defect of VPS35 mutant fibroblasts and neurons was fully rescued by LRRK2 kinase inhibitors as well as by overexpression of PPM1H, a phosphatase that dephosphorylates multiple RAB substrates of LRRK2. Finally, in situ proximity ligation experiments revealed that endogenous VPS35 and LRRK2 are proximity partners in human dopaminergic neurons and that this proximity relationship is enhanced by the VPS35 mutation. In conclusion, the VPS35 mutation impairs PINK1/parkin-mediated mitophagy via a gain-of-function mechanism that involves stimulation of LRRK2 kinase activity. Thus, a VPS35/LRRK2 axis linked to dominant Parkinson's disease intersects with a pathway mediated by proteins encoded by the recessive Parkinson's disease genes.

Keywords:  Parkinson’s disease; RAB; autophagy; induced pluripotent stem cell; lysosome; mitochondrion

DOI:  https://doi.org/10.1093/brain/awaf414
Int J Mol Sci. 2025 Oct 20. pii: 10178. [Epub ahead of print]26(20):

Developing Endogenous Autophagy Reporters in Caenorhabditis elegans to Monitor Basal and Starvation-Induced Autophagy.

Kincső Bördén, Tibor Vellai, Tímea Sigmond.

  Autophagy (cellular self-eating) is a tightly regulated catabolic process of eukaryotic cells during which parts of the cytoplasm are sequestered and subsequently delivered into lysosomes for degradation by acidic hydrolases. This process is central to maintaining cellular homeostasis, the removal of aged or damaged organelles, and the elimination of intracellular pathogens. The nematode Caenorhabditis elegans has proven to be a powerful genetic model for investigating the regulation and mechanism of autophagy. To date, the fluorescent autophagy reporters developed in this organism have predominantly relied on multi-copy, randomly integrated transgenes. As a result, the interpretation of autophagy dynamics in these models has required considerable caution due to possible overexpression artifacts and positional effects. In addition, starvation-induced autophagy has not been characterized in detail using these reporters. Here, we describe the development of two endogenous autophagy reporters, gfp::mCherry::lgg-1/atg-8 and gfp::atg-5, both inserted precisely into their endogenous genomic loci. We demonstrate that these single-copy reporters reliably track distinct stages of the autophagic process. Using these tools, we reveal that (i) the transition from the earliest phagophore to the mature autolysosome is an exceptionally rapid event because the vast majority of the detected fluorescent signals are autolysosome-specific, (ii) starvation triggers autophagy only after a measurable lag phase rather than immediately, and (iii) the regulation of starvation-induced autophagy depends on the actual life stage, and prevents excessive flux that could otherwise compromise cellular survival. We anticipate that these newly developed reporter strains will provide refined opportunities to further dissect the physiological and pathological roles of autophagy in vivo.

Keywords:  ATG-5; C. elegans; LGG-1; TOR; autophagy; endogenous reporters; starvation

DOI:  https://doi.org/10.3390/ijms262010178
Cell Mol Life Sci. 2025 Oct 30. 82(1): 380

Lysosome heterogeneity and diversity mapped through its distinct cellular functions.

Indira Chavan, Arindam Bhattacharjee.

  Lysosomes respond to cellular nutrient availability and diverse oncoming vesicle traffic such as endocytosis and autophagy by switching between anabolic signaling or catabolic hydrolase activity, which coincides with a drastic shift in their cellular distribution, organelle contacts, ion homeostasis, membrane proteome and lipidome. Emerging evidence now reveals a dynamic remodeling of lysosomal membrane to counter membrane damage, acting via extensive lipid transfer from the endoplasmic reticulum or by localized membrane repair. Functionally, lysosomes play a key role in lipid metabolism and intracellular calcium signaling. Unsurprisingly, disease-associated lysosomes are either often hyperactive- thus promoting abnormal tissue growth, or hypoactive, promoting storage. Taken together, this presents an incredible functional diversity among the cellular population of lysosomes. Here, we discuss this intracellular heterogeneity and intercellular diversity in context of lysosomal function in health and disease.

Keywords:  Lipid storage disorders; Lysosome plasticity; Lysosome quality control; Lysosome subpopulations; Phosphoinositides

DOI:  https://doi.org/10.1007/s00018-025-05883-7
Cardiovasc Res. 2025 Oct 27. pii: cvaf203. [Epub ahead of print]

Recent progress regarding the role of autophagy in cardiac disease.

Yasuhiro Maejima, Allen Sam Titus, Daniela Zablocki, Junichi Sadoshima.

Autophagy is a lysosomal-dependent mechanism of cellular degradation characterized by the presence of double membraned vesicles called autophagosomes. Increasing lines of evidence suggest that both non-selective autophagy and cargo-specific forms of autophagy, such as the mitochondria-specific form of autophagy, termed mitophagy, are activated in the heart in response to stress. However, their activation is often transient and insufficient during the chronic phase of cardiac conditions, including both pressure and volume overload, heart failure with preserved ejection fraction, obesity and diabetic cardiomyopathy and aging cardiomyopathy. Indeed, interventions to restore the levels of autophagy and mitophagy often alleviate cardiac dysfunction in animal models of heart failure. It is, therefore, important to understand the molecular mechanisms that inhibit or activate autophagy and mitophagy during the chronic phase of heart failure. Under some conditions, autophagy can become dysregulated in the heart and induce cellular dysfunction and death. For example, lysosomal function is attenuated through multiple mechanisms. Autosis, a specific form of cell death caused by autophagy dysregulation, is characterized by unique morphologies, including perinuclear space, and sensitivity to cardiac glycoside, and contributes to the late phase of myocardial ischemia/reperfusion injury. Over the past decade, previously unrecognized functions of autophagy have been discovered, including organelle- and protein-specific degradation, and even inter-cellular communication through secretion of extracellular vesicles, which may also contribute to the pathogenesis of heart disease. The purpose of this review is to highlight recent progress in autophagy research in the heart, with a particular focus on underlying signaling mechanisms, cargo-specific autophagy and pharmacological interventions.

DOI: https://doi.org/10.1093/cvr/cvaf203
Elife. 2025 Oct 28. pii: RP102663. [Epub ahead of print]13

The Rab7-Epg5 and Rab39-ema modules cooperatively position autophagosomes for efficient lysosomal fusions.

Attila Boda, Villő Balázs, Anikó Nagy, Dávid Hargitai, Mónika Lippai, Zsófia Simon-Vecsei, Márton Molnár, Fanni Fürstenhoffer, Gábor Juhász, Péter Lőrincz.

  Macroautophagy, a major self-degradation pathway in eukaryotic cells, utilizes autophagosomes to transport self-material to lysosomes for degradation. While microtubular transport is crucial for the proper function of autophagy, the exact roles of factors responsible for positioning autophagosomes remain incompletely understood. In this study, we performed a loss-of-function genetic screen targeting genes potentially involved in microtubular motility. A genetic background that blocks autophagosome-lysosome fusions was used to accurately analyze autophagosome positioning. We discovered that pre-fusion autophagosomes move towards the non-centrosomal microtubule organizing center (ncMTOC) in Drosophila fat cells, which requires a dynein-dynactin complex. This process is regulated by the small GTPases Rab7 and Rab39 together with their adaptors: Epg5 and ema, respectively. The dynein-dependent movement of vesicles toward the nucleus/ncMTOC is essential for efficient autophagosomal fusions with lysosomes and subsequent degradation. Remarkably, altering the balance of kinesin and dynein motors changes the direction of autophagosome movement, indicating a competitive relationship where normally dynein-mediated transport prevails. Since pre-fusion lysosomes were positioned similarly to autophagosomes, it indicates that pre-fusion autophagosomes and lysosomes converge at the ncMTOC, which increases the efficiency of vesicle fusions.

