bims-auttor 2025-12-14 papers

bims-auttor

Biomed News

on Autophagy and mTOR

Issue of 2025–12–14
twenty-six papers selected by
Viktor Korolchuk, Newcastle University

Autophagy-NAD+ axis: emerging insights into neuronal homeostasis and neurodegenerative diseases.
Ubiquitin signaling in PINK1/Parkin-dependent mitophagy.
Antiretroviral Drugs Impact Autophagy Differently in Primary Human Astrocytes.
Molecular mechanisms underlying p62-dependent secretion of the Alzheimer-associated ubiquitin variant UBB+1.
Neuronal hyperactivity becomes mTORC1 independent due to transcriptional changes in tuberous sclerosis complex disease models.
Ubiquitin-Specific Protease 20 Promotes CCCP-Induced Mitophagy Through Deubiquitination and Stabilization of Serine/Threonine Protein Kinase PINK1.
Autophagy beyond earth: dr. Ghada Alsaleh on aging, cells, and space.
TFEB-mediated autophagy stimulation as an anabolic strategy for bone: insights from TFEB activation in the osteoblast lineage.
Retrograde signaling is required for Slm35-mediated negative regulation of mitophagy in yeast.
ESRRA-ATG5-Mediated mitophagy enhances arginine metabolism to alleviate diabetic kidney disease.
Autophagy and mitophagy in dermatological disease: a comprehensive review from molecular pathways to therapeutic frontiers.
Trans-Golgi network-associated noncanonical autophagy depends on the V-ATPase-ATG16L1 axis and mediates IL1B secretion.
Autophagy regulates PVALB (parvalbumin) interneuron excitability and memory.
A non-canonical AKT1-TERT pathway coordinates autophagy and ERphagy.
Dysregulated mTOR signaling in Alzheimer's disease: Linking pathogenic mechanisms to emerging therapeutic strategies.
Dual mechanism of autophagy gene repression by PHF23 and therapeutic potential of its inhibition in protein aggregation disorders.
Restoring autophagy flux by rolipram attenuates ototoxicity in Hearing loss.
Exercise regulates mitophagy to alleviate parkinsonian neurodegeneration.
HSPA12A impairs lipophagy to exaggerate septic cardiomyopathy by promoting MTOR's competition against LC3-II in binding with PNPLA2.
Autophagy and Mitophagy in Diabetic Retinopathy: The Effects and Mechanism of Action on the Neurovascular Unit.
Doxorubicin induces cardiotoxicity by enhancing autophagy via mTOR signaling in hiPSC- and hESC-derived cardiomyocytes.
Valproic acid boosts hair follicle stem cell resilience to oxygen-glucose deprivation through autophagy induction and AKT/mTOR suppression.
Skin deep: Unconventional autophagy eats away TNF-driven skin inflammation.
Detection and quantitation of ferritinophagy using halo-tag tracing.
Functionally diversified Caenorhabditis elegans BiP orthologs control body growth, reproduction, stress resistance, aging, and autophagy.
Differential contribution of TFE3 isoforms to cell motility and invasion.

Front Mol Biosci. 2025 ;12 1695486

Autophagy-NAD+ axis: emerging insights into neuronal homeostasis and neurodegenerative diseases.

Gamze Kocak, Mylla M Dimas, Luiz F S E Silva, Danyelle Silva-Amaral, Congxin Sun, Sophie Cruddas, Timothy Barrett, Daniel Martins-de-Souza, Edecio Cunha-Neto, Patricia S Brocardo, Tetsushi Kataura, Viktor I Korolchuk, Sovan Sarkar.

  Autophagy is an evolutionarily conserved catabolic process that plays a central role in maintaining cellular homeostasis by degrading and recycling damaged or surplus proteins, organelles, and other cellular macromolecules and components. A growing body of evidence highlights a bidirectional relationship between autophagy and nicotinamide adenine dinucleotide (NAD+), a vital metabolic cofactor involved in numerous cellular processes, including energy metabolism, genomic maintenance, stress resistance, and cell survival. Autophagy supports NAD+ homeostasis by recycling metabolic precursors, while NAD+-dependent enzymes such as sirtuins and PARPs regulate autophagy initiation and lysosomal function. Disruption of this autophagy-NAD+ axis has emerged as a common feature in several neurodegenerative diseases, where impaired cellular clearance and metabolic dysfunction contribute to neuronal vulnerability. In this review, we summarize the advances of the molecular links between autophagy and NAD+ metabolism, with a particular focus on their roles in mitochondrial quality control, bioenergetic regulation, and cellular resilience. We also discuss the therapeutic potential of targeting the autophagy-NAD+ axis to promote neuroprotection in neurodegenerative disease.

Keywords:  NAD+; NAD+ precursor; NAD+ supplementation; NAD+-dependent enzyme; autophagy; autophagy inducer; neuronal cell death; neuroprotection

DOI:  https://doi.org/10.3389/fmolb.2025.1695486
J Biochem. 2025 Dec 10. pii: mvaf079. [Epub ahead of print]

Ubiquitin signaling in PINK1/Parkin-dependent mitophagy.

Kei Okatsu, Shuya Fukai.

  Mitochondrial quality control plays a critical role in maintaining cellular homeostasis by eliminating dysfunctional mitochondria. The PINK1/Parkin-dependent mitophagy mediates the selective clearance of damaged mitochondria. Dysfunction of PINK1 and Parkin is closely linked to Parkinson's disease. Upon mitochondrial depolarization, PINK1 accumulates on the outer membrane and phosphorylates both ubiquitin and the UBL domain of Parkin to initiate a positive feedback loop of ubiquitination. Parkin catalyzes the assembly of heterogeneous ubiquitin chains on outer mitochondrial membrane proteins, which serve as signals for autophagy adaptors. These adaptors are regulated by kinases such as TANK-binding kinase (TBK1). Deubiquitinating enzymes such as USP30 act as negative regulators. Recent structural and biochemical studies have advanced our understanding of the PINK1/Parkin-dependent mitophagy. Nonetheless, important questions remain regarding the regulatory mechanisms of PINK1, the catalytic mechanism of ubiquitin chain formation by Parkin, and the recognition of ubiquitin chains by autophagy adaptors. Here, we review the current understanding and outstanding questions on the molecular mechanisms underlying the PINK1/Parkin-dependent mitophagy with a focus on ubiquitin signaling.

