bims-auttor 2025-07-27 papers

bims-auttor

Biomed News

on Autophagy and mTOR

Issue of 2025–07–27
forty-one papers selected by
Viktor Korolchuk, Newcastle University

Secretory autophagy mediates lysosomal and autophagic degradation for α-synuclein proteostasis.
Bidirectional Regulation of Neuronal Autophagy in Ischemic Stroke: Mechanisms and Therapeutic Potential.
PSAT1 inhibits mTORC1 activation by preventing Rag heterodimer formation in lung adenocarcinoma.
Sirtuins in mitophagy: key gatekeepers of mitochondrial quality.
Coping with stress: the essential role of brain autophagy in emotional homeostasis.
TM9SF3 is a mammalian Golgiphagy receptor that safeguards Golgi integrity and glycosylation fidelity.
Unraveling the mystery: How autophagy deficiency in dopaminergic neurons drives human Parkinson's disease.
The V-ATPase a3 subunit deficiency affects osteoarthritis via mTOR-Mediated autophagy levels in subchondral bone.
Npl3 is required for efficient autophagosome-vacuole fusion.
An overview of autophagy inhibition as a potential clinical strategy in cancer therapy.
Taurine ameliorates viral encephalitis by restoring PRKN-mediated mitophagy.
Ceramide and the membrane-fusion activity of LC3/GABARAP autophagy proteins.
TFEB overexpression alleviates autophagy-lysosomal deficits caused by progranulin insufficiency.
The rapidly expanding role of LC3-interacting regions in autophagy.
Mechanistic insights into the iron-sulfur cluster-dependent interaction of the autophagy receptor NCOA4 with the E3 ligase HERC2.
TRAF2 binds to TIFA via a novel motif and contributes to its autophagic degradation.
Autophagy and Cellular Senescence in Alzheimer's Disease: Key Drivers of Neurodegeneration.
Structural insights into cholesterol sensing by the LYCHOS-mTORC1 pathway.
Therapeutic potential of melatonin-induced mitophagy in the pathogenesis of Alzheimer's disease.
mTORC1 senses glutamine and other amino acids through GCN2.
ATG8ylation-mediated tonoplast invagination mitigates vacuole damage.
Mortalin and PINK1/Parkin-Mediated Mitophagy Represent Ovarian Cancer-Selective Targets for Drug Development.
Interplay of neuropeptide Y and autophagy in Alzheimer's disease: Therapeutic perspectives and mechanistic insights.
PTEN-L dephosphorylates Parkin and Ub Ser65 to aggravate mitophagy dysfunction in prion disease cell models.
PERK and IRE1α promote exosome secretion via blocking lysosomal degradation of multiple vesicular body.
FNIP1 Deficiency: Pathophysiology and Clinical Manifestations of a Rare Syndromic Primary Immunodeficiency.
Endosome-ER contact sites in phagophore formation.
Regulation of autophagy and its role in late preimplantation during mouse embryo development.
AHSA1/Hsp90α complex facilitates microglial mitophagy by targeting TOMM70 in Parkinson's disease.
Rapamycin Does Not Compromise Exercise-Induced Muscular Adaptations in Female Mice.
PNPLA7 mediates Parkin-mitochondrial recruitment in adipose tissue for mitophagy and inhibits browning.
PDK4 and nutrient responses explain muscle specific manifestation in mitochondrial disease.
NAD+-Boosters Improve Mitochondria Quality Control In Parkinson's Disease Models Via Mitochondrial UPR.
PEAK1 maintains tight junctions in intestinal epithelial cells and resists colitis by inhibiting autophagy-mediated ZO-1 degradation.
Stressful situations: molecular insights on mitochondrial quality control pathways.
Inhibition of anti-apoptotic Bcl-2 family members promotes synergistic cell death with ER stress inducers by disrupting autophagy in glioblastoma.
Computational Approaches for Delineating Lysosomes and Related Intracellular Trafficking Vesicles in Confocal and Other Fluorescence Datasets.
Autophagy inhibition in LGALS9-overexpressing nasopharyngeal carcinoma unleashes immune response.
DSS1 inhibits autophagy to activate epithelial-mesenchymal transition in a pro-metastatic niche of renal cell carcinoma.
Molecular features of TNBC govern heterogeneity in the response to radiation and autophagy inhibition.
The Evolution of Alzheimer's Disease: From Mitochondria to Microglia.

J Biol Chem. 2025 Jul 17. pii: S0021-9258(25)02324-5. [Epub ahead of print] 110474

Secretory autophagy mediates lysosomal and autophagic degradation for α-synuclein proteostasis.

Taiki Sawai, Yoshitsugu Nakamura, Shigeki Arawaka.

  Autophagy has two distinct pathways, degradation and secretion. Autophagic degradation plays a pivotal role in proteostasis. However, the role of autophagic secretion in proteostasis maintenance is not fully understood. Here, we investigate how the blockade of autophagic secretion impairs proteostasis in SH-SY5Y cells. siRNA-mediated knockdown of a modulator for autophagosome formation, ATG5, BECN1 or FIP200 inhibited autophagic flux and secretion, causing accumulation of Triton X-100-insoluble α-synuclein, which is an aggregate-prone protein responsible for neuronal loss in Parkinson's disease. The blockade of autophagic secretion by knockdown of t-SNARE SNAP23 or STX4 increased autophagic flux for p62 degradation, but these knockdowns induced enlargement and membrane damage of lysosomes as well as lysosomal dysfunction. SNAP23 or STX4 knockdown caused accumulation of Triton X-100-insoluble α-synuclein against induction of lysophagy. GBA knockdown showed lysosomal damage with the increase in autophagic secretion. RAB8A, a small GTPase regulator of polarized sorting to the plasma membrane, knockdown blocked autophagic secretion and produced lysosomal damage. SNAP23, STX4 or RAB8A knockdown further accelerated accumulation of Triton X-100-insoluble α-synuclein caused by a lysosomal protease inhibitor cocktail. Collectively, these findings suggest that SNAP23, STX4 or RAB8A knockdown blocks autophagic secretion and upregulates autophagic flux as a compensatory response to help maintain degradation. However, these knockdowns impair α-synuclein proteostasis because of lysosomal damage that they induce, counteracting compensatory effects of autophagic degradation, including lysophagy. Autophagic secretion and degradation may collaboratively form the clearance pathway required for maintaining lysosomal function by reducing the burden of aggregate-prone protein cargo.

Keywords:  Parkinson disease; autophagy; lysosome; protein secretion; proteostasis; synuclein

DOI:  https://doi.org/10.1016/j.jbc.2025.110474
Ageing Res Rev. 2025 Jul 22. pii: S1568-1637(25)00188-6. [Epub ahead of print] 102842

Bidirectional Regulation of Neuronal Autophagy in Ischemic Stroke: Mechanisms and Therapeutic Potential.

Yige Wu, Zhu Li, Tao Ding, Yunqi Yang, Congmin Wei, Shanshan Zhang, Xiang Fan.

  Ischemic stroke, characterized by cerebral blood flow disruption, triggers complex pathophysiological responses where neuronal autophagy plays a bidirectional regulation role in neuroprotection and injury. Autophagy, activated by energy deprivation, hypoxia, and endoplasmic reticulum stress, dynamically regulates neuronal survival through selective autophagy (e.g., mitophagy, endoplasmic reticulum-phagy, ferritinophagy) of damaged organelles and protein aggregates. Early-stage moderate autophagy exerts neuroprotection by clearing cytotoxic aggregates and maintaining metabolic homeostasis, while excessive or prolonged autophagy exacerbates neuronal death via energy depletion and activation of apoptosis/ferroptosis pathways. Key regulatory mechanisms involve AMPK/mTOR, PI3K/AKT, HIF-1, and MAPK signaling, which modulate autophagic flux and crosstalk with oxidative stress, inflammation, and mitochondrial dynamics. Notably, selective autophagy pathways exhibit spatiotemporal specificity: mitophagy via PINK1/Parkin and BNIP3/FUNDC1 balances mitochondrial quality control, while ferritinophagy-mediated iron dysregulation drives ferroptosis. Pharmacological interventions targeting autophagy-related pathways (e.g., rapamycin, 3-MA, NCOA4 inhibitors) or natural compounds (e.g., Ginkgolide B, HSYA) demonstrate therapeutic potential by fine-tuning autophagic activity. However, challenges remain in defining optimal autophagy thresholds and translating preclinical findings to clinical applications. This review highlights the critical importance of spatiotemporal regulation of neuronal autophagy to develop precise neuroprotective strategies for ischemic stroke, with a particular focus on the interaction between autophagy modulators and the pathophysiological mechanisms of ischemia.

Keywords:  Endoplasmic Reticulum Stress; Ferritinophagy; Ischemic Stroke; Mitophagy; Neurons; Selective Autophagy

DOI:  https://doi.org/10.1016/j.arr.2025.102842
Autophagy. 2025 Jul 23. 1-16

PSAT1 inhibits mTORC1 activation by preventing Rag heterodimer formation in lung adenocarcinoma.

Yuhan Liu, Zhujun Cheng, Jinjin Zhang, Yi Zhang, Tao Zhao, Longhua Sun, Guilan Wen, Tianyu Han, Jianbin Wang.

