bims-auttor 2025-10-05 papers

bims-auttor

Biomed News

on Autophagy and mTOR

Issue of 2025–10–05
forty-six papers selected by
Viktor Korolchuk, Newcastle University

Expansion of lysosomal capacity in early adult neurons driven by TFEB/HLH-30 protects dendrite maintenance during aging in Caenorhabditis elegans.
The PP2A-B55α phosphatase is a master regulator of mitochondrial degradation and biogenesis.
Autophagy-dependent proteostasis suppresses breast cancer metastasis.
Persistent mTORC1 activation underlies sex dimorphic progression of MASLD in mice with hepatocyte prohibitin-1 deficiency.
Unveiling the Paradoxical Nature of Autophagy in Cancer Cell Fate.
BCL11A deficiency protects epidermis from UVB-induced damage through promotion of autophagy.
Exploring Autophagy Inducing Molecules: Targeting Diverse Pathways in Alzheimer's Disease Management.
GABAergic disinhibition through the STING-dependent autophagic pathway in the dorsal horn underlies diabetic neuropathic pain pathogenesis.
The role of autophagy in chronic pain.
The crosstalk of caveolin-1 and autophagy in different diseases.
Revisiting the evolution of the yeast Atg1 complex.
Bacterial RNA promotes proteostasis through inter-tissue communication in C. elegans.
Mitochondrial ROS triggers mitophagy through activating the DNA damage response signaling pathway.
A Review of FUN14 Domain-Containing 1 Involvement in Mitochondrial Biological Processes and Mechanisms Across Various Systems.
Double-edged mitophagy: balancing inflammation and resolution in lung disease.
Regulating osteogenic differentiation of bone marrow mesenchymal stem cells by mTORC1 signaling pathway inhibits bone defect repair in mice.
Atlas of Lysosomal Aging Reveals a Molecular Clock of Storage Disorder-Associated Metabolites.
Novel Function of Osteoprotegerin in the Modulation of Glucose Metabolism in the Liver via mTORC1.
Targeted glycophagy ATG8 therapy reverses diabetic heart disease in mice and in human engineered cardiac tissues.
Propylparaben disrupts early embryonic development by causing oxidative stress-induced organelle dysfunction and actin zipper abnormality.
Targeted genome editing of ZKSCAN3 mitigates the neurotoxicity caused by mutant HTT (huntingtin) in a Huntington disease animal model and three-dimensional cell culture of Huntington disease.
Common Mechanism Underlying Synaptic Dysfunction Caused by Preformed Fibril-Induced Accumulation of α-Synuclein or Tau in a Culture Propagation Model.
MSC-Derived Exosomes in Preserving Autophagy through Key Signaling Pathways: A Preventive Strategy against Cardiovascular Aging.
Teleost HMGB1 paralogues mediate protective autophagy by interacting with NOD2 and ATG16L1 and activating ROS/Akt/mTOR pathway against Aeromonas hydrophila infection.
Aging-rewired metabolic cues promote autophagy and senescence via DRAM1.
BNIP3L/NIX-mediated mitophagy: Future directions in Alzheimer's disease.
Pioglitazone Reduces Hepatic Alpha-1 Antitrypsin Accumulation Through Autophagy and AMPK Activation in Alpha-1 Antitrypsin Deficient Mice.
Rapalink-1 reveals TOR-dependent genes and an agmatinergic axis-based metabolic feedback regulating TOR activity and lifespan in fission yeast.
Unravelling the oncogenic role of eukaryotic elongation factor 2 kinase: A revisited review from underlying mechanisms to targeted therapy.
Methionine sulfoxide reductase A deficiency impairs zebrafish heart regeneration via inhibiting Prohibitin 2-Pink1-mediated mitophagy.
Dihydropyrazine activates the CAMKK2-AMPK-ULK1 signaling pathway in human hepatoma HepG2 cells.
A nile red fluorescence assay for LC3 autophagy protein binding to lipid bilayers.
Direct modulation of TRPM8 ion channels by rapamycin and analog macrolide immunosuppressants.
A human Staufen1 BAC transgenic mouse exhibits abnormal autophagy and neurodegeneration across the central nervous system.
Three-dimensional human mucopolysaccharidosis IVA chondrocyte culture reveals significant impairments in the lysosomal-mitochondrial crosstalk.
APP family is a regulator of endo-lysosomal membrane vulnerability.
GCN1 couples GCN2 to ribosomal state to initiate amino acid response pathway signaling.
Mitochondrial dysfunction drives cellular senescence: Molecular mechanisms of inter-organelle communication.
SFPQ-TFE3 reciprocally regulates mTORC1 and induces lineage plasticity in a mouse model of renal tumorigenesis.
Targeted glycophagy ATG8 therapy reverses diabetic heart disease in mice and in human engineered cardiac tissues.
Neurodegeneration emerges at a cellular tipping point between aggregate accumulation and removal.
Large-scale visualization of α-synuclein oligomers in Parkinson's disease brain tissue.
A Common PD-Risk GBA1 Variant Disrupts LIMP2 Interaction, Impairs Glucocerebrosidase Function, and Drives Lysosomal and Mitochondrial Dysfunction.
Hsp104-Hsp70-Hsp110 chaperones disintegrate kinase aggregates formed upon stress in Saccharomyces cerevisiae.
Rewiring the mTOR, CDH1, APC/C, PFKFB3 axis: a glycolytic pulse to ignite the G0/G1 gateway.
AMPK activation mitigates α-synuclein pathology and dopaminergic degeneration in cellular and mouse models of Parkinson's disease.

PLoS Biol. 2025 Sep 30. 23(9): e3002957

Expansion of lysosomal capacity in early adult neurons driven by TFEB/HLH-30 protects dendrite maintenance during aging in Caenorhabditis elegans.

Ruiling Zhong, Claire E Richardson.

Lysosomes are essential for neuronal homeostasis, providing degradation and recycling functions necessary to support neurons' complex operations and long lifespans. However, the regulation of lysosomal degradative capacity in healthy neurons is poorly understood. Here, we investigate the role of HLH-30, the sole Caenorhabditis elegans homolog of Transcription Factor EB (TFEB), a master regulator of lysosome biogenesis and autophagy that is thought to predominantly function in the context of starvation or stress. We demonstrate that HLH-30 is dispensable for neuronal development but acts cell-intrinsically to expand lysosomal degradative capacity during early adulthood. Loss of HLH-30 leads to lysosomal dysfunction and delayed turnover of synaptic vesicle proteins from the synapse. Notably, we show that basal HLH-30 activity is sufficient to expand neuronal lysosomal capacity without nuclear enrichment, in contrast to the nuclear translocation associated with starvation- and stress-induced activation of TFEB and HLH-30. Furthermore, we show that neuronal lysosomal function declines with age in wild-type animals, and this corresponds to a decrease in basal HLH-30-mediated transcription. We further demonstrate that basal HLH-30 activity is crucial for neuron maintenance: lysosomal dysfunction due to inadequate HLH-30 activity leads to dendrite degeneration and aberrant outgrowths. In summary, our study establishes a critical role for HLH-30/TFEB in promoting lysosomal capacity to preserve neuronal homeostasis and structural integrity of mature neurons in vivo.

DOI: https://doi.org/10.1371/journal.pbio.3002957
Sci Adv. 2025 Oct 03. 11(40): eadw7376

The PP2A-B55α phosphatase is a master regulator of mitochondrial degradation and biogenesis.

Valentina Cianfanelli, Monica Nanni, Samantha Corrà, Sofia Mauri, David Sumpton, Sergio Lilla, Rossella De Cegli, Matteo Bordi, Giacomo Milletti, Caterina Ferraina, Arnaldur Hall, Michele Petraroia, Valentina Clausi, Ezio Giorda, Marco Scarsella, Alessandra Barbiera, Giulia Cadeddu, Marco Colasanti, Tiziana Persichini, Kenji Maeda, Apolinar Maya-Mendoza, Jiri Bartek, Chiara Di Malta, Franco Locatelli, Sara Zanivan, Shehab Ismail, Elena Ziviani, Francesco Cecconi.

Mitochondrial homeostasis relies on a tight balance between mitochondrial biogenesis and degradation. Although mitophagy is one of the main pathways involved in the clearance of damaged or old mitochondria, its coordination with mitochondrial biogenesis is poorly characterized. Here, by unbiased approaches including last-generation liquid chromatography coupled to mass spectrometry and transcriptomics, we identify the protein phosphatase PP2A-B55α/PPP2R2A as a Parkin-dependent regulator of mitochondrial number. Upon mitochondrial damage, PP2A-B55α determines the amplitude of mitophagy induction and execution by regulating both early and late mitophagy events. A few minutes after the insult, ULK1 is released from the inhibitory regulation of PP2A-B55α, whereas 2 to 4 hours later, PP2A-B55α promotes the nuclear translocation of TFEB, the master regulator of autophagy and lysosome genes, to support mitophagy execution. Moreover, PP2A-B55α controls a transcriptional program of mitochondrial biogenesis by stabilizing the Parkin substrate and PGC-1α inhibitor PARIS. PP2A-B55α targeting rescues neurodegenerative phenotypes in a fly model of Parkinson's disease, thus suggesting potential therapeutic application.

DOI: https://doi.org/10.1126/sciadv.adw7376
Autophagy. 2025 Oct 02.

Autophagy-dependent proteostasis suppresses breast cancer metastasis.

Jayanta Debnath, Gourish Mondal.

  In breast cancer, macroautophagy/autophagy suppresses key steps of the metastatic cascade, including colonization and outgrowth at distant sites. However, the molecular mechanisms behind this suppression have remained unclear. Our recent study shows that increased metastasis observed in the setting of autophagy deficiency is driven by the accumulation of phase-separated biomolecular condensates containing the autophagy cargo receptors NBR1 and SQSTM1. These NBR1-SQSTM1 condensates sequester ITCH, an E3 ubiquitin ligase responsible for degrading TP63, a transcription factor that promotes basal differentiation. Hence, ITCH sequestration stabilizes and activates TP63 in breast cancer cells, hence promoting an aggressive, pro-metastatic basal-like differentiation state. Overall, our findings suggest that the potential benefits of targeting autophagy in cancer therapy are accompanied by defects in proteostasis, which disrupts epithelial lineage fidelity and enhances metastatic potential. We propose that targeting NBR1-SQSTM1 condensates may offer new therapeutic avenues to prevent metastasis, particularly in the context of autophagy deficiency.

Keywords:  Autophagy; autophagy cargo receptors; biomolecular condensates; lineage infidelity; metastasis

DOI:  https://doi.org/10.1080/15548627.2025.2569677
Res Sq. 2025 Sep 25. pii: rs.3.rs-7481614. [Epub ahead of print]

Persistent mTORC1 activation underlies sex dimorphic progression of MASLD in mice with hepatocyte prohibitin-1 deficiency.

