bims-auttor 2025-10-26 papers

bims-auttor

Biomed News

on Autophagy and mTOR

Issue of 2025–10–26
39 papers selected by
Viktor Korolchuk, Newcastle University

A paradoxical role of autophagy: promoting protein aggregates and hindering rejuvenation in a Caenorhabditis elegans L1 arrest model.
The connection between autophagy and Alzheimer's disease.
The Drosophila ZER1 homolog interacts with ref(2)P to regulate autophagy and Keap1-cnc/NFE2L2/Nrf2-mediated oxidative stress.
The multifaceted role of autophagy and mitophagy in cardiovascular health and disease.
ATG9 assists lipid replenishment for lysosome membrane repair.
Reticulophagy receptor FAM134C restrains BMP receptor signaling.
Optineurin is an adaptor protein for ubiquitinated substrates in Golgi membrane-associated degradation.
Targeting macroautophagy to combat neurodegenerative disease: strategies and considerations.
Interplay of autophagy and Th1/Th2-mediated macrophage polarization in host-pathogen dynamics.
TfR in focus: Orchestrating autophagosome biogenesis.
Exploring mitophagy levels in Drosophila Malpighian tubules unveils the pivotal role of mitophagy in kidney function and diabetic kidney disease.
Dietary monounsaturated fatty acid facilitates lipid droplet turnover through chaperone HSP90A-mediated lysosomal degradation of PLIN2 in hepatocellular carcinoma.
ITCH regulates Golgi integrity and proteotoxicity in neurodegeneration.
Cleavage of Beclin 1 by metacaspase 1 activates antiviral autophagy in plants.
Insights into key kinase regulatory network of LARP1 based on co-occurring phosphorylation events.
Roles of lysosomal small-molecule transporters in metabolism and signaling.
STX1A localizes to the lysosome and controls its exocytosis.
Mitophagy in the adaptation to pancreatic β cell stress in diabetes.
Oxidative stress-mediated DNA damage promotes selective degradation of nuclear components via noncanonical autophagy in triple-negative breast cancer cells.
Vacuolar transport and function of Saccharomyces cerevisiae sterol ester hydrolase Tgl1.
Pharmacologic targeting of eEF2K in cardiovascular diseases: Mechanisms and potential clinical applications.
SerpinB1a induces hepatopulmonary syndrome by promoting CTSG/AMPK/mTOR pathway-mediated mitophagy.
Delayed protein translocation protects mitochondria against toxic CAT-tailed proteins.
Entrectinib binds to HMGB1 and activates cardiomyocyte autophagy by inhibiting OTUD5-MTORC1 signaling to induce cardiotoxicity.
SIK2-mediated phosphorylation of GABARAPL2 facilitates autophagosome-lysosome fusion and rescues neurodegeneration in an Alzheimer's disease model.
Lysosomal homeostasis regulates myocardial ischemia-reperfusion injury through autophagy pathway.
TM9SF1 drives the lipophagic flux via AMPK-ULK1 signaling to sustain metabolic fitness in HER2-positive breast cancer.
Roles of the Keap1/Nrf2 pathway and mitophagy in liver diseases.
Adenosine Monophosphate-Activated Protein Kinase Activation and Mammalian Target of Rapamycin Complex 1 Inhibition: A Mechanistic Rationale for Anti-Aging Therapy in Type 2 Diabetes.
ATG9A-mediated autophagy prevents inflammatory skin disease by limiting TNFR1-driven STING activation and ZBP1-dependent cell death.
Extracellular vesicles: cargo loading, degradation and secretory pathways, and their intersection with autophagy.
IL-11 exacerbates cisplatin-induced acute kidney injury by facilitating apoptosis in renal tubular epithelial cells via ERK1/2-Drp1/TFEB-mediated defective autophagy.
TMEM175 does not function as a proton-selective ion channel to prevent lysosomal over-acidification.
Internalized SNCA/α-synuclein fibrils become truncated and resist degradation in neurons while glial cells rapidly degrade SNCA fibrils.
p53 drives lung cancer regression through a TSC2/TFEB-dependent senescence program.
The Proteostasis Network is a Therapeutic Target in Acute Myeloid Leukemia.
Elevated TFEB expression with limited activation in peripheral blood mononuclear cells reflects altered lysosomal enzyme dynamics in Parkinson's disease.
FUNDC1 deficiency aggravates endothelial senescence and retinal dysfunction.
Mitochondrial homeostasis collapse to cardiac remodeling: From mechanisms to novel targeted therapeutic avenues.

Autophagy. 2025 Nov;21(11): 2311-2312

A paradoxical role of autophagy: promoting protein aggregates and hindering rejuvenation in a Caenorhabditis elegans L1 arrest model.

Yuxiang Huang, Daniel J Klionsky.

  Macroautophagy (hereafter referred to as autophagy) is widely recognized as a central pathway for the clearance of protein aggregates and the maintenance of proteostasis. However, a recent study by Murley et al. challenges this conventional view. Using a Caenorhabditis elegans L1 arrest aging model, the authors found that autophagy activation impedes rejuvenation by promoting the accumulation of intra- 10 lysosomal protein aggregates and inducing lysosomal membrane damage. This unexpected finding reveals that autophagy may play dual, context-dependent roles in proteostasis, acting not only as a protective mechanism but also, under certain conditions, as a contributor to cellular stress.

Keywords:  Aging; autophagy; protein aggregates; proteostasis; rejuvenation; stress

DOI:  https://doi.org/10.1080/15548627.2025.2541430
Inflamm Res. 2025 Oct 22. 74(1): 148

The connection between autophagy and Alzheimer's disease.

Nechushtai Lior, Dahan Chen, Frenkel Dan, Pinkas-Kramarski Ronit.

  Alzheimer's disease (AD) is the most prevalent neurodegenerative disease associated with accumulation of amyloid beta peptides and intracellular neurofibrillary tangles formed by hyperphosphorylated Tau. Autophagy, an evolutionarily conserved process of self-degradation and turnover of cellular constituents, is important for normal cell growth but may be defective in diseases. A growing body of data implies that autophagy strongly affects AD pathogenesis. Autophagy mediates degradation of damaged organelles and proteins as well as neurotoxic aggregates, by regulating their clearance. Thus, impaired autophagy may account for the accumulation of protein aggregates. Since AD is characterized by neuroinflammation, impaired mitochondrial and lysosomal functions, and the accumulation of protein aggregates, the roles of autophagy/mitophagy in Alzheimer's will be extensively evaluated. In the current review, we will discuss the connection between autophagy/mitophagy and Alzheimer's. It seems that Alzheimer-related proteins such as APOE4, TREM2, PSEN1/2, APP and Tau can regulate autophagy. In turn, depending on the cellular system and animal model, autophagy regulating proteins such as Atg7, BECN1, GSK3B, MAP1LC3B, SQSTM1, TFEB and VCP can affect AD progression as discussed. We will also describe the effect of sex and lifestyle impact on autophagy and AD. Finally, we will describe how the current knowledge may contribute to potential therapeutic strategies.

Keywords:  Alzheimer’s disease (AD); Amyloid β; Apolipoprotein E4 (APOE4); Autophagy

DOI:  https://doi.org/10.1007/s00011-025-02118-0
Autophagy. 2025 Oct 20.

The Drosophila ZER1 homolog interacts with ref(2)P to regulate autophagy and Keap1-cnc/NFE2L2/Nrf2-mediated oxidative stress.

Yi-Ting Wang, Ya-Ting Shen, Hsuan-Yu Weng, Jung-Kun Wen, Guang-Chao Chen.

  The ubiquitin-proteasome system (UPS) and macroautophagy/autophagy are two major pathways for maintaining cellular protein homeostasis. Increasing evidence has highlighted the complex interactions and crosstalk between these pathways; however, the specific molecules and mechanisms mediating the interplay between the UPS and autophagy are still not fully elucidated. In this study, we discovered that knocking down the Drosophila Cul2 (Cullin 2)-RING ubiquitin ligase complex adaptor CG12084/DmZer1 impedes autophagy and autophagic flux. DmZer1 interacts with the Drosophila SQSTM1/p62 homolog ref(2)P, promoting its association with ubiquitinated proteins and degradation. ref(2)P is a crucial player in regulating autophagy and the Keap1-cnc/NFE2L2 pathway-mediated antioxidant response. Knockdown of DmZer1 leads to the formation of ref(2)P bodies, which sequester Keap1 and promote cnc/NFE2L2-mediated antioxidant responses under oxidative stress conditions. These findings reveal the pivotal role of DmZer1 in regulating autophagy and the ref(2)P-Keap1-cnc/NFE2L2-mediated oxidative stress response.

Keywords:  Drosophila; SQSTM1/p62; ZER1; autophagy; oxidative stress; ubiquitin-proteasome system

DOI:  https://doi.org/10.1080/15548627.2025.2577771
Autophagy Rep. 2025 ;4(1): 2572511

The multifaceted role of autophagy and mitophagy in cardiovascular health and disease.

