bims-auttor 2025-06-15 papers

bims-auttor

Biomed News

on Autophagy and mTOR

Issue of 2025–06–15
33 papers selected by
Viktor Korolchuk, Newcastle University

Guts for Self-Eating: Role of Autophagy in Gastrointestinal Health and Disease.
Phosphoribosyl ubiquitination of SNARE proteins regulates autophagy during Legionella infection.
Conformation-specific synthetic intrabodies modulate mTOR signaling with subcellular spatial resolution.
Tumorous cholesterol biosynthesis curtails anti-tumor immunity by preventing MTOR-TFEB-mediated lysosomal degradation of CD274/PD-L1.
Unconventional role of ATG16L1 in the control of ATP compartmentalization during apoptosis.
Cell-Type-Specific Autophagy in Human Leukocytes.
Broken Balance: Emerging Cross-Talk Between Proteostasis and Lipostasis in Neurodegenerative Diseases.
Melatonin attenuates kidney injury by alleviating lysosomal damage in diabetic kidney disease.
AKT-mediated phosphorylation of TSC2 controls stimulus- and tissue-specific mTORC1 signaling and organ growth.
The critical role of mitophagy in cell senescence-mediated pulmonary fibrosis and potential therapeutic strategies.
The role of TP53INP2 as an adaptor protein in the regulation of lipophagy in mature adipocytes.
Targeting mitophagy in the heart: Exploring the therapeutic potential of MicroRNAs.
SETD5-Coordinated LC3B Methylation Inhibits Autophagy in Ovarian Cancer.
Leveraging autophagy and pyrimidine metabolism to target pancreatic cancer.
Lysosomal ion channels and pain.
A Narrative Review about Metabolic Pathways, Molecular Mechanisms and Clinical Implications of Intermittent Fasting as Autophagy Promotor.
Ultraviolet radiation induces caspase cleavage and nuclear translocation of heme oxygenase 1 (HO-1) to activate autophagy in skin keratinocytes.
Small molecule disruption of RARα/NCoR1 interaction inhibits chaperone-mediated autophagy in cancer.
TNFα impairs platelet function by inhibiting autophagy and disrupting metabolism via Syntaxin-17 downregulation.
Small but mighty: ATG9A-positive vesicles are a branch of the intracellular nanovesicle superfamily.
Decoding extracellular matrix-lysosome cross-talk and its implications for neurodegenerative diseases.
Autophagy-Unlocking New Dimensions in the Pathology and Treatment of Depression.
MARCH6 suppresses Tembusu virus replication by targeting viral NS5 protein for TOLLIP-mediated selective autophagic degradation.
Unraveling mitochondrial influence on mammalian pluripotency via enforced mitophagy.
Mitochondrial fumarate inhibits Parkin-mediated mitophagy.
ADP ribosylation factor-like GTPase 6-interacting protein 5 (ARL6IP5): a prenylated Rab acceptor protein 1 (PRA1) family protein that shapes the ER membrane and regulates ER-phagy.
Rethinking Parkinson's: The role of proteostasis networks and autophagy in disease progression.
Ketogenesis is dispensable for the metabolic adaptations to caloric restriction.
Influenza A virus subverts the LC3-pericentrin dynein adaptor complex for host cytoplasm entry.
Integrative Chemical Genetics Platform Identifies Condensate Modulators Linked to Neurological Disorders.
Antagonizing Neuronal Toll-like Receptor 2 Prevents Synucleinopathy by Activating Autophagy.
Low Dose Rapamycin Alleviates Clinical Symptoms of Fatigue and PEM in ME/CFS Patients via Improvement of Autophagy.
mTOR Modulates NLRP3 Inflammasome Activation via Nuclear Translocation and STAT1 Inhibition.

Gastro Hep Adv. 2025 ;4(6): 100654

Guts for Self-Eating: Role of Autophagy in Gastrointestinal Health and Disease.

Prashant Nighot, Jonathan Stine, Kofi Clarke.

  Autophagy, a highly conserved cellular degradation pathway promotes cell survival via lysosomal degradation of aberrant cellular proteins and recycling of the nutrients. A variety of human diseases are now linked to defective autophagy and there is ever-growing interest in the application of autophagy in healthy living as well as disease prevention and therapies. Autophagy plays very important and complex functions in the gastrointestinal tract which are an intense focus of the current research efforts. Autophagy maintains cellular homeostasis mainly through proteostasis, lipid regulation, mitigation of damaged mitochondria, removal of intracellular infectious agents and foreign material, and reduction in reactive oxygen species and inflammasome. Recent studies show that although autophagy is mostly beneficial, it can induce damaging effects depending upon the cellular contexts such as homeostatic or inflammatory conditions. We summarize that this double-edge effect of autophagy is associated with cell-specific and cell-autonomous functions of autophagy, noncanonical autophagic effects, and autophagy-independent functions of autophagy-related proteins. We review opposing effects of autophagy pathway and its differential cellular functions specifically relevant to gastrointestinal homeostasis. We highlight the impacts of autophagy-related genetic defects in inflammatory bowel disease and the evolving role of autophagy in gastrointestinal and liver diseases including fibrosis and neoplastic processes. We also provide a contemporary perspective on the clinical studies related to autophagy and highlight the context-specific outcomes of autophagy and their relevance. The growing knowledge of the diverse autophagy regulatory mechanisms will provide further insights into how this life-friendly, self-cleansing cellular process can be harnessed for therapeutic advantages in gastrointestinal and liver diseases.

Keywords:  Autophagy; Fibrosis; Inflammatory Bowel Disease; Intestinal Homeostasis

DOI:  https://doi.org/10.1016/j.gastha.2025.100654
EMBO J. 2025 Jun 12.

Phosphoribosyl ubiquitination of SNARE proteins regulates autophagy during Legionella infection.

Rukmini Mukherjee, Anshu Bhattacharya, Ines Tomaskovic, João Mello-Vieira, Melinda Elaine Brunstein, Marion Başoğlu, Tineke Veenendaal, Henry Bailey, Thomas Colby, Mohit Misra, Stefan Eimer, Judith Klumperman, Christian Münch, Ivan Matic, Ivan Dikic.

  Legionella pneumophila is an intracellular pathogen that causes Legionnaires' disease. The bacteria release effector proteins, some of which remodel host autophagic-lysosomal pathways. One such effector is RavZ, which delipidates ATG8 proteins, making compromising autophagy in Legionella-infected cells. Here we show that SidE effectors also affect these pathways, by mediating phosphoribosyl-ubiquitination (PR-Ub) of the autophagic SNARE proteins STX17 and SNAP29. STX17 modification induces recruitment of STX17-positive membranes from the endoplasmic reticulum to Legionella-containing phagosomes, forming replicative vacuoles. Using proximity labeling, biochemistry and Legionella infection studies, we define a mechanism by which autophagy is hijacked by bacteria to recruit ER membranes to the bacterial vacuole, via a structure bearing autophagy markers but not fusing with lysosomes. Mass-spectrometric identification of PR-Ub sites and mutational studies show that phosphoribosyl-ubiquitination of STX17 alters its interaction with ATG14L, which causes ER membranes to be recruited to the bacterial vacuole in a PI3K-dependent manner. On the other hand, phosphoribosyl-ubiquitination of SNAP29 inhibits the formation of the autophagosomal SNARE complex (STX17-SNAP29-VAMP8) via steric hindrance, thus preventing the fusion of bacterial vacuoles with lysosomes.

Keywords:   Legionella pneumophila ; Autophagy; Syntaxin17; Ubiquitin; Xenophagy

DOI:  https://doi.org/10.1038/s44318-025-00483-4
Proc Natl Acad Sci U S A. 2025 Jun 17. 122(24): e2424679122

Conformation-specific synthetic intrabodies modulate mTOR signaling with subcellular spatial resolution.