Amany A Alowaisi, Jolonda C Mahoney, Ran Huo, Islam A Berdaweel, Rachel A Crawford, Kendall J Mallaro, Jared M McLendon, Ethan J Anderson.

Prohibitins (PHB1,2) are highly conserved lipid-raft associated proteins that physically interact to form a multimeric ring supercomplex in mitochondrial and plasma membranes where they are intimately involved in regulating cellular metabolism. Prior studies in disparate cell models have implicated PHB1 as a mediator of insulin signaling and its downstream effector, the mechanistic target of rapamycin complex 1 (mTORC1), but the mechanisms and physiological implications of these interactions are unclear. Here, we examined the role of PHB1 in regulating insulin and nutrient mediated activation of mTORC1 in liver using genetic and pharmacological approaches in mice and hepatocyte culture. Interestingly, male mice with hepatocyte-specific PHB1 haploinsufficiency (hPHB1-KD) at 6 months displayed features consistent with metabolic dysfunction-associated steatotic liver disease (MASLD), characterized by liver steatosis and impaired glucose tolerance with hyperinsulinemia, while these parameters were unaffected or even mildly improved in age-matched hPHB1-KD females. Both sexes of hPHB1-KD mice displayed increased basal phosphorylation of mTORC1 and its downstream targets (S6, 4EBP1) in liver compared with WT in fasted state, with minimal responsiveness to insulin. Transcriptomic data revealed strong upregulation of Lpin1 gene in male hPHB1-KD mice, a phosphatidic acid phosphatase regulated by mTORC1 that critically regulates hepatic lipid metabolism. Integrated transcript-/metabolomic analysis showed enriched glycerolipid metabolism and upregulation of MASLD pathway in the liver of hPHB1-KD males. Parallel experiments in AML12 hepatocytes confirmed that PHB1 knockdown causes hyper-activation of mTORC1 signaling, increased cytoplasmic lipin-1 expression and localization, and increased lipid droplet formation. Furthermore, one week of treatment with mTORC1 inhibitor Torin1 reduced hepatic triglycerides and normalized mTORC1 signaling in hPHB1-KD males to levels comparable with WT. Collectively, these findings demonstrate that PHB1 is essential for maintaining metabolic homeostasis in liver via control of mTORC1-lipin1 axis, and further confirm that metabolic effects of PHB1 deficiency in liver are sexually dimorphic.

DOI: https://doi.org/10.21203/rs.3.rs-7481614/v1
Cancer Control. 2025 Jan-Dec;32:32 10732748251384365

Unveiling the Paradoxical Nature of Autophagy in Cancer Cell Fate.

Jannatul Shifa, Tasbir Amin, Md Fakruddin, Kazi Rahman, S M Bakhtiar Ul Islam.

  Autophagy is an ancient conserved and catabolic process required to maintain cellular homeostasis through sequestration and lysosomal degradation of cytosolic dysfunctional contents. The bulk degradation of cytosolic material through autophagy provides the necessary nutrients that cells utilize under starvation. Autophagy can play a mixed role in both the growth and survival of cancer cells. As a damaged cellular content-clearing mechanism, autophagy is involved in the early stage of tumor regression. Subsequently, in a mature tumor cell microenvironment, autophagy protects tumor cells from cellular stress, immune evasion, and therapeutic resistance. Therapeutic resistance mediated by autophagic regulators can make anticancer therapy less effective. This review discusses the molecular mechanism of mammalian autophagy, evaluates the dynamic role of autophagy in cancer, highlights autophagy-mediated therapeutic resistance, and suggests the use of biomarkers. In cancer therapy, the addition of biomarkers can provide specific identification, and the conjugation of biomarkers with chemo-drugs can reduce the side effects and ensure normal cell integrity.

Keywords:  ATGs; autophagic biomarkers; dichotomous role; mammalian autophagy; therapeutics resistance

DOI:  https://doi.org/10.1177/10732748251384365
Commun Biol. 2025 Oct 02. 8(1): 1417

BCL11A deficiency protects epidermis from UVB-induced damage through promotion of autophagy.

Xuyi Deng, Hui Liu, Xiaoxu Wang, Xinfeng Dong, Zhengzheng Fu, Xinli Niu, Zhi Guo, Peiqi Lian, Yinyun Deng, Zhenhua Ding, Yinghui Wang, Meijuan Zhou.

As a major environmental pathogenic factor for various skin diseases, UVB radiation leads to oxidative stress and biomacromolecule damage. Autophagy is a highly conserved catabolic process and serves as one of the main mechanisms to maintain cellular homeostasis. Here, by CRISPR/Cas9-mediated gene deletion, we demonstrate that the essential transcriptional repressor BCL11A is involved in autophagy regulation and participates in the UVB-induced stress response. BCL11A deficiency increases autophagosome formation and enhances the intensity of autophagy flux with or without UVB stress. Mechanistically, ACSS3, rather than autophagy-related genes, is identified as the direct target gene and transcriptionally repressed by BCL11A. Further, BCL11A deficiency reduces DNA damage and ROS to promote survival and inhibit apoptosis under UVB irradiation, which is blocked by pharmacological inhibition of autophagy or BCL11A overexpression. Collectively, BCL11A deficiency promotes autophagy activation to clear ROS and DNA damage, thereby protecting epidermal cells from UVB-induced death.

DOI: https://doi.org/10.1038/s42003-025-08814-1
Med Res Rev. 2025 Sep 29.

Exploring Autophagy Inducing Molecules: Targeting Diverse Pathways in Alzheimer's Disease Management.

Baljinder Singh, Shubham Mahajan, Sadikalmahdi Abdella, Rehan Khan, Sanjay Garg.

  Neurodegenerative disorders, including Alzheimer's disease (AD), impose a significant burden on society due to their progressive nature and the associated healthcare costs. Autophagy, a vital cellular degradation process, has emerged as a promising therapeutic target in these disorders. This review aims to provide a comprehensive overview of autophagy's role in neurodegenerative diseases, focusing on AD. The pathogenesis of AD involves the accumulation of misfolded proteins, such as beta-amyloid (Aβ) and tau, leading to neuronal dysfunction and cognitive impairment. Autophagy can be crucial in clearing these protein aggregates and maintaining cellular homeostasis. Nevertheless, autophagic dysregulation and mitochondrial dysfunction contribute to further progression of neurodegeneration. Furthermore, recent studies have demonstrated the therapeutic potential of several plant-based phytoconstituents and repurposed molecules that modulate autophagy. These compounds target both mTOR-dependent and independent pathways, highlighting their potential to alleviate disease pathology. This review aims to pave the way for future research and development in this field.

Keywords:  autophagy inducers; neurodegenerative disorders; phytoconstituents; repurposed molecules; senile dementia

DOI:  https://doi.org/10.1002/med.70013
Neurosci Lett. 2025 Sep 28. pii: S0304-3940(25)00280-0. [Epub ahead of print] 138391

GABAergic disinhibition through the STING-dependent autophagic pathway in the dorsal horn underlies diabetic neuropathic pain pathogenesis.

Ya-Jie Zhao, Hong-Zhen Bai, Yi-Na Wang, Yu-Kun Liu, Long-Biao Zhao, Zhao Li, Hui-Zhou Li, Xiu-Li Wang, Peng Liu.

  Our previous study demonstrated that STING/ATG5-mediated autophagy in the spinal dorsal horn contributes to diabetic neuropathic pain (DNP), although the underlying mechanisms remained unclear. In this study, we investigated how STING-driven autophagy leads to impaired spinal inhibition via lysosomal degradation of GABA receptors. In a rat model of DNP, spinal levels of STING and ATG5 were elevated, while P62, GABAA receptor, and GABAB receptor expression were reduced. Behavioral tests showed that intrathecal administration of a STING inhibitor increased mechanical pain thresholds and upregulated P62 and GABA receptors. Conversely, treatment with a STING agonist worsened hyperalgesia and further suppressed GABA receptor expression. Knockdown of ATG5 via siRNA similarly alleviated pain and restored GABA receptor levels. Interestingly, although the mTOR inhibitor rapamycin alleviated neuropathic pain, it unexpectedly increased spinal P62 expression compared to the DNP group. Administration of leupeptin, a lysosomal protease inhibitor, significantly increased paw withdrawal thresholds on days 1-3 and elevated GABA receptor expression, whereas the proteasomal inhibitor MG132 had no effect. These results demonstrate that STING/ATG5-mediated autophagy promotes DNP through autophagic-lysosomal degradation of GABA receptors, highlighting this pathway as a promising therapeutic target for treating diabetic neuropathic pain.

Keywords:  Diabetic neuropathic pain; Dorsal spinal cord; Downregulation; GABAergic receptors; STING-mediated Autophagy

DOI:  https://doi.org/10.1016/j.neulet.2025.138391
J Neuroimmunol. 2025 Sep 13. pii: S0165-5728(25)00238-3. [Epub ahead of print]409 578757

The role of autophagy in chronic pain.

Fu-Qi Zhu, Wen-Jun Zhang, Bao-Zhu Guan.

  Pain is the biggest factor affecting patients' daily life, and how to alleviate patients' pain and prevent it from developing into chronic pain has always been a key therapeutic goal for clinicians. There are three main causes of chronic pain, which are inflammation, nerve and tumor. And autophagy, as an important pathway to maintain homeostasis of the organism, not only affects the normal autophagy function, but also plays an important role in anti-inflammation, maintenance of nerve cell homeostasis, and inhibition of cancer occurrence and metastasis. Based on the above characteristics, we believe that autophagy has great potential in reducing and avoiding chronic pain. In this paper, after introducing chronic pain and autophagy-related genes, we delve into the pathological mechanisms of chronic pain generation, search for the relationship between autophagy and the three major causes of chronic pain, and find that autophagy may have a powerful therapeutic effect in reducing pain. We believe that autophagy can be a new target for the treatment of chronic pain.

Keywords:  Autophagy; Chronic pain; Pathological mechanisms; Treatment

DOI:  https://doi.org/10.1016/j.jneuroim.2025.578757
Front Immunol. 2025 ;16 1648757

The crosstalk of caveolin-1 and autophagy in different diseases.

Yuting Yang, Qiqi Ma, Mei Yang, Ruixue Wei, Zhiguo Wang, Chunmeng Jiang, Hui Liu, Mei Han.

  Caveolin-1 (Cav-1) is an important structural protein that constitutes the caveolae on the cell membrane. Cav-1 is expressed in various cells, especially in white adipocytes and endothelial cells. Cav-1 plays an important physiological role in regulating substance transport, signal transduction, and multiple metabolic pathways in the body. Autophagy degrades damaged organelles within cells and recycles them, thus playing an important role in maintaining homeostasis of the internal environment. Previous studies have found that Cav-1 is involved in the occurrence and development of multiple systemic diseases by regulating autophagy. In addition, autophagy can also affect the expression level of Cav-1 by degrading it. Therefore, there is a close regulatory relationship between Cav-1 and autophagy. Based on recent research progress, this article provides a detailed overview of the importance of the crosstalk between Cav-1 and autophagy in various systemic diseases such as cardiovascular, respiratory, and digestive systems. It aims to provide a more comprehensive understanding of the interaction between Cav-1 and autophagy, in order to promote further research and achieve clinical applications as soon as possible.