Keywords:  D. melanogaster; autophagosome; cell biology; dynein; fusion; lysosome; microtubular transport; ncMTOC

DOI:  https://doi.org/10.7554/eLife.102663
Autophagy. 2025 Oct 28. 1-24

Trans-synaptic signaling through GRID1/glutamate receptor delta-1 and CBLN1/cerebellin-1 facilitates autophagic flux in central amygdala and prevents chronic pain.

Kishore Kumar S Narasimhan, Poojashree B Chettiar, Takaki Kiritoshi, Guangchen Ji, Volker Neugebauer, Shashank M Dravid.

  Central amygdala (CeA) is a component of the spino-parabrachio-amygdala nociceptive pathway. Neuroplasticity in this pathway, such as increased cellular excitability and excitatory neurotransmission, play a key role in the development and persistence of chronic pain. However, the underlying mechanisms of neuroplastic changes in the CeA remain poorly understood. We recently demonstrated that GRID1/GluD1 (glutamate ionotropic receptor delta type subunit 1) and its binding partner CBLN1 (cerebellin 1 precursor) are downregulated in models of inflammatory and neuropathic pain. Furthermore, we have shown that GRID1-CBLN1 signaling regulates autophagy in multiple brain regions. Here, we tested the causal relationship between GRID1-CBLN1 downregulation, macroautophagy impairment, and subsequent hyperalgesia, using models of inflammatory and neuropathic pain. During pain, the downregulation of GRID1 and CBLN1 was accompanied by neuroplastic changes, as evidenced by an increase in excitatory neurotransmission and AMPA receptor (AMPAR) expression. In addition, significant downregulation of BECN1 and upregulation of SQSTM1 and MAP1LC3B, demonstrating impaired autophagic flux, were observed in the pain state. These changes appear to be cell type-specific, as observed by the higher localization of BECN1 and LAMP1, a marker for autolysosomes, to PRKCD+ neurons, in which GRID1 is preferentially expressed. Using a GRID1 C-terminal-derived peptide (Tat-HRSPN), we demonstrate that GRID1 directly facilitates autophagy and subsequently reduces AMPAR expression in normal animals. This effect may be attributable to the direct interaction of GRID1 with mediators of autophagy, such as neuronal (n)GOPC/nPIST, BECN1 and LAMP1. Together, these results identified a novel GRID1/GluD1-dependent trans-synaptic autophagy mechanism, the deficit of which drives chronic pain.Abbreviations: aCSF: artificial cerebro spinal fluid; AMPARs: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors; ATG: autophagy related; BAPTA: 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; BECN1: beclin 1; CBLN1: cerebellin 1 precursor; CeA: central amygdala; CFA: complete Freund's adjuvant; CRH/CRF: corticotropin releasing hormone; CTD: carboxy-terminal domain; DHPG: dihydroxy phenyl glycine; GOPC/PIST: golgi associated PDZ and coiled-coil motif containing; GRID1/GluD1: glutamate ionotropic receptor delta type subunit 1; GRIN/NMDAR: glutamate ionotropic receptor NMDA type; iGluRs: ionotropic glutamate receptors; KO: knockout; LA/BLA; lateral amygdala/baso-lateral amygdala; LAMP1: lysosomal associated membrane protein 1; LTD: long-term depression; MAP1LC3: microtubule associated protein 1 light chain 3; mEPSCs: miniature excitatory post-synaptic currents; GRM: glutamate metabotropic receptor; MTOR: mechanistic target of rapamycin kinase; nGOPC/nPIST: neuronal GOPC/PIST; NRXN1a: neurexin 1 alpha; PB: parabrachial nucleus; PBS: phosphate-buffered saline; PB-CeLC: parabrachio-central laterocapsular amygdala; PI3K: phosphoinositide 3-kinase; PRKCD+: protein kinase C delta positive; rCBLN1: recombinant CBLN1; SDS-PAGE: sodium dodecyl sulfate-polyacrylamide gel electrophoresis; SQSTM1: sequestosome 1; SNL: spinal nerve ligation; SST+: somatostatin positive; TBD11: Tat-beclin 1 D11; TBST: Tris-buffered saline with Tween 20; WT: wild type.

Keywords:  AMPARs; BECN1; CBLN1; GRID1/GluD1; LAMP1; chronic pain

DOI:  https://doi.org/10.1080/15548627.2025.2574968
Cell Death Dis. 2025 Oct 27. 16(1): 762

Impairment of lysosomal quality control in Huntington disease.

Paola Rusmini, Francesco Mina, Marta Valenza, Martina Vitali, Veronica Ferrari, Barbara Tedesco, Elena Casarotto, Marta Cozzi, Marta Chierichetti, Ali Mohamed, Paola Pramaggiore, Laura Cornaggia, Carmelo Milioto, Maria Brodnanova, Rocio Magdalena, Prashant Koshal, Margherita Piccolella, Riccardo Cristofani, Mariarita Galbiati, Valeria Crippa, Angelo Poletti.

Huntington disease (HD) is a neurodegenerative disease caused by a polyglutamine expansion (polyQ) in the Huntingtin protein (muHTT), which makes it prone to misfolding and aggregation. muHTT aggregates sequester a wide variety of proteins essential for cell homeostasis, including chaperones and transcription factors, and their depletion may contribute to HD pathogenesis. Lysosomes are the main hubs for degradative and signaling activities in cells, and their functionality is crucial for cell homeostasis, especially for neurons. Different forms of cellular stresses, including proteotoxic stresses, can alter lysosome integrity and induce lysosomal membrane permeabilization (LMP). Damaged lysosomes are recognized by galectins, in particular galectin-3 (LGALS3) with activation of the lysosome quality control (LQC) system responsible for repairing, degrading, or replacing leaky lysosomes. The system is transcriptionally regulated by the transcription factors EB and E3 (TFEB and TFE3, respectively). Using HD mouse and cell models, we demonstrated that TFEB and TFE3 are sequestered in muHTT aggregates, and muHTT proteins associates with LMP triggering the translocation of LGALS3 to the lumen of lysosomes, with a close relation between polyQ size and severity of these events. Moreover, we demonstrated that TFEB and TFE3 silencing or overexpression modulate muHTT aggregation. TFEB and TFE3 knockdown worsens muHTT aggregation, while their overexpression reduces muHTT inclusions and concurrently reduces LGALS3 accumulation via lysophagy and lysosome replacement. Our findings suggest that both TFEB and TFE3 are implicated in HD, and their sequestration in muHTT inclusions increase the vulnerability of neurons to lysosome injury, altering LQC and contributing to disease pathogenesis. In physiologial conditions, lysosome membrane permeabilization occurs and activates TFEB and TFE3 triggering a response to induce lysophagy and lysosome biogenesis. In HD, muHTT sequesters TFEB and TFE3 into inclusions and the reduced TFEB/TFE3 bioavailability prevents the activation of lysophagy and leading to the accumulation of damaged lysosomes. Created in BioRender.

DOI: https://doi.org/10.1038/s41419-025-08103-z
EMBO Mol Med. 2025 Oct 30.