  The mechanistic target of rapamycin complex 1 (mTORC1) integrates environmental cues, especially amino acids, to regulate metabolism and ultimately cancer progression. Phosphoserine aminotransferase 1 (PSAT1) is a key enzyme in de novo serine synthesis and its overexpression has been reported to promote oncogenesis in various cancers. Knockdown of PSAT1 inhibits the proliferation and migration of cancer cells. However, our study found an interesting phenomenon that either PSAT1 overexpression or knockout promoted cell proliferation in lung adenocarcinoma (LUAD) which seemed to contradict traditional views. The mechanism was that PSAT1 preferentially bound to GTP-loaded RagB GTPases, preventing the formation of Rag heterodimers. This restricted the lysosome localization of mTORC1 and enhanced the basal level of macroautophagy/autophagy, which promoted the proliferative ability of LUAD cells. PSAT1 knockout resulted in Rag heterodimer formation and mTORC1 activation, promoting protein synthesis and cell proliferation. Additionally, PSAT1 knockout caused a compensatory upregulation of the serine transporter solute carrier family 1 member 5 (SLC1A5), increasing exogenous serine uptake. In conclusion, our study reveals a novel function of PSAT1 in regulation of mTORC1 that affects the proliferation of LUAD cells.Abbreviations: ATG5: autophagy-related 5; BECN1: Beclin 1; CQ: chloroquine; 4EBP1: eukaryotic translation initiation factor 4E binding protein 1; GAP: GTPase-activating protein; GDP: Guanosine nucleotide diphosphate; GTP: Guanosine triphosphate; GTPase: guanosine triphosphatase; LAMP2: lysosome-associated membrane protein 2; LC3: microtubule-associated protein 1 light chain-3, LUAD: lung adenocarcinoma; mTORC1: mechanistic target of rapamycin complex 1; PCC: Pearson's correlation coefficient; PSAT1: Phosphoserine aminotransferase 1; Rag: Ras-related GTP binding; Raptor: regulatory-associated protein of mTOR; S6: ribosomal protein S6; S6K1: substrates S6 kinase 1; SLC1A5: solute carrier family 1 member 5; SSP: serine biosynthetic pathway; ULK1: unc-51 like autophagy activating kinase 1.

Keywords:  Autophagy; PSAT1; lung adenocarcinoma; mTORC1; rag GTPases

DOI:  https://doi.org/10.1080/15548627.2025.2535765
Mol Cell Biochem. 2025 Jul 24.

Sirtuins in mitophagy: key gatekeepers of mitochondrial quality.

Francisco Alejandro Lagunas-Rangel.

  Mitochondria are highly dynamic organelles essential for cellular energy production. However, they are also a primary source of reactive oxygen species, making them particularly vulnerable to oxidative damage. To preserve mitochondrial integrity, cells employ quality control mechanisms such as mitophagy, a selective form of autophagy that targets damaged or dysfunctional mitochondria for degradation. Among the key regulators of mitophagy are the sirtuins, a family of NAD+-dependent deacetylases. SIRT1, SIRT3, and SIRT6 generally promote mitophagy, whereas SIRT2, SIRT4, SIRT5, and SIRT7 often act as negative regulators. Sirtuin-mediated regulation of mitophagy is critical for maintaining cellular homeostasis and is implicated in a variety of physiological and pathological conditions. The aim of this review is to provide an overview focused on describing how sirtuins influence the mitophagy process. It highlights the different molecular mechanisms by which individual members of the sirtuin family modulate mitophagy, either by promoting or suppressing it, depending on the context. In addition, the review explores the relevance of sirtuin-regulated mitophagy in health and disease, emphasizing some conditions under which altered sirtuin activity could be harnessed for therapeutic benefit.

Keywords:  FOXO transcription factors; Mitochondria; PINK1-PARKIN pathway; Receptor-mediated mitophagy; Ubiquitin-mediated mitophagy

DOI:  https://doi.org/10.1007/s11010-025-05358-0
Autophagy. 2025 Aug;21(8): 1621-1622

Coping with stress: the essential role of brain autophagy in emotional homeostasis.

Dimitra Dialynaki, Daniel J Klionsky.

DOI: https://doi.org/10.1080/15548627.2025.2520091
Autophagy. 2025 Jul 25.

TM9SF3 is a mammalian Golgiphagy receptor that safeguards Golgi integrity and glycosylation fidelity.

Jiejie Yang, Yixian Cui.

  Selective autophagy of the Golgi apparatus, or Golgiphagy, depends on receptor proteins that recognize and deliver fragmented Golgi membranes into phagophores for lysosomal degradation. We recently identified TM9SF3, a Golgi-resident transmembrane protein, as a receptor mediating this process under nutrient stress and various Golgi stress conditions. TM9SF3 binds to all six mammalian Atg8 (ATG8) proteins via multiple N-terminal LC3-interacting regions (LIRs). Knockout of TM9SF3 inhibits nutrient stress-induced Golgi fragmentation, reduces autophagic delivery of Golgi components, and hinders Golgi protein degradation. In addition to nutrient stress, TM9SF3 is essential for Golgiphagy induced by monensin, brefeldin A, and glycosylation perturbations. Knockout or LIR mutation of TM9SF3 disrupts protein glycosylation, whereas its overexpression promotes the degradation of aberrantly glycosylated proteins. Notably, TM9SF3 promotes breast cancer cell proliferation, and its high expression correlates with poor patient prognosis. Our findings establish TM9SF3 as a Golgiphagy receptor essential for maintaining Golgi integrity and glycosylation fidelity, and implicate its role in supporting cancer progression.

Keywords:  Atg8 (ATG8); TM9SF3; breast cancer; golgiphagy; protein glycosylation; receptor

DOI:  https://doi.org/10.1080/15548627.2025.2539928
Mol Brain. 2025 Jul 24. 18(1): 66

Unraveling the mystery: How autophagy deficiency in dopaminergic neurons drives human Parkinson's disease.

Sachiko Noda, Nobutaka Hattori.

  Alpha-synuclein (α-synuclein), a key component of Lewy body pathology, is a classical hallmark of Parkinson's disease. In previous studies, our group has examined dopaminergic neuron-specific Atg7 autophagy-deficient mice, observing α-synuclein aggregation in vivo. This pathological process led to dopamine neuron loss and age-related motor impairments. Further, in a recent study, we developed a new mouse model by crossing human α-synuclein bacterial artificial chromosome transgenic mice with dopaminergic neuron-specific Atg7 conditional knockout mice to further investigate these mechanisms. These model mice exhibited accelerated Lewy body-like pathology and motor dysfunction, providing additional evidence that autophagy deficiency exacerbates synuclein toxicity in vivo. This nano-review provides essential clues that autophagy deficiency in dopamine neurons may contribute to the onset of human synuclein diseases.

Keywords:  Autophagy; Dopaminergic neurons; Parkinson’s disease; Α-synuclein

DOI:  https://doi.org/10.1186/s13041-025-01235-5
Biochem Pharmacol. 2025 Jul 18. pii: S0006-2952(25)00445-9. [Epub ahead of print] 117180

The V-ATPase a3 subunit deficiency affects osteoarthritis via mTOR-Mediated autophagy levels in subchondral bone.

Jianxin Qiu, Xiaohang Zheng, Jiajing Ye, Tao Yang, Xiaotong Wei, Ting Jiang, Yuhang Gong, Zhenghua Hong, Haixiao Chen, Jie Xiang.

  Autophagy is an evolutionarily conserved cellular self-degradation process that eliminates damaged organelles and misfolded proteins, thereby maintaining cellular homeostasis and delaying apoptosis and tissue degeneration. The efficient progression of autophagy depends on the maintenance of intracellular homeostasis, in which vacuolar ATPases (V-ATPases) play a crucial role by facilitating lysosomal acidification. Among these, the a3 subunit of V-ATPase, encoded by the T-cell immune regulator 1 (TCIRG1, also known as ATP6V0a3), is highly expressed in osteoclasts. However, its regulatory function in osteoarthritis (OA) remains largely unexplored. Our study found a reduction in TCIRG1 expression in the subchondral bone of OA patients and DMM (destabilization of the medial meniscus) mice. Additionally, TCIRG1 heterozygous knockout (HET) mice exhibited an abnormally thickened subchondral bone phenotype and impaired bone resorption. TCIRG1 is critical for lysosomal acidification and facilitates the completion of autophagy by promoting the fusion of late phagosomes with lysosomes. We further used rapamycin to restore partial autophagy and found that the treatment restored osteoclast resorption and also protected the articular cartilage matrix. Our findings demonstrate that TCIRG1 contributes to OA progression through regulation of autophagic activity. The results offer novel mechanistic insights into OA pathogenesis and support the potential of TCIRG1 as both a therapeutic target and a diagnostic biomarker.

Keywords:  Autophagosome-lysosome fusion; Autophagy; Bone resorption; Osteoarthritis; TCIRG1; mTOR

DOI:  https://doi.org/10.1016/j.bcp.2025.117180
Autophagy. 2025 Jul 23.

Npl3 is required for efficient autophagosome-vacuole fusion.

Zhangyuan Yin, Zhihai Zhang, Xu Liu, Daniel J Klionsky.

  Macroautophagy/autophagy is a highly conserved catabolic membrane trafficking process through which various intracellular constituents, from proteins to organelles, are targeted for vacuolar/lysosomal degradation. Autophagy is tightly regulated both temporally and in magnitude at multiple levels to prevent either excessive or insufficient activity. To date, only a few RNA-binding proteins have been characterized as regulating the expression of genes essential for autophagy, and the contribution of post-transcriptional regulation in autophagy activity remains poorly understood. Here, through a genetic screen for autophagy-defective mutants, we identified Npl3, a nucleus-cytoplasm shuttling mRNA-binding protein, as essential for both bulk and selective types of autophagy. Deletion of NPL3 does not affect autophagosome biogenesis, closure, or maturation; however, it severely impairs autophagosome-vacuole fusion and results in minimal autophagosome turnover. We further demonstrated that this regulation depends on the RNA-binding domain of Npl3 and its capability for nuclear re-import. Together, our results reveal a novel layer of post-transcriptional regulation of autophagy.