Keywords:  autophagy; kinase; mitophagy; ubiquitin

DOI:  https://doi.org/10.1093/jb/mvaf079
Cells. 2025 Dec 01. pii: 1904. [Epub ahead of print]14(23):

Antiretroviral Drugs Impact Autophagy Differently in Primary Human Astrocytes.

Laura Cheney, Grace McDermott, Hillary Guzik, Joan W Berman.

  While antiretroviral therapy (ART) has significantly improved the morbidity of HIV infection, ART may contribute to the pathogenesis of HIV associated neurocognitive impairment (HIV-NCI) by interfering with autophagic processes in astrocytes. Autophagy and mitophagy remove unwanted/damaged material and mitochondria from the intracellular environment, respectively. Dysregulated autophagy in astrocytes, abundant CNS cells with crucial homeostatic functions, contributes to many neurodegenerative diseases. Few studies have examined effects of ART on autophagy in astrocytes. We treated primary human astrocytes with a common ART regimen and performed LC3B-II and p62 turnover assays. ART significantly inhibited both LC3B-II and p62 turnover. Since p62, one autophagy receptor that mediates mitophagy, autophagic clearance of mitochondria, turnover was inhibited, we also examined mitophagy. While ART decreased BNIP3L/Nix homodimers, there were no changes in PINK1, Parkin, Mt-CO2, mitochondrial mass, or mitochondria-lysosome colocalization, indicating that ART did not inhibit mitophagy. We show that antiretroviral drugs have distinct effects on autophagic processes in astrocytes, which represents an alteration in their homeostasis, a major function of autophagy. This likely contributes to HIV-NCI. Understanding these impacts is important for improving ART for PWH, who have, by necessity, ongoing ART exposure. It also facilitates development of therapies for HIV-NCI that may include modulation of autophagy.

Keywords:  BNIP3L/Nix; HIV associated neurocognitive impairment; LC3B; PINK1-Parkin; antiretroviral therapy; astrocytes; macroautophagy; mitophagy; p62; selective autophagy

DOI:  https://doi.org/10.3390/cells14231904
Proc Natl Acad Sci U S A. 2025 Dec 16. 122(50): e2504528122

Molecular mechanisms underlying p62-dependent secretion of the Alzheimer-associated ubiquitin variant UBB+1.

Ajay R Wagh, Michael H Glickman.

  UBB+1, a ubiquitin variant protein resulting from a frameshift in the ubiquitin-B gene, is a pathological hallmark of Alzheimer disease (AD). At the cellular level, UBB+1 disrupts the ubiquitin-proteasome system while inducing autophagy. Notably, UBB+1 itself is secreted via autophagosome-like vesicles. Here, we demonstrate that UBB+1 can be removed from the cell by degradative and secretory autophagy. Sequestosome 1 (SQSTM1)/p62 functions as a pivotal ubiquitin receptor for UBB+1, recognizing its ubiquitin domain and facilitating loading into autophagosomes. Oligomerization of SQSTM1/p62 was critical to isolate UBB+1 in bodies preventing its aggregation. Intriguingly, both gain- and loss-of-function SQSTM1/p62 suppressed UBB+1 secretion, causing intracellular retention: SQSTM1/p62 knockout led to UBB+1 accumulation in insoluble aggregates, while its overexpression promoted the formation of p62-UBB+1 bodies. We further identified distinct roles for SNARE-mediated membrane fusion in secretory autophagy of UBB+1. Specifically, the R-SNARE SEC22B and the Q-SNAREs Syntaxin-4 and SNAP23 participated in UBB+1 exocytosis. Disruption of SEC22B impaired the fusion of UBB+1-containing autophagosomes with the plasma membrane, reducing UBB+1 secretion without affecting its intracellular turnover. Inhibition of lysosomes partially stabilized UBB+1 indicating that degradation and secretion are complementary processes that determine the fate of UBB+1. This study elucidates the dual roles of autophagy in managing neurotoxic proteins, highlighting SQSTM1/p62 as a key mediator of UBB+1 trafficking and secretion. Although ubiquitin typically acts as a degradation signal, our findings reveal a rare instance of a ubiquitin-related protein driving secretory autophagy. These findings advance our understanding of cellular mechanisms underlying the clearance of misfolded proteins in neurodegenerative diseases.

Keywords:  Alzheimer’s disease; autophagy; p62; trafficking; ubiquitin

DOI:  https://doi.org/10.1073/pnas.2504528122
Cell Rep. 2025 Dec 10. pii: S2211-1247(25)01436-6. [Epub ahead of print]44(12): 116664

Neuronal hyperactivity becomes mTORC1 independent due to transcriptional changes in tuberous sclerosis complex disease models.

Wardiya Afshar-Saber, Juan F Ruiz, Isabel Gisser, Ziqin Yang, Leena Mehendale, Nicole A Teaney, Rachel Hobson, Madison R Glass, Truc T Pham, Elizabeth Bainbridge, Mustafa Sahin, Kellen D Winden.

  Tuberous sclerosis complex (TSC) is caused by variants in either TSC1 or TSC2, which cooperate to inhibit the mechanistic target of rapamycin complex 1 (mTORC1). TSC is associated with neurological disorders that are attributed to disinhibition of mTORC1, but the mechanisms connecting dysregulation of mTORC1 to molecular and physiological changes in neurons remain unclear. In this study, we aim to understand transcriptional changes in TSC and identify downregulation of the immediate-early gene EGR1 in TSC2-deficient excitatory neurons. Furthermore, we find that activity-dependent transcription is impaired in TSC due to abnormalities in maturation-dependent DNA demethylation. Finally, we determine that mTORC1 inhibition started late in neuronal maturation of human neurons is only partially effective in reversing gene expression changes and ineffective in reducing spontaneous neuronal hyperactivity in TSC. These data demonstrate a critical window in early brain development where mTORC1 dysregulation leads to transcriptional changes that contribute to persistent neuronal abnormalities.