Defective chaperone-mediated autophagy in the retinal pigment epithelium of age-related macular degeneration patients.

Juan Ignacio Jiménez-Loygorri, Peng Shang, Ibrahim Bayramoglu, Raquel Gómez-Sintes, Adrián Martín-Segura, Helena Ambrosino, Johnson Hoang, Antonio Díaz, Zhaohui Geng, Evripidis Gavathiotis, James R Dutton, Jörn Dengjel, Ana Maria Cuervo, Deborah A Ferrington, Patricia Boya.

  Autophagy is one of the main intracellular recycling systems and its impairment is considered a primary hallmark of the aging process. Defective macroautophagy in the retinal pigment epithelium (RPE) has been described in age-related macular degeneration (AMD), a blindness-causing disease that affects roughly 200 million patients worldwide. The relevance of chaperone-mediated autophagy (CMA), a selective type of autophagy for proteins containing a KFERQ-like motif, in RPE cell biology and homeostasis remains to be elucidated. Here we describe decreased CMA activity in the RPE of AMD patients compared to healthy age-matched controls, along with accumulation of substrate proteins, and in donor-derived iPSC-RPE cells, which we used to further characterize AMD-associated alterations of cellular homeostasis derived from proteotoxicity. Treatment with CA77.1 (CMA activator) restores proteostasis and remodels specific subsets of the proteome in cells from healthy and AMD donors. CA77.1-treated AMD iPSC-RPE display reduced oxidative stress and improved mitochondrial function. These findings may explain the specific vulnerability of the RPE during AMD and shed light on CMA as a new druggable target for this as-of-now incurable disease.

Keywords:  Age-related Macular degeneration; Chaperone-mediated Autophagy; Oxidative Stress; Proteostasis; RPE

DOI:  https://doi.org/10.1038/s44321-025-00329-w
Int J Mol Sci. 2025 Oct 14. pii: 9989. [Epub ahead of print]26(20):

Characterization of Corneal Defects in ATG7-Deficient Mice.

Thomas Volatier, Andreas Mourier, Johanna Mann, Berbang Meshko, Karina Hadrian, Claus Cursiefen, Maria Notara.

  Regulated proteolysis via autophagy is essential for cellular homeostasis, yet the specific role of autophagy-related gene 7 (ATG7) in corneal epithelial maintenance remains unclear. Using a conditional knockout mouse model (Atg7f/f K14Cre+/-), we investigated the impact of ATG7 deficiency on corneal epithelial autophagy, morphology, and vascular dynamics. Loss of ATG7 disrupted autophagosome formation, evidenced by increased LC3B expression but reduced LC3B-positive puncta and absence of autophagosomes ultrastructurally. Although gross corneal morphology was preserved, ATG7 deficiency led to thickened epithelium and increased peripheral lymphatic vessel sprouting, indicating a pro-inflammatory and pro-lymphangiogenic microenvironment. Proteomic analysis revealed upregulation of RAB8, TM9S3, and RETR3, suggesting activation of compensatory pathways such as exophagy, reticulophagy, and Golgiphagy. Inflammatory and angiogenic components were downregulated, suggesting a moderate loss of inhibitory capacity based on the lymphatic phenotypes observed. At the same time, while these two compensatory changes occur, other proteins that positively regulate lysosome formation are reduced, resulting in a phenotype linked to deficient autophagy. These findings demonstrate that ATG7-mediated autophagy maintains corneal epithelial homeostasis and immune privilege, with implications for understanding corneal inflammation and lymphangiogenesis in ocular surface diseases.

Keywords:  ATG7; autophagy; cornea; corneal epithelium; corneal homeostasis

DOI:  https://doi.org/10.3390/ijms26209989
Antioxidants (Basel). 2025 Oct 17. pii: 1244. [Epub ahead of print]14(10):

Autophagy: The Last Antioxidant to Unravel.

Álvaro F Fernández, Marina García-Macia.

Christian de Duve used the term "Autophagy" for the first time during a conference focused on lysosomes in 1963, but the scientific revolution caused by this cellular recycling system could not be foreseen at that moment [...].

DOI: https://doi.org/10.3390/antiox14101244
Autophagy. 2025 Oct 29.

NRBF2 homodimerization by its coiled-coil domain strengthens association with the PtdIns3K complex mediated by the mit domain to promote autophagy.

Na Li, Xiaohua Li, Xianxiu Qiu, Xuehua Pan, Shuai Wu, Jingyi Chen, Rong Liu, Jiahong Lu, Zhenyu Yue, Yanxiang Zhao.

  The mammalian class III phosphatidylinositol-3-kinase complex (PtdIns3K) forms two biochemically and functionally distinct subcomplexes including the ATG14-containing complex I (PtdIns3K-C1) and the UVRAG-containing complex II (PtdIns3K-C2). Both subcomplexes adopt a V-shaped architecture with a BECN1-ATG14 or UVRAG adaptor arm and a PIK3R4/VPS15-PIK3C3/VPS34 catalytic arm. NRBF2 is a pro-autophagic modulator that specifically associates with PtdIns3K-C1 to enhance its kinase activity and promotes macroautophagy/autophagy. How NRBF2 exerts such a positive effect is not fully understood. Here we report that NRBF2 binds to PIK3R4/VPS15 with moderate affinity through a conserved site on its N-terminal MIT domain. The NRBF2-PIK3R4/VPS15 interaction is incompatible with the UVRAG-containing PtdIns3K-C2 because the C2 domain of UVRAG outcompetes NRBF2 for PIK3R4/VPS15 binding. Our crystal structure of the NRBF2 coiled-coil (CC) domain reveals a symmetric homodimer with multiple hydrophobic pairings at the CC interface, which is in distinct contrast to the asymmetric dimer observed in the yeast ortholog Atg38. Mutations in the CC domain that rendered NRBF2 monomeric led to weakened binding to PIK3R4/VPS15 and only partial rescue of autophagy deficiency in nrbf2 knockout cells. In comparison, NRBF2 with its CC domain replaced by a dimeric Gcn4 module showed proautophagic activity comparable to wild type while NRBF2 carrying a tetrameric Gcn4 module showed further enhanced activity. We propose that the oligomeric state of NRBF2 mediated by its CC domain is critical for strengthening the moderate NRBF2-PIK3R4/VPS15 interaction mediated by its MIT domain to fully activate PtdIns3K-C1 and promote autophagy.

Keywords:  Autophagy; MIT; NRBF2; PIK3R4/VPS15; PtdIns3K; coiled-coil

DOI:  https://doi.org/10.1080/15548627.2025.2580438
Cell Rep. 2025 Oct 29. pii: S2211-1247(25)01265-3. [Epub ahead of print]44(11): 116494

Phospho-proteome profiling in human neurons reveals targets of TBK1 in ALS/FTD-associated autophagy networks.

Julie Smeyers, Juan A Oses-Prieto, Lin Yadanar, Man Wang, Marci Iadarola, Serena Lu, Karen S Wang, Taylor H Watanabe, Jayanta Debnath, Alma L Burlingame, Daniel A Mordes.

