bims-auttor 2025-07-06 papers

bims-auttor

Biomed News

on Autophagy and mTOR

Issue of 2025–07–06
forty-two papers selected by
Viktor Korolchuk, Newcastle University

Coupling of glucose metabolism with mitophagy via O-GlcNAcylation of PINK1.
SESN2 inhibits tubular exosome secretion and diabetic kidney disease progression by restoring the autophagy‒lysosome pathway.
A bitopic mTORC inhibitor reverses phenotypes in a tuberous sclerosis complex model.
Rapid proteasomal degradation of the stress response protein REDD2 is mediated by the E3 ligase HUWE1.
Mechanisms underlying the interplay between autophagy and the inflammasome in age-related diseases: Implications for exercise immunology.
Chaperone-Mediated Autophagy: A Critical Regulator of Neuroinflammation and Neurodegeneration.
You are what you eat: autophagy guides CD8+ T cell function through metabolism.
Progress on multifunctional transmembrane protein ATG9A.
The N-degron pathway governs autophagy to promote thermotolerance in Arabidopsis.
The lysosomal carrier SLC29A3 supports anti-bacterial signaling and promotes autophagy by activating TRPML1 in mouse dendritic cells.
Lipid metabolites affected by deficient autophagy antagonize the occurrence of autophagy through AMPK signaling in insects.
Neuroprotective effect of Kaempferol through modulation of autophagy.
C9orf72 deficiency impairs the autophagic response to aggregated TDP-25 and exacerbates TDP-25-mediated neurodegeneration in vivo.
Interconnections of insulin/IGF-1 signaling and autophagy abnormalities in Alzheimer's disease.
Time-of-day effect of high-intensity muscle contraction on mTOR signaling and protein synthesis in mice.
Autophagy controls differentiation of Drosophila blood cells by regulating Notch levels in response to nutrient availability.
Evaluating cell cycle- and autophagy-associated cellular accumulation of lipid-based nanoparticles.
Mitophagy mitigates mitochondrial fatty acid β-oxidation deficient cardiomyopathy.
DRAM1 promotes the stability of lysosomal VAMP8 to enhance autolysosome formation and facilitates the extravasation.
Muscle-specific AXIN1 and AXIN2 double knockout does not alter AMPK/mTORC1 signalling or glucose metabolism.
Fisetin Attenuates Mutant SOD1 Aggregation in Amyotrophic Lateral Sclerosis via Nrf2-Mediated Autophagy Activation.
Differential response of neurons to autophagy modulation in Huntington's disease.
More TOR: The expanding role of mTOR in regulating immune responses.
Stabilisation of PRCP by deubiquitinase-targeting chimera (DUBTAC) to replenish autophagy for ameliorating pathological cardiac hypertrophy.
Neuronal glycolysis meets mitophagy to govern organismal wellbeing.
ATF7-PINK1 Axis Governs Mitophagy and Intestinal Inflammation in Ulcerative Colitis.
RAB7 protects against ischemic heart failure via promoting non-canonical TUFM mitophagy pathway.
WSTF nuclear autophagy regulates chronic but not acute inflammation.
The autophagy-ferroptosis axis as a critical factor in diabetic-associated cognitive dysfunction.
Targeted degradation of α-synuclein by arginine-based PROTACs.
Powering Up the Brain: Intercellular Mitochondrial Quality Control and Its Implication in Stroke.
L-NAME improves the morphology and necrosis of skeletal muscle by activating PINK1-PARKIN mediated mitophagy in mdx mice.
TM9SF3 is a Golgi-resident ATG8-binding protein essential for Golgi-selective autophagy.
SPNS1 variants cause multi-organ disease and implicate lysophospholipid transport as critical for mTOR-regulated lipid homeostasis.
Circadian gene BMAL1 ameliorates renal ischaemia-reperfusion injury in diabetic mice by enhancing mitophagy via the HIF-1/BNIP3 pathway.
SRT2104 enhances dendritic outgrowth and spine formation through Sirtuin 1-mediated mTORC1 signaling.
Targeting autophagy in doxorubicin-induced cardiotoxicity: A comprehensive review of scientific landscapes and therapeutic innovations.
A novel isoquinoline mitophagy inducer ameliorates paclitaxel-induced peripheral neuropathy in Drosophila and mouse models.
Study on the regulation of gastric cancer cell apoptosis by LACTB through mitochondrial autophagy pathway.
Genetically encoded and modular subcellular organelle probes reveal dysfunction in lysosomes and mitochondria driven by PRKN knockout.
Imbalanced TGFβ signalling and autophagy drive erythroid priming of hematopoietic stem cells in β-thalassemia.
The Multifaceted Influence of Beta-Hydroxybutyrate on Autophagy, Mitochondrial Metabolism, and Epigenetic Regulation.

Int J Biol Sci. 2025 ;21(9): 4252-4269

Coupling of glucose metabolism with mitophagy via O-GlcNAcylation of PINK1.

Zhiwei Xu, Xiangzheng Gao, Dade Rong, Jingyao Wang, Liangliang Gao, Mingzhu Tang, Yiguan Chen, Yichi Zhang, Liming Xie, Liming Wang, Guang Lu, Jia-Hong Lu, Wei Liu, Han-Ming Shen.

  Mitophagy is a selective form of autophagy for the clearance of damaged and dysfunctional mitochondria via the autophagy-lysosome pathway. As mitochondria are the most important metabolic organelles, the process of mitophagy is tightly regulated by glucose metabolism. At present, it is known that glucose is required for the mitophagy process, while the underlying mechanisms remain to be further elucidated. In this study, we establish a novel regulatory role of glucose metabolism in mitophagy via protein O-GlcNAcylation. First, we found that acute mitochondrial damage enhanced glucose uptake and promoted protein O-GlcNAcylation. Second, we provided evidence that protein O-GlcNAcylation promotes PINK1-Parkin-dependent mitophagy. Next, we attempted to illustrate the molecular mechanisms underlying the regulation of O-GlcNAcylation in mitophagy by focusing on PTEN-induced kinase 1 (PINK1). One important observation is that PINK1 is O-GlcNAcylated upon acute mitochondrial damage, and suppression of O-GlcNAcylation impairs PINK1 protein stability and its phosphorylated ubiquitin, leading to impaired mitophagy. More importantly, we found that glucose metabolism promotes mitophagy via regulating O-GlcNAcylation. Taken together, this study demonstrates a novel regulatory mechanism connecting glucose metabolism with mitophagy via O-GlcNAcylation of PINK1. Therefore, targeting the O-GlcNAcylation may provide new strategies for the modulation of mitophagy and mitophagy-related human diseases.

Keywords:  HBP; O-GlcNAcylation; PINK1; glucose metabolism; mitophagy

DOI:  https://doi.org/10.7150/ijbs.112672
Int J Biol Sci. 2025 ;21(9): 4215-4230

SESN2 inhibits tubular exosome secretion and diabetic kidney disease progression by restoring the autophagy‒lysosome pathway.

Zongji Zheng, Jiaqi Chen, Xiaoquan Xue, Xiaoqin Ma, Shuting Zhang, Ming Wang, Yaoming Xue, Yijie Jia.

  During diabetic kidney disease (DKD), tubulointerstitial fibrosis persists, although several methods have been applied to reduce albuminuria levels. In this research, we found that bovine serum albumin (BSA)-induced renal tubular cell injury could also spread to normal tubular cells through exosomes, which may explain why tubulointerstitial fibrosis persists. Our previous studies revealed that SESN2 overexpression alleviates tubular dysfunction. In this study, we showed that SESN2 overexpression in donor HK2 cells interrupted this "doom loop" and confirmed that SESN2 may mediate this process by reducing exosome secretion. By using RNA-seq and IP-MS, we found that SESN2 could inhibit BSA-induced Rab-7a ubiquitination, thus promoting autophagosome and lysosome fusion and accelerating MVB degradation. We also showed that SESN2 promotes the nuclear translocation of TFEB through the mTOR pathway, thus further alleviating lysosomal function and promoting MVB degradation. We also found that SESN2 not only slowed DKD progression but also promoted renal tubular cell secretion of protective exosomes, which also slowed DKD progression. In conclusion, SESN2 can interrupt the progression of albuminuria-induced tubular injury by inhibiting exosome secretion and promoting MVB degradation. Thus, SESN2 may be a new therapeutic target for DKD treatment.

Keywords:  Diabetic kidney disease; SESN2; autophagy; exosomes; lysosome

DOI:  https://doi.org/10.7150/ijbs.109799
Sci Rep. 2025 Jul 01. 15(1): 20367

A bitopic mTORC inhibitor reverses phenotypes in a tuberous sclerosis complex model.