Keywords:  CP: molecular biology; CP: neuroscience; DNA methylation; activity-dependent transcription; mTOR complex 1; tuberous sclerosis complex

DOI:  https://doi.org/10.1016/j.celrep.2025.116664
J Mol Neurosci. 2025 Dec 13. 75(4): 162

Ubiquitin-Specific Protease 20 Promotes CCCP-Induced Mitophagy Through Deubiquitination and Stabilization of Serine/Threonine Protein Kinase PINK1.

Ga Hyun Park, Hye In Park, Donghyuk Shin, Kwang Chul Chung.

  While Parkinson's disease (PD) is predominantly sporadic, various mutations in the PTEN-induced putative kinase 1 (PINK1) gene have been linked to the autosomal recessive form of PD. PINK1, a serine/threonine protein kinase, holds a pivotal role in mitophagy - a process that selectively eliminates damaged mitochondria, overseeing mitochondrial quality control and ultimately safeguarding against neuronal cell loss in PD. Understanding the regulation of PINK1 stability is essential in comprehending PD pathology, given its involvement in a pro-survival pathway. Although some components of the ubiquitin-proteasome system (UPS) are recognized for mediating the proteolysis of PINK1, the specific enzyme(s) responsible for positively influencing PINK1 stability have remained elusive. In this study, we demonstrated that ubiquitin-specific protease 20 (USP20) functions as a novel deubiquitinating enzyme targeting PINK1. We found that USP20 positively regulates PINK1 levels by hydrolyzing Lys 48-linked polyubiquitin chains, promoting mitophagy under the treatment of mitochondrial depolarizing agent carbonyl cyanide m-chlorophenyl hydrazine (CCCP). Furthermore, CCCP treatment accelerates the deubiquitinating activity of USP20, facilitating the degradation of impaired mitochondria and enhancing mitochondrial quality control via PINK1 accumulation. Taken together, these findings unveil a novel enzyme, USP20, positively impacting PINK1 level and promoting CCCP-induced mitophagy. In addition, this study establishes a comprehensive map depicting how PINK1 can be regulated both positively and negatively through the coordinated action of multiple members in the UPS.

Keywords:  CCCP; Deubiquitinating enzyme; Mitophagy; PINK1; Parkinson’s disease; USP20; Ubiquitination

DOI:  https://doi.org/10.1007/s12031-025-02457-x
Autophagy. 2025 Dec 10.

Autophagy beyond earth: dr. Ghada Alsaleh on aging, cells, and space.

supported by Women In Autophagy

  N/A.

Keywords:  NASA; WIA; aging; interview; space innovation lab

DOI:  https://doi.org/10.1080/15548627.2025.2601858
Autophagy Rep. 2025 ;4(1): 2596422

TFEB-mediated autophagy stimulation as an anabolic strategy for bone: insights from TFEB activation in the osteoblast lineage.

Melda Onal.

  Autophagy in the osteoblast lineage is essential for bone formation and skeletal homeostasis, yet the mechanisms through which it supports bone formation remain unclear. To investigate these mechanisms and evaluate the anabolic potential of autophagy stimulation, we generated a genetic mouse model in which transcription factor EB (Tfeb), a master regulator of autophagy and lysosomal biogenesis, was elevated specifically in osteoblast-lineage cells. Tfeb elevation increased the expression of autophagy and lysosomal genes and enhanced autophagic flux in osteoblasts. Stimulation of autophagy increased bone formation in both cortical and cancellous bone compartments, leading to gains in bone mass and strength. Single-cell RNA sequencing revealed reduced osteoblast apoptosis, suggesting improved cell survival as a contributor to the observed increase in osteoblast number. Our ex vivo studies also suggest that autophagy stimulation increases proliferation of osteoblats lineage cells. In addition to increasing osteoblast number, Tfeb elevation also enhanced osteoblast function, likely by increasing transcription and translation of extracellular bone matrix components. Taken together, these findings demonstrate that elevation of Tfeb in the osteoblast lineage cells stimulates autophagy, promotes bone formation, and leads to increased bone mass and strength, supporting further investigation of TFEB or autophagy activation as a potential therapeutic strategy for osteoporosis.

Keywords:  Autophagy; bone; bone anabolic; bone formation; osteoblast; osteoprogenitor TFEB

DOI:  https://doi.org/10.1080/27694127.2025.2596422
Biol Open. 2025 Dec 10. pii: bio.062106. [Epub ahead of print]

Retrograde signaling is required for Slm35-mediated negative regulation of mitophagy in yeast.

Hilario Ruelas-Ramírez, Ariann E Mendoza-Martínez, P Abril Medina-Flores, Soledad Funes.

  Mitophagy is essential for mitochondrial quality control, selectively removing damaged or superfluous mitochondria to maintain cellular health and metabolic homeostasis. While positive regulators of mitophagy are relatively well characterized, the mechanisms governing its downregulation remain less understood. In this study, we investigate the role of Saccharomyces cerevisiae Slm35-a protein previously involved in oxidative stress response-in the regulation of mitophagy. We discovered that Slm35 is a soluble mitochondrial matrix protein and functions as a novel negative regulator of mitophagy and the mitochondrial retrograde (RTG) signaling pathway. Our results show that Slm35 modulates mitophagy through the RTG pathway, independently of Atg32 proteolytic processing by Yme1 or mitochondrial membrane potential (MMP) dissipation. Notably, Slm35 is crucial for the dynamic regulation of the RTG pathway in mitophagy-inducing conditions. These findings highlight the importance of Slm35 in fine-tuning mitochondrial quality control in response to metabolic cues and suggest a critical role for dynamic RTG pathway regulation in mitophagy control.

Keywords:  Atg32; Mitochondria; Mitochondrial retrograde signaling; Mitophagy; Yeast

DOI:  https://doi.org/10.1242/bio.062106
Autophagy. 2025 Dec 10.

ESRRA-ATG5-Mediated mitophagy enhances arginine metabolism to alleviate diabetic kidney disease.

Hongtu Hu, Qian Yang, Jijia Hu, Yanqing Fan, Zongwei Zhang, Keju Yang, Weiwei Li, Zhuan Peng, Zhaowei Chen, Guohua Ding, Wei Liang.