  Loss-of-function variants in TBK1, encoding a protein kinase, are strongly associated with familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, how haploinsufficiency for TBK1 leads to age-related neurodegeneration remains unresolved. Here, we utilize sets of isogenic induced pluripotent stem cells (iPSCs) with loss of TBK1 or loss of optineurin (OPTN) for quantitative global proteomics and phospho-proteomics in both stem cells and excitatory neurons. We found that TBK1 sustains the abundance and phosphorylation of its interacting adapter proteins, AZI2/NAP1, TANK, and TBKBP1/SINTBAD. Moreover, TBK1 regulates the phosphorylation of endo-lysosomal proteins, such as GABARAPL2, the late-endosome GTPase RAB7A, and selective autophagy cargo receptor proteins-including novel phospho-sites in p62/SQSTM1-in neurons. Finally, we provide a census of the phospho-proteome in nascent human neurons for further studies. Overall, TBK1 serves as a point of convergence in ALS/FTD-linked endo-lysosomal networks that act in a cell-autonomous manner to maintain protein homeostasis in neurons.

Keywords:  ALS; CP: Molecular biology; CP: Neuroscience; OPTN; TBK1; autophagy; dementia; iPSC disease modeling; neurodegeneration; phospho-proteomics; proteomics

DOI:  https://doi.org/10.1016/j.celrep.2025.116494
Nat Commun. 2025 Oct 27. 16(1): 9213

Intrinsically accelerated cellular degradation is amplified by TDP-43 loss in ALS-vulnerable motor neurons in a zebrafish model.

Kazuhide Asakawa, Takuya Tomita, Shinobu Shioya, Hiroshi Handa, Yasushi Saeki, Koichi Kawakami.

Selective neuronal vulnerability is a defining feature of neurodegenerative disorders, exemplified by motor neuron degeneration in amyotrophic lateral sclerosis (ALS). The nature of motor neurons underlying this selectivity remains unresolved. Here, by monitoring autophagy at single-cell resolution across the translucent zebrafish spinal cord, we identify motor neurons as the cell population with the highest autophagic flux. Large spinal motor neurons (SMNs), most susceptible to ALS, exhibit higher flux compared to smaller SMNs and ALS-resistant ocular motor neurons. Notably, large SMNs accelerates both autophagy and proteasome-mediated degradation, which are further augmented by TDP-43 loss. Additionally, acceleration of multiple unfolded protein response pathways indicates their innate tendency to accumulate misfolded proteins. Enhanced cellular degradation in large SMNs is neuroprotective as its inhibition halts axon outgrowth. These findings propose that cell size-associated degradation load underlies selective neuronal vulnerability in ALS, highlighting the alleviation of catabolic stress as a target of therapy and prevention.

DOI: https://doi.org/10.1038/s41467-025-65097-0
J Huntingtons Dis. 2025 Oct 29. 18796397251391110

Huntingtin knockdown dysregulates autophagic degradation of Apolipoprotein E.

Gianna M Fote, Nicolette R McClure, Robert M Bragg, Jharrayne McKnight, Leslie M Thompson, Jeffrey B Carroll, Joan S Steffan.

  BackgroundThe HTT protein, mutated in Huntington's disease, is expressed throughout the body, and loss of HTT function as an autophagic scaffold may affect tissues and cellular processes. These processes include lipid metabolism potentially regulated upstream by Apolipoprotein E (APOE) and clearance of APOE itself.ObjectiveTo determine the impact of HTT reduction on autophagy and clearance of APOE in cell culture and in mouse liver in vivo.MethodsWestern blot analysis was performed on liver tissue from tamoxifen-treated mice with and without UBC-Cre expression, required for tamoxifen-induced HTT knockout (KO). siRNA was used to knockdown (KD) HTT in HepG2 immortalized liver cells.ResultsHTT KO in mouse liver reduces levels of LAMP2A, a protein essential for chaperone-mediated autophagy (CMA) which we previously found is required for optimal degradation of APOE and HTT in cultured cells. In turn, APOE levels were increased with HTT KO in mouse liver, while HTT KD in cell culture decreased levels of APOE.ConclusionsIn the context of liver tissue, reduced CMA may contribute to accumulation of APOE and autophagic cargo resulting from a loss of HTT function in autophagy. The extent to which macroautophagy is upregulated to cope with reduced CMA found with HTT KO may be tissue specific, which may relate to the selectivity of tissue pathogenesis observed in Huntington's disease where loss of normal HTT function may be involved. This study may help elucidate the consequences of systemic HTT reduction on autophagy in liver tissue.

Keywords:  Huntingtin; Huntington's disease; apolipoprotein E; chaperone-mediated autophagy; liver; macroautophagy

DOI:  https://doi.org/10.1177/18796397251391110
Autophagy. 2025 Oct 29.

CircAASS alleviates renal injury and fibrosis by regulating mitochondrial homeostasis in tubular epithelial cells.

Tongtong Ma, Yanmei Yu, Huasheng Luo, Ziqi Zhang, Miaotao Wei, Chunjie Tian, Xianmou Fan, Zhenyi Yan, Shaowu Zhang, Junfeng Hao, Peng Wang.

  Acute kidney injury (AKI) is characterized by the dysfunction of renal tubular epithelial cells (TECs), often leading to renal fibrosis. Mitochondrial impairment is a common hallmark across various types of AKI. However, the potential role of circular RNAs (circRNAs) in modulating mitochondrial homeostasis during AKI and subsequent renal fibrosis remains underexplored. Our findings reveal a significant reduction of circAass levels in the renal cortex across all three AKI models. Mechanistically, circAASS mitigates TEC apoptosis and inflammatory responses by promoting mitochondrial homeostasis, thereby attenuating AKI. Specifically, cytoplasmic circAASS acts as a competing endogenous RNA (ceRNA) by sequestering MIR324-3p, which in turn enhances the expression of PINK1, a critical regulator of mitophagy. Additionally, nuclear circAASS directly interacts with the PPARGC1A/PGC-1α protein, inhibiting its ubiquitin-mediated degradation and thereby promoting mitochondrial biogenesis. Furthermore, we demonstrated that the RNA-binding protein IGF2BP2 suppresses circAASS biogenesis by binding to intronic sequences in the AASS pre-mRNA. Restoring circAass in AKI mouse models improves both mitochondrial biogenesis and mitophagy, ameliorating pro-inflammatory responses of TECs and thus mitigating renal fibrosis. Decreased circAASS expression and its association with impaired mitochondrial function in TECs, followed by more severe renal fibrosis, are observed in AKI patients. Collectively, our results suggest that circAASS protects against AKI by regulating mitochondrial homeostasis, highlighting its potential as a therapeutic target for kidney injury.

Keywords:  acute kidney injury; autophagy; chronic kidney disease; circular RNA; mitochondrial dysfunction; mitophagy

DOI:  https://doi.org/10.1080/15548627.2025.2581212
BMB Rep. 2025 Oct 31. pii: 6609. [Epub ahead of print]

Improved efficiency of protein aggregate removal using ubiquitin with a signal peptide.

Taek-Yeong Kim, Kwon-Yul Ryu.