Sulagna Mukherjee, Matthew J Wolan, Mary K Scott, Victoria A Riley, Aidan M Sokolov, David M Feliciano.

  Neural stem cells (NSCs) of the ventricular-subventricular zone (V-SVZ) generate diverse cell types including striatal glia during the neonatal period. NSC progeny uncouple stem cell-related mRNA transcripts from being translated during differentiation. We previously demonstrated that Tsc2 inactivation, which occurs in the neurodevelopmental disorder Tuberous Sclerosis Complex (TSC), prevents this from happening. Loss of Tsc2 causes hyperactivation of the protein kinase mechanistic target of rapamycin complex 1 (mTORC1), altered translation, retention of stemness in striatal glia, and the production of misplaced cytomegalic neurons having hypertrophic dendrite arbors. These phenotypes model characteristics of TSC hamartomas called subependymal giant cell astrocytomas (SEGAs). mTORC1 inhibitors called rapamycin analogs (rapalogs) are currently used to treat TSC and to assess the role of mTORC1 in regulating TSC-related phenotypes. Rapalogs are useful for treating SEGAs. However, they require lifelong application, have untoward side effects, and resistance may occur. They also incompletely inhibit mTORC1 and have limited efficacy. Rapalink-1 is a bitopic inhibitor that links rapamycin to a second-generation mTOR ATP competitive inhibitor, MLN0128. Here we explored the effect of Rapalink-1 on a TSC hamartoma model. The model is created by neonatal electroporation of mice having conditional Tsc2 genes. Prolonged Rapalink-1 treatment could be achieved with 1.5 or 3.0 mg/Kg injected intraperitoneally every five days. Rapalink-1 inhibited the mTORC1 pathway, decreased cell size, reduced neuron dendrite arbors, and reduced hamartoma size. In conclusion, these results demonstrate that cellular phenotypes in a TSC SEGA model are reversed by Rapalink-1 which may be useful to resolve TSC brain hamartomas.

Keywords:  MTORC1; Neurogenesis; Rapalink-1; SEGA; Subependymal giant cell Astrocytoma; Subependymal nodule; TSC; Tsc2; Tuberous sclerosis complex

DOI:  https://doi.org/10.1038/s41598-025-08345-z
Biochem Biophys Res Commun. 2025 Jun 28. pii: S0006-291X(25)00985-4. [Epub ahead of print]777 152270

Rapid proteasomal degradation of the stress response protein REDD2 is mediated by the E3 ligase HUWE1.

Ashley M VanCleave, Siddharth Sunilkumar, Christopher M McCurry, Allyson L Toro, Scot R Kimball, Michael D Dennis.

  The stress response proteins regulated in development and DNA damage (REDD)1 and REDD2 act as negative regulators of mechanistic target of rapamycin complex 1 (mTORC1). Prior studies support that REDD1 is rapidly degraded via both chaperone-mediated autophagy (CMA) and the ubiquitin proteasome system (UPS). Compared to REDD1, relatively little is known regarding the regulation of REDD2. The objective here was to investigate the molecular mechanisms that control the cellular abundance of REDD2. Genetic and pharmacologic interventions were used to manipulate protein synthesis and proteolysis. We found that both REDD1 and REDD2 were rapidly degraded with half-lives of <20 min. Interestingly, REDD2 expression reduced the rate of REDD1 degradation, suggesting that the molecular mechanism through which they are degraded overlaps. However, in contrast with REDD1, CMA activation did not promote REDD2 degradation, despite the conservation of a putative KFERQ-like motif sequence in REDD2. Instead, we provide evidence that the rapid degradation of REDD2 was mediated by the UPS, the E3 ligase HUWE1, and K119/K120 of REDD2. The findings support that the cellular abundance of both REDD1 and REDD2 are controlled at the level of protein stability.

Keywords:  DDIT4; DDIT4L; Proteasome; Proteolysis

DOI:  https://doi.org/10.1016/j.bbrc.2025.152270
Ageing Res Rev. 2025 Jul 01. pii: S1568-1637(25)00167-9. [Epub ahead of print]110 102821

Mechanisms underlying the interplay between autophagy and the inflammasome in age-related diseases: Implications for exercise immunology.

Eliézer Lucas Pires Ramos, Ivo Vieira de Sousa Neto, Ana Paula Pinto, Dennys Esper Cintra, Eduardo Rochete Ropelle, José Rodrigo Pauli, Ellen Cristini de Freitas, Tiago Wilson Patriarca Mineo, Adelino Sanchez Ramos da Silva.

  Aging is a multifactorial process characterized by cellular dysfunction and increased susceptibility to age-related diseases. The interplay between autophagy and inflammasome has emerged as a critical factor influencing the aging process. Autophagy, which is responsible for degrading damaged cellular components, declines with age, leading to the accumulation of dysfunctional organelles and misfolded proteins. At the same time, the inflammasome, a key mediator of inflammatory responses, becomes hyperactivated in aging tissues, contributing to chronic low-grade inflammation, commonly referred to as "inflammaging." This dysregulated interaction between autophagy and inflammasome activation plays a significant role in the development and progression of several age-related diseases. In cancer, reduced autophagic activity promotes tumorigenesis, while increased inflammasome activation establishes an inflammatory microenvironment that supports cancer progression. In arthritis, including both osteoarthritis and rheumatoid arthritis, impaired autophagy and inflammasome-driven inflammation contribute to joint degeneration. Neurodegenerative diseases such as Alzheimer's and Parkinson's are marked by defective autophagic clearance of protein aggregates and heightened inflammasome activation, leading to neuronal loss. Cardiovascular diseases, including atherosclerosis and myocardial dysfunction, also involve compromised autophagy and persistent inflammation, which accelerate vascular aging and cardiac damage. Exercise has emerged as a promising intervention for modulating the autophagy NLRP3 inflammasome axis. Moderate-intensity physical activity enhances autophagic flux by upregulating proteins such as BECLIN1, LC3, and ATG12, promoting mitochondrial quality control and reducing protein aggregates. This effect leads to decreased ROS production and suppression of NLRP3 inflammasome activation, lowering IL-1β and IL-18 levels, thereby helping to restore cellular homeostasis and reduce age-associated inflammation. Irisin also showed the importance of inhibiting inflammasome activation by promoting mitophagy after exercise. In both animal and human experiments, exercise has been shown to reduce systemic inflammation, improve cognitive function, attenuate joint degradation, and decrease cardiovascular risk, largely through these molecular pathways. This review explores recent findings that underscore the beneficial role of exercise in mitigating the effects of aging and preventing age-related diseases by regulating autophagy and inflammasome activities.

Keywords:  Age-related diseases; Aging; Autophagy; Exercise; Inflammasome

DOI:  https://doi.org/10.1016/j.arr.2025.102821
Adv Biol (Weinh). 2025 Jul 02. e00191

Chaperone-Mediated Autophagy: A Critical Regulator of Neuroinflammation and Neurodegeneration.

Ying-Ying Han, Xin-Yue Huang, Ying Su, Jing-Jing Ma, Jin Wu.

  Neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD), are characterized by hallmark pathological features such as the accumulation of misfolded proteins and neuroinflammation. Chaperone-mediated autophagy (CMA), a selective lysosomal pathway, facilitates the degradation of proteins containing KFERQ-like motifs via the receptor lysosome-associated membrane protein type 2A (LAMP2A). In the recent review, the pivotal role of CMA in regulating proteostasis and modulating inflammatory responses is highlighted. This commentary explores the multifaceted roles of CMA in neurodegenerative disease progression, emphasizing its involvement in age-related decline, feedback loops between CMA dysregulation and neurodegeneration, and potential as a therapeutic target. Emerging CMA activators and the challenges of modulating CMA for clinical use are also discussed.

Keywords:  aging; chaperone‐mediated autophagy; neurodegenerative diseases; neuroinflammation; therapeutic potential

DOI:  https://doi.org/10.1002/adbi.202500191
Immunometabolism (Cobham). 2025 Jul;7(3): e00064

You are what you eat: autophagy guides CD8+ T cell function through metabolism.

Caio Loureiro Salgado, Henrique Borges da Silva.