Kelly M O'Leary, Tomasz Slezak, Anthony A Kossiakoff.

  Subcellular compartmentalization is integral to the spatial regulation of mechanistic target of rapamycin (mTOR) signaling. However, the biological outputs associated with location-specific mTOR signaling events are poorly understood and challenging to decouple. Here, we engineered synthetic intracellular antibodies (intrabodies) that are capable of modulating mTOR signaling with genetically programmable spatial resolution. Epitope-directed phage display was exploited to generate high affinity synthetic antibody fragments (Fabs) against the FKBP12-Rapamycin binding site of mTOR (mTORFRB). We determined high-resolution crystal structures of two unique Fabs that discriminate distinct conformational states of mTORFRB through recognition of its substrate recruitment interface. By leveraging these conformation-specific binders as intracellular probes, we uncovered the structural basis for an allosteric mechanism governing mTOR complex 1 (mTORC1) stability mediated by subtle structural adjustments within mTORFRB. Furthermore, our results demonstrated that synthetic binders emulate natural substrates by employing divergent yet complementary hydrophobic residues at defined positions, underscoring the broad molecular recognition capability of mTORFRB. Intracellular signaling studies showed differential time-dependent inhibition of S6 kinase 1 and Akt phosphorylation by genetically encoded intrabodies, thus supporting a mechanism of inhibition analogous to the natural product rapamycin. Finally, we implemented a feasible approach to selectively modulate mTOR signaling in the nucleus through spatially programmed intrabody expression. These findings establish intrabodies as versatile tools for dissecting the conformational regulation of mTORC1 and should be useful to explore how location-specific mTOR signaling influences disease progression.

Keywords:  allosteric; inhibition; intrabody; mTOR; spatial

DOI:  https://doi.org/10.1073/pnas.2424679122
Autophagy. 2025 Jun 12.

Tumorous cholesterol biosynthesis curtails anti-tumor immunity by preventing MTOR-TFEB-mediated lysosomal degradation of CD274/PD-L1.

Huina Wang, Xiuli Yi, Di Qu, Xiangxu Wang, Hao Wang, Hengxiang Zhang, Yuqi Yang, Tianwen Gao, Weinan Guo, Chunying Li.

  Enhanced cholesterol biosynthesis is a hallmark metabolic characteristic of cancer, exerting an oncogenic role by supplying intermediate metabolites that regulate intracellular signaling pathways. The pharmacological blockade of cholesterol biosynthesis has been well documented as a promising therapeutic approach in cancer. Particularly, cholesterol biosynthesis is linked to macroautophagy/autophagy and lysosome metabolism, with the engagement of the critical autophagy regulators like MTOR to be fully activated by lysosomal cholesterol trafficking and accumulation. Previous studies have primarily focused on the role of cholesterol biosynthesis in tumor cell-intrinsic biological processes, whereas its involvement in tumor immune evasion and the underlying mechanisms related to autophagy or lysosome metabolism remain elusive. Herein, through bioinformatics analysis we discovered a negative correlation between cholesterol biosynthesis and the score of tumor-infiltrating lymphocytes in cancers. Inhibition of tumor cell cholesterol biosynthesis leads to increased infiltration and activation of CD8+ T cells in the tumor microenvironment, which is largely responsible for the impairment of tumor growth. Mechanistically, cholesterol biosynthesis inhibition impairs the activation of MTOR at lysosomes, thereby promoting the nuclear translocation of TFEB and downstream lysosome biosynthesis, facilitating the degradation of CD274/PD-L1 within lysosomes in tumor cells. Ultimately, the HMGCR-MTOR-LAMP1 axis that connects cholesterol, lysosome and tumor immunology, predicts poor response to immunotherapy and worse prognosis of patients with melanoma. These findings unveil an immunomodulatory role of tumorous cholesterol biosynthesis via the regulation of CD274 lysosomal degradation. Targeting cholesterol biosynthesis holds promise as a potential therapeutic strategy in cancer, particularly when combined with immune checkpoint blockade.

Keywords:  Cholesterol; PD-L1; TFEB; immune evasion; lysosome; protein degradation

DOI:  https://doi.org/10.1080/15548627.2025.2519066
Autophagy. 2025 Jun 12.

Unconventional role of ATG16L1 in the control of ATP compartmentalization during apoptosis.

Elena Terraza-Silvestre, Julia Bandera-Linero, Daniel Oña-Sánchez, Felipe X Pimentel-Muinos.

  The autophagy mediator ATG16L1 forms part of a complex that is essential for MAP1LC3/LC3 lipidation and autophagosome formation in the canonical macroautophagic/autophagic pathway. However, ATG16L1 is also involved in unconventional activities where LC3 becomes lipidated in single-membrane structures unrelated to double-membrane autophagosomes. Such atypical activities usually require the C-terminal domain of the molecule that includes 7 WD40-type repetitions (WD40 domain, WDD). The WDD acts as a docking site for upstream inducers that engage the LC3 lipidation ability of ATG16L1 in alternative membrane compartments. Given that this domain is absent in the yeast Atg16 ortholog, an intriguing idea proposes that it was added to the primitive protein during evolution to perform new physiological roles required by the appearance of multicellularity. Identification of such atypical activities and their physiological implications at the organismal level are important issues that remain to be clarified. In a recent report we describe an unconventional autophagic pathway that restrains the immunogenic potential of apoptosis, a key feature of homeostatic and developmentally regulated cell death in multicellular organisms. This signaling route emanates from apoptotic mitochondria and induces the formation of single-membrane, LC3-positive vesicles through a mechanism that requires the WDD of ATG16L1. The induced vesicles sequester ATP to inhibit the amount of ATP released from apoptotic cells and, consequently, prevent the activation of co-cultured phagocytes. Thus, this is a pathway that contributes to maintain the immunosilent nature of apoptotic cell death.

Keywords:  ATG16L1; ATP secretion; Apoptosis; BAK; immunogenic cell death; unconventional autophagy

DOI:  https://doi.org/10.1080/15548627.2025.2519051
FASEB J. 2025 Jun 30. 39(12): e70708

Cell-Type-Specific Autophagy in Human Leukocytes.

Linh V P Dang, Alexis Martin, Julian M Carosi, Jemima Gore, Sanjna Singh, Timothy J Sargeant.

  Autophagy is a naturally conserved mechanism crucial for degrading and recycling damaged organelles and proteins to support cell survival. This process slows biological aging and age-related disease in preclinical models. However, there has been little translation of autophagy to the clinic, and we have identified a lack of measurement tools for physiological human autophagy as a barrier. To address this, we have previously developed a direct measurement tool for autophagy in pooled human peripheral blood mononuclear cells (PBMCs) in the context of whole blood. In order to better understand how autophagy behaves and changes in humans, we measured human autophagic flux using flow cytometry in 19 cell subpopulations in whole blood to retain physiological flux. Autophagic flux was different between different cell types, being different within different monocyte, B lymphocyte, natural killer cell, and T lymphocyte subtypes. Autophagic flux also varied with sex, being higher in monocytes in females compared with males. In keeping with previous observations in humans, autophagy also increased with aging at subpopulation levels. Importantly, we found that only monocytes-specifically, nonclassical monocytes-displayed robust increased autophagic flux following amino acid withdrawal, underscoring the importance of population selection for measurement of autophagic flux during nutrient restriction studies in humans. Collectively, these data show PBMC population-level analysis improves sensitivity of human autophagic flux measurement.

Keywords:  aging; autophagic flux; autophagy; blood; human; sex

DOI:  https://doi.org/10.1096/fj.202402377R
Cells. 2025 Jun 04. pii: 845. [Epub ahead of print]14(11):

Broken Balance: Emerging Cross-Talk Between Proteostasis and Lipostasis in Neurodegenerative Diseases.

Jessica Tittelmeier, Carmen Nussbaum-Krammer.

  Neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease, are characterized by progressive neuronal loss, leading to cognitive and motor impairments. Although these diseases have distinct clinical manifestations, they share pathological hallmarks such as protein aggregation and lysosomal dysfunction. The lysosome plays a vital role in maintaining cellular homeostasis by mediating the degradation and recycling of proteins, lipids, and other macromolecules. As such, it serves as a central hub for both proteostasis and lipostasis. This review outlines genetic and mechanistic parallels between rare lysosomal lipid storage diseases, such as Gaucher disease and Niemann-Pick disease, and more prevalent neurodegenerative diseases. We discuss how impaired lysosomal sphingolipid metabolism compromises lysosomal integrity, disrupts proteostasis, and contributes to neurodegeneration. Furthermore, we describe how age-related decline in lysosomal function may similarly drive neurodegeneration in the absence of overt genetic mutations. Taken together, this review highlights the lysosome as a central integrator of protein and lipid homeostasis and emphasizes the bidirectional relationship between lipostasis and proteostasis, whereby disruption of one adversely affects the other in the pathogenesis of multiple neurodegenerative diseases.

Keywords:  lipostasis; lysosomal lipid storage diseases; lysosome; neurodegenerative diseases; prion-like propagation; proteostasis; sphingolipidoses

DOI:  https://doi.org/10.3390/cells14110845
Acta Biochim Biophys Sin (Shanghai). 2025 Jun 13.

Melatonin attenuates kidney injury by alleviating lysosomal damage in diabetic kidney disease.

Jiaqi Chen, Shuting Zhang, Xiaoquan Xue, Xiaoqin Ma, Aomiao Chen, Yichuan Wu, Geningyue Wang, Qian Zhang, Yaoming Xue, Yijie Jia, Zongji Zheng.

  Proteinuria-induced damage to renal tubular epithelial cells is one of the main causes of diabetic kidney disease (DKD), and the clearance of overloaded albumin by lysosomes is crucial for maintaining the homeostasis of renal tubular epithelial cells. Therefore, lysosomal damage is closely related to the pathogenesis of DKD, but effective prevention and treatment measures are still lacking. Melatonin (MLT) is secreted by the pineal gland and can not only regulate circadian rhythms but also maintain lysosomal homeostasis. In this study, we demonstrate the presence of significant lysosomal damage in the renal tubules of DKD patients, which causes autophagy impairment and a concomitant oxidative stress imbalance; however, MLT can upregulate transcription factor EB (TFEB) to improve lysosomal damage and restore the biosynthesis of this organelle. Mechanistically, MLT may protect lysosomes via the upregulation of TFEB and the miR-205-5p‒LRP-1 pathway in renal tubules, thus improving autophagy dysfunction and oxidative imbalance in DKD.

Keywords:  TFEB; diabetic kidney disease; lysosome; melatonin; tubular epithelial cell

DOI:  https://doi.org/10.3724/abbs.2025034
Dev Cell. 2025 May 30. pii: S1534-5807(25)00319-3. [Epub ahead of print]

AKT-mediated phosphorylation of TSC2 controls stimulus- and tissue-specific mTORC1 signaling and organ growth.

Yann Cormerais, Samuel C Lapp, Krystle C Kalafut, Madi Y Cissé, Jong Shin, Benjamin Stefadu, Jean Personnaz, Sandra Schrötter, Jessica Freed, Angelica D'Amore, Emma R Martin, Catherine L Salussolia, Mustafa Sahin, Suchithra Menon, Vanessa Byles, Brendan D Manning.

  Mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) integrates diverse growth signals to regulate cell and tissue growth. How the molecular mechanisms regulating mTORC1 signaling-established through biochemical and cell biological studies-function under physiological states in specific mammalian tissues is undefined. Here, we characterize a genetic mouse model lacking the five phosphorylation sites on the tuberous sclerosis complex 2 (TSC2) protein through which the growth factor-stimulated protein kinase AKT can activate mTORC1 signaling in cell culture models. These phospho-mutant mice (TSC2-5A) are developmentally normal but exhibit reduced body weight and the weight of specific organs, such as the brain and skeletal muscle, associated with cell-intrinsic decreases in growth factor-stimulated mTORC1 signaling. The TSC2-5A mice demonstrate that TSC2 phosphorylation is a primary mechanism of mTORC1 regulation in response to exogenous signals in some, but not all, tissues and provide a genetic tool to study the physiological regulation of mTORC1.

Keywords:  PI3K; RHEB; feeding; insulin; lean mass; lysosome; microcephaly; myotubes; neurons; phosphoinositide 3-kinase

DOI:  https://doi.org/10.1016/j.devcel.2025.05.008
Mol Biol Rep. 2025 Jun 07. 52(1): 565

The critical role of mitophagy in cell senescence-mediated pulmonary fibrosis and potential therapeutic strategies.

Xing-Yi Chen, Dong-Mei Wang, Ya Zhou, Li Liu, Tao Zhu, Zhao Ran, Mei-Hong Lu, Ben-Rong Mu.

Pulmonary fibrosis is often associated with aging, marked notably by the senescence of lung epithelial cells and the development of interstitial fibrosis. Mitophagy plays a crucial role in aging by degrading damaged mitochondria, thereby maintaining mitochondrial quality and cellular homeostasis. When mitophagy is disrupted or impaired, damaged mitochondria fail to be properly degraded by lysosomes. This results in the persistence of dysfunctional mitochondria, which can further damage cells, induce cell senescence and trigger inflammatory responses. These processes can worsen pulmonary fibrosis. Restoring proper mitophagy could be a promising strategy for managing pulmonary fibrosis and countering stress-induced premature cell senescence, potentially improving or even reversing lung function in aging lungs. This review will explore the complex relationship between cell senescence and pulmonary fibrosis, detailing the senescence characteristics in fibrotic lungs. It will also highlight recent advancements in understanding how mitophagy influences lung senescence and fibrosis and discuss potential therapeutic strategies to address mitophagy dysfunction in treating pulmonary fibrosis.

DOI: https://doi.org/10.1007/s11033-025-10665-2
Life Sci. 2025 Jun 06. pii: S0024-3205(25)00437-0. [Epub ahead of print] 123802

The role of TP53INP2 as an adaptor protein in the regulation of lipophagy in mature adipocytes.

Mouliganesh Sekar, Kavitha Thirumurugan.

   AIM: Lipid droplet (LD) accumulation is caused by an imbalance between energy intake and expenditure, leading to adipose tissue dysfunction, obesity, and other metabolic disorders. Lipophagy is a selective autophagy process responsible for LD degradation. However, no specific adaptor proteins have been identified as regulators of lipophagy. This study investigates the role of TP53INP2 as a potential adaptor protein in the regulation of the lipophagy process.
METHODS: Murine 3T3L1 cells were subjected to starvation treatment to stimulate autophagy, followed by gene and protein expression analysis to evaluate markers associated with autophagy, adipogenesis, and lipophagy, providing insights into lipid degradation and the lipophagy process. Co-IP analysis of autophagy receptors and lipophagy adaptor proteins provided evidence supporting TP53INP2's role as a potential adaptor protein. Additionally, siRNA-mediated TP53INP2 knockdown further validated its function in lipophagy regulation.
KEY FINDINGS: Our findings demonstrated that TP53INP2 negatively regulates adipocyte differentiation while promoting autophagy. In mature adipocytes, TP53INP2 actively promotes lipophagy by targeting LDs through interaction with the membranous protein perilipin 1 (PLIN1). The Co-IP analysis confirmed that TP53INP2 directly binds to PLIN1 and the autophagosome receptor LC3 via its LIR motif. Furthermore, TP53INP2 knockdown in mature adipocytes impaired lipophagy, preventing the degradation of PLIN1 despite the continued function of general autophagy through the common adaptor protein p62 with LC3. These findings suggest that TP53INP2 may serve as an adaptor protein in regulating lipophagy in mature adipocytes.