Lipocalin-2 (LCN2) is a protein secreted by activated astrocytes, and its signal peptide (SP) is essential for secretion and recruitment to the autophagic pathway. SP is a short sequence present at the N-terminus of secreted proteins, such as LCN2, which facilitates transport to the endoplasmic reticulum (ER). Although SP is cleaved during the initial stages of translation in the ER, it influences the subsequent pathways of mature proteins produced in the ER lumen. ER-generated proteins are secreted or recruited to the autophagic pathway. To explore this further, we sought to determine the functional role of SP from a novel perspective. In this study, we fused LCN2 SP to the N-terminus of ubiquitin (Ub), an intracellular protein used for the proteasomal degradation of misfolded proteins and autophagic degradation of protein aggregates. We demonstrated that SP enabled the secretion of free Ub and facilitated the targeting of Ub conjugates to the autophagic pathway. We also found that SP affected intracellular Ub conjugate levels by regulating their degradation via the autophagic pathway. Furthermore, the ER-generated Ub (UbE) showed increased participation in polyubiquitinating protein aggregates generated under proteotoxic stress conditions, promoting the formation of perinuclear aggresome-like structures, and recruitment to the autophagosome. It is highly likely that UbE shares a common route with protein aggregates before being recruited to autophagosomes. Thus, this study suggests that UbE confers an altered trafficking pathway compared with endogenous Ub, thereby facilitating protein aggregate clearance without altering Ub's intrinsic biochemical activity.
EMBO Rep. 2025 Oct 31.

GABARAP proteins regulate the packaging of HIV-1 genomic RNA into virions.

Marjory Palaric, Margaux Versapuech, Delphine Judith, Corentin Aubé, Marjorie Leduc, Jacques Dutrieux, Emilie-Fleur Gautier, Jean-Christophe Paillart, Sarah Gallois-Montbrun, Clarisse Berlioz-Torrent.

  In addition to their role in canonical autophagy, autophagy proteins (ATG) contribute to various cellular processes, including phagocytosis, membrane remodeling, and vesicle secretion. Several viruses also exploit components of the autophagy pathway for their own replication. Here, we explore the role of ATG proteins in HIV-1 assembly. Postulating that host proteins crucial for virion assembly are present at the assembly site and can be incorporated within virions, we analyze the proteome of HIV-1 preparations using mass spectrometry. We identify an enrichment of macroautophagy-related terms, notably 3 of the 6 ATG8 (LC3/GABARAP) proteins. Functional studies reveal that GABARAP proteins are critical for the production of infectious virions. Knockout of GABARAP proteins reduces the packaging of viral genomic RNA (gRNA) into particles, impairing virion infectivity. GABARAPL1 associates with gRNA and interacts with Gag in an RNA-dependent manner. Additionally, GABARAP knockout increases cellular Gag:gRNA complexes and decreases gRNA association with membranes, suggesting that GABARAP proteins regulate gRNA fate during HIV-1 assembly by facilitating its packaging. This study uncovers a novel role for GABARAP proteins in HIV-1 genome packaging.

Keywords:  Autophagy Protein; GABARAP; Genome Packaging; HIV-1; RNA

DOI:  https://doi.org/10.1038/s44319-025-00607-1
Antioxidants (Basel). 2025 Oct 20. pii: 1263. [Epub ahead of print]14(10):

Roles of Autophagy and Oxidative Stress in Cardiovascular Disease.

Hyeong Rok Yun, Manish Kumar Singh, Sunhee Han, Jyotsna S Ranbhise, Joohun Ha, Sung Soo Kim, Insug Kang.

  Autophagy and oxidative stress influence cardiovascular pathology. Autophagy mediates lysosome-dependent clearance of damaged proteins and organelles and maintains mitochondrial quality control, proteostasis, and metabolic flexibility. Reactive oxygen species (ROS) originate from mitochondrial respiration and enzymatic reactions during stress. At physiological levels, ROS function as redox signals that activate degradation and recycling, whereas excess oxidants damage lipids, proteins, and nucleic acids and promote cell loss. This review integrates evidence across cardiovascular disease, including atherosclerosis, ischemia reperfusion injury, pressure overload remodeling, heart failure, diabetic cardiomyopathy, arrhythmia, aging, and inflammation.

Keywords:  autophagy; cardiovascular disease; oxidative stress

DOI:  https://doi.org/10.3390/antiox14101263
Autophagy. 2025 Oct 25.

XIAP-ULK1-Mediated mitophagy modulates carnitine metabolism to mitigate diabetic kidney disease.

Hongtu Hu, Rui Ji, Yiqun Hao, Zikang Liu, Jian Yang, Yun Cao, Qian Yang.

  Diabetic kidney disease (DKD) is a major complication of diabetes, characterized by progressive renal dysfunction and mitochondrial impairment. Mitophagy, a selective form of macroautophagy/autophagy that maintains mitochondrial quality, is essential for kidney homeostasis. However, the molecular mechanisms by which mitophagy links these pathways to DKD remain poorly understood. This study investigated the role of XIAP-ULK1-mediated mitophagy in regulating carnitine metabolism and its therapeutic potential in alleviating DKD. Through a combination of renal biopsy analysis from DKD patients, diabetic mouse models, high-glucose-treated tubular epithelial cells, and molecular docking, we determined that XIAP upregulation led to ULK1 degradation via K48-linked polyubiquitination, impairing mitophagy and disrupting carnitine metabolism. Restoring ULK1 expression through the ULK1 agonist echinacoside and L-carnitine supplementation improved mitophagy and carnitine homeostasis, reducing kidney injury and enhancing mitochondrial function in diabetic mouse models. These findings suggested that targeting the XIAP-ULK1 axis to restore mitophagy and stabilize carnitine metabolism hold significant promise as a therapeutic strategy for DKD, highlighting the importance of metabolic regulation in kidney disease management.

Keywords:  XIAP-ULK1 signaling; carnitine metabolism; diabetic kidney disease; mitochondrial dysfunction; mitophagy; therapeutic strategies

DOI:  https://doi.org/10.1080/15548627.2025.2581214
Int J Mol Sci. 2025 Oct 11. pii: 9900. [Epub ahead of print]26(20):

microRNA-22 Inhibition Stimulates Mitochondrial Homeostasis and Intracellular Degradation Pathways to Prevent Muscle Wasting.

Simone Tomasini, Emanuele Monteleone, Anna Altieri, Francesco Margiotta, Fereshteh Dardmeh, Hiva Alipour, Anja Holm, Sakari Kauppinen, Riccardo Panella.

  MicroRNA-22 (miR-22) is a negative regulator of mitochondrial biogenesis, as well as lipid and glucose metabolism, in metabolically active tissues. Silencing miR-22 holds promise as a potential treatment of obesity and metabolic syndrome, as it restores metabolic capacity-enhancing oxidative metabolism-and reduces ectopic fat accumulation in chronic obesity, a driver of impaired metabolic flexibility and muscle mass loss. Intramuscular adipose accumulation and defective mitochondrial function are features associated with obese-mediated muscle atrophy and hallmarks of neuromuscular disorders such as Duchenne muscular dystrophy. Therefore, miR-22 could represent a compelling molecular target to improve muscle health across various muscle-wasting conditions. This study describes a pharmacological strategy for the inhibition of miR-22 in skeletal muscle by employing a mixmer antisense oligonucleotide (ASO, anti-miR-22). Administration of the ASO in a mouse model of obesity positively modulated myogenesis while protecting dystrophic mice from muscle function decline, enhancing fatigue resistance, and limiting pathological fibrotic remodeling. Mechanistically, we show that anti-miR-22 treatment promotes derepression of genes involved in mitochondrial homeostasis, favoring oxidative fiber content regardless of the disease model, thus promoting a more resilient phenotype. Furthermore, we suggest that miR-22 inhibition increases autophagy by transcriptional activation of multiple negative regulators of mammalian target of rapamycin (mTOR) signaling to decrease immune infiltration and fibrosis. These findings position miR-22 as a promising therapeutic target for muscle atrophy and support its potential to restore muscle health.