  The differentiation of naive CD8+ T cells into effector or memory populations requires dynamic remodeling of cellular metabolism and proteome composition. In a recent study published in Nature Immunology, Sinclair et al offer critical insights into the role of autophagy, particularly mitophagy, in regulating these processes during CD8+ T cell differentiation. Autophagy, a conserved catabolic mechanism, is traditionally associated with cellular homeostasis and survival during nutrient deprivation. In contrast, Sinclair et al reveal that, in the immune system, autophagy is not simply a survival mechanism but a fine-tuned regulator of CD8+ T cell metabolism and function, fine-tuning CD8+ T cell effector vs quiescence choices.

Keywords:  CD8+ T cells; autophagy; cytotoxic T cell; mitophagy; naive T cells

DOI:  https://doi.org/10.1097/IN9.0000000000000064
Cell Commun Signal. 2025 Jul 01. 23(1): 314

Progress on multifunctional transmembrane protein ATG9A.

Xi Lin, Lin Liang, Shan Liao, Yanling Li, Yanhong Zhou.

  ATG9A is the only transmembrane protein among the components required for autophagosome formation and participates in multiple cellular biological processes. ATG9A undergoes intracellular transport via microtubules and actin. As a lipid scramblase, ATG9A facilitates the random movement of lipid molecules between the inner and outer leaflets of lipid bilayers. Additionally, it can influence the homeostasis of the plasma membrane and membranous organelles. In autophagy, ATG9A is recruited to autophagic initiation sites to initiate cellular autophagy and subsequently participates in the process by promoting lipid transfer. Moreover, ATG9A also plays roles in maintaining neuronal homeostasis and is involved in embryonic development, infection, and immune responses. In this review, we comprehensively and systematically summarize the roles and mechanisms of ATG9A, aiming to provide a new perspective for understanding its functions.

Keywords:  ATG9A; Autophagosome formation; Autophagy; Disease progression; Regulatory factors

DOI:  https://doi.org/10.1186/s12964-025-02317-6
Nat Commun. 2025 Jul 01. 16(1): 5889

The N-degron pathway governs autophagy to promote thermotolerance in Arabidopsis.

Seu Ha Kim, Jun Seok Park, Myoung-Hoon Lee, Joongyu Seo, Jaekwan Kim, Woo Seok Yang, Jihye Park, Kwangmin Yoo, Jungmin Choi, Jong-Bok Seo, Hyun Kyu Song, Ohkmae K Park.

Autophagy is a vital process that enables plants to adapt to various environmental changes. During heat stress (HS), misfolded and denatured proteins accumulate in cells, necessitating autophagy for their removal. Here, we show that a core autophagy component ATG8a is targeted for degradation via the Arg/N-degron pathway. ATG8a is expressed as two alternatively spliced transcripts encoding ATG8a isoforms, namely ATG8a(S) and ATG8a(L), with distinct N-termini. While ATG8a(S) remains stable, ATG8a(L) is N-terminally processed to expose the Arg/N-degron, leading to its degradation. Ubiquitin protein ligase E3 component N-recognin 7 (UBR7), identified as an N-recognin, is responsible for ubiquitination and proteasomal degradation of ATG8a(L). Notably, ATG8a(S) and ATG8a(L) show dynamic expression patterns, fluctuating ATG8a levels during the HS and recovery periods. Our findings highlight the crucial role of ATG8a turnover in conferring thermotolerance, which is governed by Arg/N-degron-mediated regulation. Understanding the molecular basis of ATG8a stability will provide valuable insights into plant resilience to HS under changing climatic conditions.

DOI: https://doi.org/10.1038/s41467-025-61191-5
bioRxiv. 2025 Jun 17. pii: 2025.06.11.659112. [Epub ahead of print]

The lysosomal carrier SLC29A3 supports anti-bacterial signaling and promotes autophagy by activating TRPML1 in mouse dendritic cells.

Daniel J Netting, Cynthia López-Haber, Zachary Hutchins, José A Martina, Rosa Puertolano, Adriana R Mantegazza.

The solute carrier (SLC)29A3 exports nucleosides from lysosomes into the cytosol, maintaining solute homeostasis and providing metabolic intermediates for cellular processes. Loss-of-function mutations in SLC29A3 cause H syndrome, characterized by hyperinflammation and immunodeficiency. While dysfunctions in various cell types contribute to H syndrome and to SLC29A3 deficiency in mice, the mechanisms driving hyperinflammation and immunodeficiency are incompletely understood. Remarkably, the possible role played by dendritic cells (DCs), the most efficient antigen presenting cells and the main link between innate and adaptive immune responses, remains unknown. We show that, in murine DCs, SLC29A3 is recruited to phagosomes after bacterial capture, maintains phagosomal pH homeostasis, and ensures optimal phagosomal signaling to the production of IL-6, IL-12, and CCL-22. In addition, SLC29A3 promotes Ag presentation on MHC-II molecules to initiate adaptive immune responses. Notably, SLC29A3 supports the activity of the lysosomal calcium channel TRPML1, promoting transcription factor TFEB nuclear translocation and inducing autophagy, a major anti-inflammatory mechanism. Overexpression of human SLC29A3, but not the transport mutant G437R, in SLC29A3-deficient murine DCs restores cytokine production in response to bacteria phagocytosis, suggesting that SLC29A3 transport activity is required to drive anti-bacterial phagosomal signaling. Our data indicate that SLC29A3 plays a dual role in supporting immune function in DCs by promoting effective anti-microbial signaling and Ag presentation and inducing autophagy to control inflammation. Our findings also uncover a novel TRPML1-dependent mechanism by which SLC29A3 activates TFEB and suggest that defects in phagosomal signaling, TFEB activation and autophagy may contribute to immunodeficiency and hyperinflammation in SLC29A3 disorders.

DOI: https://doi.org/10.1101/2025.06.11.659112
BMC Biol. 2025 Jul 01. 23(1): 193

Lipid metabolites affected by deficient autophagy antagonize the occurrence of autophagy through AMPK signaling in insects.

Ling Tian, Qien Zhong, Yubei Yang, Wenmei Wu, Yang Xiao, Sheng Li, Kang Li.

   BACKGROUND: Autophagy is essential for removing damaged organelles and intracellular materials as well as invasive pathogens. The autophagic degradation of intracellular lipids plays a key role in maintaining cellular homeostasis. However, the mechanism of lipid metabolism regulated by autophagy, as well as whether or how lipid metabolites affect autophagy, remain unclear.
RESULTS: RNAi of the key autophagy-related (Atg) genes, notably Atg1 and Atg8, suppressed autophagy, while overexpression of these Atg genes facilitated lipid degradation in both Bombyx mori and Drosophila melanogaster. In addition, disrupting autophagosome-lysosome fusion by chloroquine treatment inhibited lipid degradation during both metamorphosis and starvation. LC-MS/MS analysis showed that overexpression of DmAtg1:DmAtg13 mainly degraded glycerolipids, while DmAtg1 mutation predominantly accumulated glycerophospholipids. Notably, the significantly upregulated GPs following autophagy blockage, including C24H50NO7P (LPE, 19:0), C25H52NO7P (LPC, 0:0/17:0), C27H56NO7P (LPC, 0:0/19:0), and C28H58NO7P (LPC, 20:0/0:0), exerted a suppressive effect on autophagy occurrence mainly through the downregulation of AMPK signaling.
CONCLUSIONS: Autophagosome and autolysosome formations are both critical for lipid degradation. Conversely, the metabolites accumulated due to dysfunctional autophagy inhibit autophagy occurrence by downregulation of AMPK signaling, thereby forming a regulatory loop in insects. Collectively, our results provide valuable insights into applications for beneficial insects and pest management, while also present potential chemicals applied on human diseases related to autophagy or lipid metabolism.

Keywords:   Bombyx mori ; Drosophila melanogaster ; Autophagy; Lipid degradation; Metabolites

DOI:  https://doi.org/10.1186/s12915-025-02274-z
Nutr Neurosci. 2025 Jun 30. 1-17

Neuroprotective effect of Kaempferol through modulation of autophagy.

Razieh Moalefshahri, Seyed Isaac Hashemy, Hossein Hosseini, Amirhossein Sahebkar.

  Objective: Autophagy is a critical cellular mechanism that ensures the breakdown of damaged or unnecessary components. This process helps ensure cellular health by maintaining cellular balance, protecting cells from stress, and providing an alternative energy source during metabolic stress. Disruptions in autophagy have been linked to neurological disorders.Method: In this review, the neuroprotective effects of Kaempferol through autophagy modulation are elaborated. Methods: An electronic search in scientific databases was performed to find relevant studies exploring the neuroprotective effects of kaempferol mediated via modulation of autophagy.Results: Kaempferol, a natural flavonoid found in fruits, vegetables, and plant-based products like tea, has been shown to demonstrate a variety of health-promoting properties, including antimicrobial, antioxidant, and antiinflammatory effects. This review summarizes the current understanding of how Kaempferol modulates autophagy and discusses its potential impact on various neurological disorders, including Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, ischemic stroke, and depression. Studies increasingly indicate that Kaempferol could be a vital factor in maintaining neural health by influencing autophagy mechanisms.Conclusion: Numerous studies have established Kaempferol's neuroprotective potential through autophagy regulation, which suggests opprotunities for potential therapeutic applications.