Mireia Nàger, Mauro Calvoli, Kenneth B Larsen, Asa B Birgisdottir.

  The cardiovascular system, consisting of the heart and blood vessels, ensures delivery of oxygen and nutrient-rich blood throughout the whole body. The major cell types include cardiomyocytes, endothelial cells, and vascular smooth muscle cells. Dramatic consequences, sometimes with a deadly outcome, may arise when the activity of cardiovascular cells is compromised. The cardiomyocytes are terminally differentiated cells and thus do not normally regenerate. To sustain the high energy demand of the beating heart, the cardiomyocytes contain a high amount of energy producing mitochondria. Adaptation to metabolic demands is an integral part of cellular homeostasis and involves autophagy. Autophagy is an evolutionary conserved intracellular degradation pathway of cellular constituents. Mitophagy refers to selective degradation of damaged, and thus potentially harmful, mitochondria through autophagy. Both autophagy and mitophagy are widely implicated in physiological and pathological processes within cardiovascular cells. In this review, we highlight studies applying genetic modifications in mouse models to reveal the impact of autophagy and mitophagy on cardiovascular health and disease.

Keywords:  Aging; atherosclerosis; development; genetic mouse models; heart failure; myocardial infarction

DOI:  https://doi.org/10.1080/27694127.2025.2572511
Dev Cell. 2025 Oct 20. pii: S1534-5807(25)00570-2. [Epub ahead of print]60(20): 2701-2702

ATG9 assists lipid replenishment for lysosome membrane repair.

Hemmo Meyer, Bojana Kravic.

Lysosomal membranes can be permeabilized under various conditions with detrimental consequences for the cell. In this issue, de Tito et al. report that the lipid scramblase ATG9, best known for its role in autophagosome formation, helps distribute lipids from the ER to reseal the limiting membrane and restore lysosomal function.

DOI: https://doi.org/10.1016/j.devcel.2025.09.010
EMBO J. 2025 Oct 20.

Reticulophagy receptor FAM134C restrains BMP receptor signaling.

Shuchen Gu, Hanchenxi Zhang, Jin Cao, Zhou He, Jianfeng Wu, Xia Liu, Mingjie Zheng, Ting Liu, Bin Zhao, Pinglong Xu, Qiming Sun, Jianping Jin, Xia Lin, Yi Yu, Jiahuai Han, Xin-Hua Feng.

  FAM134/RETREG family members are ER-phagy receptors that maintain cellular homeostasis by regulating endoplasmic reticulum turnover. However, possible non-ER-phagy functions of FAM134 proteins remain elusive. Here, we show that RETREG3/FAM134C functions as a selective autophagy receptor for the type I BMP receptor (BMPRIA/ALK3) and recruits BMPRIA into LC3-containing autophagosomes for subsequent degradation. FAM134C-induced degradation diminishes the availability of BMP receptors and thus the strength of BMP signaling. Inhibition of autophagy through chemical means or knockdown of key autophagy regulators, ATG5 or Beclin-1, prevents BMPR1A degradation. Additionally, disruption of the putative LC3-interacting region (LIR) motif in FAM134C completely abolishes its interaction with LC3, thereby impeding its ability to degrade BMPR1A. Moreover, FAM134C-deficient mice exhibit enhanced BMP responses in the intestines, which affects intestinal crypt regeneration. Our findings suggest that FAM134C acts as a specific receptor that controls BMP signaling through the autophagic degradation of the type I BMP receptor, independent of its canonical role in ER-phagy.

Keywords:  Autophagy; Degradation; RETREG; Smad; TGF-β

DOI:  https://doi.org/10.1038/s44318-025-00581-3
Nat Commun. 2025 Oct 20. 16(1): 8966

Optineurin is an adaptor protein for ubiquitinated substrates in Golgi membrane-associated degradation.

Yoichi Nibe-Shirakihara, Shinya Honda, Satoko Arakawa, Satoru Torii, Hajime Tajima Sakurai, Hirofumi Yamaguchi, Shigeru Oshima, Ryuichi Okamoto, Michael Lazarou, Hideshi Kawakami, Shigeomi Shimizu.

Golgi membrane-associated degradation (GOMED) is a process that leading to the degradation of proteins that have passed through the trans-Golgi membranes upon Golgi stress. GOMED is morphologically similar to autophagy, but the substrates degraded are different, and they thus have different biological roles. Although the substrate recognition mechanism of autophagy has been clarified in detail, that of GOMED is completely unknown. Here we report that GOMED degrades its substrate proteins selectively via optineurin (OPTN), as we found that the degradation of GOMED substrates is s`uppressed by the loss of OPTN. OPTN binds to K33 polyubiquitin-tagged proteins that have passed through the Golgi, which are then incorporated into GOMED structures for eventual degradation. In vivo, GOMED is known to be involved in the removal of mitochondria from erythrocytes, and in Optn-deficient mice, mitochondria are not degraded by GOMED, resulting in the appearance of erythrocytes containing mitochondria. These findings provide insight into the substrate recognition mechanism of GOMED.

DOI: https://doi.org/10.1038/s41467-025-64400-3
Autophagy Rep. 2025 ;4(1): 2571940

Targeting macroautophagy to combat neurodegenerative disease: strategies and considerations.

Glenn M Duncan, Ai Yamamoto.

  Upon demonstration that basal macroautophagy plays an essential role in maintaining protein homeostasis in the mammalian CNS, there has been excitement around modulating this form of autophagy as a therapeutic strategy to combat neurodegenerative disease. Nonetheless, the initial genetic studies that spawned this excitement did little to reveal the complex physiology of autophagy regulation in neural cells, or the predicament of compartment-specific events upon which these cells rely. Pursuit of therapeutic strategies further highlighted how this intricacy extends across the different organs of the body, raising question as to how we may harness the power of macroautophagy for good while minimizing the bad. Fortunately, since these early studies, the field has made significant gains toward understanding the molecular, cellular and physiological basis of macroautophagy. Together with technological advances, they have refueled the exploration into how this powerful pathway may provide the much-needed therapeutic advances for these yet untreatable diseases. In this review, we will contextualize the insights gained over the last decade with the traditional and novel strategies that have been explored to combat disease-associated events such as abnormal protein accumulation. In addition, we will discuss key considerations and strategies that can influence how a therapeutic approach might be designed.

Keywords:  Autophagy; neurodegeneration; selective autophagy; therapeutics

DOI:  https://doi.org/10.1080/27694127.2025.2571940
Front Cell Infect Microbiol. 2025 ;15 1679514

Interplay of autophagy and Th1/Th2-mediated macrophage polarization in host-pathogen dynamics.

Gaurav Shoeran, Namrata Anand.

  Autophagy, host immune responses, and macrophage polarization form a tightly regulated network. This network significantly influences the outcome of intracellular pathogenic infections. Autophagy acts as a critical cellular defense mechanism. It degrades intracellular pathogens and helps with antigen presentation in antigen presenting cells like macrophages. Intracellular parasites have evolved diverse strategies to modulate autophagy. They may inhibit autophagosome formation, block autophagosome-lysosome fusion, or redirect autophagic flux for their survival. These manipulations allow pathogens to evade degradation and persist within host cells. Macrophage polarization further influences autophagic activity: M1 macrophages typically exhibit enhanced autophagy, supporting antimicrobial functions, while M2 macrophages show reduced autophagic flux, contributing to immune regulation and tissue repair. Autophagy itself can influence macrophage phenotypes, with its activation promoting M1-like characteristics and its inhibition favoring M2-like responses. The macrophage polarization states influence T cell polarization and infection outcome. This bidirectional relationship between autophagy and macrophage polarization plays a pivotal role in determining host resistance or susceptibility to intracellular pathogens. In this review, we highlight findings from macrophage-infecting pathogens that manipulate autophagy, macrophage and T cell to enhance their survival within the host.

Keywords:  M1/M2 macrophage polarization; Mycobacterium; Salmonella; Th1/Th2 response; Toxoplasma gondii; autophagy; host-parasite interaction; immune response

DOI:  https://doi.org/10.3389/fcimb.2025.1679514
Dev Cell. 2025 Oct 20. pii: S1534-5807(25)00568-4. [Epub ahead of print]60(20): 2697-2699

TfR in focus: Orchestrating autophagosome biogenesis.

Yan G Zhao, Hong Zhang.

Transferrin receptors, responsible for iron importation into cells, exhibit additional iron-independent functions. In this issue, Puri et al. reveal that the transferrin receptor recruits the VPS34 complex I, stimulating PI(3)P synthesis. This PI(3)P production aids in autophagosome elongation and closure by facilitating recruitment of the LC3 conjugation system and ESCRT, respectively.

DOI: https://doi.org/10.1016/j.devcel.2025.09.008
Exp Mol Med. 2025 Oct 23.

Exploring mitophagy levels in Drosophila Malpighian tubules unveils the pivotal role of mitophagy in kidney function and diabetic kidney disease.