Keywords:  ASO; DMD; antimiRs; autophagy; fibrosis; miR-22; miRNA therapeutics; microRNA; muscle atrophy; oxidative metabolism

DOI:  https://doi.org/10.3390/ijms26209900
Neurobiol Dis. 2025 Oct 28. pii: S0969-9961(25)00379-1. [Epub ahead of print] 107162

Mitophagy in Alzheimer's disease and its potential as a therapeutic target.

Jiahua Wei, Tiegang Xiao, Jialu Lyu, Yueshuang Zhao, Yang Zhang, Xiangyu Du, Ying He, Mengqing Zhao, Xiaoyi Yang, Yutong Yao, Jun Ruan, Kaili Liu, Li Zhang, Jiangbo Zhao, Jun Xu, Bing Wang.

  Accumulation of damaged mitochondria is a well-established hallmark of age-related neurodegenerative disorders, including Alzheimer's disease (AD). Increasing evidence suggests that mitophagy, a selective autophagic degradation of damaged mitochondria, plays an important role in AD progression. The interaction between mitophagy deficits and amyloid-β (Aβ) or Tau pathology may establish a vicious cycle that ultimately results in neuronal damage and death. Mitochondrial dysfunction exacerbates AD pathogenesis by activating the NLRP3 inflammasome, whereas modulation of mitophagy may confer neuroprotection by attenuating inflammation in neurons and microglia. Pathological ferroptosis has emerged as a potential key driver of AD, with mitophagy intriguingly demonstrating a dual role in this process. In this review, we elucidate the molecular mechanisms underlying mitophagy and its involvement in AD, thereby providing insights into its pathogenesis. We further highlight the therapeutic potential of targeting mitophagy as a promising strategy for AD intervention.

Keywords:  Alzheimer's disease; Ferroptosis; Mitochondrial dysfunction; Mitophagy; Neuroinflammation

DOI:  https://doi.org/10.1016/j.nbd.2025.107162
Mol Biomed. 2025 Oct 31. 6(1): 92

MITF regulates autophagy and extracellular vesicle cargo in gastrointestinal stromal tumors.

Elizabeth Proaño-Pérez, Eva Serrano-Candelas, Mario Guerrero, David Gómez-Peregrina, Carlos Llorens, Beatriz Soriano, Ana Gámez-Valero, Marina Herrero-Lorenzo, Eulalia Martí, César Serrano, Margarita Martin.

  The role of Microphthalmia-associated Transcription Factor (MITF) in gastrointestinal stromal tumors (GISTs) remains unclear, although previous studies suggest it contributes to tumor growth regulation. Previously, we demonstrated that MITF depletion reduces GIST cell proliferation and viability, accompanied by decreased expression of BCL-2 and CDK2. To elucidate the mechanisms underlying MITF function in GISTs, we performed chromatin immunoprecipitation and sequencing (ChIP-seq) as well as RNA sequencing. Integrated analyses revealed that MITF directly regulates genes involved in lysosome biogenesis, vesicle trafficking, autophagy, and the mTOR signaling pathway. Transcriptomic profiling following MITF silencing further demonstrated enrichment of differentially expressed genes in PI3K/ mTOR signaling, with downstream effects on tumor growth and autophagy. We next examined the functional consequences of MITF loss on mTOR inhibition-induced autophagy and on extracellular vesicle (EV) content and secretion, given their known interplay in tumor progression. MITF depletion reduced LC3-II levels and impaired autophagy flux, confirming its role in regulating autophagy in GISTs. EV size and number remained unaffected; however, silencing MITF altered EV cargo and notably decreased KIT expression in both cells and EVs. As KIT-containing EVs have been implicated in GIST invasion, these findings suggest that MITF contributes to tumor progression through coordinated regulation of autophagy and EV-mediated signaling. Collectively, our results identify MITF as a key regulator of GIST biology, highlighting its potential as a therapeutic target to limit tumor growth and metastasis.

Keywords:  Autophagy; ChIP-seq; Extracellular vesicles; Gastrointestinal stromal tumors (GIST); MITF

DOI:  https://doi.org/10.1186/s43556-025-00329-9
J Biol Chem. 2025 Oct 29. pii: S0021-9258(25)02727-9. [Epub ahead of print] 110875

Sertad1 is elevated and plays a necessary role in neuron loss and cognitive impairment in a mouse model of Alzheimer's disease.

Naqiya Ambareen, Kusumika Gharami, Ananya Mondal, Uday Aditya Sarkar, Subhas C Biswas.

  Aberrant activation of autophagy contributes to neuronal cell death and plays a pivotal role in the pathogenesis of Alzheimer's disease (AD). To study this further, we assessed autophagy-related proteins in 5xFAD mice at different ages and found a progressive inappropriate elevation of autophagic proteins in these mice. We identified a transcriptional coregulator, Sertad1 which plays a necessary role in neuron death, as a key regulator of aberrant autophagy in AD. We found a progressive elevation in Sertad1 levels in 5xFAD mice with age compared to wild-type (WT) mice. Sertad1 knockdown in 5xFAD mice brain lowered levels of autophagy-related proteins and lysosomal proteins, suggesting its role in the regulation of the autophagy-lysosomal pathway. We found that Sertad1 knockdown restored Akt activity which is inhibited in AD and blocked the activation of its target, FoxO3a which is translocated to the nucleus in absence of active Akt and mediates neuron death by apoptosis and autophagy. Further, we showed that lentivirus mediated RNAi targeting of Sertad1 in 5xFAD mice led to better performance in behavioural experiments compared to 5xFAD mice treated with non-targeting shRNA, accompanied by significant restoration of synaptic integrity. Overall, our results demonstrated that autophagy is robustly induced with disease progression but autophagy-related proteins accumulate in the brain due to their impaired clearance; Sertad1 knockdown restored synaptic failure and improved cognition in 5xFAD mice by enhancing clearance of autophagy-related proteins and neuronal survival. Hence, Sertad1 could be an excellent target for therapeutic intervention to combat the multifaceted pathologies of AD.

Keywords:  Alzheimer’s disease; Sertad1; autophagy; cognition; learning and memory; neurodegeneration; neuron death; synapse

DOI:  https://doi.org/10.1016/j.jbc.2025.110875
Sci Adv. 2025 Oct 31. 11(44): eady0415

Chaperone-mediated autophagy controls brown adipose tissue thermogenic activity.

Alberto Mestres-Arenas, Tania Quesada-López, Albert Blasco-Roset, Aleix Gavaldà-Navarro, Francisco J Godoy-Nieto, Rubén Cereijo, Susmita Kaushik, Antonio Diaz, Marta Giralt, Francesc Villarroya, Ana Maria Cuervo, Joan Villarroya.

Brown adipose tissue (BAT) protects against obesity, diabetes, and cardiovascular disease. During BAT activation, macroautophagy is inhibited, while chaperone-mediated autophagy (CMA) is induced, promoting thermogenic gene expression, adipokine release, oxidative activity, and lipolysis. Aging reduces BAT function and lowers levels of LAMP2A, the rate-limiting CMA component. Pharmacological CMA activation restores BAT activity in aged mice. To explore the CMA's role in BAT, we generated LAMP2A-deficient brown adipocytes and found that CMA regulates proteins essential for thermogenesis and metabolism. Blocking CMA in BAT reduced energy expenditure, raised blood triglycerides, impaired secretion, and led to an increase of thermogenesis repressors. These findings show that CMA is essential for maintaining BAT function, especially during adaptive thermogenesis. By degrading repressors of thermogenesis, CMA supports BAT activity under cold or metabolic stress. This work highlights CMA as a key regulator of BAT plasticity and a promising therapeutic target for treating age-related metabolic disorders.