Keywords:  autophagy; caveolin-1; disease mechanisms; molecular regulation; signaling pathways

DOI:  https://doi.org/10.3389/fimmu.2025.1648757
Autophagy Rep. 2025 ;4(1): 2555835

Revisiting the evolution of the yeast Atg1 complex.

Kha M Nguyen, Hannah R Shariati, Calvin K Yip.

  The budding yeast Saccharomyces cerevisiae Atg1 complex coordinates the initiation of nonselective autophagy and consists of the Atg1 kinase, Atg13 regulatory subunit, and an S-shaped scaffold formed by Atg17, Atg29, and Atg31. In contrast, the fission yeast Schizosaccharomyces pombe Atg1 complex incorporates Atg101 instead of Atg29 and Atg31 and features a rod-shaped Atg17 scaffold. The timing of this divergence and its impact on the structural evolution of Atg17 remain unclear. Our systematic composition analysis revealed that Atg101 is found in the Atg1 complex of several budding yeast species, including two that contain both Atg29/Atg31 and Atg101. Structural modeling and negative stain EM analysis indicated that budding yeast species with Atg101 exhibit a rod-shaped Atg17. Additionally, we found that the Atg13 HORMA domain of S. pombe may possess a stabilizing cap, suggesting an alternative function for Atg101. Collectively, our findings delineate the potential evolutionary trajectories of the Atg1 complex in yeast. Abbreviations: ATG, autophagy-related; BLAST, basic local alignment search tool; C-Mad2, closed Mad2; EAT, Early Autophagy Targeting/Tethering; EM, electron microscopy; His-MBP, histidine-maltose binding protein; HORMA, Hop1, Rev7, and Mad2; IDR, intrinsically disordered region; O-Mad2, open Mad2; iTOL, Interactive Tree of Life; PAS, phagophore assembly site; PI3K, phosphatidylinositol 3-kinase; PMSF, phenylmethylsulfonyl fluoride; pTM, predicted template modeling; RMSD, root mean square deviation; TOR, target of rapamycin; TORC1, TOR complex 1.

Keywords:  AlphaFold3; Atg1 complex; Atg17; budding yeast; fission yeast

DOI:  https://doi.org/10.1080/27694127.2025.2555835
Nat Commun. 2025 Oct 01. 16(1): 8650

Bacterial RNA promotes proteostasis through inter-tissue communication in C. elegans.

Emmanouil Kyriakakis, Chiara Medde, Danilo Ritz, Geoffrey Fucile, Alexander Schmidt, Anne Spang.

Life expectancy has been increasing over the last decades, which is not matched by an increase in healthspan. Besides genetic composition, environmental and nutritional factors influence both health- and lifespan. Diet is thought to be a major factor for healthy ageing. Here, we show that dietary RNA species improve proteostasis in C. elegans. Inherent bacterial-derived double stranded RNA reduces protein aggregation in a C. elegans muscle proteostasis model. This beneficial effect depends on low levels of systemic selective autophagy, the RNAi machinery in the germline, even when the RNA is delivered through ingestion in the intestine and the integrity of muscle cells. Our data suggest a requirement of inter-organ communication between the intestine, the germline and muscles. Our results demonstrate that bacterial-derived RNAs elicit a systemic response in C. elegans, which protects the animal from protein aggregation during ageing, which might extend healthspan.

DOI: https://doi.org/10.1038/s41467-025-63987-x
Proc Natl Acad Sci U S A. 2025 Oct 07. 122(40): e2502841122

Mitochondrial ROS triggers mitophagy through activating the DNA damage response signaling pathway.

Qi-Qiang Guo, Shan-Shan Wang, Xiao-You Jiang, Xiao-Chen Xie, Yu Zou, Jing-Wei Liu, Yang Guo, Yu-Han Li, Xi-Yan Liu, Shuang Hao, Xin-Yue Zhang, Xiao-Xu Wu, Song-Ming Lu, Hong-De Xu, Wen-Dong Guo, Yan-Ling Feng, Chuan-Gui Wang, Sheng-Ping Zhang, Jia-Bin Li, Chen Liu, Xiao-Yu Song, Toren Finkel, Liu Cao.

  The homeostatic link between the production of mitochondrial ROS (mtROS) and mitophagy plays a significant role in how cells respond to various physiological and pathological conditions. However, it remains unclear how cells translate oxidative stress signals into adaptive mitophagy responses. Here, we show that mtROS act as signaling molecules that activate the ataxia-telangiectasia mutated (ATM)-cell cycle checkpoint kinase 2 (CHK2), a DNA damage response (DDR) pathway. When activated, CHK2 regulates three critical steps in mitophagy. First, CHK2 phosphorylates mitochondrial membrane protein ATAD3A at Ser371, which inhibits the transport of PINK1 to the inner mitochondrial membrane and leads to the accumulation of PINK1 and the commencement of mitophagy. Second, activated CHK2 targets the autophagy adaptor OPTN at Ser177 and Ser473, thereby enhancing the targeting of ubiquitinated mitochondria to autophagosomes. Finally, CHK2 phosphorylates Beclin 1 at Ser90 and Ser93, hence promoting the formation of autophagosomal membranes. Consistent with these effects, Chk2-/- mice show impaired mitophagic induction and impaired recovery in a ROS-dependent model of renal ischemia-reperfusion. Our study reveals a mtROS-triggered adaptive pathway that coordinates mitophagic induction, in order to protect cells and tissues exposed to pathophysiological stress-induced damage.

Keywords:  ATM; CHK2; PINK1; mitophagy; mtROS

DOI:  https://doi.org/10.1073/pnas.2502841122
Cell Biochem Funct. 2025 Oct;43(10): e70125

A Review of FUN14 Domain-Containing 1 Involvement in Mitochondrial Biological Processes and Mechanisms Across Various Systems.

Hailun He, Xin Zhang, Lidan Xiong, Xiao Qin.

  FUN14 domain-containing 1 (FUNDC1), an outer mitochondrial membrane protein, has emerged as a critical regulator of mitochondrial quality control and cellular homeostasis. Initially identified as a mitophagy receptor, FUNDC1 orchestrates hypoxia-induced mitophagy through phosphorylation-dependent interactions with LC3. Recent studies reveal its multifaceted roles in mitochondrial dynamics (fission/fusion), mitochondria-associated endoplasmic reticulum membranes (MAMs), and metabolic regulation, mediated by posttranslational modifications (phosphorylation, ubiquitination, acetylation). FUNDC1 dysfunction is implicated in cardiovascular diseases, neurodegeneration, cancer, and dermatological pathologies. It modulates oxidative stress primarily through impaired clearance of ROS-generating mitochondria via disrupted mitophagy, while also influencing apoptosis, pyroptosis, and inflammation via crosstalk with Bcl-2 family proteins, MOMP, mPTP, and cGAS-STING pathways. This review synthesizes FUNDC1's molecular mechanisms, highlighting its dual role as a protector (clearing damaged mitochondria) and potentiator of injury (excessive mitophagy). We also discuss therapeutic targeting of FUNDC1-dependent pathways in mitochondrial disorders.

Keywords:  FUNDC1; MAMs; metabolic diseases; mitochondrial dynamics; mitophagy

DOI:  https://doi.org/10.1002/cbf.70125
Clin Sci (Lond). 2025 Sep 30. pii: CS20256705. [Epub ahead of print]139(19):

Double-edged mitophagy: balancing inflammation and resolution in lung disease.

Sijia Tian, Yingyi Zhang, Chuanchuan Liu, Huajing Zhang, Qianying Lu, Yanmei Zhao, Haojun Fan.

  Inflammatory lung diseases, such as chronic obstructive pulmonary disease (COPD), acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), and asthma, are driven by mitochondrial dysfunction and aberrant immune responses, yet the regulatory role of mitophagy-a selective autophagy eliminating damaged mitochondria-remains poorly defined. This review synthesizes evidence from in vivo and in vitro studies to dissect the molecular interplay between mitophagy and inflammation. Key fundings reveal that mitophagy exerts context-dependent effects: Protective mitophagy (via PTEN-induced putative kinase 1 [PINK1]-Parkin or FUN14 domain-containing protein 1 [FUNDC1] pathways) clears mitochondrial reactive oxygen species (mtROS)/mitochondrial DNA (mtDNA), suppressing NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome activation and pyroptosis, but excessive mitophagy exacerbates mitochondrial fragmentation and necroptosis. Notably, bidirectional cross-talk exists, and therapeutic strategies-genetic and pharmacological-could restore mitophagy flux, attenuating inflammation in preclinical models. However, challenges persist in targeting tissue-specific mitophagy (such as alveolar and bronchial epithelia). This work underscores mitophagy as a double-edged sword in lung inflammation and proposes precision interventions to balance mitochondrial quality control, offering novel avenues for inflammatory lung diseases.

Keywords:  inflammation; lung diseases; mitophagy; mtROS; therapeutic targeting

DOI:  https://doi.org/10.1042/CS20256705
J Orthop Surg Res. 2025 Sep 29. 20(1): 860

Regulating osteogenic differentiation of bone marrow mesenchymal stem cells by mTORC1 signaling pathway inhibits bone defect repair in mice.

Zhuobin Huang, Ziming Zhang, Cheng Yang, Qiguang Mai, Ruanbing Li, Siteng Li, Shicai Fan, Jing Yang.

   BACKGROUND: Bone defects caused by traumatic injuries and orthopedic diseases have emerged as the most common challenges in contemporary orthopedics, characterized by treatment difficulty, long treatment time, and high economic costs. This study aims to demonstrate that the activated mTOR pathway in mesenchymal stromal cells regulates the bone repair process.
METHODS: Initially, the mammalian target of rapamycin (mTOR) pathway-activated mouse model was constructed by specifically knocking down the tuberous sclerosis complex 1 (TSC1) molecule in bone marrow mesenchymal stem cells (BMMSCs). Then, the differences in bone repair between transgenic mice and littermate control mice in a single-layer cortical bone defect model were evaluated by histological, immunohistochemical, and micro-CT analyses. Further, the effects of the mTOR pathway on the osteoinductive differentiation ability of BMMSCs and its mechanism were mainly verified by cellular osteogenic staining and Western blotting experiments.
RESULTS: The activated mTORC1 in mesenchymal stromal cells during bone defect repair in mice inhibited not only the healing rate of bone but also their ability to differentiate into osteoblasts, resulting in a decrease in the number of osteoblasts. The ability of mTORC1 in mesenchymal stromal cells to regulate osteoblastic differentiation might be related to the NOTCH pathway.
CONCLUSION: The activated mTOR pathway during bone defect repair could inhibit the osteogenic ability of BMMSCs and hinder the bone healing process. Accordingly, regulating the activation of the mTOR pathway might promote the repair of bone defects.