Kang-Min Lee, Jihun Kim, Hye Lim Jung, Young Yeon Kim, Jihoon Lee, Yeon-Ju Lee, Eunhee Yoo, Hyi-Seung Lee, Jeanho Yun.

Mitophagy has been implicated in kidney function and related diseases. However, a direct analysis of mitophagy in kidney models, including disease models, remains notably lacking. Here we analyzed mitophagy levels in Drosophila Malpighian tubules, a functional analog of the human kidney, using a transgenic model of the engineered mitophagy reporter mt-Keima. We found that mitophagy is highly active in the major cell types of the Malpighian tubules, including renal stem cells, principal cells and stellate cells. Notably, the suppression of mitophagy by genetic downregulation of mitophagy-related genes, such as ATG5 and ULK1, led to a significant decrease in the secretion function of the Malpighian tubules, suggesting that mitophagy is essential for their proper function. Interestingly, a continuous high-sugar diet, which is used as a model for diabetic kidney disease, caused a reduction in mitophagy levels in principal cells before the development of mitochondrial dysfunction and defective secretion. Importantly, stimulation of mitophagy with the recently developed mitophagy inducer PDE701 rescued both mitochondrial dysfunction and defective phenotypes in a diabetic kidney disease model. Our results highlight the pivotal role of mitophagy in kidney function and suggest that modulating mitophagy could be a potential strategy for treating kidney diseases.

DOI: https://doi.org/10.1038/s12276-025-01558-2
Autophagy. 2025 Oct 22.

Dietary monounsaturated fatty acid facilitates lipid droplet turnover through chaperone HSP90A-mediated lysosomal degradation of PLIN2 in hepatocellular carcinoma.

Xiaoqing Luo, Jinqing Zhao, Qianqian Chen, Dianhan Liu, Qiannan Lu, Chuan Tian, Huan Liu, Xinyu Yu, Jia He, Xiong Z Ruan, Ping Yang, Yaxi Chen.

  Dietary lipids are emerging as critical regulators of tumor metabolism. However, the understanding of how dietary lipid molecules remodel tumor metabolism to drive malignancy remains incomplete. In this study, we revealed that monounsaturated fatty acids (MUFAs) selectively promote hepatocellular carcinoma (HCC) progression by rewiring lipid droplet (LD) metabolism through a selective autophagy mechanism. Proteomic profiling of LD-binding proteins identified HSP90A (heat shock protein 90 alpha) as a MUFA-induced factor translocated to LDs. The recruitment of HSP90A subsequently initiated the breakdown of LDs, releasing FAs from LDs for mitochondrial respiration. Mechanistically, MUFAs facilitated the specific interaction between HSP90A and PLIN2 to stimulate the degradation of PLIN2 in non-canonical lysosomal pathway. Although this process requires LAMP2A, similar to chaperone-mediated autophagy, it relies on HSP90 rather than HSPA8/HSC70 for the recognition of PLIN2. Targeting HSP90A dampened LD mobilization and effectively prevented orthotopic HCC tumor growth induced by dietary MUFA. Collectively, our data demonstrated that dietary MUFA exhibits a distinctive tumor-promoting effect on HCC through HSP90A-mediated LD mobilization and suggested that targeting HSP90A-regulated autophagy may serve as a therapeutic strategy for the treatment of HCC.

Keywords:  Autophagy; HCC; fatty acid oxidation; lipid droplet; lysosome; mitochondria

DOI:  https://doi.org/10.1080/15548627.2025.2579138
Sci Adv. 2025 Oct 24. 11(43): eado4330

ITCH regulates Golgi integrity and proteotoxicity in neurodegeneration.

Qiwang Xiang, Yuning Lu, Hongjin Wang, Hao Chen, Peng Chen, Xiaofeng Zhao, Larissa Cortes Morales, Yiwei Yang, Junqin Yang, Tao Zhang, Jiou Wang.

Golgi fragmentation is an early and common feature of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD). However, whether a shared mechanism drives Golgi fragmentation across different neurodegenerative conditions remains unclear. Here, we identify the E3 ubiquitin-protein ligase Itchy homolog (ITCH) as a key regulator of proteotoxicity through its role in inducing Golgi fragmentation. Disease-associated accumulation of ITCH promotes fragmentation of both the cis- and trans-Golgi networks, disrupting protein sorting and impairing lysosomal functions. The ITCH-dependent lysosomal dysfunction compromises the clearance of misfolded proteins associated with several neurodegenerative diseases. Inhibition of ITCH protects against proteotoxicity in both mammalian neurons and Drosophila models of neurodegeneration. The accumulation of ITCH in patients with ALS and AD is attributed to up-regulation of the ubiquitin-specific protease USP11, which deubiquitinates and stabilizes ITCH. These results uncover a pathogenic pathway regulating Golgi integrity and contributing to the development of neurodegenerative diseases.

DOI: https://doi.org/10.1126/sciadv.ado4330
Mol Plant. 2025 Oct 23. pii: S1674-2052(25)00365-X. [Epub ahead of print]

Cleavage of Beclin 1 by metacaspase 1 activates antiviral autophagy in plants.

Rujian Hu, Qinglin Pi, Meng Yang, Wen Song, Zhihao Jiang, Chenchen Zhong, Huanxi Han, Cheng-Gui Han, Yongliang Zhang, Dawei Li.

  Beclin 1/ATG6 plays a critical role in the biogenesis of autophagosomes and various cellular processes, but how Beclin 1-dependent autophagy is activated in plants remains elusive. Here, we found that the cysteine protease metacaspase 1 (MC1) functions as a new positive regulator of autophagy and cleaves Beclin 1 behind residues R97 and R99 in tobacco (Nicotiana benthamiana). Genetic analysis further demonstrated that the MC1-Beclin 1 cleavage module is both necessary and sufficient for the activation of plant autophagy. Mechanistically, this cleavage releases the N-terminal fragment of Beclin 1 (aa 1-97) which exhibits intrinsic autophagy-inducing activity and is dependent on the PI3K complex. Moreover, the activated autophagy boosts broad-spectrum antiviral responses, while the barley stripe mosaic virus (BSMV)-encoded γb protein targets MC1 and suppresses MC1-mediated Beclin 1 cleavage to optimize viral infection. The cleavage of Beclin 1 is thought to abolish its autophagic function in mammals; however, our findings unveil a distinctive plant autophagy mechanism whereby Beclin 1 activation necessitates MC1-mediated cleavage to drive antiviral autophagy.

Keywords:  Beclin 1; autophagy; barley stripe mosaic virus; cleavage; metacaspase 1 (MC1); γb protein

DOI:  https://doi.org/10.1016/j.molp.2025.10.015
Biochim Biophys Acta Proteins Proteom. 2025 Oct 16. pii: S1570-9639(25)00041-X. [Epub ahead of print]1874(1): 141103

Insights into key kinase regulatory network of LARP1 based on co-occurring phosphorylation events.

Ashika Bangera, Nazah Naurah, Samseera Ummar, Poornima Ramesh, Rajesh Raju.

  LARP1 (La-related protein 1) is an important mediator of translation regulation that stabilizes terminal oligopyrimidine motif-containing mRNAs. LARP1, being a direct target of mechanistic Target of Rapamycin Complex 1 (mTORC1), undergoes phosphorylation in the presence of growth factors. Phosphorylation-dependent conformational changes in LARP1 dictate its ability to stabilize or repress mRNAs with 5' terminal oligopyrimidine (TOP), which code for key proteins in ribosome biogenesis and translation. Due to this important role, LARP1 is involved in cancer cell survival, facilitating selective translation of oncogenic proteins with a tradeoff in cap-dependent translation. As the function of LARP1 is governed by phosphorylation, this review provides phosphoproteomics-based regulatory network of LARP1, identifying major phosphorylation sites, upstream kinases, and interactors, with mutual co-differential regulation events. Extensive literature synthesis identified 11 major phosphorylation sites of LARP1, and an understanding of interaction dynamics that contribute to functional plasticity of LARP1. Specially, this article synthesizes the co-regulatory network of LARP1 with other proteins, and the interactions central to mTOR signaling, phosphorylation of LARP1, and its functional role in disease manifestation. This approach focusing on the LARP1-kinase regulatory network is crucial in untangling its miscellaneous role in cancer, which provides novel therapeutic paths for malignancies.

Keywords:  Co-regulation; Data integration; Kinases; LARP1; Mass spectrometry; Phosphoproteomics

DOI:  https://doi.org/10.1016/j.bbapap.2025.141103
Trends Cell Biol. 2025 Oct 17. pii: S0962-8924(25)00222-3. [Epub ahead of print]

Roles of lysosomal small-molecule transporters in metabolism and signaling.

Markus Damme, Océane Guelle, Christian Löw, Bruno Gasnier.