Keywords:  Autophagy; RNA-binding protein; membrane trafficking

DOI:  https://doi.org/10.1080/15548627.2025.2537559
Mol Pharmacol. 2025 Jun 13. pii: S0026-895X(25)15316-9. [Epub ahead of print]107(8): 100056

An overview of autophagy inhibition as a potential clinical strategy in cancer therapy.

Ahmed M Elshazly, Nayyerehalsadat Hosseini, Aya A Elzahed, David A Gewirtz.

  Autophagy is a cellular process responsible for the recycling of misfolded proteins and damaged organelles, contributing to cellular homeostasis and energy production. Tumor cells often exploit this mechanism, particularly through the form of autophagy that is cytoprotective, to survive endogenous and exogenous stress and resist chemotherapeutic agents as well as radiation therapy. Although several autophagy inhibitors have been developed to block the protective form of autophagy, their clinical application is often limited due to a lack of selectivity and significant side effects. In addition to the cytoprotective form, cytotoxic, cytostatic, and nonprotective functions of autophagy have been identified. In this review, we summarize a series of publications, largely from our own laboratory, exploring how various antineoplastic agents trigger different forms of autophagy and assess whether autophagy inhibition or modulation could serve as an effective adjuvant approach to enhance therapeutic responses. Furthermore, we discuss recent advancements in the autophagy field and the potential for improving cancer therapeutic strategies. SIGNIFICANCE STATEMENT: This work provides an overview of our previous work investigating the different forms of autophagy induced by various antineoplastic modalities across different tumor models. The purpose of this effort is to draw tentative conclusions regarding the potential of targeting autophagy as a strategy to enhance the efficacy of these therapeutic agents. Additionally, we offer insights into recent advances in the autophagy field.

Keywords:  Autophagy; Cancer; Clinical trials; Cytoprotective; Resistance

DOI:  https://doi.org/10.1016/j.molpha.2025.100056
Autophagy. 2025 Jul 24. 1-3

Taurine ameliorates viral encephalitis by restoring PRKN-mediated mitophagy.

Xiaowei Song, Yifei Wang, Kai Zheng.

  Mitophagy is a selective type of autophagy that removes damaged mitochondria to maintain mitochondrial homeostasis and regulate the antiviral immune response. Despite increasing evidence that herpes simplex virus type 1 (HSV-1) infection causes mitochondrial damage, the regulatory mechanisms governing mitochondrial homeostasis and its biological implications in the context of HSV-1 infection and viral encephalitis remain unclear. In our recent work, we find that HSV-1 infection causes the accumulation of damaged mitochondria via defective mitophagy in vitro and in brain tissue of mice. The viral proteins ICP34.5 and US11 inhibit the EIF2S (eukaryotic translation initiation factor 2 subunit alpha)-ATF4 (activating transcription factor 4) axis to transcriptionally suppress PRKN/Parkin expression and subsequently impede PRKN-dependent mitophagy. Consequently, modulation of mitophagy significantly affects HSV-1 infection and NFKB/NF-κB-mediated neuroinflammation, as well as the severity of viral encephalitis in mice. Moreover, taurine, a metabolite differentially regulated by HSV-1 infection, transcriptionally promotes PRKN-mediated mitophagy, thereby limiting HSV-1 infection both in vitro and in vivo. This work reveals a protective function of mitophagy in restricting viral encephalitis and highlights the ATF4-PRKN axis as a potential therapeutic approach for the treatment of neurotropic virus-related diseases.Abbreviations: Aβ: amyloid β protein; AD: Alzheimer disease; ATF4: activating transcription factor 4; EIF2AK2/PKR: eukaryotic translation initiation factor 2 alpha kinase 2; EIF2S1: eukaryotic translation initiation factor 2 subunit alpha; HSE: herpes simplex encephalitis; HSV-1: herpes simplex virus type 1.

Keywords:  EIF2S1-ATF4 axis; PRKN; herpes simplex encephalitis; mitophagy; neuroinflammation; taurine

DOI:  https://doi.org/10.1080/15548627.2025.2538767
Cell Mol Life Sci. 2025 Jul 19. 82(1): 283

Ceramide and the membrane-fusion activity of LC3/GABARAP autophagy proteins.

Yaiza R Varela, Camila C Aguirre, Marina N Iriondo, Uxue Ballesteros, M Isabel Collado, Asier Etxaniz, L Ruth Montes, Felix M Goñi, Alicia Alonso.

  Macroautophagy is a cellular degradation process characterized by the formation of the double-membrane structure termed autophagosome (AP). The process of AP formation is not fully understood, but it is thought to happen through the combined action of direct lipid transfer and incorporation of new vesicles to the edges of the growing structure. Human LC3/GABARAP autophagy-related proteins are known to induce vesicle tethering and lipid mixing in vitro, which makes them suitable for the latter expansion mechanism. Ceramide (Cer) is a sphingolipid previously described to facilitate membrane fusion. Cer has also been related to macroautophagy modulation previously, although its specific role remains unclear. Moreover, the presence of sphingolipids in the AP has been suggested by recent experiments, increasing the relevance of Cer in macroautophagy. The present work has investigated the potential role that Cer could have on the proposed fusion of new vesicles to the nascent AP membrane. Interaction of purified ATG proteins with lipid vesicles of defined composition has been quantified using fluorescence spectroscopic techniques. Our results suggest that, if present, Cer could promote the vesicle tethering and leakage-free intervesicular lipid mixing induced by GABARAP and GABARAPL1, which would in turn mediate AP membrane expansion.

Keywords:  Autophagosome; Autophagy; Ceramide; LC3/GABARAP; Membrane fusion

DOI:  https://doi.org/10.1007/s00018-025-05811-9
Sci Rep. 2025 Jul 19. 15(1): 26217

TFEB overexpression alleviates autophagy-lysosomal deficits caused by progranulin insufficiency.

Wren O Nader, Kaylan S Brown, Nicholas R Boyle, Azariah K Kaplelach, Shaimaa M Abdelaziz, Skylar E Davis, Qays Aljabi, Ahmad R Hakim, Amelia G Davidson, Giacynta A Vollmer, Leah C Wright, J Bailey Echols, Joelle Saad, Nicholas S Pena, Andrew E Arrant.

  Progranulin is a pro-protein that is necessary for maintaining lysosomal function. Loss-of-function progranulin (GRN) mutations are a dominant cause of frontotemporal dementia (FTD). Brains of people with FTD due to GRN mutations accumulate lysosomal storage material and exhibit increased expression of lysosomal transcripts, which may be driven by TFEB and related transcription factors. While this may be a compensatory response to lysosomal impairment, overproduction of lysosomal proteins may also contribute to FTD pathogenesis. To investigate how TFEB may contribute to disease in people with GRN mutations, we analyzed the effects of TFEB overexpression in progranulin-insufficient cells and mice. We generated GRN knockout HEK-293 cells (GRN KO cells), which exhibited increased nuclear localization of TFEB and expression of lysosomal transcripts, but impaired autophagy. TFEB overexpression in GRN KO cells further increased lysosomal transcripts and partially normalized autophagy. We next injected an AAV vector expressing mouse Tfeb (AAV-TFEB) into the thalamus of Grn-/- mice, which accumulates lysosomal storage material. AAV-TFEB increased lysosomal transcripts and reduced immunoreactivity for SCMAS, a marker of lysosomal storage material, in Grn-/- thalamus. These data show that TFEB activity alleviates some autophagy-lysosomal deficits caused by progranulin insufficiency, suggesting potential utility of lysosome-based therapies for GRN-associated diseases.

Keywords:  Autophagy; Lysosomes; Progranulin; TFEB

DOI:  https://doi.org/10.1038/s41598-025-12268-0
J Cell Biol. 2025 Aug 04. pii: e202504076. [Epub ahead of print]224(8):

The rapidly expanding role of LC3-interacting regions in autophagy.

Brian J North, Dorotea Fracchiolla, Michael J Ragusa, Sascha Martens, Christopher J Shoemaker.

LC3-interacting regions (LIRs), or Atg8-interacting motifs (AIMs), are short linear motifs found in unstructured loops or intrinsically disordered regions of many autophagy-related proteins. LIRs were initially identified for their role in binding to Atg8 family proteins on autophagosomal membranes. However, emerging evidence suggests that LIRs and their surrounding residues mediate interactions with a wide array of proteins beyond Atg8s. This broadens the biological significance of LIRs in autophagy, rendering them an organizing principle of the autophagy machinery. In this perspective, we explore recent advances highlighting the multifunctional roles of LIRs, including their capacity to mediate binding with diverse factors. We discuss insights into the mechanisms underlying LIR-mediated interactions and propose an updated model to explain Atg8 diversification in higher eukaryotes. We conclude by addressing key challenges and outlining future directions for understanding LIR biology and its broader implications for cellular homeostasis.

DOI: https://doi.org/10.1083/jcb.202504076
Proc Natl Acad Sci U S A. 2025 Jul 29. 122(30): e2510269122

Mechanistic insights into the iron-sulfur cluster-dependent interaction of the autophagy receptor NCOA4 with the E3 ligase HERC2.