Keywords:  Adaptor protein; Adipose tissue; Autophagy; Lipid droplet; Lipophagy; Obesity; PLIN1; TP53INP2

DOI:  https://doi.org/10.1016/j.lfs.2025.123802
Mech Ageing Dev. 2025 Jun 06. pii: S0047-6374(25)00058-2. [Epub ahead of print]226 112082

Targeting mitophagy in the heart: Exploring the therapeutic potential of MicroRNAs.

Amin Javadifar, Masoud Tahani, Sorousha Khayat, Shiva Rakhshani Nasab, Sercan Karav, Prashant Kesharwani, Amirhossein Sahebkar.

  Mitophagy, a selective form of autophagy, plays an indispensable role in preserving mitochondrial integrity by eliminating dysfunctional mitochondria, thereby sustaining cellular homeostasis. This process is particularly critical in cardiomyocytes, which rely heavily on high-quality mitochondria to meet their substantial energy demands. Impaired mitophagy has been implicated in the pathogenesis of various cardiovascular diseases, including ischemic heart disease, heart failure, and cardiomyopathy. Emerging evidence highlights the pivotal regulatory role of microRNAs (miRNAs)-small non-coding RNA molecules-in modulating mitophagy by targeting key genes such as PINK1, Parkin, and FUNDC1, which are integral to mitochondrial quality control. This review comprehensively examines the dual capacity of miRNAs to either enhance or suppress mitophagy and evaluates the implications of these regulatory actions for cardiovascular health. For instance, miRNAs such as miR-24-3p and miR-125a-5p modulate mitophagy pathways, influencing cardiac function in distinct ways. Additionally, miRNAs like miR-34a and miR-330-3p may exert broader effects on mitochondrial homeostasis in cardiac tissue. This paper further explores the therapeutic potential of targeting miRNAs to restore mitophagy equilibrium and mitigate mitochondrial dysfunction, offering novel avenues for cardiovascular disease management. By synthesizing recent findings, this review underscores the promise of miRNA-based interventions and identifies critical directions for future research.

Keywords:  Cardiac health; Cardiovascular diseases; MicroRNAs; Mitochondrial quality control; Mitophagy; Therapeutic targets

DOI:  https://doi.org/10.1016/j.mad.2025.112082
FASEB J. 2025 Jun 15. 39(11): e70700

SETD5-Coordinated LC3B Methylation Inhibits Autophagy in Ovarian Cancer.

Yanan Hou, Mingyang Li, Ziwei Zhang, Bowen Zhang, Ting Huang, Yifan Yang, Aiqin Sun, Qiong Lin, Genbao Shao.

  MAP1LC3/LC3 is an essential autophagy regulator involved in both the formation of autophagosome and the recruitment of autophagy cargo. Although several post-translational modifications (PTMs) have been identified to regulate the function of LC3, the effect of protein methylation on its function has not been well characterized. Here, we show that SETD5 interacts with and methylates nuclear LC3B (a member of the LC3 subfamily) at lysines 5 and 65, leading to its nuclear retention. In the nucleus of human ovarian cancer (OC) cells, methylated LC3B binds the nuclear transcription factor PRDM10 to the promoter regions of autophagy-related genes (ATGs), including ATG2a, ATG7, ATG12, and ATG16L1, to suppress their transcription, thereby resulting in reduced formation of autophagosomes. Moreover, the methylation of LC3B facilitates OC cell migration by inhibiting autophagy. Overall, our study defines a novel modification of LC3B and unveils a SETD5-mediated methylation-dependent regulatory mechanism controlling nuclear LC3B function in autophagy and migration in OC cells, offering potential therapeutic targets for OC.

Keywords:  LC3B; SET domain containing 5; autophagy; ovarian cancer; posttranslational modification

DOI:  https://doi.org/10.1096/fj.202402487R
bioRxiv. 2025 Jun 05. pii: 2025.05.29.656904. [Epub ahead of print]

Leveraging autophagy and pyrimidine metabolism to target pancreatic cancer.

Suzanne Dufresne, Ramya S Kuna, Kristiana Wong, Anvita Komarla, Angelica Rock, Joel Rosada-Encarnación, Celina Shen, Payel Mondal, Louis R Parham, Fabiana Izidro Layng, Kristina L Peck, Alexandra Fowler, Andrew M Lowy, Dannielle Engle, Herve Tiriac, Reuben Shaw, Nicholas Cosford, Christian Metallo, Christina Towers.

Autophagy inhibitors are promising compounds to treat pancreatic ductal adenocarcinoma (PDA) but their efficacy in patients is unclear, highlighting a need to understand mechanisms of resistance. We used a novel approach to uncover metabolic adaptations that bypass autophagy inhibition. Utilizing PDA cells with acquired resistance to different autophagy inhibitors, we found that severe autophagy depletion induces metabolic rewiring to sustain TCA intermediates and nucleotides for biosynthesis. Long-term autophagy inhibition results in altered pyruvate metabolism likely regulated by lower pyrimidine pools. Cells adapting to loss of autophagy preferentially salvage pyrimidines to replenish these pools instead of synthesizing them de novo. Exploiting this metabolic vulnerability, we found that acquired resistance to autophagy inhibition promotes increased salvage and therefore sensitivity to pyrimidine analogues, including gemcitabine and trifluridine/tipiracil leading to combinatory effects with autophagy inhibitors and pyrimidine analogs. These studies provide mechanistic insight defining how autophagy inhibition can be leveraged to treat pancreatic cancer.

DOI: https://doi.org/10.1101/2025.05.29.656904
Pain Rep. 2025 Aug;10(4): e1282

Lysosomal ion channels and pain.

Wanxue Liu, Yiming Li, Yuhan Bao, Zhi-Yong Tan.

  Lysosomes are recycling centers of nearly all types of eukaryotic cells. Lysosomal ion channels maintain ion homeostasis of lysosomes and exchange ions with neighboring cytoplasm and subcellular structures. In these ways, lysosomal ion channels contribute to major function of lysosomes such as autophagy and lysosomal exocytosis. Deficiency in some lysosomal ion channels results in lysosome storage disorders such as mucolipidosis IV that is associated with early-onset neurodegeneration. Moreover, lysosomal ion channels are involved in a variety of conditions such as cancer, infectious diseases, respiratory diseases, cardiovascular and kidney diseases. This narrative review aims to summarize current evidence that supports the potential role of lysosomal ion channels in pain. Lysosomal P2X4 may contribute to pain through trafficking to plasma membrane as well as lysosomal exocytosis. In dorsal root ganglion neurons, lysosomal TRPM8 functions as a constitutive supply from lysosomal to plasma membrane, whereas lysosomal TRPA1 may mediate vehicle exocytosis of neurotransmitters. Moreover, recent studies suggest that Tmem63A forms a mechanosensory ion channel in lysosomal membrane and that Tmem63A of dorsal root ganglion neurons contributes to mechanical hypersensitivity in chronic pain models. Furthermore, evidences indicating a potential role of TRPMLs in pain include ROS sensitivity of TRPML1, chemokine release mediated by TRPML2, and re-expression of TRPML3 upon nerve injury. However, despite the current supporting evidence, the role of lysosomal ion channels in pain is just being explored, and future studies are needed to address the significance, mechanism, and potential translation of lysosomal ion channels in pain.

Keywords:  Lysosomal ion channels; P2X4; Pain; TRPM8; Tmem63A

DOI:  https://doi.org/10.1097/PR9.0000000000001282
Curr Nutr Rep. 2025 Jun 06. 14(1): 78

A Narrative Review about Metabolic Pathways, Molecular Mechanisms and Clinical Implications of Intermittent Fasting as Autophagy Promotor.