  Lysosomes degrade damaged or unwanted cell/tissue components and recycle their building blocks through small-molecule transporters of the lysosomal membrane. They also act as signaling hubs that sense and signal internal cues, such as amino acids, to coordinate cell responses. Recently, the activity of several lysosomal metabolite transporters has been elucidated, bringing new insights into lysosomal functions. Cell biological and structural studies of lysosomal transporters have also highlighted their roles in recruiting signaling complexes to lysosomes and delineated how their substrates gate such hybrid transporter/receptor, or 'transceptor', function. In this review, we summarize recent progress in our understanding of lysosomal transporters, with a focus on the export of lysosomal degradation intermediates, the existence of lysosomal amino acid shuttles that regulate the redox state and pH of the lysosomal lumen, and the role of lysosomal transceptors in nutrient and immune signaling.

Keywords:  lysosomes; metabolism; signaling; transceptor; transporter

DOI:  https://doi.org/10.1016/j.tcb.2025.09.004
Mol Biol Cell. 2025 Oct 22. mbcE25040196

STX1A localizes to the lysosome and controls its exocytosis.

Anshul Milap Bhatt, Bishal Singh, Prince Singh, Subba Rao Gangi Setty.

Lysosome exocytosis is one of the critical functions of lysosomes in maintaining cellular homeostasis and plasma membrane repair. At the basal level, the SNAREs regulating the lysosome fusion with the cell surface have been poorly defined. Here, we identified a Qa-SNARE STX1A, localized majorly to lysosomes and a cohort to the plasma membrane in HeLa cells. Overexpression of GFP-STX1A in HeLa cells causes decreased lysosome number and their peripheral dispersion. However, STX1A knockdown in HeLa cells displayed an accumulation of lysosomes beneath the cell surface with reduced lysosome exocytosis. Consistently, TIRF imaging microscopy demonstrated an enhanced enrichment of LAMP1-positive vesicles at the cell surface in STX1A depleted compared to control cells. Moreover, STX1A depletion reduces proteolytic activity without affecting the lysosome content or acidity. Additionally, these cells showed enhanced lysosome dispersion and autolysosome accumulation. Functionally, GFP-STX1A also localizes to LLOMe-induced GAL3-positive damaged lysosomes and reduces their number by enhancing exocytosis. Biochemically, STX1A forms a SNARE complex with SNAP23 or SNAP25 (Qbc) and VAMP2 (R), and their knockdown in HeLa cells mimics the STX1A-depletion phenotypes. Overall, these studies demonstrate a unique function of STX1A in regulating lysosomal exocytosis by localizing to these degradative organelles. [Media: see text] [Media: see text].

DOI: https://doi.org/10.1091/mbc.E25-04-0196
Trends Endocrinol Metab. 2025 Oct 17. pii: S1043-2760(25)00201-2. [Epub ahead of print]

Mitophagy in the adaptation to pancreatic β cell stress in diabetes.

Elena Levi-D'Ancona, Ava M Stendahl, Belle A Henry-Kanarek, Rebecca K Davidson, Emily M Walker, Scott A Soleimanpour.

  Mitophagy is a crucial quality control process that preserves metabolic efficiency by selectively targeting damaged mitochondria for removal. Given the high metabolic demand of pancreatic β cells' insulin secretion, disruption of mitophagy contributes to the mitochondrial dysfunction and β cell failure that are a common feature of both type 1 and type 2 diabetes (T1D and T2D). We review the impact of mitophagy on β cell responses to (patho)physiologic stressors that underlie the development of T1D and T2D. We examine how β cells engage mitophagy in the adaptive response to metabolic, inflammatory, and oxidative damage. We also dissect the importance of ubiquitin- and receptor-mediated mitophagy, methodological advances to quantify mitophagy in β cells, and ongoing efforts to pharmacologically target mitophagy to preserve β cell health and improve glycemic control.

Keywords:  CLEC16A; Parkin; islet; mitochondria; ubiquitin

DOI:  https://doi.org/10.1016/j.tem.2025.09.009
Free Radic Biol Med. 2025 Oct 16. pii: S0891-5849(25)01278-X. [Epub ahead of print]242 37-53

Oxidative stress-mediated DNA damage promotes selective degradation of nuclear components via noncanonical autophagy in triple-negative breast cancer cells.

Nishakumari Chentunarayan Singh, Nisha Yadav, Rakesh Kumar Sharma, Pragya Gupta, Jayanta Sarkar, Kalyan Mitra.

  SK (SK), a secondary plant metabolite from Lithospermum erythrorhizon, is an inducer of oxidative stress and a DNA Topoisomerase inhibitor with promising anticancer properties. However, the underlying mechanisms, especially the involvement of autophagy in cancer cell death, are poorly understood. Here, we report a novel mechanism of action that activates a noncanonical, Beclin1-independent but ATG5-dependent autophagy pathway triggered by oxidative stress in two distinct subtypes of triple-negative breast cancer (TNBC) cell lines: mesenchymal stem cell-like MDA-MB-231 and basal-like-1 MDA-MB-468. We observed that this noncanonical autophagy pathway specifically targets and degrades nuclear material by nucleophagy. Electron microscopy analysis of both cell lines revealed distinct nuclear alterations, including envelope-limited chromatin sheets (ELCS), nuclear buds, and micronuclei after SK treatment. Furthermore, numerous autophagosomes and lysosomes were found in close proximity to the nuclear membrane, suggesting the occurrence of nucleophagy. The localization of γ-H2AX in nuclear buds and micronuclei observed by confocal microscopy indicated cytosolic leakage of damaged DNA. Additionally, Western blot analysis confirmed the role of the cGAS-STING pathway, which is essential for detecting damaged DNA in the cytosol. Inner nuclear membrane protein Lamin B1 was found to interact with LC3II and was subsequently degraded through the nucleophagy pathway. Knockout of ATG5 using CRISPR-Cas9 reduced autophagy, while Beclin1 knockdown did not reduce LC3II conversion, indicating that the process follows a noncanonical autophagy pathway that is dependent on ATG5 and independent of Beclin1. SK induces oxidative stress, leading to mitochondrial depolarization and DNA damage accumulation, which subsequently triggers autophagy and ultimately causes apoptotic cell death. Treatment with the ROS scavenger N-acetylcysteine (NAC) reduced nuclear stress, mitochondrial dysfunction, autophagy, and cell death, emphasizing the role of oxidative stress in SK-induced cell death. MDA-MB-468 cells exhibited greater sensitivity to SK-induced nuclear stress and cell death compared to MDA-MB-231 cells. Taken together, we demonstrate that SK exerts its anticancer effects in TNBC cells through the generation of oxidative stress and noncanonical autophagy, thus highlighting SK's potential for targeted anticancer therapeutics.

Keywords:  Apoptosis; Non-canonical autophagy; Nucleophagy; Oxidative stress; Triple negative breast cancer

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.10.264
FEBS Lett. 2025 Oct 18.

Vacuolar transport and function of Saccharomyces cerevisiae sterol ester hydrolase Tgl1.

Takumi Nakatsuji, Kosuke Shiraishi, Chuqian Wang, Hiroya Yurimoto, Yasuyoshi Sakai, Masahide Oku.

  Sterol ester hydrolases (SEHs) play an important role in the quantitative regulation of sterols. Mammalian cells are known to possess SEHs both on the surface of lipid droplets and inside lysosomes. However, to date, no studies on the yeast Saccharomyces cerevisiae have identified active SEHs in the vacuole, which is the corresponding organelle to the mammalian lysosome. Here, we show that S. cerevisiae Tgl1 functions as the major SEH in the vacuole after being transported into the organelle lumen, in addition to its role in the cytoplasm. The transport of Tgl1 into the vacuole was independent of macroautophagy and ESCRT (endosomal sorting complex required for transport) complex-0 component Vps27 but dependent on ESCRT-I-III components. This study also revealed the mechanism of formation of vacuolar membrane microdomains supported by the SEHs.

Keywords:  ESCRT; autophagy; sterol ester; vacuolar membrane microdomain

DOI:  https://doi.org/10.1002/1873-3468.70196
Eur J Pharmacol. 2025 Oct 16. pii: S0014-2999(25)01007-6. [Epub ahead of print]1007 178253

Pharmacologic targeting of eEF2K in cardiovascular diseases: Mechanisms and potential clinical applications.

Aysa Rezabakhsh, Solomon Habtemariam, Elnaz Khani, Batool Ghorbani Yekta, Raha Rahmani, Hadis Iraji, Seyed Mohammad Nabavi.