Haobo Liu, Liqiang Shen, Xinyu Gong, Xindi Zhou, Yichao Huang, Yuqian Zhou, Zhenpeng Guo, Hanbo Guo, Shichao Wang, Lifeng Pan.

  NCOA4, a dedicated autophagy receptor for mediating selective autophagy of ferritin (ferritinophagy), plays a vital role in maintaining cellular iron homeostasis. The cellular abundance of NCOA4 is regulated by the E3 ligase HERC2 that can specifically target NCOA4 for proteasomal degradation under iron-replete conditions. However, the detailed molecular mechanism governing the iron-dependent recognition of NCOA4 by HERC2 remains elusive. Here, using multidisciplinary approaches, we systematically characterize the HERC2-binding domain (HBD) of NCOA4 and its interaction with HERC2. We uncover that NCOA4 HBD harbors a [2Fe-2S] cluster and can exist in two different states, the apo-form state and the [2Fe-2S] cluster-bound state. Moreover, we unravel that HERC2 can effectively recognize the [2Fe-2S] cluster-bound NCOA4 HBD through its Cullin-7-PARC-HERC2 (CPH) domain and iron-sulfur cluster-dependent NCOA4-binding domain (INBD) with a synergistic binding mode. The determined crystal structures of HERC2(2540-2700) and its complex with the [2Fe-2S] cluster-bound NCOA4 HBD together with relevant biochemical and cellular results not only elucidate how NCOA4 HBD specifically senses cellular iron level by binding a [2Fe-2S] cluster but also reveal the molecular basis underlying the specific interaction of HERC2 with the [2Fe-2S] cluster-bound NCOA4 HBD. In summary, our findings provide mechanistic insights into the iron-dependent turnover of NCOA4 by HERC2 and expand our understanding of the regulatory mechanism of NCOA4-mediated ferritinophagy.

Keywords:  HERC2; NCOA4; autophagy; ferritinophagy; ubiquitination

DOI:  https://doi.org/10.1073/pnas.2510269122
FEBS Lett. 2025 Jul 22.

TRAF2 binds to TIFA via a novel motif and contributes to its autophagic degradation.

Tom Snelling, Kodi Hunter, Celest W S Tay, Nicola T Wood, Philip Cohen.

  A signal transduction pathway has been defined in which ADP-heptose activates the mammalian protein kinase ALPK1, which phosphorylates the adaptor protein TIFA, inducing its polymerisation and interaction with the E3 ubiquitin ligases TRAF2/c-IAP1 and TRAF6. These E3 ligases drive activation of the transcription factors NF-κB and AP-1, culminating in the production and secretion of inflammatory mediators to combat microbial infection. TRAF6 is essential in this process, but how TRAF2 interacts with TIFA and its role in the pathway is unclear. Here, we identify two conserved sequence motifs in TIFA essential for TRAF2 interaction, one of which (Pro159-Xaa-Xaa-Glu162) is novel. We additionally report that ADP-heptose induces TIFA degradation by autophagy and that both TRAF2 and TRAF6 contribute to this process. These findings advance understanding of how TRAF2 regulates the ALPK1-TIFA signalling pathway.

Keywords:   alphafold3 ; ALPK1; Autophagy; TIFA; TRAF2

DOI:  https://doi.org/10.1002/1873-3468.70110
CNS Neurosci Ther. 2025 Jul;31(7): e70503

Autophagy and Cellular Senescence in Alzheimer's Disease: Key Drivers of Neurodegeneration.

Md Sadique Hussain, Neetu Agrawal, Baby Ilma, Rekha M M, Priya Priyadarshini Nayak, Mandeep Kaur, Anil Khachi, Kavita Goyal, Arcot Rekha, Saurabh Gupta, Gaurav Gupta, Kamal Dua.

   BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder in the elderly, characterized by extracellular amyloid β‑ (Aβ) plaque deposition and intracellular neurofibrillary tangles (NFTs). Impaired autophagy, the cellular pathway for degrading damaged organelles and misfolded proteins, and cellular senescence, permanent cell cycle arrest with proinflammatory secretions, have emerged as key contributors to AD pathogenesis.
METHODS: We performed a narrative review of recent mechanistic and preclinical studies investigating (1) autophagic flux and its role in Aβ and tau clearance; (2) the accumulation and secretory phenotype of senescent cells in the aging brain; (3) interactions between autophagy impairment and senescence; and (4) the efficacy of autophagy enhancers (e.g., rapamycin and metformin) and senolytic agents in rodent models of AD.
RESULTS: Defective autophagosome-lysosome fusion in AD causes autophagic vacuole buildup with amyloid precursor protein and β‑secretase, boosting Aβ generation and hindering tau clearance, promoting neurofibrillary tangles. In AD models, senescent neurons and microglia release pro‑inflammatory cytokines (SASP), fueling neuroinflammation and synaptic dysfunction. Decline in autophagy induces senescence and blocks clearance in a vicious cycle. Rapamycin and metformin restore autophagic flux, reduce Aβ and tau pathologies, and improve memory. Senolytics clear senescent cells, reduce inflammation, and rescue cognition.
CONCLUSION: Dysregulated autophagy and cellular senescence interact to drive the progression of AD. Targeting these pathways with autophagy-boosting drugs and senolytic agents holds promise for disease-modifying therapies aimed at halting or reversing neurodegeneration in Alzheimer's disease.

Keywords:  aging brain; neurodegeneration; neuroinflammation; senolytics

DOI:  https://doi.org/10.1111/cns.70503
Nat Commun. 2025 Jul 23. 16(1): 6792

Structural insights into cholesterol sensing by the LYCHOS-mTORC1 pathway.

Shang Yu, Jin-Hui Ding, Jia-le Wang, Weize Wang, Peng Zuo, Ao Yang, Zonglin Dai, Yuxin Yin, Jin-Peng Sun, Ling Liang.

The lysosomal cholesterol sensor LYCHOS regulates mTORC1 signaling by coupling cholesterol sensing to GATOR1-Rag GTPase modulation, yet its structural mechanisms remain unclear. Here we report six cryo-electron microscopy structures of human LYCHOS, depicting five distinct states. These are categorized into a contracted state when complexed with a sufficient amount of the cholesterol analogue cholesteryl hemisuccinate (CHS), and an expanded state when CHS is deficient. The structure forms a homodimer, within each monomer the transmembrane region is divided into a permease-like domain (PLD) and a GPCR-like domain (GLD) with two clearly defined adjacent cholesterol binding sites between them. Cholesterol binding induces a translation of GLD towards PLD and exposes the cytosolic extension of transmembrane 15, which interacts with GATOR1. Our results elucidate the structural mechanism of cholesterol sensing by the mTORC1 pathway, providing a structural basis for developing inhibitors that selectively target mTORC1 pathway by blocking LYCHOS in its expanded state.

DOI: https://doi.org/10.1038/s41467-025-61966-w
Inflammopharmacology. 2025 Jul 22.

Therapeutic potential of melatonin-induced mitophagy in the pathogenesis of Alzheimer's disease.

Pouya Goleij, Mohammad Amin Khazeei Tabari, Mohadeseh Poudineh, Pantea Majma Sanaye, Haroon Khan, Alan Prem Kumar, Danaé S Larsen, Maria Daglia.

  Neurons rely heavily on functional mitochondria for energy production. Mitochondrial dysfunction is a key player in age-related neurodegenerative diseases like Alzheimer's disease (AD). In AD, damaged mitochondria accumulate early, worsening the disease. This dysfunction disrupts cellular balance in neurons, leading to energy deficiencies, calcium imbalances, and oxidative stress. These issues further aggravate the harmful effects of amyloid beta (Aβ) plaques and tau tangles, ultimately leading to synaptic dysfunction, memory loss, and cognitive decline. While a complex link exists between mitochondrial dysfunction and AD hallmarks like Aβ plaques and tau tangles, the exact cause-and-effect relationship remains unclear. Additionally, recent evidence suggests impaired mechanisms for mitophagy in AD. Mitophagy is crucial for neuronal health, and studies have found changes to proteins involved in this process, mitochondrial dynamics, and mitochondrial production in AD. Impaired mitophagy might also be linked to problems with how cells fuse waste disposal compartments (autophagosomes) with lysosomes, and issues with maintaining proper acidity within lysosomes. Interestingly, melatonin, a hormone known for regulating sleep, has recently emerged as a potential neuroprotective agent. Studies using a mouse model of AD showed that melatonin treatment improved cognitive function by enhancing mitophagy. These findings suggest that melatonin's ability to improve mitophagy may be a promising avenue for future AD therapies. Therefore, in this review, we discuss the therapeutic effect of melatonin on mitochondrial dysfunction, especially mitophagy, in AD.

Keywords:  Alzheimer’s disease; Amyloid-beta; Melatonin; Mitochondrial dysfunction; Mitophagy; Oxidative stress; Tau pathology

DOI:  https://doi.org/10.1007/s10787-025-01859-y
EMBO J. 2025 Jul 21.

mTORC1 senses glutamine and other amino acids through GCN2.

Gianluca Figlia, Sandra Müller, Fabiola Garcia-Cortizo, Marilena Neff, Glynis Klinke, Gernot Poschet, Aurelio A Teleman.

  mTORC1 promotes cell growth when nutrients such as amino acids are available. While dedicated sensors relaying availability of leucine, arginine and methionine to mTORC1 have been identified, it is still unclear how mTORC1 senses glutamine, one of its most potent inducers. Here, we find that glutamine is entirely sensed through the protein kinase GCN2, whose initial activation is not triggered by depletion of glutamine itself, but by the concomitant depletion of asparagine. In turn, GCN2 leads to a succession of events that additively inhibit mTORC1: within 1 h, GCN2 inhibits mTORC1 through the Rag GTPases, independently of its function as an eIF2α kinase. Later, GCN2-mediated induction of ATF4 upregulates Ddit4 followed by Sestrin2, which together cause additional mTORC1 inhibition. Additionally, we find that depletion of virtually any other amino acid also inhibits mTORC1 through GCN2. GCN2 and the dedicated amino acid sensors thus represent two independent systems that enable mTORC1 to perceive a wide spectrum of amino acids.