  Diabetic kidney disease (DKD) is increasingly recognized as a consequence of impaired mitochondrial quality control in renal tubular epithelial cells (TECs). In this study we show that the nuclear receptor ESRRA (estrogen related receptor alpha) transcriptionally activates ATG5 (autophagy related 5) to sustain PINK1 (PTEN induced kinase 1)-dependent mitophagy and preserve tubular homeostasis. ESRRA and ATG5 expression were markedly reduced in human DKD biopsies, and their abundance correlated positively with estimated glomerular filtration rate and inversely with albuminuria. Conditional deletion of Esrra in mouse tubules or CRISPR-Cas9 knockout in primary TECs suppressed mitophagy, exacerbated mitochondrial dysfunction and aggravated tubulointerstitial fibrosis, whereas tubular Esrra re-expression or Atg5 overexpression restored mitophagy and attenuated renal injury. Multi-omics and mechanistic assays identified the natural polyphenol salvianolic acid C (SAC) as a high-affinity ESRRA agonist that binds Asp326, Phe382 and Ala396, stabilizes the receptor and upregulates ATG5. SAC dose-dependently improved proteinuria, renal function, mitochondrial respiration and insulin sensitivity in db/db and high-fat diet-streptozotocin DKD models without overt toxicity. Metabolomic profiling revealed that ESRRA-ATG5-driven mitophagy targets ARG2 (arginase 2) for autophagy-lysosomal degradation, thereby shifting L-arginine flux from urea production toward nitric-oxide synthesis; exogenous L-arginine partly rescued renal injury in Esrra-deficient mice. Collectively, this study uncovers an ESRRA-ATG5 axis that couples selective mitophagy to L-arginine metabolism as a pivotal defense against DKD, and identifies SAC as a first-in-class, naturally derived ESRRA activator with therapeutic potential.

Keywords:  ATG5; Arginine metabolism; ESRRA; diabetic kidney disease; mitophagy; salvianolic acid C

DOI:  https://doi.org/10.1080/15548627.2025.2601874
Biol Direct. 2025 Dec 06.

Autophagy and mitophagy in dermatological disease: a comprehensive review from molecular pathways to therapeutic frontiers.

Luca D'Ambrosio, Maria Elisabetta Greco, Maurizio Forte, Daniele Vecchio, Sonia Schiavon, Flavio Di Nonno, Shazia Tahir, Vittorio Picchio, Claudia Cozzolino, Gianmarco Sarto, Marco Bernardi, Luigi Spadafora, Beatrice Simeone, Mattia Vinciguerra, Sebastiano Sciarretta, Giacomo Frati, Ernesto Greco, Concetta Potenza, Ilaria Proietti, Jacopo Morroni, Elisa Dietrich, Leonardo Schirone.

  Autophagy - the cell's built-in recycling and quality-control programme - touches every layer of cutaneous biology. In keratinocytes it sculpts the cornified envelope; in melanocytes it balances pigment synthesis and oxidative stress; in immune and appendageal cells it fine-tunes defence, repair and hair-follicle cycling. When this choreography falters, skin disorders emerge. This review journeys from basic mechanisms (ULK1 signalling, Beclin-1/VPS34 nucleation, LC3B lipidation, selective mitophagy) to their fingerprints in health and disease. We dissect how autophagy malfunctions drive psoriasis hyper-proliferation, atopic-dermatitis barrier leakiness, vitiligo depigmentation and the metabolic rewiring of melanoma. Non-melanoma cancers, infectious dermatoses, wound repair, ageing and photo-damage are mapped onto the same autophagic atlas. Therapeutically, the pathway is a double-edged sword. mTOR or caloric-restriction mimetics jump-start a protective flux; chloroquine derivatives and ULK1 blockers clip tumour survival circuits; cannabinoids, photodynamic therapy and immune-checkpoint combinations exploit context-specific toggling between induction and brake. Emerging biomarkers (LC3B-II, p62, AMBRA1) promise patient-stratified interventions. By weaving together molecular detail, pre-clinical insight and clinical translation, we show why autophagy is no longer a backstage process but a star player in dermatology - and how targeting its switches could reshape future treatment algorithms.

Keywords:  Autophagy; Dermatological disease; Immunodermatology; Mitophagy; Skin disorders; Skin homeostasis

DOI:  https://doi.org/10.1186/s13062-025-00703-1
Autophagy. 2025 Dec 08.

Trans-Golgi network-associated noncanonical autophagy depends on the V-ATPase-ATG16L1 axis and mediates IL1B secretion.

Jiahui Long, Huazhong Xie, Hao Shan, Ruoqing Chen, Jialing Zhong, Jiuge Tang, Dongmei Fang, Yao Wang, Peiqing Liu, Xiao-Ming Yin, Min Li.

  Formation of MAP1LC3/LC3 (microtubule associated protein 1 light chain 3)-positive structures that does not require all of the core ATG (autophagy related) proteins is emerging in the process of noncanonical autophagy (NCA). While LC3 lipidation on endolysosomal membranes has been well characterized, the involvement of other membrane sources and the regulatory mechanisms governing LC3 lipidation in alternative forms of NCA remain poorly understood. Here, we demonstrate the occurrence of LC3 lipidation on the trans-Golgi network (TGN) platform. Different from canonical autophagosomes, these LC3-positive structures do not fuse with lysosomes, and fail to degrade long-lived proteins. In addition, the functional vacuolar-type H+-translocating ATPase (V-ATPase)-ATG16L1 axis is found to be essential for TGN-associated NCA. Notably, in this process, the cytosolic but not lysosomal V1 complex of the V-ATPase assembles at the TGN and plays a pivotal role in further induction of NCA. Eventually, IL1B/IL-1β (interleukin 1 beta) secretion is found to be efficiently enhanced by such TGN-associated NCA, independently of GSDM (gasdermin)-mediated pore formation. Thus, besides the known endolysosome-related NCA, we identify a distinct form of TGN-associated NCA mediated by the V-ATPase-ATG16L1 axis. Such NCA might work as a protein-transport route for the extracellular secretion of IL1B, revealing a mechanism linking Golgi-derived NCA to inflammatory cytokines release.

Keywords:  ATG16L1; CASM; TGN; V-ATPase; membrane atg8ylation; unconventional protein secretion

DOI:  https://doi.org/10.1080/15548627.2025.2601896
Autophagy. 2025 Dec 07.