  Eukaryotic elongation factor 2 kinase (eEF2K) is a calcium/calmodulin-dependent enzyme that regulates protein synthesis by phosphorylating eukaryotic elongation factor 2 (eEF2). Activation of eEF2K under stress conditions such as nutrient deprivation, hypoxia, and oxidative stress helps conserve cellular energy and supports cell survival. Although eEF2K has been extensively studied in cancer and neurodegenerative diseases, increasing evidence emphasizes its crucial role in cardiovascular diseases (CVD), including hypertension, pulmonary arterial hypertension (PAH), ischemia/reperfusion injury, and atherosclerosis. This review outlines the structural and regulatory features of eEF2K and examines how its modulation affects cardiomyocyte survival, autophagy, mitochondrial quality control, and endothelial function. Additionally, preclinical studies indicate that pharmacological inhibition of eEF2K can enhance vascular remodeling, improve hemodynamics, and promote endothelial function. Conversely, activating eEF2K may offer protection against ischemic injury through enhanced autophagy and metabolic adaptation. Additionally, controlling sirtuin (SIRT), 5'-adenosine monophosphate (AMP)-activated protein kinase (AMPK), mechanistic target of rapamycin complex-1 (mTORC1), and autophagy/mitophagy flux via eEF2K modulation could help safeguard cardiomyocytes and endothelial cells from ischemic damage. These findings underscore the dual, context-dependent roles of eEF2K in CVD. We also review emerging small-molecule inhibitors, natural compounds, and innovative strategies, such as eEF2K degraders, highlighting their therapeutic potential and the challenges associated with clinical translation. Main limitations include issues of selectivity, potential toxicity, and the absence of validated biomarkers for patient stratification and treatment monitoring. Overall, targeting eEF2K offers a promising and complex strategy for CVD treatment. Further research into selective modulators, biomarker development, and clinical trials is essential to translate preclinical results into effective therapies.

Keywords:  Autophagy; Cardiovascular disease; Eukaryotic elongation factor 2 kinase (eEF2K); Pharmacologic target

DOI:  https://doi.org/10.1016/j.ejphar.2025.178253
Cell Biol Toxicol. 2025 Oct 21. 41(1): 142

SerpinB1a induces hepatopulmonary syndrome by promoting CTSG/AMPK/mTOR pathway-mediated mitophagy.

Liang Li, Jianzhong Li, Wendeng Li, Yuefeng Ma, Shaomin Li.

  Mitophagy, as an important mechanism for selective removal of damaged mitochondria in cells, plays a crucial role in upholding cellular homeostasis. Mounting evidence suggests that autophagy is associated with lung disease. However, the potential molecular mechanisms affecting mitophagy are still obscure in hepatopulmonary syndrome (HPS) development. In this study, elevated SerpinB1a levels were detected in HPS patients' serum, showing a significant inverse correlation with arterial oxygen saturation. In the CBDL-induced rat HPS model, SerpinB1a knockdown attenuated pulmonary hemorrhage, microvascular dilation, and hepatic fibrosis. In vitro studies demonstrated that treatment of PMVECs with serum from HPS rats induced pathological proliferation, migration, and angiogenesis. Silencing of SerpinB1a effectively suppressed these aberrant cellular processes. Mechanistically, SerpinB1a promoted PMVEC dysfunction by interacting with and upregulating Cathepsin G (CTSG), thus activating the VEGF / AMPK / mTOR pathway and subsequent induction of mitophagy. In conclusion, SerpinB1a knockdown attenuated pulmonary microvascular dilation and HPS progression by inhibiting this CTSG/VEGF/AMPK/mTOR axis. These findings elucidate the mechanistic role of SerpinB1a in HPS progression and suggest its potential as a novel therapeutic target for HPS.

Keywords:  CTSG/VEGF/AMPK/mTOR signaling pathway; Hepatopulmonary syndrome; Mitophagy; Pulmonary microvascular dilatation; SerpinB1a

DOI:  https://doi.org/10.1007/s10565-025-10082-y
Mol Cell. 2025 Oct 20. pii: S1097-2765(25)00815-9. [Epub ahead of print]

Delayed protein translocation protects mitochondria against toxic CAT-tailed proteins.

Nils Bertram, Toshiaki Izawa, Felix Thoma, Serena Schwenkert, Stéphane Duvezin-Caubet, Sae-Hun Park, Nikola Wagener, Anne Devin, Christof Osman, Walter Neupert, Dejana Mokranjac.

  Ribosome-associated protein quality control (RQC) protects cells against the toxic effects of faulty polypeptides produced by stalled ribosomes. However, mitochondria are vulnerable to C-terminal alanyl and threonyl (CAT)-tailed proteins that are generated in this process, and faulty nuclear-encoded mitochondrial proteins are handled by the recently discovered mitoRQC. Here, we performed a genome-wide screen in yeast to identify additional proteins involved in mitoRQC. We found that peptidyl-tRNA hydrolase 2 (Pth2), present in the mitochondrial outer membrane, influences aggregation of CAT-tailed proteins without majorly affecting the CAT-tailing process itself. Peptidyl-tRNA hydrolase activity is essential during this process, yet the activity of Pth2 can be substituted by another peptidyl-tRNA hydrolase upon proper localization. Our data suggest that Pth2 acts by modulating protein translocation and that the mitochondrial proteostasis network is relieved through increased access of CAT-tailed proteins to cytosolic chaperones. Other hits obtained in the screen show that, in general, delayed protein translocation protects mitochondria against toxic CAT-tailed proteins.

Keywords:  RQC; TOM complex; cellular homeostasis; mitoRQC; mitochondria; peptidyl-RNA hydrolase; protein translocation

DOI:  https://doi.org/10.1016/j.molcel.2025.09.030
Autophagy. 2025 Oct 20.

Entrectinib binds to HMGB1 and activates cardiomyocyte autophagy by inhibiting OTUD5-MTORC1 signaling to induce cardiotoxicity.

Zizheng Gao, Jiaqi Zhang, Huangxi Fu, Shaoyin Zhang, Jian Chen, Haiyang Zhou, Xueqin Chen, Xiaochen Zhang, Hao Yan, Bo Yang, Qiaojun He, Zhifei Xu, Peihua Luo.

  Entrectinib stands unparalleled as the sole neurotrophic tyrosine receptor kinase (NTRK) inhibitor that has demonstrated clinical efficacy in treating brain metastases across various cancer types. However, its potential to induce severe cardiotoxicity, compounded by the current lack of effective intervention strategies, poses a substantial risk of treatment failure, underscoring the critical need for in-depth research on the molecular mechanism. Here, we utilized proteomics analysis and a murine model with cardiomyocyte-specific atg7 deletion to reveal that entrectinib activated autophagy in cardiomyocytes, subsequently triggering apoptosis and leading to cardiac dysfunction. Mechanistically, entrectinib directly bound to the HMGB1 protein at the 103rd phenylalanine residue, enhancing its nuclear localization. In the nucleus, HMGB1 suppressed the transcription of the deubiquitinating enzyme OTUD5, a vital regulator of the MTORC1 pathway, which subsequently inhibited the MTORC1 pathway, culminating in the activation of macroautophagy/autophagy. Furthermore, our research demonstrated that HMGB1 inhibition could prevent the cardiotoxicity induced by entrectinib in both in vivo and in vitro models. Specifically, we found that tanshinone IIA could mitigate the cardiotoxic effects of entrectinib by reducing HMGB1 protein levels. Taken together, our findings elucidated the mechanism underlying entrectinib-induced cardiotoxicity, offering a theoretical foundation for the safer clinical application of this targeted therapy.

Keywords:  Autophagy; HMGB1; MTORC1; cardiac dysfunction; cardiotoxicity; entrectinib; tanshinone IIA

DOI:  https://doi.org/10.1080/15548627.2025.2576619
Transl Neurodegener. 2025 Oct 23. 14(1): 53

SIK2-mediated phosphorylation of GABARAPL2 facilitates autophagosome-lysosome fusion and rescues neurodegeneration in an Alzheimer's disease model.

Xiaoman Dai, Ziling Ye, Chen Wang, Yufei Huang, Yun Chen, Tianqing Han, Weijie Gao, Xin Wu, Jing Zhang, Xiaochun Chen.

   BACKGROUND: Defective autophagic flux is implicated in Alzheimer's disease (AD), but the molecular mechanisms underlying this process are not fully understood. Salt-inducible kinase 2 (SIK2) is associated with autophagic function. However, its specific involvement in autophagic flux regulation and AD pathogenesis remains unclear.
METHODS: We evaluated hippocampal SIK2 expression and its age-related changes in postmortem AD patients and 5 × FAD mice by bioinformatics analysis, immunofluorescence, qPCR, and Western blotting. To investigate the functional role of SIK2, we employed adeno-associated virus-mediated SIK2 knockdown and overexpression in combination with behavioral tests (Morris water maze), electrophysiological recordings (long-term potentiation, LTP), and ultrastructural analysis (electron microscopy) to evaluate cognitive function and synaptic plasticity. Autophagic flux was measured using LC3B/p62 turnover assays, mRFP-GFP-LC3 tandem fluorescence assay, and transmission electron microscopy. Mechanistic insights were gained through co-immunoprecipitation assay, GST-pull down assay, phosphoproteomics, and site-directed mutagenesis. Additionally, phosphorylation-mimetic (S72E) and non-phosphorylatable (S72A) mutants of GABA type A receptor-associated protein-like 2 (GABARAPL2) were intrahippocampally delivered to 5 × FAD mice to explore their effects.
RESULTS: Our study identified SIK2 as a critical regulator that is progressively downregulated in hippocampal neurons of AD patients and 5 × FAD mice, correlating with spatial memory deficits. Reducing SIK2 levels exacerbates cognitive impairment and amyloid-β (Aβ) plaque burden in mice, whereas restoring SIK2 levels mitigates these deficits, restores LTP amplitude, reverses synaptic ultrastructural pathology, and reduces Aβ deposition. Mechanistically, SIK2 enhances autophagic flux by phosphorylating GABARAPL2 at Ser72, a modification essential for autophagosome-lysosome fusion. Remarkably, hippocampal delivery of the phosphorylation-mimetic GABARAPL2-S72E mutant replicated the beneficial effects of SIK2, alleviating Aβ pathology and synaptic dysfunction in 5 × FAD mice. In contrast, the non-phosphorylatable S72A mutant failed to show any protective effects.
CONCLUSIONS: These findings establish the SIK2-GABARAPL2 axis as a novel signaling cascade governing autophagic flux through lysosomal fusion competence. Dysfunction in this axis contributes to Aβ deposition in AD, offering new insights into the pathogenic mechanisms underlying autophagosome-lysosome fusion in AD and highlighting its potential as a therapeutic target.