DOI: https://doi.org/10.1126/sciadv.ady0415
Mol Biol Rep. 2025 Oct 29. 53(1): 22

Autophagy-senescence interplay in kidney disease: mechanistic insights and therapeutic potential.

Jiajun Sang, Kexin Zhang, Qiming Fan, Chengxia Kan, Ruiyan Pan, Xiaodong Sun, Zhentao Guo.

  Autophagy and cellular senescence are intimately linked processes that play pivotal roles in renal homeostasis, aging, and disease progression. Autophagy preserves intracellular integrity by degrading damaged organelles, misfolded proteins, and metabolic waste through lysosomal pathways, thereby maintaining energy balance and delaying senescence. However, with advancing age or persistent stress, autophagic activity declines, leading to the accumulation of senescent cells, mitochondrial dysfunction, and chronic inflammation. In the kidney, a metabolically demanding organ, this imbalance contributes to the pathogenesis of chronic kidney disease (CKD) and acute kidney injury (AKI). Senescent cells secrete a senescence-associated secretory phenotype, which amplifies inflammation, fibrosis, and tissue remodeling. The bidirectional interplay between impaired autophagy and cellular senescence exacerbates renal tubular atrophy, glomerulosclerosis, and interstitial fibrosis, thereby promoting CKD progression and maladaptive repair following AKI. Emerging therapeutic strategies, including autophagy activators, senolytics, antioxidants, and stem cell based interventions, have shown promise in restoring cellular homeostasis and delaying renal aging. Nonetheless, challenges remain in achieving cell type specific modulation while avoiding the deleterious effects of excessive activation. This review highlights recent advances in understanding the mechanistic interplay between autophagy and senescence in renal physiology and disease, outlines their contributions to CKD and AKI, and explores evolving therapeutic strategies aimed at restoring autophagic flux and eliminating senescent cells. Targeting the autophagy senescence axis represents a compelling avenue for precision therapy in kidney disease and may redefine future approaches in nephrology.

Keywords:  AKI; Autophagy; CKD; Cellular senescence

DOI:  https://doi.org/10.1007/s11033-025-11180-0
Curr Res Physiol. 2025 ;8 100166

The senescent synapse: A look at autophagy, calcium handling, and mitochondrial bioenergetics at the synapse in ageing and Parkinson's disease.

Shahzabe Mukhtar, Shikha Kataria, Gloria Cimaglia, Dayne Beccano-Kelly.

The synapse is a vitally important physiological structure fundamental to electrochemical communication between neurones, and is required for basic and important functions we perform daily. Underpinning the normal physiological function of the synapse are crucial processes such as autophagy, calcium homeostasis, and mitochondrial bioenergetics, all of which are modified during ageing. It is necessary to understand how ageing affects these processes at the synapse, from a fundamental need to understand natural ageing, and in order to identify how these processes may become aberrant and indeed, pathological, in the context of ageing-related disorders, such as Parkinson's. This review addresses the importance of the aforementioned processes, autophagy, calcium homeostasis, and mitochondrial bioenergetics at the synapse in normal physiology, and discusses how they are altered during ageing, and in Parkinson's, an example of accelerated ageing.

DOI: https://doi.org/10.1016/j.crphys.2025.100166
Life Sci. 2025 Oct 26. pii: S0024-3205(25)00691-5. [Epub ahead of print]382 124055

Disrupted proteostasis and ionic imbalance in TDP-43 and tauopathies: Dual drivers of neurodegeneration.

Tejas Bhatia, Angel Godad.

  Neurodegenerative diseases (NDDs), including Alzheimer's Disease (AD), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS), are characterized by progressive neuronal dysfunction and protein aggregation. There is a growing body of evidence suggesting that the collapse of proteostasis, the failure of protein homeostasis, is an important contributor to neurotoxicity. In this review, we suggest that this collapse is exacerbated by ionic dysregulation, an important but under-addressed cause of neurodegeneration. Importantly, breakdowns in chloride, bicarbonate, sodium, and calcium homeostasis alter fundamental aspects of cellular physiology, including important aspects of TDP-43 phase separation and tau hyperphosphorylation and aggregation. We suggest that the relationship of proteostasis failure and ionic dysregulation is a bidirectional feedback loop that accelerates the progression of neurodegeneration. Some therapeutic strategies aimed at correcting these mechanisms-including small-molecule chaperone inducers, autophagy inducers, and ion-channel modulators-might hold the potential for disease modification. In this review, we document the complex intersections of proteostasis failure and ionic dysregulation in TDP-43 and tauopathies and provide new ideas for therapies and future studies.

Keywords:  Autophagy; Bicarbonate; Chloride; Ionic dysregulation; Neurodegeneration; Phase separation; Proteostasis; TDP-43; Tau

DOI:  https://doi.org/10.1016/j.lfs.2025.124055
J Biol Chem. 2025 Oct 27. pii: S0021-9258(25)02712-7. [Epub ahead of print] 110860

Substrate recognition by the human mitochondrial processing peptidase and its processing of PINK1.

Andrew N Bayne, Danielle M Simons, Naoto Soya, Karl Grenier, Gergely L Lukacs, Edward A Fon, Jean-François Trempe.

  Nuclear-encoded mitochondrial proteins rely on N-terminal targeting sequences (N-MTS) for their import. Most N-MTSs are cleaved in the matrix by the mitochondrial processing peptidase (MPP), a heterodimeric metalloprotease composed of (α) and catalytic (β) subunits, essential for the maturation of imported proteins. Import and processing of PINK1, a kinase implicated in Parkinson's disease, govern its ability to sense mitochondrial damage. The current paradigm suggests PINK1 undergoes two sequential processing steps: first, MPP removes the PINK1 N-MTS in the matrix; second, the inner mitochondrial membrane protease PARL cleaves the PINK1 transmembrane domain, leading to PINK1 degradation. Upon depolarization, PINK1 escapes proteolysis and accumulates on mitochondria to initiate mitophagy. However, the MPP cleavage site on PINK1, the role of MPP in PINK1 signalling, and the mechanisms of substrate recognition by human MPP remain unclear. Here, we define the MPP cleavage site on PINK1 between Ala28-Tyr29 and show it is inefficiently processed compared to canonical N-MTSs. In cells, MPP cleavage is dispensable for both PARL processing and PINK1 function, decoupling PINK1 import and damage sensing from its N-MTS removal. However, in vitro, the PINK1 N-MTS binds potently to MPP, inhibits the cleavage of other substrates, and traps MPP in a slowly processing complex. Exploiting PINK1 as a mechanistic probe, we use hydrogen-deuterium exchange mass spectrometry to map the PINK1 binding site on MPPα. We identify a two-step mechanism involving MPPα lid rearrangement followed by active site engagement, providing key insight into PINK1's unique import pathway and fundamental MPP processing mechanisms.