Keywords:  Amino Acid Sensors; Asparagine; GCN2; Glutamine; mTORC1

DOI:  https://doi.org/10.1038/s44318-025-00505-1
Nat Commun. 2025 Jul 18. 16(1): 6621

ATG8ylation-mediated tonoplast invagination mitigates vacuole damage.

Xuanang Zheng, Juncai Ma, Jing Li, Siyu Chen, Jun Luo, Jianxiong Wu, Kaiyan Zhang, Changlian Peng, Yonglun Zeng, Faqiang Li, Byung-Ho Kang, Caiji Gao, Jun Zhou.

While ATG8ylation, the lipidation of ATG8-family proteins, is canonically linked to double-membrane autophagosome formation, emerging studies demonstrate its non-canonical association with single-membrane organelles. The functional significance of ATG8ylation in these compartments, however, remains unclear. Here, we demonstrate that ionophores rapidly trigger ATG8 conjugation to the vacuolar membrane (tonoplast), a process reliant on the ATG conjugation system rather than the upstream autophagic regulators. Inhibiting reactive oxygen species (ROS) generation or V-ATPase function greatly impedes the targeting of ATG8 to the tonoplast. Intriguingly, the attachment of ATG8 to the tonoplast enhances its invagination and fosters the formation of intraluminal vesicles within vacuoles, which is achieved independently of the ESCRT machinery or cytoskeletal components. The emergence of ATG8-positive vesicles may facilitate the restoration of vacuolar acidification by redirecting proton flow from the vacuole-to-cytoplasm to an intravacuolar direction, which aids in the rapid recovery of plant growth after removal of monensin. Furthermore, under alkaline stress, ATG8 targets the tonoplast and induces vacuolar membrane invagination via a regulatory mechanism similar to that of monensin, indicating that ATG8ylation-mediated vacuolar remodeling represents an adaptive mechanism against environmental alkalinization in plants.

DOI: https://doi.org/10.1038/s41467-025-62084-3
Adv Sci (Weinh). 2025 Jul 20. e05592

Mortalin and PINK1/Parkin-Mediated Mitophagy Represent Ovarian Cancer-Selective Targets for Drug Development.

Vishal Chandra, Justin Garland, Rajani Rai, Donghua Zhao, Charuksha Walgama, Sadagopan Krishnan, Andrew T Long, Tongzu Liu, Laura Adhikari, Doris M Benbrook.

  Mortalin is an essential chaperone for the import of nuclear-encoded proteins into mitochondria and is elevated in ovarian cancer in association with poor patient prognosis. The investigational new drug, SHetA2, interacts with mortalin releasing its client proteins. In this study, interactions of SHetA2 moieties and mortalin substrate binding domain (SBD) amino acids are demonstrated by surface plasmon resonance (SPR) and nuclear magnetic resonance (NMR) to occur at low micromolar SHetA2 concentrations that selectively kill cancer cells over noncancerous cells. In both ovarian cancer and noncancerous cells SHetA2 reduces: mitochondria import of mortalin, degradation of mortalin's mitochondrial localization sequence (MLS), mortalin/inositol 1,4,5-trisphosphate receptors complexes and oxidative phosphorylation. In cancer cells only, SHetA2 reduces calcium levels, mitochondrial length and fusion proteins, while inducing autophagy and PTEN-induced kinase 1 (PINK1)/PARKIN-mediated mitophagy. Noncancerous cells exhibit increased mitochondrial branch length in response to SHetA2 and a low level of inducible autophagy that is resistant to SHetA2. Inhibition of autophagosome-lysosome fusion reduces, or increases, SHetA2 cytotoxicity in ovarian cancer or noncancerous cells, respectively. SHetA2 inhibits mortalin and growth, and induces mitophagy in ovarian cancer xenografts and increases survival post-surgical tumor removal. In conclusion, SHetA2 binds directly to mortalin's SBD and causes distinct responses in ovarian cancer and noncancerous cells.

Keywords:  PINK1; SHetA2; autophagy; mitochondrial networking; mitophagy

DOI:  https://doi.org/10.1002/advs.202505592
Neuropeptides. 2025 Jul 17. pii: S0143-4179(25)00047-2. [Epub ahead of print]113 102547

Interplay of neuropeptide Y and autophagy in Alzheimer's disease: Therapeutic perspectives and mechanistic insights.

Dhiraj Lanjewar, Raj Katariya, Vinita Kale, Brijesh Taksande, Milind Umekar, Madhura Vinchurney.

  Alzheimer's disease (AD) is a progressive, chronic, neurodegenerative disorder involving cognitive impairment, neuronal loss, autophagy dysregulation, and toxic protein aggregates build-up, including amyloid-β plaques and hyperphosphorylated tau tangles. Autophagy dysregulation is a central driving force behind AD pathogenesis, interfering with the clearance of these aggregates and resulting in synaptic disruption and enhanced neurodegeneration. Neuropeptide Y (NPY) is abundantly present in the CNS. NPY has been identified as a promising candidate due to its neuropeptidergic activity. It plays a central role in regulating autophagy, anti-inflammation, and the induction of synaptic plasticity. NPY regulates the AMPA-mTOR pathway to restore cellular homeostasis and enhance neuronal survival through improved autophagic flux. It facilitates the clearance of aggregate proteins and dysfunctional cellular components, which lessen the signs of AD pathology. Moreover, NPY plays an important role in stabilizing the mitochondria and enhancing antioxidant action, in effect sustaining cognitive function. The modulatory influence of NPY on autophagy represents a potential novel direction in AD therapy, advanced delivery systems, such as nanoparticle-based carriers, offer promising targeted brain delivery mechanisms. However, clinical application is hindered by the need for a receptor-specific agonist to mitigate side effects and the lengthy trials necessary to assess long-term efficiency. Further research should aim to optimise NPY delivery and autophagy-targeted therapies to develop more effective treatments; such research challenges may position NPY as a breakthrough candidate for slowing cognitive and functional impairment in AD.

Keywords:  Alzheimer's disease; Autophagy; Neurodegeneration; Neuroinflammation; Neuropeptide Y

DOI:  https://doi.org/10.1016/j.npep.2025.102547
Life Sci. 2025 Jul 18. pii: S0024-3205(25)00495-3. [Epub ahead of print] 123860

PTEN-L dephosphorylates Parkin and Ub Ser65 to aggravate mitophagy dysfunction in prion disease cell models.

Xueyuan Li, Jie Li, Fengting Gou, Yuexin Dai, Mengyang Zhao, Dongdong Wang, Zhixin Sun, Pei Wen, Jingjing Wang, Qing Fan, Tianying Ma, Xiaoyu Wang, Deming Zhao, Lifeng Yang.

  PINK1-Parkin-dependent mitophagy dysfunction is a critical contributor to the accumulation of damaged mitochondria in prion disease, leading to impaired autophagy and neurons apoptosis. However, the specific molecular mechanisms underlying mitophagy dysfunction in prion disease remain unclear. Phosphorylation of Parkin at Ser65 (pSer65-Parkin) is a key determinant for the initiation of PINK1-Parkin-mediated mitophagy. In the prion disease cell model, we observed a significant reduction in pSer65-Parkin and pSer65-Ub expression. PTEN-L, an isoform of the PTEN family, has been implicated in the regulation of PINK1-Parkin-mediated mitophagy. Here, we demonstrate that PTEN-L acts as a phosphatase for Parkin and Ub, exerting a regulatory role in mitophagy in prion disease. We found that PTEN-L expression and mitochondrial translocation were elevated in PrP106-126-treated SH-SY5Y cells. Increased PTEN-L dephosphorylates pSer65-Parkin pSer65-Ub, leading to reduced pSer65-Parkin and pSer65-Ub, then impaired mitophagy initiation. Overexpression of PTEN-L in SH-SY5Y cells mimicked the effects of PrP106-126 treatment, reducing Parkin mitochondrial translocation and pSer65-Parkin levels. PTEN-L knockout alleviates these deficits, restoring Parkin and ubiquitin recruitment to mitochondria and increasing Ser65 phosphorylation in prion disease cell models. Furthermore, PTEN-L deficiency mitigated mitophagy dysfunction and apoptosis in neurons exposed by PrP106-126. These findings suggest that PrP106-126 upregulates PTEN-L, enhancing dephosphorylation of pSer65-Parkin and pSer65-Ub, thereby impairing mitophagy initiation. Targeting PTEN-L expression or activity may represent a novel therapeutic strategy for prion disease.

Keywords:  Mitophagy; PTEN-L; Parkin; Prion disease; Ubiquitin

DOI:  https://doi.org/10.1016/j.lfs.2025.123860
J Biol Chem. 2025 Jul 21. pii: S0021-9258(25)02354-3. [Epub ahead of print] 110504

PERK and IRE1α promote exosome secretion via blocking lysosomal degradation of multiple vesicular body.

Shixin Zhou, Zihan Zhou, Si Chen, Ming Wang, Likun Wang.