Keywords:  Alzheimer's disease; Autophagic flux; Autophagosome–lysosome fusion; GABARAPL2; Neurodegeneration; Salt-inducible kinase 2

DOI:  https://doi.org/10.1186/s40035-025-00514-4
Sci Rep. 2025 Oct 22. 15(1): 36952

Lysosomal homeostasis regulates myocardial ischemia-reperfusion injury through autophagy pathway.

Yi Li, Yanfang Liu, Hui Wu, Songlin Zhang, Di Liu, Xiaoli Huang, Gang Zhou, Dong Zhang, Xiaoting Yang, Tian Zhou, Yan Xiong.



Keywords:  Autophagy; Autosis; Ischemia-reperfusion injury; Lysosome homeostasis

DOI:  https://doi.org/10.1038/s41598-025-20853-6
Cell Death Dis. 2025 Oct 24. 16(1): 755

TM9SF1 drives the lipophagic flux via AMPK-ULK1 signaling to sustain metabolic fitness in HER2-positive breast cancer.

Xiaofen Li, Xiaoqin Yu, Kaiyan Huang, Xin Yu, Shiping Luo, Xiewei Huang, Chuangui Song.

Therapeutic resistance and recurrence in human epidermal growth factor receptor 2-positive breast cancer (HER2 + BC) remain critical challenges that portend poor patient outcomes. Dysregulated autophagy and lipid metabolism contribute to tumor progression, yet the crosstalk between these pathways is poorly understood. This study investigates the role of transmembrane 9 superfamily member 1 (TM9SF1) in lipophagy and lipid metabolic reprogramming in HER2 + BC under metabolic stress. Clinically, TM9SF1 was significantly upregulated in HER2 + BC tissues and correlated with poor prognosis. Functionally, its expression correlated with markers of enhanced autophagy and lysosomal lipid catabolism, and it promoted tumor cell proliferation in vitro and in vivo. Conversely, TM9SF1 knockdown suppressed lipophagy under both basal and starvation conditions, inhibiting lipid droplet (LD) hydrolysis and the conversion of triglycerides to free fatty acids. This suppression was phenotypically characterized by LD accumulation, reduced autophagosomes and lipophagosomes, and altered enzymatic and lipidomic profiles. Mechanistically, TM9SF1 sustained lipophagy by promoting the phosphorylation of AMP-activated protein kinase at Thr172 and UNC-51-like kinase 1 at Ser555. Consequently, TM9SF1 was pivotal for lipid metabolic reprogramming, maintaining energy homeostasis and enhancing adaptation to nutrient deprivation through lipophagy. Overall, our findings identify TM9SF1 as a key HER2 + BC-associated regulator that drives lipophagy via the AMP-activated protein kinase-UNC-51-like kinase 1 pathway, facilitating LD turnover and free fatty acids utilization to sustain energy homeostasis in HER2 + BC. This work establishes a critical link between malignant phenotypes and metabolic resilience. Targeting this regulatory network represents a promising strategy to dismantle the metabolic scaffolds underlying HER2 + BC aggressiveness and therapeutic resistance.

DOI: https://doi.org/10.1038/s41419-025-08093-y
J Zhejiang Univ Sci B. 2025 Aug 28. pii: 1673-1581(2025)10-0972-23. [Epub ahead of print]26(10): 972-994

Roles of the Keap1/Nrf2 pathway and mitophagy in liver diseases.

Qihui Zhou, Panpan Cen, Zhi Chen, Jie Jin.

  Nuclear factor erythroid 2-related factor 2 (Nrf2) is an intracellular transcription factor that helps protect against oxidative stress in different types of cells under pathological conditions. Mitochondria are vital organelles that function in diverse metabolic processes in the body, including redox reactions, lipid metabolism, and cell death. Mitophagy, a specific form of autophagy for damaged mitochondria, plays a critical role in the pathophysiology of liver diseases. In this review, we explain in detail the roles of the Nrf2 signaling pathway and mitophagy, and the relationship between them, in various hepatic diseases (nonalcoholic fatty liver disease, viral hepatitis, alcoholic liver disease, drug-induced liver injury, autoimmune hepatitis, hepatic ischemia‒reperfusion injury, and liver cancer). We also offer some potential insights and treatments relevant to clinical applications.

Keywords:  Liver disease; Mitophagy; Nrf2 signaling pathway

DOI:  https://doi.org/10.1631/jzus.B2400053
J Clin Med Res. 2025 Oct;17(9): 469-489

Adenosine Monophosphate-Activated Protein Kinase Activation and Mammalian Target of Rapamycin Complex 1 Inhibition: A Mechanistic Rationale for Anti-Aging Therapy in Type 2 Diabetes.

Hidekatsu Yanai, Hiroki Adachi, Mariko Hakoshima, Hisayuki Katsuyama.

  Aging is a complicated biological process that induces a decline in the human organs' structure and function and elevates the risks of aging-related diseases such as Alzheimer's disease (AD) and type 2 diabetes. Type 2 diabetes accelerates all clinical manifestations of aging. Metabolic disorders in type 2 diabetes are unfavorably associated with all hallmarks of aging, such as inflammation and mitochondrial dysfunction. Adenosine monophosphate-activated protein kinase (AMPK) and the mammalian target of rapamycin complex 1 (mTORC1) are key players in cellular metabolism, and AMPK activation and mTORC1 inhibition improve all hallmarks of aging. AMPK activation and mTORC1 inhibition are favorably associated with diabetic complications. Nutritional interventions, such as caloric restriction, resveratrol, and astaxanthin, have AMPK-activating and mTORC1-inhibitory effects and improve metabolic abnormalities in type 2 diabetes. Anti-diabetic drugs, metformin, sodium-glucose cotransporter-2 inhibitors, and glucagon-like peptide 1 receptor agonists have been reported to have AMPK-activating and mTORC1-inhibiting effects and show prevention of aging-related diseases such as cardiovascular disease. The therapeutic interventions that activate AMPK and inhibit mTORC1 may be optimal treatments for type 2 diabetes from the perspective of anti-aging medicine. Furthermore, senolytics may be a promising, direct anti-aging therapeutic strategy specifically for type 2 diabetes and its complications.

Keywords:  AMP-activated protein kinase; Aging; Mammalian target of rapamycin complex 1; Metformin; Type 2 diabetes

DOI:  https://doi.org/10.14740/jocmr6370
Immunity. 2025 Oct 20. pii: S1074-7613(25)00430-3. [Epub ahead of print]

ATG9A-mediated autophagy prevents inflammatory skin disease by limiting TNFR1-driven STING activation and ZBP1-dependent cell death.

Dario Priem, Jon Huyghe, Barbara Gilbert, Simon Verdonck, Tom Delanghe, Bruno Verstraeten, Esther Hoste, Peter Vandenabeele, Jonathan Maelfait, Geert van Loo, Mathieu J M Bertrand.

  Tumor necrosis factor (TNF) is a central pro-inflammatory cytokine with pathologic roles in chronic inflammatory and autoimmune disorders. The mechanisms by which TNF sensing drives the pathogenesis of these diseases are not fully understood. We previously showed that the lack of the autophagic lipid scramblase ATG9A in mouse keratinocytes leads to severe dermatitis and systemic inflammation, with features resembling human skin disorders. We now demonstrate that the disease is initiated by TNF but caused by cGAS/STING-dependent type I interferon (IFN) production and subsequent ZBP1-dependent apoptosis and necroptosis. ATG9A prevented the pathogenesis of the disease by engaging both light-chain 3 (LC3)-dependent and -independent autophagy. These results uncover an additional pathological arm of TNF signaling, opening avenues for alternative therapeutic interventions for TNF-driven diseases. Moreover, this study reveals another pathophysiological function of LC3-independent autophagy in restraining type I IFN production, which triggers the development or exacerbation of an interferonopathy in mice and humans.