Keywords:  Bone defects; Mesenchymal stromal cells; NOTCH pathway; Osteogenic differentiation; mTOR pathway

DOI:  https://doi.org/10.1186/s13018-025-06249-2
bioRxiv. 2025 Sep 26. pii: 2025.09.25.678303. [Epub ahead of print]

Atlas of Lysosomal Aging Reveals a Molecular Clock of Storage Disorder-Associated Metabolites.

Anna M Puszynska, Thao P Nguyen, Andrew L Cangelosi, Andrea Armani, Justin M Roberts, Kristin A Singh, James C Cameron, Tenzin Tseyang, Grace Y Liu, Steven Lai, Hans-Georg Sprenger, Jason Yang, William N Colgan, Jibril F Kedir, Kathrin M Kajderowicz, Theodore K Esantsi, Yuancheng Ryan Lu, Millenia Waite, Tenzin Kunchok, Caroline A Lewis, Fabian Schulte, George W Bell, David M Sabatini, Jonathan S Weissman.

Lysosomal dysfunction is a well-recognized feature of aging, yet its systematic molecular investigation remains limited. Here, we employ a suite of tools for rapid lysosomal isolation to construct a multi-tissue atlas of the metabolite changes that murine lysosomes undergo during aging. Aged lysosomes in brain, heart, muscle and adipose accumulate glycerophosphodiesters and cystine, metabolites that are causally linked to juvenile lysosomal storage disorders like Batten disease. Levels of these metabolites increase linearly with age, preceding organismal decline. Caloric restriction, a lifespan-extending intervention, mitigates these changes in the heart but not the brain. Our findings link lysosomal storage disorders to aging-related dysfunction, uncover a metabolic lysosomal "aging clock," and open avenues for the mechanistic investigation of how lysosomal functions deteriorate during aging and in age-associated diseases.
One-Sentence Summary: Aging in mice is tracked by a lysosomal "clock", where glycerophosphodiesters and cystine - metabolites causally linked to juvenile lysosomal storage disorders - gradually accumulate in lysosomes of the brain, heart, skeletal muscle and adipose tissue.

DOI: https://doi.org/10.1101/2025.09.25.678303
Diabetes. 2025 Sep 30. pii: db250207. [Epub ahead of print]

Novel Function of Osteoprotegerin in the Modulation of Glucose Metabolism in the Liver via mTORC1.

Sheng Qiu, Xia Wang, Ke Li, Siliang Zhang, Yerui Lai, Qiao Mi, Min Yang, Dongfang Liu, Ling Li, Qinan Wu, Mengliu Yang.

ARTICLE HIGHLIGHTS: Methylation of the Opg promoter inhibits hepatic OPG expression in obese mice. Hepatic OPG regulates glucose metabolism and insulin sensitivity in obese mice. OPG regulates glucose metabolism through interaction with mammalian target of rapamycin complex 1 (Raptor). Opg deficiency in mice reduces age-related metabolic dysfunction.

DOI: https://doi.org/10.2337/db25-0207
Nat Cardiovasc Res. 2025 Sep 29.

Targeted glycophagy ATG8 therapy reverses diabetic heart disease in mice and in human engineered cardiac tissues.

K M Mellor, U Varma, P Koutsifeli, C L Curl, J V Janssens, L J Daniels, G B Bernasochi, A J A Raaijmakers, M Annandale, X Li, S L James, D J Taylor, K Raedschelders, K L Weeks, R J Mills, R G Parton, X Hu, J R Bell, T J O'Brien, R Katare, E R Porrello, J E Hudson, R P Xiao, J E Van Eyk, R A Gottlieb, L M D Delbridge.

Diabetic heart disease is highly prevalent and is associated with the early development of impaired diastolic relaxation. The mechanisms of diabetic heart disease are poorly understood, and it is a condition for which there are no targeted therapies. Recently, disrupted glycogen autophagy (glycophagy) and glycogen accumulation have been identified in the diabetic heart. Glycophagy involves glycogen receptor binding and linking with an ATG8 protein to locate and degrade glycogen within an intracellular phagolysosome. Here we show that glycogen receptor protein starch binding domain protein 1 (STBD1) is mobilized early in the cardiac glycogen response to metabolic challenge in vivo, and that deficiency of a specific ATG8 family protein, γ-aminobutyric acid type A receptor-associated protein-like 1 (GABARAPL1), is associated with diastolic dysfunction in diabetes. Gabarapl1 gene delivery treatment remediated cardiomyocyte and cardiac diastolic dysfunction in type 2 diabetic mice and the diastolic performance of 'diabetic' human induced pluripotent stem cell-derived cardiac organoids. We identify glycophagy dysregulation as a mechanism and potential treatment target for diabetic heart disease.

DOI: https://doi.org/10.1038/s44161-025-00726-x
Toxicol Appl Pharmacol. 2025 Sep 27. pii: S0041-008X(25)00357-6. [Epub ahead of print] 117581

Propylparaben disrupts early embryonic development by causing oxidative stress-induced organelle dysfunction and actin zipper abnormality.

Zhen-Nan Pan, Li-Li Zhuang, Hui-Shan Zhao, Shu-Yuan Yin, Min Chu, Xiao-Yan Liu, Hong-Chu Bao.

  Propylparaben (PrPB) is a commonly used preservative in personal care products and food items, but studies have shown that it can disrupt various physiological processes, especially in the reproductive system. Our previous research revealed the toxic effects of PrPB on mouse oocyte maturation. However, knowledge about the toxicity of PrPB in early embryos remains limited. In the present study, we demonstrated that in vitro exposure to 600 μM PrPB increased ROS levels, inducing autophagy, mitophagy and ER stress, ultimately leading to embryonic arrest at the 4-cell stage. PrPB exposure promoted autophagy through the induction of DNA damage, reflected by enhanced lysosome, LC3 and γH2A.X fluorescence signals. PrPB exposure enhanced mitophagy, as indicated by increased colocalization of mitochondria with LAMP1 and Parkin. PrPB exposure also caused ER stress, as indicated by disordered ER distribution and abnormal Ca2+ homeostasis. In addition, 600 μM PrPB exposure disrupted the formation of the actin zipper by interfering with the localization of ZO1 and E-cadherin, further affecting blastocyst formation. Although 300 μM PrPB exposure did not affect the embryo development rate, a decreased TE cell number was observed, indicating poor blastocyst quality. Taken together, the results of our study demonstrate that high-dose PrPB exposure causes oxidative stress-induced organelle dysfunction and abnormal actin zipper formation, whereas low-dose PrPB exposure affects early lineage specification.

Keywords:  Actin zipper; Autophagy; Early embryonic development; Endoplasmic Reticulum (ER) stress; Mitophagy; Propylparaben

DOI:  https://doi.org/10.1016/j.taap.2025.117581
Autophagy. 2025 Oct 02.

Targeted genome editing of ZKSCAN3 mitigates the neurotoxicity caused by mutant HTT (huntingtin) in a Huntington disease animal model and three-dimensional cell culture of Huntington disease.

Hyun Jung Park, JiYeon Kim, Jiwoo Choi, Chongsuk Ryou, Eunji Shin, Jae Young Lee.

  Huntington disease (HD) is a neurodegenerative disease caused by the expression of a mutant form of HTT (huntingtin; mHTT), caused by an abnormal expansion of polyglutamine in HTT. In HD, macroautophagy/autophagy dysfunction can cause mHTT accumulation. Moreover, the promotion of autophagy is considered a therapeutic strategy for the treatment of HD. ZKSCAN3 (zinc finger with KRAB And SCAN domains 3) has been identified as a transcriptional repressor of TFEB (transcription factor EB), a master regulator of autophagy and lysosomal functions. In this study, we conducted CRISPR-Cas9-based gene ablation to disrupt ZKSCAN3 in HD animal models and HD patient-induced pluripotent stem cell (iPSC) -derived three-dimensional (3D) spheroids. In animal models of HD, targeted in vivo zkscan3 ablation via a single adeno-associated virus (AAV) mediated CRISPR-Cas9 approach resulted in reduced mHTT levels, leading to improvements in both behavioral symptoms and the brain environment. Furthermore, CRISPR-Cas9 mediated ablation of ZKSCAN3 in 3D spheroids from HD patient-derived iPSC resulted in increased autophagy and lysosomal function, along with reduced mHTT accumulation. Specifically, in iPSC-derived neurons from HD patients, ZKSCAN3-depleted neurons demonstrated increased lysosomal function and reduced oxidative stress compared to controls. Additionally, transcriptional analysis of ZKSCAN3-edited neurons revealed an increased expression of genes involved in synaptic function and transporter activity. Taken together, these results suggest that in HD treatment strategies for improving neuronal function and the brain environment, ZKSCAN3 downregulation in neurons by autophagy activation may improve the brain environment through neuronal self-repair.

Keywords:  CRISPR-Cas9; Huntington disease; TFEB; ZKSCAN3; gene therapy; macroautophagy/autophagy

DOI:  https://doi.org/10.1080/15548627.2025.2569965
J Neurosci. 2025 Sep 30. pii: e0394252025. [Epub ahead of print]

Common Mechanism Underlying Synaptic Dysfunction Caused by Preformed Fibril-Induced Accumulation of α-Synuclein or Tau in a Culture Propagation Model.

Dimitar Dimitrov, Sruthi Raja, Humaira Noor, Tomoyuki Takahashi.

In sporadic neurodegenerative diseases, the endogenous proteins α-synuclein in Parkinson's disease and tau in Alzheimer's disease undergo pathogenic prion-like propagation over many years, accumulating in both soluble and insoluble forms in neurons including synapses, where they impair synaptic transmission and potentially cause various neuronal symptoms. To investigate the functional outcome of such synaptic accumulation, we induced accumulation of endogenous proteins in murine and human synapses by incubating mouse (of either sex) neuronal cultures with pathogenic preformed fibrils (pffs). Two weeks after treatment with human α-synuclein or tau pff, the respective endogenous proteins accumulated in neurons including presynaptic terminals, where we also observed tubulin accumulation, suggesting microtubule over-assembly. These were not associated with mRNA upregulation and were prevented by pharmacological stimulation of autophagy. Both pffs caused accumulation of p62 in cell bodies, suggesting compromised protein degradation. pHluorin imaging in synapses indicated a marked prolongation of vesicular endocytic time, which was rescued by pharmacological depolymerization of microtubules or by the over-expression of full-length dynamin 1. Since dynamin is a high-affinity binding partner of microtubules as well as an endocytic key molecule, over-assembled microtubules can sequester dynamin, thereby inhibiting endocytosis. We conclude that pff-induced accumulation of α-synuclein or tau in presynaptic terminals can disrupt vesicle endocytosis through a common mechanism. Since endocytosis-dependent vesicle recycling is critical for maintaining neurotransmitter release, its disruption can affect the neurocircuitry operations involved, thereby causing diverse symptoms associated with neurodegenerative diseases. Thus, our data suggest a common molecular mechanism underlying synaptic dysfunctions associated with Parkinson's and Alzheimer's diseases.Significance statement The accumulation of the pathogenic proteins α-synuclein and tau drives prion-like trans-neuronal propagation and underlies distinct neurodegenerative diseases, such as Parkinson's and Alzheimer's disease. Using a synaptic culture model of protein propagation, we identified a shared mechanism of synaptic dysfunction caused by these otherwise distinct proteins. In our models, propagated α-synuclein or tau disrupt protein degradation pathways, leading to their accumulation. These accumulated proteins promote excessive microtubule assembly and sequester the key endocytic protein dynamin, eventually impairing synaptic vesicle endocytosis. This cascade results in synaptic dysfunction that could compromise neurocircuit operations critical for brain functions. Our clarification of these mechanistic steps will improve our understanding of the synaptic pathophysiology underlying diverse symptoms of distinct neurodegenerative diseases.