Autophagy regulates PVALB (parvalbumin) interneuron excitability and memory.

Theodora Chalatsi, Erin Wosnitzka, Angeliki Kolaxi, Laura M J Fernandez, Jules Scholler, Laura Batti, Leonardo Restivo, Graham Knott, Anita Lüthi, Manuel Mameli, Vassiliki Nikoletopoulou.

  Macroautophagy/autophagy was previously shown to play a critical role in the hippocampus for memory formation, with age-related autophagy deficits being further linked to cognitive decline. However, the neuronal subtypes where autophagy is required to form new memories remain unknown. Given the well-established role of PVALB (parvalbumin) interneurons in hippocampus-dependent memory formation and consolidation, we examined whether autophagy in these cells is required for such complex behaviors. We show that contrary to other neuronal subtypes, the vast majority of PVALB neurons, with the exception of cerebellar Purkinje cells, survive and are maintained long-term independently of autophagy. However, autophagy controls the homeostasis of mitochondria, endoplasmic reticulum, and synaptic proteins within PVALB interneurons, ultimately regulating their synaptic excitation, neuronal excitability and excitation-inhibition balance in the hippocampus. Consequently, mice with conditional impairment of autophagy in PVALB-expressing neurons exhibit impaired inhibitory neurotransmission and deficits in hippocampus-dependent memory. Taken together, these findings identify PVALB interneurons as key cellular substrates of autophagy in the context of learning and memory.

Keywords:  Cerebellum; hippocampus; inhibitory neurotransmission; memory; neuronal death; purkinje cells

DOI:  https://doi.org/10.1080/15548627.2025.2597463
bioRxiv. 2025 Nov 26. pii: 2025.11.24.690135. [Epub ahead of print]

A non-canonical AKT1-TERT pathway coordinates autophagy and ERphagy.

Vishnu Suresh Babu, Sayan Ghosh, Sridhar Bammidi, Ryu Jiwon, Ruchi Sharma, Dominique Meyer, Stacey Hose, Padmanabhan P Pattabiraman, José-Alain Sahel, Nathan J Kidley, Natércia F Braz, Martin J Slater, Stuart Lang, Arkasubhra Ghosh, Ji Yi, Srinivasa Sripathi, Kannan Rangaramanujam, Kapil Bharti, Debasish Sinha.

Protein kinases canonically suppress autophagy, yet how cells activate autophagy during stress remains unclear. Here we reveal that AKT1 kinase promotes autophagy through a non-canonical pathway. AKT2 loss triggers compensatory AKT1 activation, which phosphorylates telomerase reverse transcriptase (TERT) at Serine 824, driving nuclear translocation. Nuclear TERT assembles with FOXO3 and c-MYC into a transcriptional complex that activates PERK, initiating a feed-forward loop. PERK-ATF4 signaling amplifies autophagy gene transcription while inducing selective ERphagy through receptors TEX264 and CCPG1. Using C. elegans , mouse models, and human iPSCs, we demonstrate this AKT1-TERT-c-MYC-FOXO3 axis is evolutionarily conserved and essential for proteostasis in post-mitotic cells. We developed a first-in-class allosteric AKT2 inhibitor through structure-guided design that selectively triggers beneficial AKT1 compensation, restoring autophagy in diseased cells. These findings reveal a transcriptional mechanism linking AKT1 activation to autophagy and provide a therapeutic strategy for diseases with defective ER quality control.

DOI: https://doi.org/10.1101/2025.11.24.690135
J Alzheimers Dis. 2025 Dec 08. 13872877251400667

Dysregulated mTOR signaling in Alzheimer's disease: Linking pathogenic mechanisms to emerging therapeutic strategies.

Siqi Zhang, Tianyi Wang, Guocheng Xue, Ruwen Zheng, Ning Ding, Jing Yang, Miao Zhang.

  Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by progressive cognitive decline and multifaceted pathogenic mechanisms (including amyloid-β [Aβ] plaques, tau neurofibrillary tangles, synaptic dysfunction, and neuroinflammation). Importantly, no effective disease-modifying treatment is currently available for AD. Emerging evidence implicates dysregulated mammalian target of rapamycin (mTOR) signaling as a key contributor to AD pathogenesis. This review analyzes how aberrant mTOR signaling influences major aspects of AD pathology, including Aβ production and clearance, tau protein hyperphosphorylation, autophagy dysfunction, synaptic plasticity impairments, neuroinflammation, and oxidative stress. Notably, hyperactivated mTOR accelerates AD progression through multiple mechanisms. It promotes Aβ accumulation and tau pathology, suppresses autophagic clearance of toxic aggregates, and disrupts neuronal homeostasis, thereby exacerbating cognitive decline. Consequently, mTOR has gained attention as a therapeutic target. This review evaluates the therapeutic potential of various mTOR-targeted interventions, such as the mTORC1 inhibitor rapamycin and its analogues (rapalogs), second-generation ATP-competitive mTOR inhibitors, and certain natural compounds and traditional Chinese medicine approaches. These strategies have demonstrated promise in mitigating AD-related pathology by enhancing autophagy, reducing Aβ/tau burden, and preserving synaptic and cognitive function in preclinical studies. However, the clinical translation of mTOR-targeted therapies faces key challenges, including poor blood-brain barrier penetration of many mTOR inhibitors, potential systemic side effects, and limited clinical validation to date. Further research is needed to optimize brain delivery, dosing regimens, and target specificity to fully realize the therapeutic potential of mTOR modulation in AD.

Keywords:  Alzheimer's disease; autophagy; mTOR inhibitors; mTOR signaling pathway

DOI:  https://doi.org/10.1177/13872877251400667
Nucleic Acids Res. 2025 Nov 26. pii: gkaf1317. [Epub ahead of print]53(22):

Dual mechanism of autophagy gene repression by PHF23 and therapeutic potential of its inhibition in protein aggregation disorders.

Seon Ah Choi, Jaebeom Kim, Young Suk Yu, Jaemin Kim, Se In Kim, Hamin Bae, Junhee Kwon, Keun Il Kim, Sung Hee Baek.