Keywords:  PTEN-induced putative kinase 1 (PINK1); Parkinson disease; hydrogen-deuterium exchange; mitochondria; mitochondrial processing peptidase (MPP); protein import; protein processing

DOI:  https://doi.org/10.1016/j.jbc.2025.110860
Int J Mol Sci. 2025 Oct 10. pii: 9858. [Epub ahead of print]26(20):

Potential Role of Membrane Contact Sites in the Dysregulation of the Crosstalk Between Mitochondria and Lysosomes in Alzheimer's Disease.

Giulia Girolimetti, Matteo Calcagnile, Cecilia Bucci.

  Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a gradual decline in cognitive abilities and a progressive loss of the neuronal system resulting from neuronal damage and death. The maintenance of neuronal homeostasis is intricately connected to the crosstalk and balance among organelles. Indeed, intracellular organelles are not just isolated compartments in the cell; instead, they are interdependent structures that can communicate through membrane contact sites (MCSs), forming physical connection points represented by proteinaceous tethers. Mitochondria and lysosomes have fundamental physiological functions within neurons, and accumulating evidence highlights their dysfunctions as AD features, strongly associated with the neurodegenerative process underlying the development and progression of AD. This review explores mitochondria-lysosome communication through MCSs, the tethering proteins and their functions in the cell, discussing the methodological challenges in measuring the structure and dynamics of contacts, and the potential role of altered mitochondria-lysosome communication in the context of organelle dysfunction related to neuron impairment in AD pathogenesis. The different abundance of the tethering proteins was considered in healthy physiological and in AD-related conditions to assess the possible organelle communication dysregulation and the subsequent cellular function alterations, and to evaluate the role of mitochondria-lysosome MCSs in the pathogenesis of this disorder.

Keywords:  Alzheimer’s disease; lysosomes; membrane contact site; mitochondria

DOI:  https://doi.org/10.3390/ijms26209858
Cell Death Dis. 2025 Oct 31. 16(1): 772

CLN7 protein functions at the interface between endolysosomes and stress granules to promote cell survival.

Aseel Sharaireh, Marta Guevara-Ferrer, Anna M Ludlaim, Jonathan D Humphries, Alexander M Phillips, Andrew W Dowsey, Zehan Zhang, John R Counsell, Richard D Unwin, Sara E Mole, Ahad A Rahim, Tristan R McKay.

Inherited biallelic mutations in the CLN7 gene result in the variant late infantile onset neuronal ceroid lipofuscinosis, a subtype of Batten disease (BD), a severe and fatal childhood neurodegenerative disease. Intriguingly, CLN7 genetic variants have also been associated with retinopathies, amyotrophic lateral sclerosis, and frontotemporal dementia. CLN7 encodes a transmembrane protein localizing to endolysosomal membranes with outward-facing chloride channel activity. Loss of CLN7 function results in cortical neurons accumulating swollen lipofuscin-containing lysosomes, leading to neuroinflammation and neurodegeneration. The molecular mechanisms underlying CLN7 BD neuropathology are not completely understood. We have generated iPSC lines from two CLN7 BD patients and age-matched unaffected controls to interrogate intracellular molecular phenotypes in iPSC-derived neural progenitor cells (iNPC). Taking a multi-omics approach we have identified disease-modified activities in endolysosomal transport in iNPCBD that lead to lysosomal dysfunction and decreased mitophagy, resulting in the accumulation of metabolically defective mitochondria. We further observe a breakdown in nuclear functions that centre on RNA processing and nuclear export, linking to CLN7 protein interactions at the stress granule. We have identified dual and distinct functions for CLN7, promoting cell survival during the cellular stress response. CLN7 loss of function in BD results in neuronal apoptosis.

DOI: https://doi.org/10.1038/s41419-025-08063-4
Adv Sci (Weinh). 2025 Oct 27. e08096

Oral Exposure to Food-Grade Nanoparticles Poses a Risk of Alzheimer's Disease-Like Symptoms by Triggering Autophagy Defects in Neurons.

Jiaxin Shang, Jun Yan, He Lou, Xuanxi Jiang, Ziyue Wang, Yue Gao, Xiaohui Fan, Xiaoyan Lu.

  Preliminary epidemiological studies have revealed a relationship between exposure to environment-related ultrafine particles and the escalation of Alzheimer's disease (AD). Oral exposure through food is a significant route of human contact with nanoparticles; however, the potential risk of AD induced by food-grade nanoparticles and the underlying mechanisms remain largely unclear. Here, this study reveals a common mechanism by which food-grade nanoparticles, including titanium dioxide, nanosilica, and nanosilver, trigger AD-like pathological changes through epigenetic alterations. Exposure to food-grade nanoparticles triggers changes in DNA methylation and aberrant ryanodine receptor-Ca2+ signaling in the mouse brain, contributing to lysosomal impairment and disrupted autophagic flux in neurons. Crucially, these autophagy defects reduced the ability to clear β-amyloid and pTau proteins, which ultimately accumulated and triggered spatial cognition and memory deficits in mice. In conclusion, this study elucidates the shared toxicological mechanisms induced by different food-grade nanoparticles, thereby offering valuable insights into ingested nanoparticle exposure and its potential association with neurodegenerative diseases.

Keywords:  Alzheimer's disease; DNA methylation; autophagy defects; food‐grade nanoparticles; potential neurotoxicity

DOI:  https://doi.org/10.1002/advs.202508096
Cell Mol Life Sci. 2025 Oct 30. 82(1): 374

The role of the SIRT1 and mTOR pathways in exercise-induced β-cell senescence reduction in type 2 diabetes mellitus.

Rastegar Hoseini, Zahra Hoseini, Ayob Kamangar.

  Type 2 diabetes mellitus (T2DM) is characterized by insulin resistance, chronic hyperglycemia, and pancreatic β-cell dysfunction, driven in part by cellular senescence and chronic inflammation. The sirtuin 1 (SIRT1) and mechanistic target of rapamycin (mTOR) pathways play critical roles in regulating cellular metabolism, stress responses, and aging, making them key targets for mitigating β-cell senescence and T2DM progression. SIRT1, a NAD + -dependent deacetylase, enhances insulin secretion, reduces oxidative stress, and suppresses inflammation by modulating transcription factors such as NF-κB and PGC-1α. Conversely, mTOR signaling, when hyperactivated, promotes cellular senescence and metabolic dysfunction. Exercise has emerged as a potent non-pharmacological intervention. It upregulates SIRT1 activity through increased NAD⁺ levels and AMP-activated protein kinase (AMPK) activation, while also downregulating excessive mTOR signaling. These effects enhance autophagy, reduce oxidative stress, and improve mitochondrial function, thereby preserving β-cell mass and function. Preclinical and clinical studies demonstrated that exercise-induced SIRT1 activation and mTOR inhibition mitigate β-cell senescence, improve glucose homeostasis, and reduce the risk of T2DM. Pharmacological strategies targeting SIRT1 activation and mTOR inhibition, such as NAD + boosters and rapamycin analogs, show promise in preclinical models but require further clinical validation. Understanding the interplay between the SIRT1 and mTOR pathways offers novel therapeutic avenues for preserving β-cell function, preventing T2DM, and promoting healthy aging. Future research should focus on optimizing exercise regimens and developing targeted interventions to harness the synergistic benefits of SIRT1 activation and mTOR inhibition in metabolic health.

Keywords:  MTOR pathway; Metabolic modulation; SIRT1; T2DM Exercise; β-cell senescence

DOI:  https://doi.org/10.1007/s00018-025-05836-0