Álvaro Andrés Vergara Nieto, Andrés Halabi Diaz, Millaray Hernández, Daniel Sagredo.

   PURPOSE OF REVIEW: This research aims to elucidate the molecular mechanisms by which intermittent fasting (IF) induces autophagy and to evaluate its therapeutic potential across a range of pathologies. By synthesizing findings from preclinical and clinical studies, the review seeks to clarify the roles of key signaling pathways-such as the AMPK-mTOR axis, sirtuins, and β-hydroxybutyrate-mediated signaling-in orchestrating autophagic processes, thereby enhancing cellular resilience and metabolic homeostasis.
RECENT FINDINGS: Recent evidence demonstrates that IF robustly activates autophagy in metabolically active tissues through conserved molecular pathways. Experimental studies reveal that fasting increases AMPK phosphorylation and inhibits mTOR activity, leading to enhanced expression of autophagy markers like LC3-II, Beclin-1, and ATG proteins. Additionally, IF has been shown to improve insulin sensitivity, reduce hepatic lipid accumulation, and mitigate neurodegenerative processes by promoting the clearance of toxic protein aggregates. Emerging clinical data further support these findings, indicating that tailored fasting protocols can modulate autophagy to yield benefits in metabolic, oncological, and neurodegenerative disorders. The scoped literature underscores IF as a promising non-pharmacological strategy to induce autophagy and improve overall health. While robust preclinical and clinical evidence supports its beneficial effects, challenges remain in standardizing fasting protocols and identifying optimal biomarkers for monitoring autophagic activity. Future research should focus on long-term, well-controlled trials and combined therapeutic approaches to refine IF strategies, ultimately translating these insights into personalized dietary interventions for disease prevention and health optimization.

Keywords:  AMPK; Autophagy; Cardiovascular; Inflammation; Intermittent Fasting; MTOR; Metabolism; Neurological

DOI:  https://doi.org/10.1007/s13668-025-00666-9
FEBS J. 2025 Jun 09.

Ultraviolet radiation induces caspase cleavage and nuclear translocation of heme oxygenase 1 (HO-1) to activate autophagy in skin keratinocytes.

Chunxiang Bian, Yan Wu, Mingwang Zhang, Lan Ge, Maojiao Zhong, Chunling Zheng, Long Chen, Mingxing Lei, Muhammad Farrukh Nisar, Charareh Pourzand, Jörg W Bartsch, Julia Li Zhong, Mei Wang.

  The skin is vulnerable to ultraviolet (UV) exposure, and as a repair mechanism, autophagy activation is essential to eliminate UV-damaged skin cells to maintain tissue homeostasis. As a UV-induced protein, heme oxygenase-1 (HO-1; 32 kDa) is implicated in protecting cells from oxidative stress and plays an important role in disease prevention. However, the mechanism of photoprotection in skin cells has yet to be fully understood. In the current study, we uncovered that UV radiation induces proteolytic cleavage of HO-1 into a 26 kDa product that accumulates in the cell nucleus. Biochemical analyses show that caspase-1 (CASP1) directly binds to HO-1 and cleaves full-length HO-1 at the C terminus. It is further unveiled that the 26 kDa HO-1 product is a stronger activator of autophagy than full-length HO-1, as demonstrated by the activation of autophagy-related genes. Moreover, the 26 kDa HO-1 cleavage product promotes translocation of the transcription factor basic helix-loop-helix ARNT-like protein 1 (Bmal1) into the cell nucleus. This translocation appears to be required for the induction of autophagy, as knocking down Bmal1 fails to activate autophagy induced by the 26 kDa HO-1 cleavage product. We conclude that a proteolytic cascade involving CASP1/HO-1/Bmal1 acts to modulate autophagy in UV-irradiated human skin keratinocytes, presumably as a mechanism to mediate UV photoprotection. Our study identified proteolysis as a regulatory event by generating a previously unknown 26 kDa form of HO-1 to play a distinct role in the activation of autophagy in UV-exposed epidermal cells.

Keywords:  Bmal1; UV damage; UV radiation; autophagy; caspase‐1; heme oxygenase 1; proteolysis

DOI:  https://doi.org/10.1111/febs.70144
EMBO Mol Med. 2025 Jun 09.

Small molecule disruption of RARα/NCoR1 interaction inhibits chaperone-mediated autophagy in cancer.

Mericka McCabe, Rajanya Bhattacharyya, Rebecca Sereda, Olaya Santiago-Fernández, Rabia R Khawaja, Antonio Diaz, Kristen Lindenau, Deniz Gulfem Ozturk, Thomas P Garner, Simone Sidoli, Ana Maria Cuervo, Evripidis Gavathiotis.

  Chaperone-mediated autophagy (CMA), a type of selective degradation of cytosolic proteins in lysosomes, is commonly upregulated in cancer cells, contributing to their survival and growth. The lack of a specific target for CMA inhibition has limited CMA blockage to genetic manipulations or global lysosomal function inhibition. Here, using genetic modulation, transcriptional analysis, and functional studies, we demonstrate a regulatory role for the interaction of the retinoic acid receptor alpha (RARα) and its corepressor, the nuclear receptor corepressor 1 (NCoR1), on CMA in non-small cell lung cancer (NSCLC). By targeting the disruption of the NCoR1/RARα complex with a structure-based screening strategy, we identified compound CIM7, a potent and selective CMA inhibitor that has no effect on macroautophagy. CIM7 preferentially inhibits CMA in NSCLC cells over normal cells, reduces tumor growth in NSCLC cells, and demonstrates efficacy in an in vivo xenograft mouse model with no observed toxicity in blood or major tissues. These findings reveal a druggable mechanism for selective CMA inhibition and a first-in-class CMA inhibitor as a potential therapeutic strategy for NSCLC.

Keywords:  Autophagy; CMA Inhibitor; NCoR1; Non-small Cell Lung Cancer; RARα

DOI:  https://doi.org/10.1038/s44321-025-00254-y
J Clin Invest. 2025 Jun 10. pii: e186065. [Epub ahead of print]

TNFα impairs platelet function by inhibiting autophagy and disrupting metabolism via Syntaxin-17 downregulation.

Guadalupe Rojas-Sanchez, Jorge Calzada-Martinez, Brandon McMahon, Aaron C Petrey, Gabriela Dveksler, Gerardo P Espino-Solis, Orlando Esparza, Giovanny Hernandez, Dennis Le, Eric P Wartchow, Ken Jones, Lucas H Ting, Catherine Jankowski, Marguerite R Kelher, Marilyn Manco-Johnson, Marie L Feser, Kevin D Deane, Travis Nemkov, Angelo D'Alessandro, Andrew Thorburn, Paola Maycotte, José A López, Pavel Davizon-Castillo.

  Platelets play a dual role in hemostasis and inflammation-associated thrombosis and hemorrhage. While the mechanisms linking inflammation to platelet dysfunction remain poorly understood, our previous work demonstrated that TNFα alters mitochondrial mass, platelet activation, and autophagy-related pathways in megakaryocytes. Here, we hypothesized that TNFα impairs platelet function by disrupting autophagy, a process critical for mitochondrial health and cellular metabolism. Using human and murine models of TNFα-driven diseases, including myeloproliferative neoplasms and rheumatoid arthritis, we found that TNFα downregulates STX17, a key mediator of autophagosome-lysosome fusion. This disruption inhibited autophagy, leading to the accumulation of dysfunctional mitochondria and reduced mitochondrial respiration. These metabolic alterations compromised platelet-driven clot contraction, a process linked to thrombotic and hemorrhagic complications. Our findings reveal a mechanism by which TNFα disrupts hemostasis through autophagy inhibition, highlighting TNFα as a critical regulator of platelet metabolism and function. This study provides new insights into inflammation-associated pathologies and suggests autophagy-targeting strategies as potential therapeutic avenues to restore hemostatic balance.