Autophagy is a conserved self-digestion pathway essential for maintaining cellular homeostasis. While the transcriptional and epigenetic activation of autophagy under nutrient-deprived condition is well studied, the repression mechanisms of autophagy under basal conditions remain poorly understood. Here, we identify plant homeodomain finger protein 23 (PHF23) as an epigenetic repressor of autophagy through a CRISPR interference screen. Importantly, PHF23 inhibits autophagy gene expression via two distinct mechanisms: by recruiting the nucleosome remodeling and deacetylase (NuRD) complex to autophagy gene promoters, and by reducing chromatin accessibility at enhancers through downregulation of AP-1 and C/EBPβ transcription factors. This dual repression requires an intact plant homeodomain (PHD) and is relieved following PHF23 degradation under amino acid starvation or mTOR inhibition. Notably, genetic or pharmacological inhibition of PHF23 induces autophagy and promotes the autophagic clearance of pathological protein aggregates, including Tau and α1-antitrypsin Z (ATZ) variant, highlighting PHF23 as a potential therapeutic target in proteotoxic diseases.

DOI: https://doi.org/10.1093/nar/gkaf1317
Eur J Pharmacol. 2025 Dec 10. pii: S0014-2999(25)01227-0. [Epub ahead of print] 178473

Restoring autophagy flux by rolipram attenuates ototoxicity in Hearing loss.

Karthikeyan A Vijayakumar, Chul Ho Jang, Gwang-Won Cho.

  Sensorineural hair cell loss is one of the major contributors to hearing loss. Failure of autophagy flux has been reported as a major factor that impairs hearing sense during various ototoxic conditions. In this study we investigated whether enhancing autophagy can mitigate kanamycin and furosemide induced cytotoxicity by using rolipram to restore the autophagy flux. Upon dose dependent treatment of kanamycin and furosemide, we observed depletion in the viability and impaired autophagy flux. Treatment with the PDE4 inhibitor rolipram restored autophagy activity and significantly improved cell survival. Consistent with an autophagy dependent mechanism, the protective effect of rolipram was abolished by chloroquine or Atg7 knockdown, confirming that intact autophagy flux is required for cellular protection. In vivo, rolipram attenuated kanamycin and furosemide induced hearing loss and preserved cochlear hair cells. Notably, ribbon synapses of inner hair cells were also maintained, indicating that autophagy enhancement protected both cellular integrity and synaptic function. These findings demonstrate that restoring autophagy flux represents a viable therapeutic strategy against ototoxic injury, and identify rolipram as a potential pharmacological agent for protecting auditory cells and hearing function.

Keywords:  Autophagy; Furosemide; Hearing loss; Kanamycin; Rolipram; Sensory hair cells

DOI:  https://doi.org/10.1016/j.ejphar.2025.178473
Front Aging Neurosci. 2025 ;17 1678460

Exercise regulates mitophagy to alleviate parkinsonian neurodegeneration.

Chang Liu, Wei He, JianHua Zhang.

  Parkinson's disease (PD) is a common neurodegenerative disorder with a rising incidence in aging populations, substantially diminishing patients' quality of life. Mitochondria are central to neuronal energy metabolism, and mitophagy plays a pivotal role in maintaining mitochondrial quality by removing damaged organelles. In PD, impaired mitophagy leads to the accumulation of dysfunctional mitochondria, exacerbating oxidative stress and bioenergetic deficits and thereby accelerating disease progression. In recent years, exercise has emerged as a safe and cost-effective intervention that alleviates PD symptoms. Exercise can activate mitophagy through key signaling pathways-including AMP-activated protein kinase (AMPK)/Unc-51-like kinase 1 (ULK1) and PTEN-induced kinase 1 (PINK1)/Parkin-thereby enhancing mitochondrial function and antioxidant capacity. This review synthesizes current evidence on how exercise modulates mitophagy to confer neuroprotection in PD, providing conceptual and practical insights for non-pharmacological management strategies in neurodegenerative disease.

Keywords:  AMPK signaling; PINK1/Parkin pathway; Parkinson’s disease; exercise intervention; mitophagy

DOI:  https://doi.org/10.3389/fnagi.2025.1678460
Autophagy. 2025 Dec 08.

HSPA12A impairs lipophagy to exaggerate septic cardiomyopathy by promoting MTOR's competition against LC3-II in binding with PNPLA2.

Yunfan Li, Shijiang Liu, Xinxu Min, Hao Cheng, Xiaojin Zhang, Jiali Liu, Yudong Xia, Xiaohui Wang, Guohua Jiang, Ruijinling Hao, Chuanfu Li, Li Liu, Qiuyue Kong, Zhengnian Ding.

  Accumulation of lipid droplets (LDs) in cardiomyocytes contributes to developmentof septic cardiomyopathy, a fatal complication of critical illness in patients.Lipophagy is a selective autophagic mechanism for LD degradation. This processis inhibited by MTOR, but is activated by PNPLA2 via its binding with LC3-II toform LD-containing autophagosomes. However, optimum lipophagic interventions tomanage septic cardiomyopathy have not been developed, thus furtherinvestigation is required to identify novel regulators of lipophagy in theseptic heart. HSPA12A (heat shockprotein 12A) encodes an atypical member of the HSPA/HSP70family. Here, we report that sepsis decreased HSPA12Aexpression in cardiomyocytes, whereas cardiomyocyte-specific HSPA12Aoverexpression aggravated sepsis-induced cardiomyocyte death and cardiacdysfunction in mice. Notably, HSPA12A promoted sepsis-induced LD accumulationin cardiomyocytes. By contrast, HSPA12A inhibited lipophagy in septiccardiomyocytes, as reflected by a decreased level of LD-containing autophagosomes,a reduced content of LC3-II, and an increased level of SQSTM1/p62. In-depthmolecular analysis revealed that HSPA12A increased phosphorylation of MTOR andthus its binding to PNPLA2 on LDs. MTOR thereby competed against LC3-II inbinding with PNPLA2 to suppress LD-containing autophagosome formation subsequentlyimpairing lipophagy and ultimately promoting cardiomyocyte death to exaggerate septiccardiomyopathy. We demonstrated that MTOR competed against LC3-II in bindingwith PNPLA2 to inhibit lipophagy and also identified HSPA12A as a driver ofthis competition with MTOR to impair lipophagy for exaggerating septic cardiomyopathy. Strategiesthat inhibit HSPA12A in cardiomyocytes might be a potential therapeuticintervention for septic cardiomyopathy.