DOI: https://doi.org/10.1523/JNEUROSCI.0394-25.2025
Cell Biochem Biophys. 2025 Oct 03.

MSC-Derived Exosomes in Preserving Autophagy through Key Signaling Pathways: A Preventive Strategy against Cardiovascular Aging.

Esteven Tanu Gunawan, Julia Windi Gunadi, Wahyu Widowati, Teresa Liliana Wargasetia.



Keywords:  Cardioprotection; Extracellular vesicles; Mesenchymal stem cells; Mitophagy; SIRT1

DOI:  https://doi.org/10.1007/s12013-025-01913-0
Fish Shellfish Immunol. 2025 Sep 25. pii: S1050-4648(25)00791-0. [Epub ahead of print]167 110902

Teleost HMGB1 paralogues mediate protective autophagy by interacting with NOD2 and ATG16L1 and activating ROS/Akt/mTOR pathway against Aeromonas hydrophila infection.

Dan Wang, Linan Chen, Xiaoyu Ma, Zhe Wang, Hong Zhou.

  As a multifunctional regulator, high mobility group box 1 (HMGB1) plays an important role in DNA transcription, autophagy, infection and inflammation in mammals based on its cellular localization. Unlike in mammals, some teleost has two HMGB1 paralogues, and the DNA-binding and pro-inflammatory functions of extracellular HMGB1 have been characterized in various fish species, but the functional role of intracellular HMGB1 in bacterial infection remains elusive. In this study, the inducible effect of Aeromonas hydrophila (A. hydrophila) on autophagy was identified by using the autophagy related gene 7 (Atg7)-knockdown Epithelioma papulosum cyprini (EPC) cells, where fish HMGB1 paralogues have been defined as the autophagy regulator in our previous study. Consistently, the HMGB1 paralogues were proved to mediate A. hydrophila-induced autophagy by knockout HMGB1 paralogues and using HMGB1 inhibitors in the same cells, and suggested the defensive role of HMGB1 paralogues against A. hydrophila infection. Mechanistically, in accordance with the findings that nucleotide-binding oligomerization domain 2 (NOD2) but not NOD1 was involved in A. hydrophila-induced autophagy, HMGB1 mediated autophagy by interaction with NOD2 and ATG16L1. In addition, transcriptomic and western blotting assays further uncovered that HMGB1 regulated A. hydrophila-induced autophagy potentially by the ROS/AKT/mTOR signaling pathway. Furthermore, the physiological importance of HMGB1-mediated autophagic mechanism was strengthened in the primary neutrophils of grass carp, in which a complete autophagy flux mediated by HMGB1 facilitated A. hydrophila clearance. Notably, two HMGB1 paralogues played the same role in aforementioned events. Taken together, the intracellular role of fish HMGB1 paralogues in the autophagic response to A. hydrophila infection provided new insights into the immunological function of fish HMGB1, and offered clues as to how fish can defend themselves against bacterial infection.

Keywords:  AKT/mTOR; Aeromonas hydrophila; Autophagy; HMGB1 paralogues; NOD2; Teleost

DOI:  https://doi.org/10.1016/j.fsi.2025.110902
Autophagy. 2025 Oct 02.

Aging-rewired metabolic cues promote autophagy and senescence via DRAM1.

Jinghong Yang, Haobin Sun, Keqing Xu, Xiaomei Zhang, Mudan Huang, Guanghui Jin, Yasong Liu, Weizhao Chen, Shunan Lin, Juan Shen, Chuan-Qi Zhong, Yan Xu, Qi Zhang, Wei Liu, Yang Yang, Jingxing Ou.

  Being a major contributor to cell senescence and aging, DNA damage activates macroautophagy/autophagy, but how this process is affected by aging-rewired metabolism in normal biological systems remains to be explored. Here in cultured human umbilical cord-derived mesenchymal stem cells (HsMSCs) and the mouse liver that accumulate DNA damage during aging, we found an elevation of DRAM1 (DNA damage regulated autophagy modulator 1) and DRAM1-mediated pro-senescent autophagy (DMPA). Confirming that DRAM1 activated AMPK, we sought DMPA-associated metabolic features and noted substantial enrichment of N-acetylhistamine (N-AcHA) and phosphatidylethanolamine (PE) products in the aging HsMSCs and mouse liver. Elevating DNA damage and senescence, N-AcHA supplements were sufficient to upregulate DRAM1 and DMPA in primary hepatocytes from young mice but not even in pre-senescent HsMSCs, hence reflecting the differential tolerance of these cell models toward cytotoxic metabolic cues. The effects of N-AcHA were further verified in mouse aging and post-hepatectomy liver regeneration models. In contrast, accumulating cellular PE contents via ethanolamine supplements augmented autophagy but not DNA damage and senescence despite tending to induce DRAM1. Combined treatments with N-AcHA and ethanolamine were sufficient to trigger DMPA in HsMSCs. Despite their differential cellular responses toward N-AcHA and ethanolamine supplements, in primary HsMSCs and mouse hepatocytes DMPA did not notably downregulate SQSTM1/p62 proteins, which differed from general macroautophagy and may constitutively support the fusion of SQSTM1-modified cargo-containing autophagosomes with lysosomes. Overall, this study reveals DMPA-promoting metabolic and molecular features. Thus, targeting certain metabolic pathways and DMPA may promote DNA repair and delay senescence/aging.

Keywords:  Aging; DNA damage; DRAM1; autophagy; metabolism; senescence

DOI:  https://doi.org/10.1080/15548627.2025.2568487
Brain Res. 2025 Sep 27. pii: S0006-8993(25)00533-5. [Epub ahead of print]1867 149970

BNIP3L/NIX-mediated mitophagy: Future directions in Alzheimer's disease.

Violina Kakoty, Khang Wen Goh, Prashant Kesharwani, Young Tag Ko.

  BCL2-interacting protein 3 like (BNIP3L) /Nip3-like protein X (NIX) is a mitochondrial outer membrane protein possessing mitophagic and pro-apoptotic properties. Mitochondrial dysfunction and subsequent mitophagy impairment are some of the early triggers for Alzheimer's Disease (AD), which is a progressive neurodegenerative condition affecting memory, thinking, and behavior. AD is associated with mitochondrial protein impairment and mitophagy failure. A recent study showed downregulation in BNIP3L expression in response to stress hormone release during Alzheimer's, and pretreatment with a BNIP3L enhancer of a corticosterone-exposed mouse upregulated mitophagy. This research proved that BNIP3L stimulation can be an effective therapeutic strategy against Alzheimer's. However, BNIP3L-mediated mitophagy studies focused on Alzheimer's have been relatively scarce, and expanding knowledge on its regulatory proteins will help lay a smoother road ahead for future Alzheimer's research. In this review, we aim to summarize all the recent findings of the downstream proteins of BNIP3L, which play an indispensable role in inducing BNIP3L-mediated mitophagy effects. The review also explicates the significance of healthy mitochondria and normally functioning mitophagy in Alzheimer's. Finally, the review states the implications of BNIP3L in other diseases, like cardiovascular conditions and cancer, underscoring the immense potential of this wonder protein.

Keywords:  Alzheimer’s Disease; BCL2-interacting protein 3-like/Nip3-like protein X; Downstream proteins; Mitophagy

DOI:  https://doi.org/10.1016/j.brainres.2025.149970
Am J Physiol Gastrointest Liver Physiol. 2025 Sep 29.

Pioglitazone Reduces Hepatic Alpha-1 Antitrypsin Accumulation Through Autophagy and AMPK Activation in Alpha-1 Antitrypsin Deficient Mice.

Yuanqing Lu, Regina Oshins, Nesmine R Maptue, Qingyang Shen, Chalermchai Khemtong, Kenneth Cusi, Mark Brantly, Nazli Khodayari.

  Background: Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder characterized by accumulation of misfolded Z α-1 antitrypsin (ZAAT) in hepatocytes, leading to liver injury and metabolic dysfunction. There is no therapy to reduce ZAAT accumulation and restore proteostasis. Pioglitazone activates AMP-activated protein kinase (AMPK), enhance autophagy, and modulate ER stress responses, suggesting a potential effect on ZAAT clearance. Our objective is to examine whether pioglitazone can protect against AATD-mediated liver disease. Methods: Huh7.5 cells expressing ZAAT (HuhZ) and Pi*Z transgenic mice were used to investigate pioglitazone treatment on hepatic ZAAT accumulation, autophagy activation, and AMPK signaling. Histological, molecular, and metabolic analyses were conducted to assess changes in ZAAT content, autophagy markers, AMPK phosphorylation, and proteostasis. Results: Pioglitazone significantly reduced intracellular ZAAT and decreased lipid droplet accumulation in HuhZ cells. Pioglitazone markedly lowered hepatic ZAAT content in Pi*Z mice, suggesting enhanced degradation. This reduction was mediated through the AMPK pathway, indicated by increased phosphorylation of AMPK and ULK1. Pioglitazone induced autophagy, shown by decreased p62 and increased ATG5 and LC3B-II. This is indicative of enhanced autophagy. Although total hepatic AAT levels were reduced, PASD-positive ZAAT aggregates exhibited only a downward trend, suggesting these may be more resistant to clearance. Conclusion: These findings demonstrate pioglitazone reduces hepatic ZAAT accumulation by activating AMPK and inducing autophagy in AATD-associated liver disease, supporting its potential for therapeutic repurposing. As pioglitazone is FDA-approved with benefits for metabolic liver health, further studies are warranted to evaluate efficacy in restoring proteostasis and reducing hepatic ZAAT.

Keywords:  alpha-1 antitrypsin deficiency; autophagy; pioglitazone

DOI:  https://doi.org/10.1152/ajpgi.00272.2025
Commun Biol. 2025 Sep 29. 8(1): 1364

Rapalink-1 reveals TOR-dependent genes and an agmatinergic axis-based metabolic feedback regulating TOR activity and lifespan in fission yeast.

Juhi Kumar, Kristal Ng, Charalampos Rallis.