Keywords:  Autophagy; Hematology; Metabolism; Mitochondria; Platelets

DOI:  https://doi.org/10.1172/JCI186065
Autophagy Rep. 2025 ;4(1): 2513467

Small but mighty: ATG9A-positive vesicles are a branch of the intracellular nanovesicle superfamily.

Mary Fesenko, Stephen J Royle.

  The molecular and functional characterization of the thousands of uncoated intracellular transport vesicles inside cells is a major challenge. Intracellular nanovesicles (INVs) are a large and molecularly heterogenous family of uncoated transport vesicles, which are comprised of multiple subtypes. As a step to characterizing these subtypes, we recently published the first INV proteome and were intrigued by the enrichment of ATG9A in it. ATG9A is the only conserved transmembrane protein with a core function in macroautophagy/autophagy, and it is found on small, uncoated vesicles, termed "ATG9A-positive vesicles". We therefore, set out to disambiguate the relationship between these two types of vesicular carriers in cells. We showed that ATG9A-containing vesicles, rather than being a distinct vesicle class, represent one subset of the INV family. We also demonstrated that this relationship is functionally important and that perturbing INV-mediated trafficking impeded starvation-induced autophagy. Here, we briefly introduce INVs, summarize the evidence supporting our definition of ATG9A-flavor INVs and present our outlook on why we hope that this classification will help to consolidate efforts to understand the functions of these vesicles in autophagy and beyond.

Keywords:  Autophagy; membrane traffic; microscopy; proteomics; transmembrane protein; transport vesicle

DOI:  https://doi.org/10.1080/27694127.2025.2513467
Sci Signal. 2025 Jun 10. 18(890): eadt1936

Decoding extracellular matrix-lysosome cross-talk and its implications for neurodegenerative diseases.

Qinghu Yang, Huan Ma, Liang Yang, Ming Jiang, Xia Liu, Zhantao Bai.

Lysosomes are versatile organelles that play pivotal roles in cellular recycling and signal transduction. They are crucial for the autophagic degradation and recycling of macromolecules, which facilitates the efficient turnover of cellular components. Beyond their intracellular roles, lysosomes also regulate the degradation and assembly of extracellular matrix (ECM) constituents, affecting ECM remodeling and the processing of signaling molecules essential for cellular communication and adaptation to the microenvironment. Conversely, the ECM regulates key lysosomal functions, including biogenesis, acidification, and subcellular positioning. In this Review, we discuss the bidirectional interaction between lysosomes and the ECM and explore its implications in the development and treatment of neurodegenerative disease.

DOI: https://doi.org/10.1126/scisignal.adt1936
Cells. 2025 May 28. pii: 795. [Epub ahead of print]14(11):

Autophagy-Unlocking New Dimensions in the Pathology and Treatment of Depression.

Qiang Luo, Yulong Zhao, Peng Ren, Xu Liu, Yingjian Chen, Qianru Ying, Junjie Zhou.

  Depression is a widespread mental disorder whose impact on an individual's health extends far beyond the psychological dimension. As a disease with a significant burden, the effective treatment of depression has become a major challenge for global public health. Although several hypotheses have been proposed for the pathogenesis of depression, its pathophysiological mechanisms remain complex and not yet fully understood. Recent studies suggest that dysfunctional autophagy may play an important role in the development of depression. Autophagy, as an important intracellular degradation mechanism, maintains neuronal function and health by removing excess proteins and damaged organelles. Current evidence suggests that the regulation of autophagic processes may provide new potential targets for the treatment of depression. In this paper, we review the pharmacological mechanisms of autophagy by different antidepressant drugs and the abnormal changes in autophagy in patients with depression and in multiple models. Importantly, we focus on the role of autophagy in different pathological mechanisms of depression and discuss current limitations as well as potential directions for future research.

Keywords:  antidepressant; autophagy; depression; pathophysiology

DOI:  https://doi.org/10.3390/cells14110795
J Virol. 2025 Jun 13. e0073525

MARCH6 suppresses Tembusu virus replication by targeting viral NS5 protein for TOLLIP-mediated selective autophagic degradation.

Peng Zhou, Wanrong Wu, Jiani Wei, Yueshan Yang, Anan Jongkaewwattana, Yuncai Xiao, Hui Jin, Hongbo Zhou, Rui Luo.

  The E3 ligase membrane-associated RING finger 6 (MARCH6) plays a pivotal role in various cellular processes; however, its role in viral defense remains largely unexplored. In this study, we have elucidated a novel antiviral mechanism of avian MARCH6 against duck Tembusu virus (TMUV), revealing a previously uncharacterized host defense strategy. Notably, MARCH6 expression was significantly upregulated during TMUV infection in several duck cell lines, suggesting a conserved cellular response. Functional analyses revealed that overexpression of MARCH6 effectively suppressed TMUV replication, whereas its knockdown markedly enhanced viral replication. Mechanistically, MARCH6 directly interacts with the viral non-structural protein 5 (NS5), mediating its targeted degradation through an unprecedented E3 ligase activity-independent mechanism. Moreover, MARCH6 recruits the autophagic cargo receptor TOLLIP, which facilitates the NS5-TOLLIP interaction independent of ubiquitin signaling and subsequently directs NS5 to phagophores for degradation. These findings reveal a novel antiviral mechanism that focuses on the MARCH6-NS5-TOLLIP axis and represents a critical host defense strategy against viral infections. This study not only provides insights into the antiviral functions of MARCH6 but also emphasizes the importance of selective autophagy as a fundamental mechanism to control viral infection.IMPORTANCETMUV, an emerging pathogenic flavivirus, has rapidly spread across major duck farming regions in Asia since 2010, causing substantial economic losses in the duck industry. More recently, TMUV has expanded its host range, raising concerns about its potential threat to mammals. Understanding TMUV-host interactions is essential for developing effective treatments and vaccines. Here, we uncover a previously uncharacterized role of avian MARCH6 in antiviral defense against TMUV. We demonstrate that MARCH6 restricts TMUV replication through an E3 ligase activity-independent mechanism by targeting the viral NS5 protein for degradation. Notably, MARCH6 promotes NS5 degradation via selective autophagy by recruiting the cargo receptor TOLLIP, bypassing conventional ubiquitin signaling. These findings reveal a novel host antiviral strategy centered on the MARCH6-NS5-TOLLIP axis, broadening our understanding of selective autophagy in antiviral defense.

Keywords:  MARCH6; NS5; TMUV replication; TOLLIP; autophagic degradation

DOI:  https://doi.org/10.1128/jvi.00735-25
Cell. 2025 Jun 05. pii: S0092-8674(25)00570-7. [Epub ahead of print]

Unraveling mitochondrial influence on mammalian pluripotency via enforced mitophagy.

Daniel A Schmitz, Seiya Oura, Leijie Li, Yi Ding, Rashmi Dahiya, Emily Ballard, Carlos Pinzon-Arteaga, Masahiro Sakurai, Daiji Okamura, Leqian Yu, Peter Ly, Jun Wu.

  Mitochondrial abundance and genome are crucial for cellular function, with disruptions often associated with disease. However, methods to modulate these parameters for direct functional dissection remain limited. Here, we eliminate mitochondria from pluripotent stem cells (PSCs) by enforced mitophagy and show that PSCs survived for several days in culture without mitochondria. We then leverage enforced mitophagy to generate interspecies PSC fusions that harbor either human or non-human hominid (NHH) mitochondrial DNA (mtDNA). Comparative analyses indicate that human and NHH mtDNA are largely interchangeable in supporting pluripotency in these PSC fusions. However, species divergence between nuclear and mtDNA leads to subtle species-specific transcriptional and metabolic variations. By developing a transgenic enforced mitophagy approach, we further show that reducing mitochondrial abundance leads to delayed development in pre-implantation mouse embryos. Our study opens avenues for investigating the roles of mitochondria in development, disease, and interspecies biology.