Keywords:  Cardiomyocyte; HSPA12A; MTOR; PNPLA2; lipophagy; septic cardiomyopathy

DOI:  https://doi.org/10.1080/15548627.2025.2600895
Exp Eye Res. 2025 Dec 09. pii: S0014-4835(25)00575-5. [Epub ahead of print] 110802

Autophagy and Mitophagy in Diabetic Retinopathy: The Effects and Mechanism of Action on the Neurovascular Unit.

Yuyan Ren, Huazhi Zhang, Lanqing Ping, Jingwen Tang, Yilan Li, Ziying Wang, Yapeng Wang.

  While diabetic retinopathy (DR) is the primary cause of vision impairment and blindness in people with diabetes, current treatments fail to target early pathogenic mechanisms to halt disease progression. The development of DR involves complex cellular stress responses associated with metabolic dysregulation. Recent studies have highlighted the critical functions of autophagy, particularly mitophagy, in DR and how it contributes to the malfunction of the retinal neurovascular unit (NVU) and disease progression. Emerging insights have elucidated the interplay between autophagy, ER stress, and regulatory genes such as DRAM2, with pivotal roles for mitophagy-related pathways, including PINK1/Parkin and BNIP3/NIX-FUNDC1. This review systematically organizes and analyzes recent advances in research on how autophagy and mitophagy regulate ER stress, mitochondrial homeostasis, and the function of diverse NVU cell types. We present evidence that dysregulation of these processes compromises NVU integrity and accelerates DR progression. By clarifying the molecular links between autophagy, mitophagy, and NVU dysfunction, this review offers new insights for developing precision interventions and innovative therapies for early intervention of DR.

Keywords:  Diabetic retinopathy (DR); autophagy; mitophagy; retinal neurovascular unit (NVU)

DOI:  https://doi.org/10.1016/j.exer.2025.110802
Front Cell Dev Biol. 2025 ;13 1616235

Doxorubicin induces cardiotoxicity by enhancing autophagy via mTOR signaling in hiPSC- and hESC-derived cardiomyocytes.

Minxia Ke, Hao Wang, Kailun Yang, Meng Ji, Nianmin Qi, Yuehong Wu.

   Introduction: Doxorubicin (DOX) is a highly effective anti-cancer drug, but its clinical applications are limited by its cardiotoxicity. The mechanisms underlying DOX-induced cardiotoxicity (DIC) remain incompletely understood. Human induced pluripotent stem cells (hiPSCs) and human embryonic stem cells (hESCs) offer an advanced platform for investigating DIC, as they accurately recapitulate human cardiac physiology and pathology. However, the roles and mechanisms of DIC in hiPSC-CMs and hESC-CMs, especially regarding autophagy dynamics and regulation, are still not well-defined.
Methods: Cell viability, apoptosis, reactive oxygen species production, and DNA damage were assessed. Autophagy was evaluated by transmission electron microscope, LC3-II/LC3-I ratio, and autophagy flux assays. The role of autophagy and mTOR signaling was investigated using 3-methyladenine (3-MA) and rapamycin (RAPA), respectively.
Results: DOX reduced cell viability and induced apoptosis in hiPSC-CMs and hESC-CMs. Additionally, DOX caused an increase in reactive oxygen species production and DNA damage. Furthermore, DOX significantly upregulated autophagy, confirmed by the accumulation of autophagosomes and autolysosomes, and an increase in the LC3-II/LC3-I ratio. Autophagy flux assays showed that DOX induced autophagy in a time-dependent manner. The autophagy mediated by DOX was partially attenuated by 3-MA. Moreover, this activation was due to mTOR signaling inhibition. The downregulation of mTOR signaling by RAPA increased cell death of hESC-CMs. Interestingly, minor variations in injury severity and cellular sensitivity were observed between these two models.
Conclusion: Our study uncovered the multifaceted effects of DOX on hiPSC-CMs and hESC-CMs, revealing a shared mechanism in which DOX enhances autophagy via inhibition of the mTOR signaling pathway. These findings reveal key insights into DIC pathogenesis and suggest that autophagy modulation may be a promising therapeutic strategy.

Keywords:  MTOR signaling; autophagy; cardiomyocytes; doxorubicin; human embryonic stem cells; human induced pluripotent stem cells

DOI:  https://doi.org/10.3389/fcell.2025.1616235
Sci Rep. 2025 Dec 10.

Valproic acid boosts hair follicle stem cell resilience to oxygen-glucose deprivation through autophagy induction and AKT/mTOR suppression.

Fatemeh Keshavarzi, Mohammad Saied Salehi, Sareh Pandamooz, Sanaz Dastghaib, Morvarid Siri, Mehdi Dianatpour, Afshin Borhani-Haghighi, Zohreh Mostafavi-Pour, Pooneh Mokarram.

  Stem cell-based therapy represents a promising strategy for the treatment of ischemic stroke. However, its therapeutic efficacy is limited by the poor survival and migration of transplanted stem cells within the hostile ischemic microenvironment. In this study, we investigated whether preconditioning human hair follicle-derived stem cells (HFSCs) with valproic acid (VPA) could enhance their survival and migration under ischemic-like conditions, with a particular focus on the roles of autophagy and the AKT/mTOR signaling pathway. HFSCs were pretreated with 1 mM VPA for 24, 72, or 168 h and then exposed to oxygen-glucose deprivation (OGD) as an in vitro model of ischemic injury. Rapamycin (RAPA), a known autophagy inducer, served as a positive control. VPA pretreatment significantly enhanced autophagic activity, as indicated by increased expression of Beclin 1 and LC3-II, decreased p62 accumulation, and augmented lysosome biogenesis. Concurrently, VPA suppressed the AKT/mTOR signaling pathway. These effects conferred protection against OGD-induced apoptosis and preserved cell viability. Notably, 72 h VPA preconditioning markedly improved the migration capacity of HFSCs under OGD conditions. Importantly, the cytoprotective and pro-migratory effects of VPA were abolished by chloroquine (CQ), an autophagy inhibitor, highlighting the essential role of autophagy in mediating these benefits. In conclusion, our findings demonstrate that VPA preconditioning enhances the survival and migration of HFSCs through autophagy activation and inhibition of the AKT/mTOR pathway. These results suggest that autophagy-based preconditioning strategies may improve the efficacy of stem cell therapies for ischemic stroke and warrant further translational research.