Keywords:  IFN; TNF; apoptosis; autophagy; cell death; inflammatory diseases; interferon; interferonopathy; necroptosis; skin inflammation; systemic lupus erythematosus; tumor necrosis factor

DOI:  https://doi.org/10.1016/j.immuni.2025.09.019
Extracell Vesicles Circ Nucl Acids. 2025 ;6(3): 360-385

Extracellular vesicles: cargo loading, degradation and secretory pathways, and their intersection with autophagy.

Jinzhe Ju, Sophie M L Neuen, Marc van Zandvoort, Tom G H Keulers, Kasper M A Rouschop.

  Extracellular vesicles (EVs) are secreted by nearly all cell types and fulfil a crucial role in intercellular communication by transporting diverse cargo, including enzymes, mRNA, growth factors, chemokines, and cytokines. Although EVs were initially thought to primarily function in waste elimination, it is now clear that they can be diverted from degradation and instead actively secreted to mediate intercellular communication. While the processes of EV biogenesis, degradation, and release have been extensively studied, many aspects remain poorly understood. The involvement of molecular pathways shared by EV biogenesis and autophagy - a lysosome-mediated disposal mechanism - suggests the existence of common regulatory controls. Despite the partial overlap in molecular machineries involved in cargo sorting, the mechanisms that balance the degradation and secretory pathways of EVs, as well as their interplay with autophagy, remain elusive. This review discusses the molecular machinery that dictates the selective cargo loading into EVs. Additionally, it examines the coordination between degradation and secretory pathways in EV biology and situates these processes within the broader context of autophagy. The substantial overlap in molecular pathways, shared proteins, and complementary mechanisms suggests a high degree of coordination between these systems.

Keywords:  ESCRT; Extracellular vesicle; autophagy; biogenesis; lysosome

DOI:  https://doi.org/10.20517/evcna.2025.21
Cell Signal. 2025 Oct 20. pii: S0898-6568(25)00597-2. [Epub ahead of print]136 112182

IL-11 exacerbates cisplatin-induced acute kidney injury by facilitating apoptosis in renal tubular epithelial cells via ERK1/2-Drp1/TFEB-mediated defective autophagy.

Danping Tao, Wenting Wu, Zerong Zheng, Hui Zhang, Yue Ji, Yiyi Zhuang, Huizhen Wang, Fenfen Peng, Xiaowen Chen, Haibo Long, Congwei Luo.

  Cisplatin-induced acute kidney injury (Cis-AKI) lacks targeted therapies. Here we identify interleukin-11 (IL-11) as a key driver of tubular injury that couples mitochondrial dynamics to autophagic flux in renal tubular epithelial cells. In a mouse Cis-AKI model, IL-11 knockdown ameliorated tubular damage and significantly improved renal function (serum creatinine, blood urea nitrogen), with concordant restoration of AQP1 and reduction of KIM-1/NGAL, indicating robust protection at the tissue and functional levels. Mechanistically, IL-11 activated ERK1/2, increased Drp1 phosphorylation and mitochondrial fission, and suppressed TFEB activity to impair lysosomal maturation and autophagic flux; ERK inhibition (SCH772984) and TFEB overexpression rescued TFEB activity, lysosomal markers, and autophagic completion, and reduced apoptosis/senscence. Tissue-level readouts (IHC for p-Drp1 and p62; immunoblots for LC3-I/II and p62) and TEM ultrastructure corroborated these pathways in vivo, linking mitochondrial fragmentation and autophagic blockade to IL-11-dependent injury. In HK-2 cells, recombinant human IL-11 (50 ng/mL) reproduced ERK-Drp1/TFEB pathway activation and phenotypes, and loss-of-function of IL-11 attenuated cisplatin-induced apoptosis and senescence. Collectively, these data define an ERK1/2-Drp1/TFEB axis by which IL-11 exacerbates Cis-AKI through mitochondrial dysfunction and autophagic flux disruption, culminating in apoptosis and cellular senescence. Targeting IL-11 or restoring TFEB activity emerges as a mechanism-based strategy to mitigate cisplatin nephrotoxicity.

Keywords:  AKI; Drp1; ERK1/2; IL-11; TFEB

DOI:  https://doi.org/10.1016/j.cellsig.2025.112182
J Cell Biol. 2026 Jan 05. pii: e202501145. [Epub ahead of print]225(1):

TMEM175 does not function as a proton-selective ion channel to prevent lysosomal over-acidification.

Erika Riederer, Vedrana Mikusevic, Tuoxian Tang, Lillian Martin, Joseph A Mindell, Dejian Ren.

The acidic pH of lysosomes required for function is established by the electrogenic V-ATPase proton pump. How lysosomes prevent hyper-acidification by the pump is not well established. Recently, the Parkinson's disease (PD)-associated protein TMEM175 was proposed as a H+-selective channel to leak protons to counter over-acidification. We rigorously address key findings and predictions of this model and show that, in the lysosome, TMEM175 predominantly conducts K+ and is not a H+-selective channel. The native lysosomal H+ leak is remarkably small, ∼0.02 fA, strongly arguing against major contributions from an ion channel. The predominant effect of TMEM175 deficiencies is lysosomal alkalinization in challenged cells, which is further evidence arguing against TMEM175 as a H+-selective channel and can be explained by K+ conductance through TMEM175. Also, lysosomes can be hyper-acidified by manipulations in the presence or absence of TMEM175. Our studies clarify a basic lysosomal biological problem and provide insights into the working mechanism of TMEM175 and its contribution to PD pathology.

DOI: https://doi.org/10.1083/jcb.202501145
Autophagy. 2025 Oct 22.

Internalized SNCA/α-synuclein fibrils become truncated and resist degradation in neurons while glial cells rapidly degrade SNCA fibrils.

Md Razaul Karim, Elizabeth Tiegs, Emilie Gasparini, Riley Schlichte, Scott C Vermilyea, Michael K Lee.

  Parkinson disease (PD) and other α-synucleinopathies are characterized by the intracellular aggregates of SNCA/α-synuclein (synuclein, alpha) thought to spread via cell-to-cell transmission. To understand the contributions of various brain cells to the spreading of SNCA pathology, we examined the metabolism of SNCA aggregates in neuronal and glial cells. In neurons, while the full-length SNCA rapidly disappeared following SNCA pre-formed-fibril (PFF) uptake, truncated SNCA accumulated with a half-life of days rather than hours. Epitope mapping and fractionation studies indicate that SNCA fibrils internalized by neurons were truncated at the C-terminal region and remained insoluble. In contrast, microglia and astrocytes rapidly metabolized SNCA fibrils as the half-lives of SNCA fibrils in these glial cells were < 6 h. Differential uptake and processing of SNCA fibrils by neurons and glia was recapitulated in vivo where injection of fluorescently labeled SNCA fibrils initially accumulated in glial cells followed by rapid clearance while neurons stably accumulated SNCA fibrils at a slower rate. Immunolocalization and subcellular fractionation studies show that internalized SNCA PFF was initially localized to endosomes followed by lysosomes. The lysosome was largely responsible for the degradation of internalized SNCA PFF as the inhibition of lysosomal function led to the stabilization of SNCA in all cell types. Significantly, SNCA PFF causes lysosomal dysfunction in neurons. In summary, we show that neurons are inefficient in metabolizing internalized SNCA aggregates, partially because SNCA aggregates cause lysosomal dysfunction, potentially generating aggregation-prone truncated SNCA. In contrast, glial cells may protect neurons from SNCA aggregates by rapidly clearing these aggregates.

Keywords:  Parkinson disease; alpha-synuclein; alpha-synuclein fibril; endosome; lysosome; neurodegeneration; proteolysis; trafficking; truncation; uptake

DOI:  https://doi.org/10.1080/15548627.2025.2579147
Cancer Discov. 2025 Oct 21.

p53 drives lung cancer regression through a TSC2/TFEB-dependent senescence program.

Mengxiong Wang, Kathryn T Bieging-Rolett, Alyssa M Kaiser, Colleen A Brady, John H Lockhart, Sofia Ferreira, Kha T Nguyen, Arati Rajeevan, Simone A Evans, Tianyu Zhao, Nitin Raj, Arielle Elkrief, Sam E Tischfield, Marc Ladanyi, Michael G Ozawa, Nam Q Bui, Christopher T Chen, Elsa R Flores, Laura D Attardi.

Pharmacological restoration of p53 tumor suppressor function is a conceptually appealing therapeutic strategy for the many deadly cancers with compromised p53 activity, including lung adenocarcinoma (LUAD). However, the p53 pathway has remained undruggable, partly because of insufficient understanding of how to drive effective therapeutic responses without toxicity. Here, we use mouse and human models to deconstruct the transcriptional programs and sequelae underlying robust therapeutic responses in LUAD. We show that p53 drives potent tumor regression by direct Tsc2 transactivation, leading to mTORC1 inhibition and TFEB nuclear accumulation, which in turn triggers lysosomal gene expression programs, autophagy, and cellular senescence. Senescent LUAD cells secrete factors to recruit macrophages, precipitating cancer cell phagocytosis and tumor regression. Collectively, our analyses reveal a surprisingly complex cascade of events underlying a p53 therapeutic response in LUAD and illuminate targetable nodes for p53 combination therapies, thus establishing a critical framework for optimizing p53-based therapeutics.