Keywords:  cell fusion; great apes; interspecies composite; interspecies hybrid; metabolism; mitochondria; mitophagy; mtDNA; pluripotent stem cells

DOI:  https://doi.org/10.1016/j.cell.2025.05.020
Mol Cell. 2025 Jun 03. pii: S1097-2765(25)00460-5. [Epub ahead of print]

Mitochondrial fumarate inhibits Parkin-mediated mitophagy.

Su Jin Ham, Sunhoe Bang, Daihn Woo, Jae-Yoon Jo, Takwon Yoo, Eunju Yoon, Yeonju Kyoung, Daehyun Baek, Jong-Seo Kim, Jongkyeong Chung.

  Here, we explore the potential involvement of fumarate, a metabolite generated from the TCA cycle, as a key regulator of PINK1-Parkin-mediated mitophagy. Fumarate engages in a process called succination, forming S-(2-succino) cysteine with protein cysteine residues. Our research demonstrates that this modification specifically targets the sulfhydryl group of cysteine 323 and 451 residues of human Parkin, leading to the inhibition of its mitochondrial localization and E3 ligase activity, thereby impeding PINK1-Parkin-mediated mitophagy. Notably, our investigation reveals that the succinatable cysteines in human Parkin are not conserved in invertebrates, including Drosophila. To assess the functional impact of Parkin succination, we generate Parkin knockin flies with succinatable cysteines. These flies exhibit robust Parkinson's disease (PD)-related phenotypes when exposed to elevated fumarate levels. Collectively, our findings underscore the significance of fumarate as an endogenous regulator of PINK1-Parkin-mediated mitophagy, offering insights into the intricate interplay between mitochondrial metabolic activities and PD pathology.

Keywords:  ANT1; PINK1; Parkinson's disease; VDAC1/2; fumarate; parkin; succination

DOI:  https://doi.org/10.1016/j.molcel.2025.05.021
Autophagy Rep. 2025 ;4(1): 2513466

ADP ribosylation factor-like GTPase 6-interacting protein 5 (ARL6IP5): a prenylated Rab acceptor protein 1 (PRA1) family protein that shapes the ER membrane and regulates ER-phagy.

Yasunori Yamamoto, Toshiaki Sakisaka.

  The prenylated Rab acceptor protein 1 (PRA1) domain is a conserved domain encompassing four transmembrane domains (TMDs). ARL6IP5 (ADP ribosylation factor-like GTPase 6-interacting protein 5) is a member of the PRA1 family and interacts with the reticulon-homology domain (RHD)-containing proteins including ARL6IP1 (ADP ribosylation factor-like GTPase 6-interacting protein 1) and FAM134B. The RHD is a conserved domain encompassing two short hairpin TMDs and acts as a membrane-shaping unit for endoplasmic reticulum (ER) morphology and ER-phagy. However, the involvement of ARL6IP5 in ER morphology and ER-phagy remains unclear. We recently characterized ARL6IP5 as an ER membrane-shaping protein and found that ARL6IP5 constricts the ER membrane in a manner similar to ARL6IP1, possibly via short hairpin configuration of the TMDs in the PRA1 domain. ARL6IP5 also plays a redundant role with ARL6IP1 in shaping the ER membrane. Importantly, depletion of ARL6IP5 impaired FAM134B-meadited ER-phagy, which is reminiscent of ARL6IP1 depletion. These results suggested that ARL6IP5 acts as an ER membrane-shaping protein that regulates ER-phagy, underscoring the importance of the PRA1 domain. Although ARL6IP5 and ARL6IP1 are confusable protein names and seem to have similar roles in ER-phagy, we clarify in this punctum that they are distinct classes of ER membrane-shaping proteins.

Keywords:  ARL6IP1; ARL6IP5; ER-phagy; Endoplasmic reticulum; prenylated Rab acceptor protein 1 domain; reticulon-homology domain

DOI:  https://doi.org/10.1080/27694127.2025.2513466
Mol Cell Neurosci. 2025 Jun 07. pii: S1044-7431(25)00033-8. [Epub ahead of print]134 104023

Rethinking Parkinson's: The role of proteostasis networks and autophagy in disease progression.

Akhil Sharma, Ashi Mannan, Thakur Gurjeet Singh.

  Protein dyshomeostasis is identified as the hallmark of many age-related NDDs including Parkinson's disease (PD). PD is a progressive neurodegenerative disorder (NDD) characterized by the accumulation of misfolded proteins, particularly α-synuclein (α-syn) leading to formation of Lewy bodies and cause degeneration of dopaminergic neurons in substantia nigra pars compacta (SNpc). Disruption of the cell's normal protein balance, which occurs when cells experience stress, plays a key role in causing the formation of harmful protein clumps. Functional proteostasis relies on coordinated mechanisms involving posttranslational modifications (PTMs), molecular chaperones, the unfolded protein response (UPR), the ubiquitin-proteasome system (UPS), and the autophagy-lysosome pathway (ALP). These networks maintain proper synthesis, folding, confirmation and degradation of protein such as α-syn protein in PD. These approaches include enhancing lysosomal function, promoting autophagy and modulating the unfolded protein response. Understanding the complex interactions between these pathways is essential for developing effective treatments. This review synthesizes current knowledge of various genes and molecular mechanisms underlying proteostasis disruption in PD and evaluates emerging therapeutic strategies that target multiple genes and pathways simultaneously. The finding highlights the potential of integrated approaches to restore protein homeostasis and prevent neurodegeneration, offering new directions for PD treatment development.

Keywords:  Autophagy-lysosome pathway (ALP); Molecular chaperones; Parkinson's disease (PD); Posttranslational modifications (PTMs); Proteostasis; Ubiquitin-proteasome system (UPS); Unfolded protein response (UPR); α-Synuclein (α-syn)

DOI:  https://doi.org/10.1016/j.mcn.2025.104023
bioRxiv. 2025 Jun 01. pii: 2025.05.29.656153. [Epub ahead of print]

Ketogenesis is dispensable for the metabolic adaptations to caloric restriction.

Chung-Yang Yeh, Lexie Borgelt, Brynn J Vogt, Alyssa A Clark, Ted T Wong, Isaac Grunow, Michelle M Sonsalla, Reji Babygirija, Yang Liu, Michaela E Trautman, Mariah F Calubag, Bailey A Knopf, Fan Xiao, Dudley W Lamming.

Caloric restriction (CR) robustly extends the health and lifespan of diverse species. When fed once daily, CR-treated mice rapidly consume their food and endure a prolonged fast between meals. As fasting is associated with a rise in circulating ketones, we decided to investigate the role of ketogenesis in CR using mice with whole-body ablation of Hmgcs2 , the rate-limiting enzyme producing the main ketone body β-hydroxybutyrate (βHB). Here, we report that Hmgcs2 is largely dispensable for many metabolic benefits of CR, including CR-driven changes in adiposity, glycemic control, liver autophagy, and energy balance. Although we observed sex-specific effects of Hmgcs2 on insulin sensitivity, fuel selection, and adipocyte gene expression, the overall physiological response to CR remains robust in mice lacking Hmgcs2 . To gain insight into why deletion of Hmgcs2 does not disrupt CR, we measured fasting βHB levels as mice began a CR diet. Surprisingly, as CR-fed mice adapt to CR, they no longer engage high levels of ketogenesis during the daily fast. Our work suggests that the benefits of long-term CR in mice are not mediated by ketogenesis.

DOI: https://doi.org/10.1101/2025.05.29.656153
Sci Adv. 2025 Jun 13. 11(24): eadu7602

Influenza A virus subverts the LC3-pericentrin dynein adaptor complex for host cytoplasm entry.