Keywords:  AKT/mTOR signaling; Autophagy; Hair follicle stem cell; Ischemic stroke; Migration; Valproic acid

DOI:  https://doi.org/10.1038/s41598-025-32125-4
Immunity. 2025 Dec 09. pii: S1074-7613(25)00510-2. [Epub ahead of print]58(12): 2920-2922

Skin deep: Unconventional autophagy eats away TNF-driven skin inflammation.

Ying Feng, Francis Ka-Ming Chan.

Tumor necrosis factor (TNF), type I interferons (IFNs), and autophagy are important biological processes, but their interactions in inflammation have not been explored. In this issue of Immunity, Priem et al. reveal that ATG9A-mediated autophagy curbs skin inflammation by suppressing STING activation and Z-DNA binding protein 1 (ZBP1)-dependent cell death.

DOI: https://doi.org/10.1016/j.immuni.2025.11.008
J Biol Chem. 2025 Dec 06. pii: S0021-9258(25)02868-6. [Epub ahead of print] 111016

Detection and quantitation of ferritinophagy using halo-tag tracing.

Sachin K Kempelingaiah, Alexandra J Straus, Grace Mavodza, Can E Senkal.

  Iron is an essential element required for critical processes such as oxygen transport, energy generation, and DNA synthesis. To be incorporated as a cofactor, iron that is stored in the cytosol within ferritin needs to be liberated by ferritinophagy. Ferritinophagy is an autophagic process in which ferritin is targeted to the lysosomes, through its interaction with nuclear receptor coactivator 4 (NCOA4) for degradation and release of labile iron. Despite its involvement in neurodegenerative diseases, anemia, cancer, and insulin resistance, a specific and sensitive method to detect ferritinophagy has been lacking. To detect and quantitate ferritinophagic flux, we generated a Halo-tagged ferritin heavy chain 1 (FTH1) construct and took advantage of stabilization of Halo fragment in the presence of its fluorescently labelled ligand. Stably expressed Halo-FTH1 operated identical to its endogenous counterpart. More importantly, using pulse-chase settings lysosomal accumulation of Halo fragment after induction of ferritinophagy was detected and quantitated by in-gel fluorescence, immunoblotting, and microscopic analyses. Finally, we found that silencing of NCOA4 prevented accumulation of TMR-Halo fragment and degradation of endogenous FTH1 under ferritinophagic conditions, confirming the specificity of our assay. Together, the HaloTag-FTH1 tool we generated can be used to specifically detect and quantitate ferritinophagy in mammalian cells with a fluorescent Halo-ligand, and this approach can be instrumental in studies focusing on cellular iron metabolism.

Keywords:  FTH1; Ferritin; Ferritinophagy; Halo-tag; NCOA4

DOI:  https://doi.org/10.1016/j.jbc.2025.111016
Nat Commun. 2025 Dec 12. 16(1): 11094

Functionally diversified Caenorhabditis elegans BiP orthologs control body growth, reproduction, stress resistance, aging, and autophagy.

Nicholas D Urban, Shannon M Lacy, Kate M Van Pelt, Benedict Abdon, Zachary Mattiola, Adam Klaiss, Sarah Tabler, Eric K F Donahue, Kristopher Burkewitz, Matthias C Truttmann.

Cellular systems governing protein folding depend on functional redundancy and diversification to maintain proteostasis. Here, using Caenorhabditis elegans, we show two homologous ER-resident HSP70 chaperones, HSP-3 and HSP-4, have overlapping and distinct roles in ER proteostasis and organismal physiology. Their expression and function vary by tissue, age, and stress, impacting ER stress resistance, reproduction, body size, and lifespan. We also find HSP-3 and HSP-4 uniquely regulate dietary restriction and reduced insulin signaling-mediated longevity in C. elegans. Notably, knockdown of hsp-4, but not hsp-3, induces autophagy and enhances tolerance to protein aggregation stress; this process requires the ortholog of ER-Phagy receptor Sec-62 (C18E9.2) and IRE-1. Finally, human cell data suggests that the dissociation of chaperone Binding Immunoglobulin Protein (BiP) from IRE-1 during times of ER stress promotes autophagy by enhancing the interaction of IRE-1 and Sec-62. These findings reveal how ER chaperone diversification maximizes stress resilience and suggest a BiP-dependent regulation of autophagy.

DOI: https://doi.org/10.1038/s41467-025-65998-0
EMBO Rep. 2025 Dec 08.

Differential contribution of TFE3 isoforms to cell motility and invasion.

Pablo S Contreras, José A Martina, Katie Rollins, Eutteum Jeong, Alberto Rissone, Rosa Puertollano.

  TFE3 orchestrates cellular responses to a variety of stress conditions, promoting restoration of cellular homeostasis and cell survival. Here we report the presence of two different TFE3 isoforms generated by the use of alternative transcription initiation sites. The long isoform (TFE3-L) undergoes continuous proteolytic degradation due to the presence of a phosphodegron in its N-terminal region and only accumulates under specific stress conditions. In contrast, the short isoform (TFE3-S) lacks the first 105 residues containing the phosphodegron and is constitutively expressed at high levels in most cell types. Both isoforms share the same Rags/mTORC1-dependent mechanism of regulation and display comparable capacity of inducing expression of lysosomal and autophagic genes upon activation. However, TFE3-L is considerably more efficient than TFE3-S promoting cell migration and invasion. Accordingly, specific TFE3-L depletion in a cellular model for tuberous sclerosis causes a significant reduction in cell motility and invasiveness. Our data reveal that the two TFE3 isoforms exhibit partial redundancy and that the appearance of TFE3-L following prolonged stress potentially correlates with metastatic behaviors.

Keywords:  Autophagy; Isoforms; Lysosomes; Motility; TFE3

DOI:  https://doi.org/10.1038/s44319-025-00659-3