The Target of Rapamycin, TOR, is a conserved signalling pathway with characterised chemical inhibitors such as rapamycin and torin1. Bi-steric third-generation inhibitors, such as rapalink-1 have been developed, however, their effects on organismal gene expression and lifespan have not been characterised. Here, we demonstrate that rapalink-1 affects fission yeast spatial and temporal growth and prolongs chronological lifespan with a distinct TORC1 selectivity profile. Endosome and vesicle-mediated transport and homeostasis processes related to autophagy render cells resistant to rapalink-1. Our study reveals TOR-regulated genes with unknown roles in ageing, including all fission yeast agmatinases, the enzymes that convert agmatine to putrescine and urea. Through genome-wide screens, we identify sensitive and resistant mutants to agmatine and putrescine. Genetic interactome assays for the agmatinase agm1 and further cell and molecular analyses demonstrate that impairing the agmatinergic branch of arginine catabolism results in TOR activity levels that are beneficial for growth but detrimental for chronological ageing. Our study reveals the anti-ageing action of agmatinases within a metabolic circuit that regulates TOR activity, protein translation levels and lifespan.

DOI: https://doi.org/10.1038/s42003-025-08731-3
Int J Biol Macromol. 2025 Sep 30. pii: S0141-8130(25)08571-X. [Epub ahead of print] 148014

Unravelling the oncogenic role of eukaryotic elongation factor 2 kinase: A revisited review from underlying mechanisms to targeted therapy.

Lingjuan Zhu, Minru Liao, Zhichao Fan, Yu Tang, Junning Wen, Qingbo Liu, Bo Liu.

  Eukaryotic elongation factor 2 kinase (eEF2K), encoded by the human eEF2K gene, belongs to the "α-kinase" family of atypical protein kinases and requires calcium ions and calmodulin (CaM) for its activity. It is overexpressed in various tumor tissues and plays a crucial role in promoting tumor growth, invasion, and metastasis. Consequently, eEF2K is considered a viable target for potential cancer therapies. This review aims to summarize the key signaling pathways that modulate eEF2K activity in tumors, including the mammalian target of rapamycin complex 1 (mTORC1)-the 70 kDa ribosomal protein S6 kinase (p70S6K)-eEF2K and adenosine monophosphate-activated protein kinase (AMPK)/eEF2K pathways. Furthermore, we explore the complex interactions between eEF2K and various aspects of cancer biology, such as cancer progression, metastasis, metabolism, autophagy, and therapeutic response. The therapeutic potential of small-molecule inhibitors targeting eEF2K is highlighted, particularly in the context of breast cancer, lung cancer, and other cancer types. We also discuss emerging therapeutic technologies, such as proteolysis-targeting chimaeras (PROTACs) and non-coding RNAs (ncRNAs), which hold promise for future cancer treatments. We aim to offer clearer insights and guidance for developing novel strategies to inhibit eEF2K in cancer therapy, thereby broadening the range of treatment options for patients.

Keywords:  Autophagy; Cancer therapy; Signaling pathway; Small-molecule inhibitor; eEF2K

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.148014
Free Radic Biol Med. 2025 Sep 27. pii: S0891-5849(25)01008-1. [Epub ahead of print]

Methionine sulfoxide reductase A deficiency impairs zebrafish heart regeneration via inhibiting Prohibitin 2-Pink1-mediated mitophagy.

Huicong Li, Xin Yang, Jiayi Li, Yan Zhao, Jieling Liang, Yanmei Liu, Fen Du, Hong Yu, Ruilin Zhang.

  Ischemic heart disease is among the cardiovascular diseases with the highest mortality rates worldwide. Redox homeostasis is critical for a wide range of biological processes, including cardiac injury and repair. Methionine sulfoxide reductase A (MSRA) has been reported as a protective factor for cardiomyocytes both in vivo and in vitro, however, the underlying mechanisms are not fully understood. Here we demonstrated that Msra deficiency in zebrafish results in heart regeneration failure after larval ventricle ablation. Using a proximity labelling assay we identified prohibitin 2a (Phb2a), an ortholog of human PHB2, as a potential substrate of Msra. We further revealed that Pink1-mediated mitophagy is inhibited, thereby impairing heart regeneration in Msra-deficient zebrafish. Moreover, mitophagy is also impeded in Msra-KO HL-1 mouse cardiomyocytes under oxidative stress. Blocking the oxidation of PHB2 by substituting its essential methionine with valine rescues Msra-KO cardiomyocytes from oxidative stress. Taken together, our findings shed light on the role that methionine redox homeostasis plays in the regulation of mitophagy in ischemic heart disease and provide a foundation for the identification of novel therapeutic targets.

Keywords:  heart regeneration; methionine sulfoxide reductase A; mitophagy; prohibitin 2; redox homeostasis

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.09.051
J Toxicol Sci. 2025 ;50(10): 577-582

Dihydropyrazine activates the CAMKK2-AMPK-ULK1 signaling pathway in human hepatoma HepG2 cells.

Madoka Sawai, Yuu Miyauchi, Hisao Kansui, Shinji Takechi.

  Dihydropyrazines (DHPs) are glycation intermediates produced by nonenzymatic glycation reactions in vivo and in foods. We previously reported that 3-hydro-2,2,5,6-tetramethylpyrazine (DHP-3) activates endoplasmic reticulum (ER) stress and inhibits autophagy, although its effect on autophagy initiation remained unclear. In this study, we examined the effect of DHP-3 on the autophagy initiation pathway in HepG2 cells. DHP-3 exposure resulted in activation of UNC-51-like kinase 1 (ULK1), the catalytic subunit of the ULK complex essential for autophagy initiation. Notably, phosphorylation of AMP-activated protein kinase (AMPK), an upstream activator of ULK1, was enhanced without a corresponding increase in the ADP/ATP ratio. Among the upstream kinases regulating AMPK, phosphorylation of calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) was increased, whereas that of liver kinase B1 (LKB1) remained unchanged. These findings suggest that DHP-3 activates the CAMKK2-AMPK-ULK1 signaling pathway, thereby inducing autophagy initiation.

Keywords:  Autophagy; Dihydropyrazine; ER stress; Glycation; HepG2 cells

DOI:  https://doi.org/10.2131/jts.50.577
Sci Rep. 2025 Oct 03. 15(1): 34571

A nile red fluorescence assay for LC3 autophagy protein binding to lipid bilayers.

Jesús Sot, Yaiza R Varela, L Ruth Montes, Félix M Goñi, Alicia Alonso.

  Autophagy consists of the degradation and recycling of defective or aging cellular components. This process occurs in all eukaryotes, and starts by the formation of a double-bilayer structure known as the autophagosome. In humans, autophagosome generation requires, among others, the action of three homologous proteins, designated as LC3A, LC3B, and LC3C. These are amphipathic proteins, which can exist either in aqueous or in membranous environments. Quantification of LC3 binding to lipid bilayers is usually achieved by a rather cumbersome procedure, involving separation of bound and free forms by density gradient centrifugation and fractional analysis of the centrifuged samples. This paper describes a simple protein binding assay based on the fluorescence properties of Nile red. This solvatochromic probe has recently been applied to the study of lipid bilayer fluidity. A red/orange intensity ratio (ROIR) index, derived from the Nile red emission spectrum, was found useful in order to normalize the results [Sot et al. 2022, doi: https://doi.org/10.1016/j.molliq.2022.119874 ]. The current results show that LC3 protein binding to bilayers was accompanied by a protein-concentration-dependent decrease of ROIR, and there was a strict correlation between the bindings measured by ultracentrifugation and by fluorescence. ROIR decreased with LC3 concentrations following a hyperbolic curve and this allowed an estimation of the maximum decrease for each lipid composition. In agreement with previous observations, the presence of cardiolipin and ceramide in the bilayer markedly facilitated binding. Even if absolute values of binding cannot be obtained, the Nile red method may become of general use in the assay of amphipathic protein interaction with bilayers.

Keywords:  Autophagy; Lipid-protein interaction; Membrane proteins; Membrane-bilayer binding; Nile red fluorescence

DOI:  https://doi.org/10.1038/s41598-025-18016-8
Elife. 2025 Sep 30. pii: RP97341. [Epub ahead of print]13

Direct modulation of TRPM8 ion channels by rapamycin and analog macrolide immunosuppressants.

Balázs István Tóth, Bahar Bazeli, Annelies Janssens, Erika Lisztes, Márk Racskó, Balázs Kelemen, Mihály Herczeg, Tamás Milán Nagy, Katalin E Kövér, Argha Mitra, Attila Borics, Tamás Bíró, Thomas Voets.

  Rapamycin (sirolimus), a macrolide compound isolated from the bacterium Streptomyces hygroscopicus, is widely used as oral medication for the prevention of transplant rejection and the treatment of lymphangioleiomyomatosis. It is also incorporated in coronary stent coatings to prevent restenosis and in topical preparations for the treatment of skin disorders. Rapamycin's in vivo activities are generally ascribed to its binding to the protein FKBP12, leading to potent inhibition of the mechanistic target of rapamycin kinase (mTOR) by the FKBP12-rapamycin complex. The specific rapamycin-induced interaction between domains from mTOR and FKBP12 is also frequently employed in cell biological research, for rapid chemically-induced protein dimerization strategies. Here, we show that rapamycin activates TRPM8, a cation channel expressed in sensory nerve endings that serves as the primary cold sensor in mammals. Using a combination of electrophysiology, Saturation Transfer Triple-Difference (STTD) NMR spectroscopy, and molecular docking-based targeted mutagenesis, we demonstrate that rapamycin directly binds to human TRPM8. We identify a rapamycin-binding site in the groove between voltage sensor-like domain and the pore domain, distinct from the interaction sites of cooling agents and known TRPM8 agonists menthol and icilin. Related macrolide immunosuppressants act as partial TRPM8 agonists, competing with rapamycin for the same binding site. These findings identify a novel molecular target for rapamycin and provide new insights into the mechanisms of TRPM8 activation, which may assist in the development of therapies targeting this ion channel. Moreover, our findings also indicate that caution is needed when using molecular approaches based on rapamycin-induced dimerization to study ion channel regulation.

Keywords:  Rapamycin; TRP ion channels; TRPM8; human; ion channel gating; mouse; neuroscience; structure-function

DOI:  https://doi.org/10.7554/eLife.97341
Res Sq. 2025 Sep 23. pii: rs.3.rs-7411941. [Epub ahead of print]

A human Staufen1 BAC transgenic mouse exhibits abnormal autophagy and neurodegeneration across the central nervous system.

Daniel Scoles, Sharan Paul, Hieu Nguyen, Mandi Gandelman, Warunee Dansithong, Karla Figueroa, Nancy Bonini, Stefan Pulst.