  The unfolded protein response (UPR) initiated under endoplasmic reticulum (ER) stress can not only maintain the ER homeostasis, but also modulate the secretion of proteins and lipids that transmit ER stress signals among cells. Exosomes are multivesicular body (MVB)-derived extracellular vesicles, constituting the unconventional protein secretion pathway. Whether and how the secretion of exosomes is regulated by the UPR remains largely unknown. Here, we reported that ER stress induces exosome secretion in an UPR-dependent way. Activation of PERK and IRE1α, two of the UPR branches, represses the acidification and catabolic activity of lysosomes. This blocked MVB-lysosome fusion, re-directing MVBs from lysosomal degradation to plasma membrane fusion, resulting in exosome release. Calcium-mediated activation of PERK, in the absence of ER stress, is sufficient to suppress lysosomal degradation and augment exosome secretion, partly through its downstream factor ATF4. Our study revealed a function of PERK and IRE1α in modulating lysosome activity and dictating the fate of MVBs, facilitating cell-cell communication via exosomes.

Keywords:  IRE1α; PERK; extracellular vesicle; lysosome; unfolded protein response

DOI:  https://doi.org/10.1016/j.jbc.2025.110504
Curr Issues Mol Biol. 2025 Apr 18. pii: 290. [Epub ahead of print]47(4):

FNIP1 Deficiency: Pathophysiology and Clinical Manifestations of a Rare Syndromic Primary Immunodeficiency.

Samuele Roncareggi, Brian M Iritani, Francesco Saettini.

  Folliculin-interacting protein 1 (FNIP1) is a key regulator of cellular metabolism and immune homeostasis, integrating nutrient signaling with proteostasis. FNIP1 forms a complex with folliculin (FLCN) to regulate the mechanistic target of rapamycin complex 1 (mTORC1), functioning as a GTPase-activating protein (GAP) for RagC/D. Additionally, FNIP1 interacts with heat shock protein 90 (HSP90) and undergoes phosphorylation, glycosylation, and ubiquitination, which dynamically regulate its stability and function. Evidence from murine models suggests that FNIP1 loss disrupts immune cell development and mitochondrial homeostasis. However, FNIP1 deficiency in humans remains incompletely characterized, and its full phenotypic spectrum is likely underestimated. Notably, FNIP1-deficient patients exhibit immunological and hematological abnormalities, immune dysregulation, and metabolic perturbations, emphasizing its role in cellular adaptation to stress. Understanding the mechanistic basis of FNIP1 dysfunction in human tissues will be critical for delineating its contributions to immune and metabolic disorders and identifying targeted interventions.

Keywords:  FNIP1 deficiency; agammaglobulinemia; hypertrophic cardiomyopathy; inborn error of immunity; neutropenia; primary immunodeficiency

DOI:  https://doi.org/10.3390/cimb47040290
Trends Cell Biol. 2025 Jul 22. pii: S0962-8924(25)00154-0. [Epub ahead of print]

Endosome-ER contact sites in phagophore formation.

Mengnan Xu, Pingping Wang, Xian-Ping Dong.

  Autophagy is a crucial 'self-eating' mechanism used by eukaryotic cells to degrade and recycle cytosolic materials. A recent study by Da Graça et al. reports that the dynamic mobilization of endosome-endoplasmic reticulum (ER) contact sites (EERCS) in response to starvation creates a confined environment that facilitates Ca2+-dependent phagophore biogenesis.

Keywords:  autophagy; calcium; endoplasmic reticulum (ER); endosome; endosome-ER contact sites (EERCS); phagophore

DOI:  https://doi.org/10.1016/j.tcb.2025.07.002
Sci Rep. 2025 Jul 18. 15(1): 26163

Regulation of autophagy and its role in late preimplantation during mouse embryo development.

Kei Uechi, Itsuki Koide, Saya Kanie, Tadashi Yamazaki, Satoshi Kishigami.

  Autophagy is a system that contributes to cellular homeostasis by degrading intracellular proteins and organelles. Autophagy is essential for the preimplantation development of mammalian embryos, lack of which results in developmental arrest at the 4/8-cell stages. The role of autophagy beyond the compaction stage remains insufficiently explored. In this study, we investigated the role of autophagy after the 4/8-cell stages in mice using chloroquine (CQ), an autophagy inhibitor. CQ treatment from the 4/8-cell to morula stage impaired development, reducing the number of Cdx2-positive cells, an effect rescued by amino acid (AA) supplementation. CQ treatment also downregulated TFAP2C, an upstream regulator of Cdx2,which was similarly restored by AA supplementation. Consistently, autophagy at this stage showed higher activity in the outer cells and lower activity in the inner cells of the embryo. Treatment with XMU-MP-1, an MST1/2 inhibitor targeting the Hippo signaling pathway, disrupted this spatial regulation by inducing autophagy in the inner cells. Stage-specific staining revealed temporal and positional regulation of autophagy activity. These findings illustrate that autophagy during the morula stage promotes differentiation into the trophectoderm by supplying AAs, a process regulated by the Hippo signaling pathway.

Keywords:  Autophagy; Embryonic development; Hippo signaling; Preimplantation; Trophectoderm differentiation

DOI:  https://doi.org/10.1038/s41598-025-11359-2
Am J Pathol. 2025 Jul 18. pii: S0002-9440(25)00240-8. [Epub ahead of print]

AHSA1/Hsp90α complex facilitates microglial mitophagy by targeting TOMM70 in Parkinson's disease.

Liang Shao, Ji Zhang, Fan Hu, Wen Chai, Yuxuan Zhou, Pengtao Zou, Ping Zhang.

  Parkinson's disease (PD) is a commonly diagnosed neurodegenerative disease with rising prevalence globally. However, the pathology of PD remains largely undefined. The aim of this study is to get better understanding of microglial mitophagy in PD. 1-methyl-1,2,3,6-tetrahydropyidine (MPTP)-induced PD mouse model was established and validated by behavior tests. Western blot and immunofluorescent (IF) showed that autophagy was enhanced in MPTP-induced PD mice. IF, qRT-PCR, western blot and co-immunoprecipitation (co-IP) also revealed that silencing of Hsp90α protected against mitophagy in PD mice. In microglia/DA neurons co-culture system, ELISA assay, Transmission Electron Microscopy (TEM), JC-1 staining, measurement of ATP content and Annexin V/PI staining showed that lack of Hsp90α in MPTP-treated microglia attenuated DA neuronal death via suppressing mitophagy. IF staining and co-IP confirmed that Hsp90α formed a complex with AHSA1, and this complex targeted the mitochondrial molecular switch TOMM70 in microglia. Hsp90α inhibitor geldanamycin (GA) and AHSA1 knockdown further revealed that AHSA1/Hsp90α complex regulated microglial mitophagy by targeting TOMM70 in MPTP-treated microglia and PD mice. In conclusion, AHSA1/Hsp90α complex facilitated microglial mitophagy by targeting TOMM70 in PD.

Keywords:  AHSA1; Hsp90α; Parkinson's disease; TOMM70; microglial mitophagy

DOI:  https://doi.org/10.1016/j.ajpath.2025.06.007
Aging Cell. 2025 Jul 24. e70183

Rapamycin Does Not Compromise Exercise-Induced Muscular Adaptations in Female Mice.

Christian J Elliehausen, Szczepan S Olszewski, Dennis M Minton, Carolyn G Shult, Aditya R Ailiani, Michaela E Trautman, Reji Babygirija, Dudley W Lamming, Troy A Hornberger, Adam R Konopka.

  An increasing number of physically active adults are taking the mTOR inhibitor rapamycin off label with the goal of extending healthspan. However, frequent rapamycin dosing disrupts metabolic health during sedentary conditions and abates the anabolic response to exercise. Intermittent once-weekly rapamycin dosing minimizes many negative metabolic side effects of frequent rapamycin in sedentary mice. However, it remains unknown how different rapamycin dosing schedules impact metabolic, physical, and skeletal muscle adaptations to voluntary exercise training. Therefore, we tested the hypothesis that intermittent rapamycin (2 mg/kg; 1×/week) would avoid detrimental effects on adaptations to 8 weeks of progressive weighted wheel running (PoWeR) in adult female mice (5-month-old) by evading the sustained inhibitory effects on mTOR signaling by more frequent dosing schedules (2 mg/kg; 3×/week). PoWeR improved maximal exercise capacity, absolute grip strength, and myofiber hypertrophy with no differences between vehicle or rapamycin-treated mice despite greater voluntary running volume with intermittent rapamycin treatment. Conversely, frequent and intermittent rapamycin-treated mice had impaired glucose tolerance and insulin sensitivity compared to vehicle-treated mice after PoWeR; however, intermittent rapamycin reduced the impact on glucose intolerance versus frequent rapamycin. Collectively, these data in adult female mice suggest that (1) rapamycin is largely compatible with the physical and skeletal muscle benefits of PoWeR and (2) the detrimental effects of rapamycin on glucose metabolism in the context of voluntary exercise may be reduced by intermittent dosing.

Keywords:   mTOR ; aging; exercise; glucose tolerance; hypertrophy; muscle

DOI:  https://doi.org/10.1111/acel.70183
Nat Commun. 2025 Jul 19. 16(1): 6651

PNPLA7 mediates Parkin-mitochondrial recruitment in adipose tissue for mitophagy and inhibits browning.