Keywords:  Kaempferol; Neurodegenerative disease; autophagy; molecular mechanisms

DOI:  https://doi.org/10.1080/1028415X.2025.2524702
Acta Neuropathol Commun. 2025 06 28. 13(1): 136

C9orf72 deficiency impairs the autophagic response to aggregated TDP-25 and exacerbates TDP-25-mediated neurodegeneration in vivo.

Lilian Tsai-Wei Lin, Marc Shenouda, Philip McGoldrick, Agnes Lau, Janice Robertson.

  Cytoplasmic aggregates of the predominantly nuclear TAR DNA-binding protein 43 (TDP-43) are a pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) cases caused by G4C2 hexanucleotide repeat expansions in C9orf72 (C9-ALS/FTD). While these repeat expansions are associated with both gain- and loss-of-function mechanisms, the contribution of C9orf72 loss of function to disease pathogenesis remains unclear. C9orf72 has been shown to regulate autophagy, and its deficiency has been shown to exacerbate phenotypes in gain-of-function G4C2 models, implicating impaired autophagic clearance in disease pathogenesis. Here, we directly test whether C9orf72 deficiency exacerbates TDP-43 pathology and neurodegeneration in vivo. Using AAV9-vectors to drive neuron-specific expression of pathologically relevant C-terminal species of TDP-43, TDP-35 and TDP-25, we established models of TDP-43 pathology that recapitulate key disease features, including cytoplasmic aggregates, motor and cognitive decline, and neuronal loss. TDP-25 expression in particular produced robust, abnormally phosphorylated, ubiquitinated and p62-labelled cytoplasmic aggregates, modelling TDP-43 pathology in disease. Loss of C9orf72 in TDP-25-expressing mice accelerated the onset of motor deficits, increased neurodegeneration, and impaired the autophagic response to TDP-25 expression. These findings reveal that C9orf72 deficiency disrupts autophagy and exacerbates TDP-25-mediated toxicity in vivo, supporting a contributory role for C9orf72 loss-of-function in driving neurodegeneration in C9-ALS/FTD.

Keywords:  Amyotrophic lateral sclerosis; Autophagy; C9orf72; Frontotemporal dementia; Neurodegeneration; Protein aggregation; TAR DNA-binding protein 43

DOI:  https://doi.org/10.1186/s40478-025-02061-5
Alzheimers Dement. 2025 Jul;21(7): e70099

Interconnections of insulin/IGF-1 signaling and autophagy abnormalities in Alzheimer's disease.

Wang Liao, Jinfeng Xuan, Woo-In Ryu, Mariana K Bormann, Yoon Lee, Haley Dion, Elizabeth Evangelista, Ruiyi Li, Lucas Trambaiolli, Jun Liu, Arthur J Siegel, Brent P Forester, Bruce M Cohen, Kai-Christian Sonntag.

   INTRODUCTION: Impaired insulin (INS) and insulin-like growth factor 1 (IGF-1) signaling are features of both brain aging and late-onset Alzheimer's disease (LOAD). However, their exact underlying mechanisms and cause-and-effect linkages, including the downstream regulation of endocytosis and autophagy, are still not well understood.
METHODS: We investigated INS/IGF-1 signaling and its connection with endocytic and autophagic processes in fibroblasts from LOAD patients and healthy young or old control individuals.
RESULTS: Compared to control old-age cells, protein levels in the INS/IGF-1 signaling cascade were elevated in LOAD cells, but activation of AKT was reduced. The activation of the INS/IGF-1/AKT/FOXO1 or mTOR axes and associated endo- and autophagic processes were largely intact in old-age but disrupted in LOAD fibroblasts.
DISCUSSION: Our results suggest that reduced AKT activation, in the context of altered INS/IGF-1 signaling, and connected alterations of endocytosis and autophagy are features of LOAD pathology but not aging, per se.
HIGHLIGHTS: Levels of insulin/insulin-like growth factor 1 (INS/IGF-1) factors in late-onset Alzheimer's disease (LOAD) cells are higher than in healthy old controls. AKT activation by INS/IGF-1 signaling is specifically diminished in LOAD cells. INS/IGF-1/AKT/forkhead box protein O1/mechanistic target of rapamycin kinase related endocytosis/autophagy are disrupted in LOAD cells. Intracellular endocytic/autophagic structure distribution is altered in LOAD cells. INS/IGF-1 reverses endocytic/autophagic processes in LOAD versus old control cells.

Keywords:  AKT; autophagy; endocytosis; forkhead box protein O1; insulin; insulin‐like growth factor 1; late‐onset Alzheimer's disease; mechanistic target of rapamycin kinase; skin fibroblasts; starvation

DOI:  https://doi.org/10.1002/alz.70099
Sci Rep. 2025 Jul 03. 15(1): 23702

Time-of-day effect of high-intensity muscle contraction on mTOR signaling and protein synthesis in mice.

Taiga Mishima, Yosuke Takenaka, Akiko Hashimoto-Hachiya, Yukiko Tanigawa, Natsumi Suzuki, Katsutaka Oishi, Riki Ogasawara.

  Resistance exercise promotes muscle protein synthesis by activating mechanistic target of rapamycin (mTOR). The magnitude of muscle hypertrophy might differ depending on the timing of resistance exercise, but the molecular mechanism remains unclear. We aimed to define whether the time of day when muscles are contracted affects mTOR signaling and muscle protein synthesis. Adult male C57BL/6 J mice were housed under a 12 h/12 h light/dark cycle, and right gastrocnemius muscles were contracted using percutaneous electrical stimulation at 1, 7, 13, or 19 h after lights on. Contractions induced more phosphorylation of downstream targets of mTOR complex 1 (mTORC1) signaling such as S6K1 and rpS6 during the light (sleep), than the dark (active) phase, while expression of the negative regulator of mTORC1 that regulates development and DNA damage responses 1 (REDD1) was anti-phasic. Basal muscle protein synthesis in the sedentary leg was higher during the light, compared to the dark phase, while contraction-induced synthesis did not significantly vary throughout the day. Muscle hypertrophy is controlled by the balance between protein synthesis and degradation. Therefore, further studies are needed to elucidate the time-of-day effects of resistance exercise on muscle hypertrophy.

Keywords:  Circadian rhythm; Muscle contraction; Protein synthesis; mTOR

DOI:  https://doi.org/10.1038/s41598-025-06709-z
Nat Commun. 2025 Jul 01. 16(1): 5858

Autophagy controls differentiation of Drosophila blood cells by regulating Notch levels in response to nutrient availability.

Maximiliano J Katz, Felipe Rodríguez, Fermín Evangelisti, Agustina G Borrat, Sebastián Perez-Pandolfo, Tomás Peters, Natalia Sommario, Graciela L Boccaccio, Mariana Melani, Pablo Wappner.

Drosophila larval hematopoiesis takes place at the lymph gland, where blood cell progenitors differentiate into two possible cell types: Plasmatocytes, analogous to mammalian macrophages, or crystal cells that share features with mammalian megakaryocytes; a third cell type, the lamellocytes, develop only upon specific immune challenges. Here we show that autophagy inhibition in blood cell progenitors results in augmented crystal cell differentiation due to Notch accumulation. Notch activation during hematopoiesis depends on the endocytic pathway, which crosstalks with autophagy: While Notch activation depends on endocytosis and endosomal maturation, Notch lysosomal degradation requires autophagy. TOR signaling inhibits autophagosome biogenesis that in turn prevents the formation of Notch-containing amphisomes, which are necessary for Notch lysosomal destruction. Reduction of Notch lysosomal degradation shifts the balance towards Notch activation at endosomal membranes, thereby enhancing differentiation of crystal cells. Our work therefore defines a mechanism of regulation of immune cell differentiation in response to the nutritional status of the organism.

DOI: https://doi.org/10.1038/s41467-025-58389-y
Nat Commun. 2025 Jul 01. 16(1): 5964

Evaluating cell cycle- and autophagy-associated cellular accumulation of lipid-based nanoparticles.