RNA-binding proteins (RBPs) play an essential role in development, normal functioning and human disease. Staufen1 (STAU1) is an RBP that regulates mRNA degradation and subcellular localization, and is part of the ATXN2 protein complex. Previously, we showed that STAU1 is overabundant in patient fibroblasts and in mouse models of Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and spinocerebellar ataxia type 2 (SCA2), where it is associated with impaired autophagic flux due to STAU1-mediated upregulation of mTOR translation. STAU1 overabundance and impaired autophagy cause accumulation of biomolecular condensates and abnormal unfolded protein response (UPR). We generated a mouse model expressing the entire human STAU1 gene (h STAU1 ) in a bacterial artificial chromosome (BAC) construct. hSTAU1 in these mice was expressed in cerebral hemispheres, cerebellum and spinal cord, as well as cultured cortical neurons and cortical and spinal cord astrocytes and microglia. Expression of hSTAU1 caused dysregulated gene expression, abnormal autophagy, glial activation, and changes in neuronal marker proteins. All of these were significantly improved by reducing STAU1 abundance by RNAi, but exacerbated in BAC-STAU1 mice crossed with Prp-TDP-43(Q331K) transgenic mice. Similar results were also obtained in eye phenotypes in ALS- and SCA2-relevant fly models upon changing staufen-1 dosage. Despite the molecular changes, we observed no overt behavioral changes in mice up to 55 weeks of age, suggesting that STAU1 may function as an epistatic modifier of neuronal degeneration. The BAC-hSTAU1 mouse will be useful for developing therapies targeting the human STAU1 gene.

DOI: https://doi.org/10.21203/rs.3.rs-7411941/v1
Sci Rep. 2025 Oct 01. 15(1): 34140

Three-dimensional human mucopolysaccharidosis IVA chondrocyte culture reveals significant impairments in the lysosomal-mitochondrial crosstalk.

Andrés Felipe Leal, Sampurna Saikia, Shaukat A Khan, Shunji Tomatsu.

Mucopolysaccharidosis IVA (MPS IVA) is a lysosomal storage disorder (LSD) caused by a deficiency of N-acetylgalactosamine-6-sulfate sulfatase enzyme. MPS IVA patients suffer from skeletal dysplasia due to the abnormal function of chondrocytes. Given the interactions of lysosomes with various intracellular organelles, it is not surprising that lysosomal dysfunction can lead to improper functioning of lysosome-interacting organelles such as mitochondria. Mitochondrial alterations have been evaluated in several LSDs; nevertheless, they have not been fully addressed in MPS IVA. In this study, we assessed the mitochondrial alterations in MPS IVA chondrocytes using a three-dimensional culture approach. Our findings revealed that MPS IVA chondrocytes exhibited an increased mitochondrial-triggered apoptosis profile, mitochondrial depolarization, and heightened oxidative stress. Additionally, the proteins associated with mitophagy, PINK1/Parkin, were significantly reduced in MPS IVA chondrocytes, whereas LC3-II and p62 were elevated. Our assessment of mitochondrial dynamics revealed increased levels of Drp1 and Fis1 along with decreased levels of Opa1. Regarding biogenesis, the mitochondrial regulators TFAM and PGC-α were upregulated in MPS IVA chondrocytes. Finally, MPS IVA chondrocytes showed a metabolic shift from mitochondrial respiration towards a glycolytic profile. Collectively, these data indicate that alterations in mitochondrial homeostasis may play a critical role in the pathogenesis of MPS IVA.

DOI: https://doi.org/10.1038/s41598-025-04871-y
J Biol Chem. 2025 Sep 27. pii: S0021-9258(25)02626-2. [Epub ahead of print] 110774

APP family is a regulator of endo-lysosomal membrane vulnerability.

Brianna Lundin, Natalia Wieckiewicz, Midori Yokomizo, Michael Sadek, Desmond Owusu Kwarteng, John R Dickson, Robert G R Sobolewski, Victoria Derosla, Gokce Armagan, Florian Perrin, Bradley T Hyman, Oksana Berezovska, Masato Maesako.

  The amyloid precursor protein (APP) is cleaved by β- and γ-secretases, resulting in the generation of β-amyloid (Aβ). Aβ peptides accumulate in the brain of Alzheimer's disease (AD), and the removal of toxic Aβ species using antibodies slows the progression of the disease. However, the potential physiological function(s) of APP and its family members remains elusive. Various studies, including ours, reported that APP C99 is primarily processed by γ-secretase in the endo-lysosomal compartments. Here, we report using a series of complementary assays that the endo-lysosomal membrane in APP/APLP2-deficient mouse embryonic fibroblasts (MEFs) is more vulnerable to leakage caused by oxidative stress, adeno-associated virus (AAV), or tau incubation, compared to that in wild-type controls. The increased vulnerability of endo-lysosome membrane is, in part, rescued by APP overexpression, suggesting the contribution of both APP and APLP2. Mechanistically, we observed distinct lipid profiles, including increased cholesterol and Hex1Cer, between the membrane of APP/APLP2 knockout and that of WT MEF cells. Furthermore, we uncovered higher APP expression in primary neurons from the cerebellum of mouse embryos compared to those from the cortex, and the endo-lysosomal membrane in the cerebellum neurons is less vulnerable to leakage than that in the cortical neurons. Taken together, our findings suggest an unrecognized role of APP and its family members in the regulation of endo-lysosomal membrane vulnerability.

Keywords:  APP; cerebellum; cortex; endo-lysosome; lipids; membrane permeability; γ-secretase

DOI:  https://doi.org/10.1016/j.jbc.2025.110774
Science. 2025 Oct 02. 390(6768): eads8728

GCN1 couples GCN2 to ribosomal state to initiate amino acid response pathway signaling.

Changqian Zhou, Miao Zhang, Jason Murray, Joao Paulo, Steve Gygi, Sichen Shao, Malcolm Whitman, Tracy Keller.

During nutrient deprivation, activation of the protein kinase GCN2 regulates cell survival and metabolic homeostasis. In addition to amino acid stress, GCN2 is activated by a variety of cellular stresses. GCN2 activation has been linked to its association with uncharged tRNAs, specific ribosomal proteins, and conditions of translational arrest, but their relative contribution to activation is unclear. Here, we used in vitro translation to reconstitute GCN2 activation by amino acid stress and compared collided ribosome populations induced by diverse translational stressors. Initiation of GCN2 signaling required the di-ribosome sensor GCN1, which recruits GCN2 to ribosomes in a collision-dependent manner, where GCN2 becomes activated by key ribosomal interactions and stably associated with collided ribosomes. Our findings define the molecular requirements and dynamics of GCN2 activation.

DOI: https://doi.org/10.1126/science.ads8728
Exp Gerontol. 2025 Oct 01. pii: S0531-5565(25)00242-6. [Epub ahead of print] 112913

Mitochondrial dysfunction drives cellular senescence: Molecular mechanisms of inter-organelle communication.

Ziyue Xie, Xinyu Zhang, Yu Li, Ruigong Zhu.

  Mitochondrial dysfunction is a central driver of cellular senescence, a core hallmark of aging. While intrinsic mechanisms have been extensively reviewed, this article offers a novel paradigm by emphasizing the critical role of interorganellar communication in mitochondria-mediated senescence. We present a systematic dissection of the molecular mechanisms underlying functional crosstalk between mitochondria and key organelles, including the endoplasmic reticulum (ER), lysosomes, and peroxisomes. A particular focus is placed on established regulatory hubs such as mitochondria-associated ER membranes (MAMs), which orchestrate calcium signaling, lipid metabolism, and inflammatory responses. We further explore emerging pathways involving lysosomal mitochondrial coordination in nutrient sensing and mitophagy, and peroxisomal mitochondrial cooperation in redox balance and lipid homeostasis. By elucidating how defects in these dynamic networks propagate mitochondrial damage and execute senescence, this review establishes a unified framework for aging as integrated organelle network dysfunction. This synthesis advances fundamental aging biology and identifies novel molecular targets, providing a foundation for developing therapeutic strategies targeting organelle networks against age related pathologies.

Keywords:  Cellular senescence; Mitochondrial dysfunction; Molecular mechanism; Organelle

DOI:  https://doi.org/10.1016/j.exger.2025.112913
Nat Commun. 2025 Oct 03. 16(1): 8822

SFPQ-TFE3 reciprocally regulates mTORC1 and induces lineage plasticity in a mouse model of renal tumorigenesis.

Kaushal Asrani, Adrianna Amaral, Juhyung Woo, Sanaz Nourmohammadi Abadchi, Thiago Vidotto, Eddie Imada, Alyza Skaist, Kewen Feng, Hans B Liu, Mithila Kasbe, Yorifumi Satou, Masaya Baba, Yuichi Oike, Patricia Outeda, Terry Watnick, Avi Z Rosenberg, Laura S Schmidt, W Marston Linehan, Pedram Argani, Tamara L Lotan.

MiT/TFE gene fusions like SFPQ-TFE3 drive both epithelial (translocation RCC) and mesenchymal (PEComas) neoplasms. However, no mouse models for SFPQ-TFE3-related tumors exist and the underlying mechanisms of lineage plasticity remain unclear. Here, we demonstrate that constitutive murine renal expression of SFPQ-TFE3 disrupts kidney development with early neonatal renal failure and death, while post-natal induction induces infiltrative epithelioid tumors, that morphologically and transcriptionally resemble human PEComas, with strong activation of mTORC1 signaling via increased V-ATPase expression. Remarkably, SFPQ-TFE3 expression is sufficient to induce lineage plasticity, with down-regulation of the PAX2/PAX8 nephric lineage factors and tubular epithelial markers, and up-regulation of PEComa differentiation markers in transgenic mice, cell lines and human tRCC. mTOR inhibition downregulates SFPQ-TFE3 expression and rescues PAX8 expression and transcriptional activity in vitro. These data provide evidence of an epithelial cell-of-origin for TFE3-driven PEComas, highlighting a reciprocal role for SFPQ-TFE3 and mTOR in driving lineage plasticity in the kidney.

DOI: https://doi.org/10.1038/s41467-025-63885-2
bioRxiv. 2025 Sep 22. pii: 2024.11.28.625926. [Epub ahead of print]

Targeted glycophagy ATG8 therapy reverses diabetic heart disease in mice and in human engineered cardiac tissues.

K M Mellor, U Varma, P Koutsifeli, C L Curl, J V Janssens, L J Daniels, G B Bernasochi, A J A Raaijmakers, M Annandale, X Li, S L James, D J Taylor, K Raedschelders, K L Weeks, R J Mills, R G Parton, X Hu, J R Bell, Terence J O'Brien, Rajesh Katare, E R Porrello, J E Hudson, R-P Xiao, J E Van Eyk, R A Gottlieb, L M D Delbridge.