Xuetao Ji, Xu Zhang, Tong Zhang, Yao Xue, Mengping He, Chaopu Li, Yun Huang, Haoyu Wang, Jing Ju, Li'e Cai, Yuzhu Wang, Ning Wang, Lijuan Fan, Hui Tong, Heng Fan, Qinsheng Chen, Qinwei Lu, Cong Li, Huiru Tang, Yongsheng Chang, Xingxing Kong, Hanming Shen, Aihua Gu, Hui Liang, Hongwen Zhou, Qian Wang, John Zhong Li.

PINK1/Parkin-mediated ubiquitin-dependent mitophagy is a critical negative regulatory machinery for browning in the inguinal white adipose tissue (iWAT). However, the precise regulatory mechanism underlying PINK1/Parkin-mediated mitophagy during browning of iWAT remains largely unknown. Here we report that PNPLA7, an Endoplasmic Reticulum and mitochondria-associated membrane (MAM) protein, inhibits browning of iWAT by promoting PINK1/Parkin-mediated mitophagy upon cold challenge or β3-adrenergic receptor agonist treatment. With genetic manipulation in mice, we show that adipose tissue overexpressing PNPLA7 induces mitophagy, abolishes iWAT browning and interrupts adaptive thermogenesis. Conversely, conditional ablation of PNPLA7 in adipose tissue promotes browning of iWAT, resulting in enhanced adaptive thermogenesis. Mechanistically, PNPLA7 interacts with Parkin to promote mitochondrial recruitment of Parkin for mitophagy activation and mitochondria degradation by disrupting PKA-induced phosphorylation of Parkin under cold challenge. Taken together, our findings suggest that PNPLA7 is a critical regulator of mitophagy that resists cold-induced browning of iWAT, thus providing a direct mechanistic link between mitophagy and browning of iWAT.

DOI: https://doi.org/10.1038/s41467-025-61904-w
Clin Transl Med. 2025 Jul;15(7): e70404

PDK4 and nutrient responses explain muscle specific manifestation in mitochondrial disease.

Swagat Pradhan, Takayuki Mito, Nahid A Khan, Sofiia Olander, Aleksandra Zhaivoron, Thomas G McWilliams, Anu Suomalainen.

   BACKGROUND: Mitochondria elicit various metabolic stress responses, the roles of which in diseases are poorly understood. Here, we explore how different muscles of one individual-extraocular muscles (EOMs) and quadriceps femoris (QFs) muscles-respond to mitochondrial disease. The aim is to explain why EOMs atrophy early in the disease, unlike other muscles.
METHODS: We used a mouse model for mitochondrial myopathy ("deletor"), which manifests progressive respiratory chain deficiency and human disease hallmarks in itsmuscles. Analyses included histology, ultrastructure, bulk and single-nuclear RNA-sequencing, metabolomics, and mitochondrial turnover assessed through in vivo mitophagy using transgenic mito-QC marker mice crossed to deletors.
RESULTS: In mitochondrial muscle disease, large QFs upregulate glucose uptake that drives anabolic glycolytic one-carbon metabolism and mitochondrial integrated stress response. EOMs, however, react in an opposite manner, inhibiting glucose and pyruvate oxidation by activating PDK4, a pyruvate dehydrogenase kinase and inhibitor. Instead, EOMs upregulate acetyl-CoA synthesis and fatty-acid oxidation pathways, and accumulate lipids. In QFs, Pdk4 transcription is not induced.- Amino acid levels are increased in QFs but are low in EOMs suggesting their catabolic use for energy metabolism. Mitophagy is stalled in both muscle types, in the most affected fibers.
CONCLUSIONS: Our evidence indicates that different muscles respond differently to mitochondrial disease even in one individual. While large muscles switch to anabolic mode and glycolysis, EOMs actively inhibit glucose usage. They upregulate lipid oxidation pathway, a non-optimal fuel choice in mitochondrial myopathy, leading to lipid accumulation and possibly increased reliance on amino acid oxidation. We propose that these consequences of non-optimal nutrient responses lead to EOMatrophy and progressive external ophthalmoplegia in patients. Our evidence highlights the importance of PDK4 and aberrant nutrient signaling underlying muscle atrophies.

Keywords:  integrated stress response; mitochondrial disease; mitochondrial myopathy; nutrient signaling; progressive external ophthalmoplegia; pyruvate dehydrogenase kinase

DOI:  https://doi.org/10.1002/ctm2.70404
Adv Sci (Weinh). 2025 Jul 20. e08503

NAD+-Boosters Improve Mitochondria Quality Control In Parkinson's Disease Models Via Mitochondrial UPR.

Shuoting Zhou, Xi Xiong, Jialong Hou, Qi Duan, Yi Zheng, Tao Jiang, Jiani Huang, Haijun He, Jiaxue Xu, Keke Chen, Wenwen Wang, Jinlai Cai, Jingjing Qian, Huijun Chen, Weihong Song, XinShi Wang, Chenglong Xie.

  Serving as a pivotal hub for cellular metabolism and intracellular signaling, the mitochondrion has emerged as a crucial organelle whose dysfunction is linked to many human diseases, including neurodegenerative disorders, particularly Parkinson's disease (PD). However, whether mitochondrial quality control (MQC) can be targeted for therapeutic interventions remains uncertain. This study uses clinical samples, molecular biology techniques, pharmacological interventions, and genetic approaches to investigate the significance of NAD+ levels in cross-species models of PD. These results reveal that treatment of rotenone-incubated cells with NAD+ boosters (such as NMN, siCD38, and NAT) increases UPRmt/mitophagy-related MQC, reduces pro-inflammatory cytokine expression, inhibits apoptosis, and strengthen redox reactions. In vivo, NMN supplementation inhibits motor deficit and forestalls the neuropathological phenotypes of MPTP-induced PD mice, which are required for the atf4-related mitochondrial UPR pathway. Notably, bulk omics signatures and metabolomic profiling analyses of the striatum reveal NMN-induced transcriptional changes in genes and proteins involved in mitochondrial homeostasis. Thus, these findings demonstrate that the accelerated pathology in PD models is probably mediated by impaired MQC and that bolstering cellular NAD+ levels alleviates mitochondrial proteotoxic stress and mitigate PD phenotypes.

Keywords:  NAD+‐boosters; Parkinson's disease; mitochondria quality control; mitochondrial unfolded protein response; nicotinamide mononucleotide

DOI:  https://doi.org/10.1002/advs.202408503
Nat Commun. 2025 Jul 24. 16(1): 6777

PEAK1 maintains tight junctions in intestinal epithelial cells and resists colitis by inhibiting autophagy-mediated ZO-1 degradation.

Zaikuan Zhang, Yajun Xie, Qiying Yi, Jianing Liu, Lin Yang, Runzhi Wang, Jing Cai, Xinyi Li, Xiaosong Feng, Shixiang Yao, Zheng Pan, Magdalena Paolino, Qin Zhou.

Tight junctions are crucial for maintaining intestinal barrier homeostasis, but how organisms modulate these junctions remain unclear. Here, we show a role for PEAK1 at cell-cell contact sites, where it interacts with ZO-1 via a conserved region spanning amino acids 714-731. This interaction masks the LC3-interacting region on ZO-1, preventing autophagy-mediated ZO-1 degradation and preserving the integrity of tight junctions in intestinal epithelial cells. Src-mediated phosphorylation of PEAK1 at Y724 promotes the binding between PEAK1 and ZO-1 to stabilize ZO-1 in intestinal epithelial cells. Additionally, PEAK1 binds to CSK to positively regulate Src activity. Loss of PEAK1 in intestinal epithelial cells leads to decreased Src activity and lower ZO-1 protein levels, resulting in disrupted tight junctions, both in vitro and in vivo. In mice, Peak1 deficiency increases intestinal epithelium permeability and exacerbates inflammation in experimentally induced colitis models. Our findings reveal PEAK1's critical role in maintaining tight junction integrity and resistance to intestinal inflammation, extending its known function from promoting tumor cell proliferation and migration to essential physiological processes. These insights refine our understanding of the mechanisms regulating tight junctions and offer potential therapeutic targets for enhancing epithelial barrier function and treating related diseases.

DOI: https://doi.org/10.1038/s41467-025-62107-z
J Biol Chem. 2025 Jul 16. pii: S0021-9258(25)02333-6. [Epub ahead of print] 110483

Stressful situations: molecular insights on mitochondrial quality control pathways.

Sabrina Romanelli, Jean-François Trempe.

Mitochondrial quality control has emerged as an important area of research over the past decade, with more than 2,000 publications exploring the molecular pathways that regulate it. Mitochondria are essential for energy production and various cellular functions but are highly susceptible to damage from stressors such as protein misfolding, reactive oxygen species, and chemicals that disrupt the electron transport chain. If left unresolved, mitochondrial dysfunction can lead to health complications, including neurodegenerative disorders, cardiovascular diseases, and cancer. To maintain cellular health, cells evolved quality control pathways to remove damaged mitochondrial components. This review focuses on three key quality control responses: the PINK1-Parkin pathway, the DELE1-HRI pathway, and the mitochondrial unfolded protein response (UPRmt). While these pathways have distinct functions, there is ongoing debate about how they overlap and which responds first in different contexts. In this review, we discuss the physiological and structural mechanisms behind each pathway, explore how they interconnect, and highlight their differences and relevance to disease. By summarizing this information in a single review, we aim to enhance the molecular understanding of mitochondrial quality control, which can help highlight avenues for novel therapeutics for diseases associated to dysfunctional mitochondria.

DOI: https://doi.org/10.1016/j.jbc.2025.110483
Cell Death Discov. 2025 Jul 24. 11(1): 340

Inhibition of anti-apoptotic Bcl-2 family members promotes synergistic cell death with ER stress inducers by disrupting autophagy in glioblastoma.