Yisha Wang, Gan Luo, Haiyang Wang, Yue Zheng, Xiao Xu, Wenbin Zhou, Junrong Lin, Baocheng Chen, Yangfu Guo, Yifeng Jin, Meihua Sui.

Little is known about how cell cycle and autophagy, two fundamental life processes, affect cellular accumulation of nanoparticles. What's even more tough is that several long-lasting methodological barriers have hindered the progress of related research. Here we firstly show the construction of a multi-functional platform for overcoming existing methodological obstacles through integrating multiple technical approaches including autophagy-related gene 7 knockout to specifically block autophagy, PIP-FUCCI transfection and mitotic shake-off to thoroughly separate cell cycle phases, and 3D reconstruction to stereoscopically evaluate cellular accumulation of nanoparticles. Further application of this platform reveals that after a 2-hour incubation of lipid-based nanoparticles, G2-phase and M-phase cells, two populations previously muddled up together as G2/M-phase cells, respectively exhibited the maximum and minimum nanoparticle accumulation. Meanwhile, our data preliminarily suggest enhanced nanoparticle accumulation by autophagy blockade. Besides cell cycle and autophagy, comprehensive statistical analyses reveal a close association between cellular accumulation of nanoparticles and nanoparticle type. This study not only provides a valuable technical strategy, but uncovers important characteristics of cellular accumulation of nanoparticles, offering new insights for optimization and application of nanomedicines.

DOI: https://doi.org/10.1038/s41467-025-60962-4
Nat Commun. 2025 Jul 01. 16(1): 5465

Mitophagy mitigates mitochondrial fatty acid β-oxidation deficient cardiomyopathy.

Nuo Sun, Hayley Barta, Samhita Chaudhuri, Kangxuan Chen, Jiacheng Jin, Hongke Luo, Mingchong Yang, Judith Krigman, Ruohan Zhang, Shridhar Sanghvi, Shiori Sekine, Hannah Sanders, Dominic Kolonay, Mudra Patel, Kedryn Baskin, Harpreet Singh, Pengyi Zhang, Gang Xin, Toren Finkel.

The healthy heart relies on mitochondrial fatty acid β-oxidation (FAO) to sustain its high energy demands. FAO deficiencies can cause muscle weakness, cardiomyopathy, and, in severe cases, neonatal/infantile mortality. Although FAO deficits are thought to induce mitochondrial stress and activate mitophagy, a quality control mechanism that eliminates damaged mitochondria, the mechanistic link in the heart remains unclear. Here we show that mitophagy is unexpectedly suppressed in FAO-deficient hearts despite pronounced mitochondrial stress, using a cardiomyocyte-specific carnitine palmitoyltransferase 2 (CPT2) knockout model. Multi-omics profiling reveals impaired PINK1/Parkin signaling and dysregulation of PARL, a mitochondrial protease essential for PINK1 processing. Strikingly, deletion of USP30, a mitochondrial deubiquitinase that antagonizes PINK1/Parkin function, restores mitophagy, improves cardiac function, and significantly extends survival in FAO-deficient animals. These findings redefine the mitophagy response in FAO-deficient hearts and establish USP30 as a promising therapeutic target for metabolic cardiomyopathies and broader heart failure characterized by impaired FAO.

DOI: https://doi.org/10.1038/s41467-025-60670-z
Nat Commun. 2025 Jul 01. 16(1): 5826

DRAM1 promotes the stability of lysosomal VAMP8 to enhance autolysosome formation and facilitates the extravasation.

Rui Zhang, Xin Zhang, Hua Bai, Qiuyu Cheng, Xia Yao, Shi Li, Vincenzo Torraca, Chaojun Yan, Xueying Dong, Siyi Miao, Xueyuan Hu, Yeping Yu, Yueyan Wu, Hongfei Tan, Xin Chen, Shicheng Liu, Hao Lyu, Shuai Xiao, Dong Guo, Qi Zhang, Xing-Zhen Chen, Zhiyin Song, Cefan Zhou, Jingfeng Tang.

Autophagy classically functions to protect cells and organisms during stressful conditions by catabolizing intracellular components to maintain energy homeostasis. Lysosome-autophagosome fusion is a critical step in emptying degraded unwanted contents. However, the mechanism of autophagosome fusion with lysosomes is still not fully understood. Here, we report that DNA Damage-Regulated Autophagy Modulator 1 (DRAM1) interacts with Vesicle Associated Membrane Protein 8 (VAMP8) to mediate the fusion of autophagosomes with lysosomes. This DRAM1-VAMP8 interaction is enhanced upon stimulation of autophagy. However, DRAM1 preferentially mediates the fusion between autophagosomes and lysosomes by enhancing the assembly of the STX17-SNAP29-VAMP8 complex. Moreover, we reveal that DRAM1 specifically promotes the stability of lysosomal VAMP8 via inhibiting VAMP8 degradation by CHIP mediating ubiquitination. We also identify that DRAM1 inhibits the ubiquitination of VAMP8 at Lys 68,72, and 75 via competitively binding with CHIP. Furthermore, we demonstrate that DRAM1 promotes the extravasation of Hepatocellular Carcinoma (HCC) cells, and this process relies on enhanced autophagosome degradation. Our study reveals a mechanism for regulating autolysosome formation by DRAM1-VAMP8 association and suggests a potential strategy to inhibit the extravasation of HCC.

DOI: https://doi.org/10.1038/s41467-025-60887-y
J Physiol. 2025 Jun 30.

Muscle-specific AXIN1 and AXIN2 double knockout does not alter AMPK/mTORC1 signalling or glucose metabolism.

Kaspar W Persson, Roberto Meneses-Valdés, Nicoline R Andersen, Frederik S Pedersen, Samantha Gallero, Sofie A Hesselager, Carlos Henriquez-Olguin, Thomas E Jensen.

  AMP-activated protein kinase (AMPK) and mechanistic target of rapamycin complex 1 (mTORC1) are crucial kinase signalling hubs that regulate the balance between catabolism and anabolism in skeletal muscle. The scaffold protein AXIN1 has been proposed to regulate the switch between these pathways and be required for GLUT4 translocation in skeletal muscle and adipocyte cell lines. Muscle-specific AXIN1 knockout (KO) mice exhibit no discernable phenotype, possibly due to compensation by AXIN2 upon AXIN1 loss. Thus we generated and characterized muscle-specific inducible AXIN1 and AXIN2 double knockout (dKO) mice. Surprisingly AXIN1/2 dKO mice displayed normal AMPK and mTORC1 signalling and glucose uptake in response to 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), insulin and in situ muscle contraction. These findings suggest that AXIN proteins are not essential for the regulation of AMPK and mTORC1 signalling or glucose uptake in skeletal muscle. This study challenges the previously indicated critical roles of AXIN1 in exercise-stimulated AMPK activation and GLUT4-mediated glucose uptake in skeletal muscle. KEY POINTS: Phenotyping of tamoxifen-inducible muscle-specific AXIN1/2 double knockout (dKO) mice. We find no evidence for AXIN-dependent AMPK or mTORC1 regulation in skeletal muscle by insulin, AMPK activation or contraction. Glucose uptake regulation by insulin and AMPK activation is normal in AXIN1/2 dKO mice.

Keywords:  AMPK; exercise; glucose transport; mTOR; skeletal muscle

DOI:  https://doi.org/10.1113/JP288854
J Mol Neurosci. 2025 Jun 28. 75(3): 84

Fisetin Attenuates Mutant SOD1 Aggregation in Amyotrophic Lateral Sclerosis via Nrf2-Mediated Autophagy Activation.

Tianhang Wang, Ying Wang, Yueqing Yang, Shuyu Wang, Xudong Wang, Honglin Feng.

  Dysregulated autophagy and copper/zinc superoxide dismutase (SOD1) protein aggregation play a crucial role in amyotrophic lateral sclerosis (ALS). Here, we used stably transfected NSC34 motor neuron-like cells: (1) SOD1G93A mutants (G93A), (2) wild-type SOD1 (WT) controls, and (3) empty vector (EV) controls to observe the effects of fisetin. Pharmacological autophagy inhibition (Bafilomycin A1, 40 nM) and nuclear factor erythroid 2-related factor 2 (Nrf2) gene silencing (siRNA transfection) were employed to dissect molecular pathways. Protein aggregation dynamics and autophagy markers (LC3, p62/SQSTM1) were quantified through immunofluorescence and immunoblotting. SOD1G93A models exhibited impaired autophagic flux evidenced by elevated LC3-II and p62 levels, correlating with increased detergent-insoluble SOD1 aggregates. Fisetin treatment (1-10 μ M) dose-dependently reduced both soluble and aggregated SOD1G93A protein, concomitantly with restored autophagic flux. Mechanistically, fisetin promoted nuclear translocation while decreasing cytoplasmic Nrf2. After administration of an autophagy inhibitor and interference with Nrf2, the regulation of fisetin on p62 and mutant hSOD1 protein was inhibited. Our findings demonstrate that fisetin ameliorates mutant SOD1 proteotoxicity through coordinated activation of Nrf2-mediated autophagy pathways, suggesting therapeutic potential for SOD1-associated ALS pathologies.