Diabetic heart disease is highly prevalent and is associated with the early development of impaired diastolic relaxation. The mechanisms of diabetic heart disease are poorly understood and it is a condition for which there are no targeted therapies. Recently, disrupted glycogen-autophagy (glycophagy) and glycogen accumulation have been identified in the diabetic heart. Glycophagy involves glycogen receptor binding and linking with an ATG8 protein to locate and degrade glycogen within an intracellular phago-lysosome. Here we show that glycogen receptor protein STBD1 (starch-binding-domain-protein-1) is mobilized early in the cardiac glycogen response to metabolic challenge in vivo , and that deficiency of a specific ATG8 family protein, Gabarapl1 (γ-aminobutyric-acid-receptor-associated-protein-like-1) is associated with diastolic dysfunction in diabetes. Gabarapl1 gene delivery treatment remediated cardiomyocyte and cardiac diastolic dysfunction in type 2 diabetic mice and diastolic performance of 'diabetic' human iPSC-derived cardiac organoids. We identify glycophagy dysregulation as a mechanism and potential treatment target for diabetic heart disease.

DOI: https://doi.org/10.1101/2024.11.28.625926
bioRxiv. 2025 Sep 22. pii: 2025.09.08.674880. [Epub ahead of print]

Neurodegeneration emerges at a cellular tipping point between aggregate accumulation and removal.

Matthew W Cotton, Shriram Venkatesan, Joseph S Beckwith, Dorothea Böken, Catherine K Xu, Jonathan C Breiter, Lexie E Berkowicz, Laura Sancho Salazar, Alex Von Schulze, Ewa A Andrzejewska, Emma E Brock, Hannah L Han, Matthias M Schneider, Danny D Sahtoe, David Baker, James B Rowe, Alain Goriely, William A McEwan, Tuomas P J Knowles, Steven F Lee, Randal Halfmann, David Klenerman, Georg Meisl.

Protein aggregates are a hallmark of pathology across neurodegenerative diseases. Yet, the disconnect between molecular-level aggregation and the emergence of disease severely limits mechanistic understanding of neurodegeneration. Here, we bridge this disconnect by showing that a cellular tipping point emerges as a universal feature across diseases from the competition between aggregate accumulation and removal. We map the resulting cellular phase transition with our high-throughput live-cell assay, measuring the tipping point that separates healthy cells from those burdened with large aggregate loads. Using super-resolution imaging of brain tissue from Alzheimer's and Parkinson's disease, we quantify how the crucial balance of accumulation and removal is shifted in disease. Combined with in vitro aggregation kinetics, we then validate our framework by predicting how designed aggregation inhibitors shift the tipping point to restore cellular homeostasis. Our results provide a mechanistic framework to connect molecular-level aggregation to disease states, paving the way for a quantitative, unified understanding of neurodegeneration and enabling predictions of the complex, non-linear dynamics that govern therapeutic efficacy.

DOI: https://doi.org/10.1101/2025.09.08.674880
Nat Biomed Eng. 2025 Oct 01.

Large-scale visualization of α-synuclein oligomers in Parkinson's disease brain tissue.

Rebecca Andrews, Bin Fu, Christina E Toomey, Jonathan C Breiter, Joanne Lachica, Joseph S Beckwith, Ru Tian, Emma E Brock, Lisa-Maria Needham, Gregory J Chant, Camille Loiseau, Angèle Deconfin, Kenza Baspin, Rebeka Popovic, James Evans, Yen Goh, Begüm Kurt, Lenart Senicar, Marisa Edmonds, Tim Bartels, Nora Bengoa-Vergniory, Peter J Magill, Zane Jaunmuktane, Oliver J Freeman, Benjamin J M Taylor, John Hardy, Tammaryn Lashley, Mina Ryten, Michele Vendruscolo, Nicholas W Wood, Lucien E Weiss, Sonia Gandhi, Steven F Lee.

Parkinson's disease (PD) is a neurodegenerative condition characterized by the presence of intraneuronal aggregates containing fibrillar ɑ-synuclein known as Lewy bodies. These large end-stage species are formed by smaller soluble protein nanoscale assemblies, often termed oligomers, which are proposed as early drivers of pathogenesis. Until now, this hypothesis has remained controversial, at least in part because it has not been possible to directly visualize nanoscale assemblies in human brain tissue. Here we present Advanced Sensing of Aggregates-Parkinson's Disease, an imaging method to generate large-scale α-synuclein aggregate maps in post-mortem human brain tissue. We combined autofluorescence suppression with single-molecule fluorescence microscopy, which together enable the detection of nanoscale α-synuclein aggregates. To demonstrate the use of this platform, we analysed ~1.2 million nanoscale aggregates from the anterior cingulate cortex in human post-mortem brain samples from patients with PD and healthy controls. Our data reveal a disease-specific shift in a subpopulation of nanoscale assemblies that represent an early feature of the proteinopathy that underlies PD. We anticipate that quantitative information about this distribution provided by Advanced Sensing of Aggregates-Parkinson's Disease will enable mechanistic studies to reveal the pathological processes caused by α-synuclein aggregation.

DOI: https://doi.org/10.1038/s41551-025-01496-4
bioRxiv. 2025 Sep 02. pii: 2025.08.28.672891. [Epub ahead of print]

A Common PD-Risk GBA1 Variant Disrupts LIMP2 Interaction, Impairs Glucocerebrosidase Function, and Drives Lysosomal and Mitochondrial Dysfunction.

Oliver B Davis, Jennifer E Kung, Sonnet S Davis, Rajarshi Ghosh, Shan V Andrews, Neal S Gould, Jillian H Kluss, Elliot Thomsen, Maayan Agam, John P Coan, Michael T Maloney, Ann H Nguyen, Hoang N Nguyen, Nicholas E Propson, Edwin I Lozano, Tianao Yuan, Kaitlin Xa, R Andres Parra Sperberg, Shourya Jain, Roger Lawrence, Julie C Ullman, Srijana Balasundar, H Paul Benton, Maja Petkovic, Ahlam N Qerqez, Xiang Wang, Sha Zhu, Gilbert Di Paolo, Mihalis S Kariolis, Cathal S Mahon, Annie Arguello, David J Vocadlo, Mark R Cookson, Jung H Suh, Lionel Rougé, Anastasia G Henry.

Variants in GBA1 cause Gaucher disease (GD), a lysosomal storage disorder, and represent the most common genetic risk factor for Parkinson's disease (PD). While some GBA1 variants are associated with both GD and PD, several coding mutations, including E326K, specifically confer risk for developing PD. It is established that GD-linked variants in β-glucocerebrosidase (GCase), the enzyme encoded by GBA1 , are loss-of-function, but it remains unclear whether variants solely associated with PD similarly reduce GCase activity. The mechanisms by which some of these variants impact GCase activity and PD-associated pathways, including lysosomal and mitochondrial function, are also poorly defined. Here, we show that the PD-linked E326K variant significantly reduces lysosomal GCase activity by impairing its delivery to lysosomes via altered interactions with its receptor, LIMP2. Biophysical and structural characterization of this variant, both alone and in complex with LIMP2, reveals a dimeric organization that appears to result from the loss of a key salt bridge between E326 and R329. Restoration of this salt bridge through the introduction of a negatively charged side chain at position 329 promotes monomeric organization and interaction with LIMP2 in cells. GBA1 -p.E326K cell models show greater deficits in PD-linked pathways compared to more severe loss of GCase function, including secondary lysosomal lipid storage and mitochondrial dysfunction. We confirm the E326K variant impacts GCase pathway activity in relevant CNS cell types, including iPSC-derived microglia, and in biofluids from heterozygous GBA1- p.E326K variant carriers. Together, our data provide key insights into the nature of GCase dysfunction in GBA1 -PD and can inform the development of GCase-targeted therapeutic strategies to treat PD.

DOI: https://doi.org/10.1101/2025.08.28.672891
FEBS Lett. 2025 Sep 29.

Hsp104-Hsp70-Hsp110 chaperones disintegrate kinase aggregates formed upon stress in Saccharomyces cerevisiae.

Pramit Bhattacharjee, Atin K Mandal.

  The cellular protein quality control (PQC) machinery maintains proteostasis. However, knowledge of PQC machinery-mediated handling of stress-induced misfolded proteins is still insufficient. We used the yeast kinase Ste11 to observe its fate upon heat stress or Hsp90 inhibition. We observed that while mild heat stress (37 °C) primarily resulted in proteasomal degradation of Ste11, severe heat stress (42 °C) resulted predominantly in aggregation. Ste11 aggregates sequestered with Hsp42 upon heat stress or Hsp90 inhibition. These aggregates associate with Hsp70 and Hsp104, the yeast disaggregase machinery. Notably, Ste11 aggregates disappear upon recovery from stress. This phenomenon is impaired in the absence of Hsp104 or Sse1, a co-chaperone recruited to the aggregates by Hsp70, suggesting the involvement of Hsp104, Hsp70 and Sse1 in aggregate mobilisation.

Keywords:  disintegration; kinase; molecular chaperones; protein quality control; spatial sequestration; ubiquitin proteasome system

DOI:  https://doi.org/10.1002/1873-3468.70174
Cell Cycle. 2025 Sep 29. 1-3

Rewiring the mTOR, CDH1, APC/C, PFKFB3 axis: a glycolytic pulse to ignite the G0/G1 gateway.

Gaetano Santulli.

DOI: https://doi.org/10.1080/15384101.2025.2567160
Neuropharmacology. 2025 Sep 26. pii: S0028-3908(25)00408-3. [Epub ahead of print]281 110700

AMPK activation mitigates α-synuclein pathology and dopaminergic degeneration in cellular and mouse models of Parkinson's disease.

Yoonha Kim, Jong Sam Lee, Sumin Son, Seobin Park, Hyungkeun Oh, Yoon Kyung Choi, Dong-Eun Kim.

  Parkinson's disease (PD) is characterized by oxidative stress, mitochondrial dysfunction, and pathological accumulation of p-α-Synuclein (p-α-Syn). AMP-activated protein kinase (AMPK) has emerged as a regulator of cellular energy homeostasis, yet its role in PD pathology remains unclear. Here, we examined the effects of AMPK activation in SH-SY5Y neuroblastoma cells and in an MPTP-induced PD mouse model. In both undifferentiated and retinoic acid-differentiated SH-SY5Y cells exposed to 6-hydroxydopamine (6-OHDA), pharmacological AMPK activation with AICAR reduced reactive oxygen species (ROS) production and p-α-Syn aggregation. These effects were associated with enhanced mitophagy, increased lysosomal degradation, and stimulation of mitochondrial biogenesis, collectively restoring mitochondrial integrity and improving dopaminergic features. In vivo, AICAR treatment attenuated nigrostriatal dopaminergic degeneration in MPTP-exposed mice, reduced p-α-Syn accumulation, and preserved tyrosine hydroxylase expression. Moreover, systemic cytokine analysis revealed that AMPK activation suppressed IL-6-mediated inflammation, while modulating IL-1β levels in a context-dependent manner. These results demonstrate that AMPK activation mitigates α-synuclein pathology, preserves mitochondrial function, and protects dopaminergic neurons in both cellular and animal PD models. Our findings support AMPK as a potential therapeutic target for disease modification in PD.

Keywords:  AMP-Activated protein kinase; Mitochondrial homeostasis; Oxidative stress; Parkinson's disease; p-α-Syn

DOI:  https://doi.org/10.1016/j.neuropharm.2025.110700