Tianyi Huang, Satoshi Takagi, Sumie Koike, Ryohei Katayama.

Glioblastoma (GBM) remains one of the most aggressive and challenging brain tumors. Unfortunately, current clinical treatment options offer limited efficacy, highlighting the necessity for uncovering novel therapeutic strategies. Here, monotherapy and combination library screening were employed, and identified that the efficacy of obatoclax, a pan-Bcl-2 family inhibitor, was improved significantly when combined with ER-stress inducers, including tunicamycin. Combinatorial knockdown of anti-apoptotic proteins confirmed that the loss of Mcl-1 and Bcl-xL synergistically enhanced apoptosis under ER stress conditions. Although ER stress inducers triggered the stress response in GBM cells, obatoclax co-treatment enhanced this response by upregulating ATF-4 and CHOP, which promoted apoptosis along with increased caspase 3/7 activity and cleavage of PARP. ATF-4 knockdown significantly decreased the apoptosis induced by obatoclax and tunicamycin co-treatment and reduced the expression of CHOP and BIM. Under ER stress responses, GBM cells exerted an autophagy response to recover from the stress condition; however, obatoclax co-treatment disrupted the autophagy responses, particularly by disrupting autophagic cargo degradation. Our findings suggest that targeting Mcl-1 and Bcl-xL, coupled with ER-stress induction, could be a promising strategy for the treatment of GBM, highlighting the potential for combination therapies involving pan-Bcl-2 family inhibitors to overcome current limitations in the treatment of GBM.

DOI: https://doi.org/10.1038/s41420-025-02632-4
Methods Mol Biol. 2025 Jul 22.

Computational Approaches for Delineating Lysosomes and Related Intracellular Trafficking Vesicles in Confocal and Other Fluorescence Datasets.

Charles Ellis, David S Chatelet, J Arjuna Ratnayaka.

  Fluorescence datasets from investigations into intracellular trafficking compartments produce images of variable quality, scales, and complexities. Investigators are therefore confronted with a choice of how to analyze this information. Here, we have used confocal immunofluorescence images of lysosomes from retinal pigment epithelial cells as an exemplar dataset, and employed three freely accessible computational approaches (Fiji, CellProfiler and Icy) to showcase their workings. A step-by-step workflow for each pipeline is described with non-specialist users in mind. These produce results including lysosomal number and shape, but also 3D outputs such as volume. Features of the three methods alongside their advantages and limitations are subsequently summarized. An important consideration, however, is that results generated from the different approaches are not necessarily comparable. Hence, users should adopt only a single method to analyze their dataset which best suit their specific requirements.

Keywords:  3D imaging; Computation; Confocal microscopy; Data integrity; Lysosome; Retinal pigment epithelium (RPE); Stem cells; Trafficking vesicles; Volume

DOI:  https://doi.org/10.1007/7651_2025_657
Autophagy. 2025 Jul 23.

Autophagy inhibition in LGALS9-overexpressing nasopharyngeal carcinoma unleashes immune response.

Clarence Pascual, Daniel J Klionsky.

  When cells within our bodies begin to exhibit tumor-specific antigens, a specialized group of immune cells, known as immune effector cells, plays a crucial role in mounting both innate and adaptive immune responses. Cancer cells are notorious for developing strategies to hide from, suppress, and manipulate the immune system, collectively known as immune evasion. In the paper by Kam et al. the authors propose that intratumoral cell-associated, as opposed to secreted, LGALS9 (galectin 9) suppresses the activation of cytotoxic T lymphocytes in a macroautophagy/autophagy-dependent manner in nasopharyngeal carcinoma (NPC) cell lines.

Keywords:  Autophagy inhibition; LGALS9; cytotoxic T lymphocytes; galectin 9; nasopharyngeal carcinoma; tumorigenicity

DOI:  https://doi.org/10.1080/15548627.2025.2534072
Nat Commun. 2025 Jul 23. 16(1): 6769

DSS1 inhibits autophagy to activate epithelial-mesenchymal transition in a pro-metastatic niche of renal cell carcinoma.

Xiaoyu Chen, Qingyuan Liu, Jingxian Wu, Pengfei Zhou, Mingming Zhao, Jing Song.

The mechanisms underlying clear cell renal cell carcinoma (ccRCC) metastasis remain largely unexplored. We demonstrate that Deleted in Split hand/Split foot protein 1 (DSS1), a critical cofactor of BRCA2 in DNA repair, is upregulated in metastatic ccRCC and promotes both tumor growth and distant metastasis. Mechanistically, DSS1 interacts with LC3 and promotes its degradation via TRIM25-mediated Lys63 (K63)-linked polyubiquitination at LC3B-K51. This impairs (macro) autophagic flux and leads to p62 accumulation, thereby stabilizing TWIST1 and facilitating its nuclear translocation, ultimately activating epithelial-mesenchymal transition (EMT). DSS1 highly expressed (DSS1hi) tumor cells are enriched in late-stage tumors and are associated with microvascular invasion within a vascularized invasive niche at the tumor-stromal interface, mediated by SPP1-ITGB1 interactions. Clinically, DSS1hi tumor cells correlate with therapeutic resistance and poorer patient outcomes. Collectively, these findings provide new insights into the mechanisms of ccRCC metastasis and suggest potential avenues for therapeutic intervention.

DOI: https://doi.org/10.1038/s41467-025-62135-9
Cell Death Dis. 2025 Jul 21. 16(1): 540

Molecular features of TNBC govern heterogeneity in the response to radiation and autophagy inhibition.

Patrick Fischer, Maximilian Schmid, Anna Ohradanova-Repic, Rebecca Schneeweiss, Jana Hadatsch, Odysseus Grünert, Johannes Benedum, Anna Röhrer, Felix Staudinger, Philipp Schatzlmaier, Niccolo Bragato, Sandra Barna, Magdalena Engl, Ava Kleinwächter, Dietmar Georg, Joachim Widder, Sylvia Kerschbaum-Gruber, Dea Slade.

Triple negative breast cancer (TNBC) is a heterogeneous and a highly aggressive type of breast cancer. Standard of care for TNBC patients includes surgery, radio-, chemo- and immunotherapy, depending on the stage of the disease. Immunotherapy is ineffective as monotherapy but can be enhanced with taxane chemotherapy or radiotherapy. Radiation can stimulate the immune system by activating the type I interferon (IFN-I) response through cGAS-STING signaling, which recognizes cytosolic double-stranded DNA (dsDNA). Cytosolic dsDNA can be cleared by autophagy, thereby preventing activation of cGAS-STING signaling. Autophagy inhibition was therefore proposed to potentiate the immunostimulatory effects of radiation. Here we show that different molecular features of TNBC cell lines influence the effect of X-ray and carbon ion (C-ion) irradiation and autophagy inhibition on immunogenic signaling. MDA-MB-468, with low basal autophagy and high cytosolic dsDNA, activates the IFN-I response after radiation. In contrast, MDA-MB-231, characterized by high autophagy rates and low cytosolic dsDNA, induces NF-κB signaling and CXCL10 expression upon autophagy inhibition with the VPS34 inhibitor SAR405. Autophagy inhibition in TNBC cells triggers a stronger activation of innate immune cells (monocytes, natural killer cells and dendritic cells) compared to radiation. In BRCA1-mutated MDA-MB-436 cells, C-ion irradiation was more potent compared to X-rays in inducing the NF-κB-driven immunogenic response but failed to activate immune cells. Upregulation of PD-L1 by X-rays, and especially C-ions, may contribute to reduced immune cell activation, underscoring the need for combination strategies with immune checkpoint blockade. Collectively, our study highlights the NF-κB-driven immunostimulatory effects of autophagy inhibition and the importance of understanding the molecular heterogeneity in TNBC with regard to autophagy rates, IFN-I and NF-κB signaling when designing effective treatments that target these pathways.

DOI: https://doi.org/10.1038/s41419-025-07873-w
Ageing Res Rev. 2025 Jul 21. pii: S1568-1637(25)00184-9. [Epub ahead of print] 102838

The Evolution of Alzheimer's Disease: From Mitochondria to Microglia.

Feng-Ge Yang, Yu-Lin Liang, Xu Wang, Jun-Ting Wang, Wei Gao, Qiu-Yan Ye, Xue-Yuan Li, Yu Yang, Hong-Lin Li.

  Alzheimer's disease (AD) represents the most prevalent neurodegenerative disorder worldwide. Recent studies highlights that mitochondrial dysfunction drives alterations in microglial function, serving as a pivotal mechanism in the pathogenesis and progression of AD. Increasingly, there is evidence that mitochondrial dysfunction encompasses energy metabolism deficits, heightened oxidative stress, impaired mitochondrial dynamics, disrupted autophagy, and calcium homeostasis imbalances. These impairments modulate microglial activation states, precipitating exacerbated neuroinflammation, altered phagocytic capacity, and increased cellular apoptosis, collectively contributing to microglial dysfunction. This paper presents a narrative review on the relationship between mitochondrial dysfunction and AD, elucidating the impact of mitochondrial impairment on microglia. It summarizes therapeutic strategies that target mitochondria to modulate microglial function, aiming to prevent and treat AD. The goal is to provide new perspectives and insights for AD research and treatment, contributing to improving patients' quality of life and prognosis.

Keywords:  Alzheimer's disease; Microglial cell polarization; Mitochondrial dysfunction; Mitophagy; Neuroinflammation; Therapeutic strategies

DOI:  https://doi.org/10.1016/j.arr.2025.102838