Keywords:  Amyotrophic lateral sclerosis; Antioxidant; Autophagy; Copper/zinc superoxide dismutase; Fisetin; Neurodegenerative disease

DOI:  https://doi.org/10.1007/s12031-025-02376-x
Autophagy Rep. 2025 ;4(1): 2519102

Differential response of neurons to autophagy modulation in Huntington's disease.

Ankit Sharma, Sushma Rao, Ravi Manjithaya, Vasu Sheeba.

  Huntington's disease (HD) is caused by the expansion of poly-glutamine repeats in the Huntingtin (Htt) gene and is associated with a wide variety of motor and physiological (sleep, metabolism, etc.) perturbations. Studies from diverse model organisms have proposed that modulation of autophagy (a key protein homeostatic pathway) can mitigate the toxic effects of mutant HTT protein. However, consistent changes are not observed across studies, and the improvements in phenotypes can be associated with changes in specific circuits/neurons affected by the mutant HTT protein. They suggest that not all neurons respond effectively to autophagy modulation. Hence, it remains to be understood whether diverse circuits/neurons affected by mutant HTT protein respond effectively to this intervention. Using a genetic approach, we expressed mutant HTT protein independently in diverse sets of neurons in male Drosophila melanogaster and asked whether genetic modulation of autophagy pathway through Atg8a overexpression can mitigate the toxic effect of mutant HTT protein. We found that in male flies, not all neurons/circuits expressing mutant HTT protein respond effectively to ATG8a protein. Circadian neurons and neurons regulating carbohydrate and lipid metabolism (Dilp2 +ve) showed improvement, while motor and neurons responding to temperature changes showed no improvement. Using cellular markers we also showed that these phenotypes can be attributed to specific changes in mutant HTT and Ref(2)P proteins (autophagy marker). Our study suggests that not all circuits respond effectively to autophagy modulation and suggests a potential cause for low success of autophagy modulators in clinical trials..

Keywords:  Drosophila melanogaster; Huntington’s disease; autophagy; circadian rhythm; metabolism; motor neurons; sleep

DOI:  https://doi.org/10.1080/27694127.2025.2519102
Immunity. 2025 Jun 25. pii: S1074-7613(25)00279-1. [Epub ahead of print]

More TOR: The expanding role of mTOR in regulating immune responses.

Chirag H Patel, Jonathan D Powell.

The mammalian/mechanistic target of rapamycin (mTOR) is an evolutionarily conserved multi-node signaling pathway that integrates critical environmental cues to control cellular growth. Decades worth of studies have intricately dissected the mTOR pathway to identify regulatory signals that are essential for regulating immune cell activation, differentiation, and function. As the mTOR field continues to evolve, so too does our understanding of these new findings in immune cells. Our group and others have previously reviewed the role of mTOR in regulating specific immune responses. Here, we provide an updated review of our current understanding of mTOR's comprehensive role in immune cell biology. In addition, we offer emerging ideas and areas of investigation where mTOR might be further explored and impactfully targeted to improve overall human health given mTOR's prominent role in aging and cancer.

DOI: https://doi.org/10.1016/j.immuni.2025.06.010
Br J Pharmacol. 2025 Jul 01.

Stabilisation of PRCP by deubiquitinase-targeting chimera (DUBTAC) to replenish autophagy for ameliorating pathological cardiac hypertrophy.

Fangchao Zhou, Jun Xia, Yingjuan Liu, Wenqi He, Hongyuan Zhang, Bernard D Keavney, Min Zi, Binh Y Nguyen, Tamer M A Mohamed, Jessica M Miller, Riham R E Abouleisa, Susanne S Hille, Elizabeth J Cartwright, Oliver J Müller, Honglin Xu, Sam Butterworth, Xin Wang.

   BACKGROUND AND PURPOSE: Autophagy is essential for cellular homeostasis, and its impairment contributes to cardiac hypertrophy. Modulating autophagy has shown potential in treating pathological hypertrophy. Prolylcarboxypeptidase (PRCP), a lysosomal enzyme that hydrolyzes angiotensin II to Ang1-7, has an unclear role in cardiac autophagy and hypertrophy. This study explores PRCP's function in regulating autophagy under hypertrophic stress and its potential as a therapeutic target.
EXPERIMENTAL APPROACH: Transverse aortic constriction (TAC) was used to induce hypertrophy in mice. PRCP-knockout (PRCPKO) mice were generated using CRISPR/Cas9, while PRCP was overexpressed in the heart using adeno-associated virus 9. Cardiac function was evaluated via echocardiography and histological analysis. Autophagy markers were assessed by immunostaining, electron microscopy, and protein expression. In vitro, PRCP expression was manipulated in H9c2 cells. A novel DUBTAC compound was also synthesized to stabilize PRCP, and its protective effects were tested in H9c2 cells and hESC-derived cardiomyocytes under isoprenaline-induced stress.
KEY RESULTS: PRCPKO mice developed more severe cardiac hypertrophy, fibrosis, and diastolic dysfunction after TAC. These mice showed reduced autophagosome formation and decreased expression of autophagy-related proteins WDR1 and WIPI1. In contrast, PRCP overexpression mitigated hypertrophy and preserved autophagy. Mechanistically, PRCP regulated autophagy via the interaction of WDR1 with WIPI1. Stabilizing PRCP with DUBTAC prevented its degradation and maintained autophagy under hypertrophic conditions.
CONCLUSIONS AND IMPLICATIONS: PRCP is a previously unrecognized regulator of autophagy in the heart. Enhancing PRCP expression or stabilizing it pharmacologically via DUBTAC represents a novel and effective therapeutic approach for managing pathological cardiac hypertrophy and improving cardiac health.

Keywords:  DUBTAC; Prolylcarboxypeptidase; autophagy; cardiac hypertrophy

DOI:  https://doi.org/10.1111/bph.70094
Trends Endocrinol Metab. 2025 Jul 02. pii: S1043-2760(25)00120-1. [Epub ahead of print]

Neuronal glycolysis meets mitophagy to govern organismal wellbeing.

Daniel Jimenez-Blasco, Rebeca Lapresa, Jesus Agulla, Angeles Almeida, Juan P Bolaños.

  Neurons are exceptionally energy-demanding cells but have limited energy storage, relying on a constant supply of fuel and oxygen. Although glucose is the brain's main energy source, neurons reduce glycolysis under normal conditions. This surprising strategy helps to protect mitochondria by preserving nicotinamide-adenine dinucleotide (NAD+), a vital cofactor consumed by glycolysis. NAD+ is needed for sirtuin-driven mitophagy, a process that removes damaged mitochondria. By saving NAD+, neurons can maintain healthy, energy-efficient mitochondria. These mitochondria then use alternative fuels such as lactate and ketone bodies from astrocytes. Here, we discuss the way in which this balance between reduced glycolysis and active mitophagy supports brain function and overall metabolic health, highlighting a sophisticated system that prioritizes mitochondrial quality for long-term cognitive performance and systemic homeostasis.

Keywords:  NAD; glycolysis; mitophay; neuron; organismal wellbeing

DOI:  https://doi.org/10.1016/j.tem.2025.05.005
FASEB J. 2025 Jul 15. 39(13): e70792

ATF7-PINK1 Axis Governs Mitophagy and Intestinal Inflammation in Ulcerative Colitis.

Yidong Chen, Xiaopeng Zhang, Junrong Li, Fang Liu, Qi Yu, Jiamin Li, Liangru Zhu.