DOI: https://doi.org/10.1158/2159-8290.CD-25-0525
Blood. 2025 Oct 20. pii: blood.2024026749. [Epub ahead of print]

The Proteostasis Network is a Therapeutic Target in Acute Myeloid Leukemia.

Kentson Lam, Yoon Joon Kim, Evelyn Li-Ting Tan, Carlo Miguel Ong, Andrea Zoey Liu, Fanny Jiahua Zhou, Mary Jean Sunshine, Bernadette Chua, Silvia Vicenzi, Katelyn Zhining Chen, Helena Yu, Pierce Ford, Jie-Hua Zhou, Yuning Hong, Eric J Bennett, Leslie A Crews, Edward D Ball, Robert Signer.

Oncogenic growth places great strain and dependence on protein homeostasis (proteostasis). This has made proteostasis pathways attractive therapeutic targets in cancer, but efforts to drug these pathways have yielded disappointing clinical outcomes. One exception is proteasome inhibitors, which are approved for frontline treatment of multiple myeloma. However, proteasome inhibitors are largely ineffective for treatment of other cancers at tolerable doses, including acute myeloid leukemia (AML), although reasons for these differences are unknown. Here, we determined that proteasome inhibitors are ineffective in AML due to inability to disrupt proteostasis. In response to proteasome inhibition, AML cells activated HSF1 and increased autophagic flux to preserve proteostasis. Genetic inactivation of HSF1 sensitized AML cells to proteasome inhibition, marked by accumulation of unfolded protein, activation of the PERK-mediated integrated stress response, severe reductions in protein synthesis, proliferation and cell survival and significant slowing of disease progression and extension of survival in vivo. Similarly, combined autophagy and proteasome inhibition suppressed proliferation, synergistically killed human AML cells, and significantly reduced AML burden and extended survival in vivo. Furthermore, autophagy and proteasome inhibition preferentially suppressed protein synthesis and colony formation, and induced apoptosis in primary patient AML cells, including AML stem/progenitor cells, compared to normal hematopoietic stem/progenitor cells. Combined autophagy/proteasome inhibition activated a terminal integrated stress response, which was surprisingly driven by Protein kinase R (PKR). These studies unravel how proteostasis pathways are co-opted to promote AML growth, progression and drug resistance, and reveal that disabling the proteostasis network is a promising strategy to therapeutically target AML.

DOI: https://doi.org/10.1182/blood.2024026749
Neurobiol Dis. 2025 Oct 22. pii: S0969-9961(25)00368-7. [Epub ahead of print] 107151

Elevated TFEB expression with limited activation in peripheral blood mononuclear cells reflects altered lysosomal enzyme dynamics in Parkinson's disease.

Yasuaki Mizutani, Kazuki Nawashiro, Souta Ito, Tsuyoshi Nakai, Reiko Ohdake, Sayuri Shima, Akihiro Ueda, Mizuki Ito, Tatsuro Mutoh, Hirohisa Watanabe.

   BACKGROUND: Lysosomal dysfunction is recognized as a key pathological feature of Parkinson's disease (PD); however, its peripheral signatures remain unclear.
METHODS: This study evaluated the peripheral profiles of lysosomal hydrolases and their regulation by transcription factor EB (TFEB), focusing on α-galactosidase A (GLA) and β-mannosidase in the peripheral blood mononuclear cells (PBMCs) of 63 PD patients and 44 healthy controls. Lysosomal enzyme activities in PBMC homogenates and serum were quantified using a fluorometric enzymatic assay with kinetic analysis. Protein concentrations were measured by ELISA, and TFEB activation status was evaluated by its phosphorylation level using western blotting.
RESULTS: GLA activity and protein concentrations were higher in the PBMCs of patients, but not for β-mannosidase. TFEB protein concentrations were also elevated and showed positive correlations with lysosomal enzyme protein concentrations. TFEB phosphorylation status showed that the ratio of non-phosphorylated to total TFEB did not differ between PD and controls. However, within the PD group, this ratio negatively correlated with TFEB concentrations, suggesting a potential uncoupling between TFEB expression and its functional activation status. Furthermore, both serum-to-PBMC ratios of GLA activity and protein concentration were lower in PD and were associated with PBMC counts, indicating impaired enzyme release from PBMC.
CONCLUSIONS: Elevated TFEB expression in PBMCs may reflect a compensatory response to PD-related cellular stress. However, this response may be functionally insufficient due to limited TFEB activity, potentially leading to reduced lysosomal enzyme release. Thus, peripheral TFEB-related lysosomal abnormalities may serve as indicators of systemic autophagy-lysosome dysregulation in PD.

Keywords:  Lysosomal hydrolases; Parkinson's disease; Peripheral blood mononuclear cells; Transcription factor EB; Transcription factor EB phosphorylation status; α-galactosidase A; β-mannosidase

DOI:  https://doi.org/10.1016/j.nbd.2025.107151
Biochim Biophys Acta Mol Basis Dis. 2025 Oct 22. pii: S0925-4439(25)00443-0. [Epub ahead of print] 168093

FUNDC1 deficiency aggravates endothelial senescence and retinal dysfunction.

Jingxin Ning, Ze Li, Yuxue Mu, Xia Li, Kaifeng Li, Wenjuan Xing, Haifeng Zhang.

  Natural aging leads to various age-related changes that impair visual function and cause ocular diseases. Endothelial cells, key components of blood vessels, play a crucial role in vascular aging and retinal degeneration. However, the exact mechanisms by which endothelial cell aging promotes retinopathy are not fully understood. Mitochondrial homeostasis is vital for endothelial cell function, with mitophagy being essential for removing damaged mitochondria. FUNDC1, a receptor involved in mitophagy, regulates cellular senescence and inflammation. This study investigates whether retinal function decline is linked to mitochondrial imbalance in retinal vessels endothelial cells due to reduced FUNDC1 expression. In aged mice, FUNDC1 expression and mitophagy were significantly lower in retinal blood vessels. Aging leads to retinal vascular dysfunction characterized by increased vascular permeability assessed by fluorescein fundus angiography. Moreover, electron microscopy images showed mitochondrial swelling in endothelial cells of aging retina, accompanied with tight junction disruption and reduced expression of junctional proteins (VE-cadherin, occludin, and ZO-1). Strikingly, endothelial knockout of FUNDC1 exacerbated the age-related decline in retinal blood vessel function and retinal function. Cell senescence induced by D-galactose exhibited significantly decreased FUNDC1, impaired mitophagy, increased reactive oxygen species (ROS), and markedly increased endothelial permeability assessed by transendothelial electrical resistance assay. Conversely, overexpression of FUNDC1 can reverse the reduction of mitochondrial autophagy, the decrease in intercellular junction protein expression and the increase in endothelial permeability caused by aging. Collectively, these data suggest that FUNDC1 serves as a potential therapeutic target for the prevention and treatment of age-related degeneration of retinal function.

Keywords:  Endothelial senescence; FUNDC1; Mitophagy; ROS; Retinal vessels

DOI:  https://doi.org/10.1016/j.bbadis.2025.168093
Cell Signal. 2025 Oct 17. pii: S0898-6568(25)00585-6. [Epub ahead of print]136 112170

Mitochondrial homeostasis collapse to cardiac remodeling: From mechanisms to novel targeted therapeutic avenues.

Qi-Yun Liu, Fan-Liang Meng, Jia-Min Du, Wen-Jing Li, Si-Yuan Zhou, Ying Li.

  Myocardial remodeling is a common pathological process in various cardiovascular diseases (CVDs) and represents the heart's adaptive response to pressure or volume overload. However, prolonged myocardial remodeling often leads to a progressive decline in cardiac function, ultimately resulting in heart failure (HF). This process is primarily characterized by myocardial hypertrophy and fibrosis, both of which are closely linked to mitochondrial dysfunction. Emerging research uncovers a pivotal orchestrator of this lethal transition: mitochondrial homeostasis. As the powerhouse of cardiomyocytes, dysfunctional mitochondria ignite a catastrophic cascade-energy bankruptcy, oxidative tsunamis, and apoptotic avalanches-propelling pathological hypertrophy and fibrosis. Although extensive research has explored mitochondrial homeostasis in cardiovascular diseases, a comprehensive summary of the specific mechanisms and effects of mitochondrial dysfunction in myocardial remodeling remains lacking. This review focuses on pathological myocardial remodeling associated with mitochondrial abnormalities and examines four critical factors: mitochondrial Ca2+ signaling, metabolism, dynamics, and mitophagy. Bridging molecular mechanisms to next-generation therapeutics, we systematically evaluates their roles in disease progression and discusses potential mitochondrial-targeted therapeutic strategies, offering new insights into research and treatment approaches for related conditions.

Keywords:  Ca(2+); Dynamics; Metabolism; Mitochondrial homeostasis; Mitophagy; Myocardial remodeling

DOI:  https://doi.org/10.1016/j.cellsig.2025.112170