Yingying Cong, Pauline Verlhac, Benjamin B Green, Jacqueline de Vries-Idema, Line Moesgaard Strauss, Clàudia Río-Bergé, Anders Etzerodt, Lene N Nejsum, Anke L W Huckriede, Fulvio Reggiori.

Influenza A virus (IAV) enters host cells via endocytosis, and fusion of the viral particles (VPs) at endosomes releases the viral ribonucleoproteins (vRNPs) into the cytoplasm. This uncoating step that is vital for IAV infection remains to be fully understood. The aggresome processing machinery (APM) plays a relevant but not essential role in this. Here, we reveal a mechanism in which light chain 3 proteins (LC3s) and pericentrin (PCNT) form an adaptor complex that is required for vRNPs binding to the dynein 1 and IAV uncoating at endosomes. This function of LC3s and PCNT is independent from their established role in autophagy and centrosome assembly, respectively. LC3s or PCNT depletion severely impairs IAV cytoplasm entry and infection, which can be further inhibited by additional silencing of histone deacetylase 6, an APM component. Collectively, our results show that IAV has adopted two redundant strategies to hijack the dynein biomolecular motors and facilitate VP uncoating.

DOI: https://doi.org/10.1126/sciadv.adu7602
bioRxiv. 2025 Jun 08. pii: 2025.06.07.658469. [Epub ahead of print]

Integrative Chemical Genetics Platform Identifies Condensate Modulators Linked to Neurological Disorders.

Dylan Poch, Chandrayee Mukherjee, Sunanda Mallik, Vanessa Todorow, E F Elsiena Kuiper, Nalini Dhingra, Yulia V Surovtseva, Christian Schlieker.

Aberrant biomolecular condensates are implicated in multiple incurable neurological disorders, including Amyotrophic Lateral Sclerosis (ALS), Frontotemporal Dementia (FTD), and DYT1 dystonia. However, the role of condensates in driving disease etiology remains poorly understood. Here, we identify myeloid leukemia factor 2 (MLF2) as a disease-agnostic biomarker for phase transitions, including stress granules and nuclear condensates associated with dystonia. Exploiting fluorophore-derivatized MLF2 constructs, we developed a high-content platform and computational pipeline to screen modulators of NE condensates across chemical and genetic space. We identified RNF26 and ZNF335 as protective factors that prevent the buildup of nuclear condensates sequestering K48-linked polyubiquitinated proteins. Chemical screening identified four FDA-approved drugs that potently modulate condensates by resolving polyubiquitinated cargo and MLF2 accumulation. Our exploratory integrated chemical-genetics approach suggests that modulation of zinc, and potentially autophagy and oxidative stress, is critical for condensate modulation and nuclear proteostasis, offering potential therapeutic strategies for neurological disorders. Application of our platform to a genome-wide CRISPR KO screen identified strong enrichment of candidate genes linked to primary microcephaly and related neurodevelopmental disorders. Two hypomorphic microcephaly-associated alleles of ZNF335 failed to rescue nuclear condensate accumulation in ZNF335 KO cells, suggesting that aberrant condensates and impaired nuclear proteostasis may contribute to the pathogenesis of microcephaly.
HIGHLIGHTS: MLF2 emerges as a disease-agnostic condensate biomarker co-localizing with TDP-43 and G3BP1FDA-approved drugs target condensates linked to perturbed proteostasis.RNF26 and ZNF335 are identified as modulators of nuclear phase transitions.Microcephaly patient disease alleles fail to counteract aberrant condensates.

DOI: https://doi.org/10.1101/2025.06.07.658469
Cell Rep. 2025 Jun 10. pii: S2211-1247(25)00658-8. [Epub ahead of print]44(6): 115887

Antagonizing Neuronal Toll-like Receptor 2 Prevents Synucleinopathy by Activating Autophagy.

Changyoun Kim, Edward Rockenstein, Brian Spencer, Hyung-Koo Kim, Anthony Adame, Margarita Trejo, Klodjan Stafa, He-Jin Lee, Seung-Jae Lee, Eliezer Masliah.

DOI: https://doi.org/10.1016/j.celrep.2025.115887
Res Sq. 2025 Jun 03. pii: rs.3.rs-6596158. [Epub ahead of print]

Low Dose Rapamycin Alleviates Clinical Symptoms of Fatigue and PEM in ME/CFS Patients via Improvement of Autophagy.

Brian T Ruan, Sarojini Bulbule, Amy Reyes, Bela Chheda, Lucinda Bateman, Jennifer Bell, Braydon Yellman, Stephanie Grach, Jon Berner, Daniel L Peterson, David Kaufman, Avik Roy, C Gunnar Gottschalk.

BACKGROUND: mTOR activation is associated with chronic inflammation in ME/CFS. Previous studies have shown that sustained mTOR activation can cause chronic muscle fatigue by inhibiting ATG13-mediated autophagy. This highlights the pivotal role of mTOR in the pathogenesis of ME/CFS.
METHODS: We conducted a decentralized, uncontrolled trial of rapamycin in 86 patients with ME/CFS to evaluate its safety and efficacy. Low-dose rapamycin (6 mg/week) was administered, and core ME/CFS symptoms were assessed on days 30 (T1), 60 (T2), and 90 (T3). Plasma levels of autophagy metabolites, such as pSer258-ATG13 and BECLIN-1, were measured and correlated with clinical outcomes, specifically MFI.
RESULTS: Rapamycin (6 mg/week) was tolerated without any SAEs. Of the 40 patients, 29 (72.5%) showed strong recovery in PEM, fatigue, and OI, along with improvements in MFI fatigue domains and SF-36 aspects. High levels of BECLIN-1 were detected in T3. Plasma pSer258-ATG13 levels were strongly downregulated at T1. Spearman's correlation analysis indicated an association between autophagy impairment and reduced activity.
CONCLUSIONS: Low-dose rapamycin effectively reduced PEM and other key symptoms in patients with ME/CFS, as measured by BAS, SSS, MFI, and SF-36. Future studies should encompass dose optimization and develop a diagnostic tool to identify responders with mTOR-mediated autophagy disruption.

DOI: https://doi.org/10.21203/rs.3.rs-6596158/v1
Eur J Immunol. 2025 Jun;55(6): e51176

mTOR Modulates NLRP3 Inflammasome Activation via Nuclear Translocation and STAT1 Inhibition.

Alvaro González-Dominguez, Shuling Zhang, Daniel Boy-Ruiz, Daniel Connors, Raquel de la Varga-Martínez, Beverly A Mock, Mario D Cordero.

The NLRP3 inflammasome has emerged as an unexpected sensor of metabolic danger and stress. Their enhanced activation has been implicated in the development of major diseases such as gout, Type 2 diabetes, obesity, cancer, and neurodegenerative and cardiovascular diseases. In this study, we showed that mammalian target of rapamycin (mTOR) regulates NLRP3 inflammasome activation in the nucleus of macrophages. mTOR binds to NLRP3 under basal conditions, and this binding is reduced after lipopolysaccharides (LPS) or LPS + adenosine triphosphate (ATP) treatment. Furthermore, rapamycin-induced downregulation of mTOR expression has an inhibitory effect on NLRP3 inflammasome activation. mTOR knockdown (KD) mice exhibit reduced protein levels of inflammasome components, and their macrophages fail to activate the NLRP3 inflammasome after LPS + ATP treatment. From a mechanistic point of view, LPS + ATP treatment induced the nuclear translocation of mTOR, leading to enhanced NLRP3 inflammasome activation. However, the mTOR inhibition by rapamycin treatment increased phosphorylation of STAT1 which repressed NLRP3 activation. When rapamycin was combined with the STAT1 inhibitor fludarabine, NLRP3 inflammasome activity was restored. Taken together, these findings suggest a role for mTOR in NLRP3 regulation and identify a potential therapeutic option for controlling inflammasome activation.

DOI: https://doi.org/10.1002/eji.202451176