  Ulcerative colitis (UC), a chronic inflammatory bowel disease, is marked by sustained inflammation and excessive apoptosis of intestinal epithelial cells (IECs). Despite progress in understanding UC pathogenesis, the role of activating transcription factors (ATFs) in disease progression remains elusive. Here, we profile the expression of ATF family members (ATF1-ATF7) in the colonic mucosa of UC patients and identify ATF7 as a critical regulator of mitophagy through its control of PTEN-induced kinase 1 (PINK1). Expression levels of ATF1-ATF7 were quantified in colonic mucosal samples from UC patients (n = 219) and healthy controls (n = 105) via quantitative PCR. Using IEC-specific ATF7 knockout mouse models and human CCD 841 CoN colonic epithelial cells, we employed ChIP-seq, dual-luciferase assays, transmission electron microscopy, and immunofluorescence to elucidate their roles in mitophagy and disease progression. Clinical correlation between ATF7 expression and disease severity was assessed using the Mayo score. ATF7 expression was significantly reduced in UC patients and inversely correlated with disease severity. Mechanistically, ATF7 was identified as a direct transcriptional activator of PINK1, a key mitophagy regulator. Loss of ATF7 or PINK1 disrupted mitophagy, exacerbating mitochondrial dysfunction, IEC apoptosis, and colonic inflammation in vivo and in vitro. Our findings uncover a pivotal ATF7-PINK1 axis that governs mitophagy and limits UC progression. The inverse correlation between ATF7 expression and UC severity highlights its potential as a therapeutic target, offering new avenues for intervention in this debilitating disease.

Keywords:  ATF7; PINK1; mitophagy; ulcerative colitis

DOI:  https://doi.org/10.1096/fj.202500813R
Theranostics. 2025 ;15(14): 6753-6767

RAB7 protects against ischemic heart failure via promoting non-canonical TUFM mitophagy pathway.

Yuling Sun, Wei Wang, Mingyan Li, Wen Guan, Zhimin Gao, Luping Wang, Guanlan Lou, Ao Shen, Jiangbin Wu, Xiyong Yu, Panxia Wang, Xiaoqian Wu.

  Rationale: Cardiomyocyte apoptosis critically contributes to ischemic heart failure (IHF) progression. While the endosome-lysosome system governs cellular homeostasis, the functional significance of its master regulator RAB7 in cardiac pathophysiology remains unexplored. Methods: Using myocardial infarction (MI) models via left anterior descending coronary artery ligation in cardiomyocyte-specific RAB7 knockout mice and adeno-associated virus-mediated RAB7 overexpression models, we assessed cardiac function and adverse remodeling through echocardiography and pathophysiological assessment. Mitophagy flux was quantified using mt-Keima mice and confocal imaging. Molecular mechanisms were dissected through immunoprecipitation coupled with mass spectrometry (IP-MS) analysis and molecular experiment validation. Results: RAB7 expression decreased in ischemic myocardium. Cardiomyocyte-specific RAB7 ablation exacerbated while RAB7 overexpression attenuated post-MI cardiac dysfunction and maladaptive remodeling. RAB7 enhanced mitophagic clearance of damaged mitochondria, reducing cardiomyocyte apoptosis under ischemic stress both in vitro and in vivo. Mechanistically, TUFM, a mitochondrial translation elongation factor, was identified as a novel effector of RAB7. RAB7 facilitated the recruitment of TUFM and LC3 to damaged mitochondria, thereby enhancing mitophagy. TUFM knockdown significantly diminished the protective effects of RAB7 on mitophagy and cardiomyocyte survival. Finally, administration of ML-098, a chemical RAB7 activator, promoted mitophagy and mitigated IHF progression in mice. Conclusion: We identify RAB7 as a novel coordinator of cardioprotective mitophagy through TUFM-mediated machinery assembly. The RAB7-TUFM axis represents a therapeutic target for IHF that warrants further clinical evaluation.

Keywords:  RAB7; TUFM; mitophagy; myocardial infarction

DOI:  https://doi.org/10.7150/thno.104124
Nature. 2025 Jul 02.

WSTF nuclear autophagy regulates chronic but not acute inflammation.

Yu Wang, Vinay V Eapen, Yaosi Liang, Athanasios Kournoutis, Marc Samuel Sherman, Yanxin Xu, Angelique Onorati, Xianting Li, Xiaoting Zhou, Kathleen E Corey, Kuo Du, Ana Maria Cabral Burkard, Chia-Kang Ho, Jing Xie, Hui Zhang, Raquel Maeso-Díaz, Xinyi Ma, Ulrike Rieprecht, Tara O'Brien, Murat Cetinbas, Lu Wang, Jihe Liu, Corey Bretz, Aaron P Havas, Zhuo Zhou, Shannan J Ho Sui, Srinivas Vinod Saladi, Ruslan I Sadreyev, Peter D Adams, Robert E Kingston, Anna Mae Diehl, Benjamin Alman, Wolfram Goessling, Zhenyu Yue, Xiao-Fan Wang, Terje Johansen, Zhixun Dou.

Acute inflammation is an essential response that our bodies use to combat infections1. However, in the absence of infections, chronic inflammation can have a pivotal role in the onset and progression of chronic diseases, such as arthritis, cancer, autoimmune disorders, metabolic-dysfunction-associated steatohepatitis (MASH), and most ageing-associated pathologies2,3. The underlying mechanisms that distinguish chronic inflammation from its acute counterpart remain unclear, posing challenges to the development of targeted therapies for these major diseases. Here we identify a mechanism that separates the two responses: during chronic but not acute inflammation, chromatin remodelling is influenced by nuclear autophagy, in which the WSTF protein of the ISWI chromatin-remodelling complex interacts with the ATG8 autophagy protein family in the nucleus. This interaction leads to WSTF nuclear export and subsequent degradation by autophagosomes and lysosomes in the cytoplasm. Loss of WSTF leads to chromatin opening over inflammatory genes, amplifying inflammation. Cell-penetrating peptides that block the WSTF-ATG8 interaction do not affect acute inflammation but suppress chronic inflammation in senescence as well as in MASH and osteoarthritis in mouse models and patient samples. The ability to specifically target chronic inflammation without blunting acute inflammation offers an approach for treating common chronic inflammatory diseases.

DOI: https://doi.org/10.1038/s41586-025-09234-1
Neuroscience. 2025 Jul 02. pii: S0306-4522(25)00717-1. [Epub ahead of print]

The autophagy-ferroptosis axis as a critical factor in diabetic-associated cognitive dysfunction.

Ensi Luo, Shaobing Guan, Hongguang Ding, Xinyu Chen, Huidan Liu, Yanwen Xie, Qibin Tang, Shangzheng Li, Huanhuan Huang, Zhifang Chen.

  Diabetic-associated cognitive dysfunction (DACD) is a critical complication of diabetes mellitus, characterized by progressive cognitive decline and neurodegeneration. This review synthesizes emerging evidence on the interplay between autophagy and ferroptosis, highlighting their roles in DACD pathogenesis. We emphasize the unique contribution of the autophagy-ferroptosis axis, particularly under hyperglycemic and insulin-resistant conditions, in driving iron overload, oxidative stress, and lipid peroxidation in brain tissue. The brain's vulnerability to ferroptosis is underscored by its high energy demand, low coenzyme Q (CoQ) content, and abundant polyunsaturated fatty acids (PUFAs), which collectively exacerbate oxidative damage. Key signaling pathways, the DNA damage inducible transcript 4 (DDIT4)-Tuberous Sclerosis Complex (TSC)-mammalian target of rapamycin (mTOR) axis are discussed as potential therapeutic targets. Notably, the DDIT4-TSC-mTOR axis links autophagy dysregulation to ferroptosis induction through iron metabolism imbalance. This review uniquely integrates these mechanisms to propose novel intervention strategies, such as ferroptosis inhibitors and natural compounds, which may mitigate DACD by restoring redox homeostasis and autophagic flux. By bridging molecular pathways with clinical implications, this work advances our understanding of DACD and provides innovative directions for therapeutic development.

Keywords:  Antioxidant; Autophagy; DNA damage inducible transcript 4; Diabetes-associated cognitive dysfunction; Ferroptosis

DOI:  https://doi.org/10.1016/j.neuroscience.2025.06.035
J Biol Chem. 2025 Jul 02. pii: S0021-9258(25)02299-9. [Epub ahead of print] 110449

Targeted degradation of α-synuclein by arginine-based PROTACs.

Linjing Shen, Jianchao Zhang, Zhaoran Wang, Yaxuan Liu, Shengjin Cui, Hai Rao.

  Parkinson's disease (PD), the second most prevalent neurodegenerative disorder, is associated with α-synuclein (α-syn) overexpression or mutation, leading to harmful aggregates and neuronal apoptosis. Effective drugs that inhibit or reduce α-syn accumulation remain challenging. Targeted protein degradation (TPD) technology offers a novel solution by utilizing the ubiquitin-proteasome pathway to target specific proteins for destruction. Here, we have developed Proteolysis Targeting Chimera (PROTAC) to target α-syn for degradation. Specifically, our PROTACs employ the amino acid arginine (Arg) as the E3 ligase ligand, and a benzothiazole-aniline variant as the warhead for α-syn. The efficacy of these PROTACs in degrading α-syn and its aggregates was tested in mammalian cells and Caenorhabditis elegans (C. elegans) models. Arg-PEG1-Tα-syn shows the highest degradation effect in mammalian cells for both wild-type α-syn and the α-syn (A53T) mutant. UBR1 is the ubiquitin E3 ligase responsible for PROTAC-mediated degradation. Furthermore, Arg-PEG1-Tα-syn significantly reduces α-syn aggregates and associated toxicities in both mammalian cells and C. elegans. These findings highlight the potential of a single amino acid-based PROTAC targeting α-syn for degradation, representing a possible therapeutic approach for PD and other synucleinopathies.

Keywords:  AATac; N-end rule; PROTAC; Parkinson's disease; amino acid; arginine; α-synuclein

DOI:  https://doi.org/10.1016/j.jbc.2025.110449
Curr Neuropharmacol. 2025 Jun 30.

Powering Up the Brain: Intercellular Mitochondrial Quality Control and Its Implication in Stroke.

Xinyu Zhou, Shenzhe Wu, Tianxi Huang, Yue Li, Jianhong Yang, Zhen Gu, Xiangnan Zhang.

  Mitochondria are critical for neuronal survival and function, and their dysregulation is closely related to the incidence and prevalence of various neurological disorders, including stroke. Mitochondrial quality control (MQC) is vital for maintaining mitochondrial integrity, particularly in neurons. Under ischemic conditions, neurons evolve a range of adaptive strategies to preserve mitochondria function dynamically, either by generating functional mitochondria or by eliminating dysfunctional ones via autophagy, both of which play key roles in keeping neuronal survival under the conditions of stroke. Besides these intracellular strategies, the intercellular mechanisms underlying MQC have been observed in the nervous system. Functional mitochondria from healthy cells can be supplemented to ischemic neurons in distinct manners and thus restore the mitochondrial network of recipient cells. Conversely, injured neurons release dysfunctional mitochondria, which can be further degraded by adjacent glial cells. Alternatively, the discarded mitochondria act as a threat to surrounding cells and can disrupt the homeostasis of the nervous system. In this review, the key discoveries in intercellular MQC in the nervous system were summarized, and further discussed the implications of intercellular MQC strategies for stroke therapy.

Keywords:  Intercellular mitochondrial quality control; intercellular mitochondrial transport; stroke.; trans mitophagy

DOI:  https://doi.org/10.2174/011570159X388351250620065716
Brain Dev. 2025 Jul 01. pii: S0387-7604(25)00070-1. [Epub ahead of print]47(4): 104388

L-NAME improves the morphology and necrosis of skeletal muscle by activating PINK1-PARKIN mediated mitophagy in mdx mice.

Junxia Li, Wenjuan Wu, Guang Ji, Hui Dong, Hongran Wu, Xueqin Song.

   BACKGROUND: This study investigates mitophagy in Duchenne muscular dystrophy (DMD, OMIM #310200), focusing on how nitric oxide synthase (NOS) inhibition improves muscle tissue pathology by affecting mitophagy, which is implicated in muscle weakness due to dystrophin deficiency and may affect DMD-related cardiomyopathy and respiratory problems.
METHODS: Histopathological analysis, immunofluorescence staining, Western blot were used to study the mitophagy status of the tibialis anterior muscle in mdx mice without treatment or mdx mice administered L-NAME (L-NG-nitro arginine methylester), an inhibitor of NOS. For in vitro experiment, the effect of S-nitrosylation enzyme, N6022, on mitophagy in C2C12 cells was assessed using TEM (transmission electron microscopy), and Western blot.
RESULTS: Mdx mice showed dystrophic muscle pathology and elevated LC3 (microtubule-mssociated protein 1 light chain) and VDAC (voltage-dependent anion channel) expression, indicating increased mitophagy. Reduced PINK1 (PTEN-induced putative kinase 1) and PARKIN (E3 ubiquitin ligase PARK2) levels suggested incomplete mitochondrial clearance. L-NAME treatment improved muscle morphology and reduced necrosis, partially restoring mitophagy by increasing LC3 without matching VDAC upregulation. However, PINK1 and PARKIN were further reduced, suggesting mitophagic inefficiency. In C2C12 cells, GSNOR(S-nitrosoglutathione reductase) inhibition via N6022 elevated nitrosylation, impaired mitophagy, and caused mitochondrial accumulation with increased PINK1 but unchanged PARKIN, highlighting a critical role of nitrosylation balance in mitophagy regulation.
CONCLUSIONS: NOS inhibition may serve as a key point for further research on the progression of DMD disease and as a potential therapeutic target for this incurable disease.

Keywords:  Duchenne muscular dystrophy; GSNOR; L-NAME; Mitophagy; PINK1-PARKIN pathway; S-nitrosylation

DOI:  https://doi.org/10.1016/j.braindev.2025.104388
Dev Cell. 2025 Jun 27. pii: S1534-5807(25)00372-7. [Epub ahead of print]

TM9SF3 is a Golgi-resident ATG8-binding protein essential for Golgi-selective autophagy.

Jiejie Yang, Yang Dong, Jiaxin Xu, Xuehong Qian, Yang Cai, Yanjun Chen, Pei Zhang, Ding Gao, Zongqiang Cui, Yixian Cui.

  Golgi degradation by selective autophagy (Golgiphagy) requires receptors to direct Golgi fragments into phagophores for sequestration within autophagosomes, followed by lysosomal degradation. Here, we show that the human Golgi transmembrane protein TM9SF3 is a receptor essential for Golgiphagy under nutrient-stress and multiple Golgi-stress conditions. TM9SF3 binds all six mammalian ATG8 proteins through its N-terminal LC3-interacting regions. In U2OS cells, TM9SF3 knockout blocks nutrient-stress-induced Golgi fragmentation and reduces the targeting of Golgi fragments to autophagosomes, resulting in decreased Golgi protein degradation. Beyond nutrient stress, TM9SF3 is required for Golgiphagy induced by monensin, brefeldin A, and disruptions in intra-Golgi protein glycosylation. Knockout of TM9SF3 and mutations in its LC3-interacting regions (LIRs) both compromise protein glycosylation, whereas TM9SF3 overexpression promotes degradation of incompletely glycosylated proteins. Further, we show that TM9SF3 is required for human breast cancer cell proliferation, and high TM9SF3 levels are associated with poor prognosis, implicating its function in breast cancer pathology.

Keywords:  ATG8; Golgi fragmentation; Golgi stress; Golgiphagy; LC3-interacting region; LIR; TM9SF3; breast cancer; lysosomal degradation; protein glycosylation; receptor

DOI:  https://doi.org/10.1016/j.devcel.2025.06.017
J Clin Invest. 2025 Jul 03. pii: e193099. [Epub ahead of print]

SPNS1 variants cause multi-organ disease and implicate lysophospholipid transport as critical for mTOR-regulated lipid homeostasis.

Menglan He, Mei Ding, Michaela Chocholouskova, Cheen Fei Chin, Martin Engvall, Helena Malmgren, Matias Wagner, Marlen C Lauffer, Jacob Heisinger, May Christine V Malicdan, Valérie Allamand, Madeleine Durbeej, Angelica M Delgado-Vega, Thomas Sejersen, Ann Nordgren, Federico Torta, David L Silver.

  SPNS1 is a lysosomal transporter mediating the salvage of lysoglycerophospholipids, the degradative products of lysosomal phospholipid catabolism. However, a role of lysolipid transport and salvage in regulating cellular lipid homeostasis and in disease is lacking. Here, we identified two families with biallelic SPNS1 loss-of-function variants that presented primarily with progressive liver and striated muscle injury. Patient fibroblasts accumulated lysophospholipids including lysoplasmalogens and cholesterol in lysosomes with reduced cellular plasmalogens. Notably, SPNS1 deficiency resulted in reduced biogenesis of cytosolic lipid droplets containing triglycerides and cholesteryl esters. Mechanistically, we found that lysophospholipids transported by SPNS1 into the cytosol quantitatively contributed to triglyceride synthesis while lysosomal buildup of lyso-ether-phospholipid inhibited lysosomal cholesterol egress, effects that were enhanced with inhibition of mTOR. These findings support a gene-disease association and reveal connectivity between lysosomal transport of lysophospholipids and storage of reserve cellular energy as triglyceride and in the regulation of cholesterol homeostasis, processes that become important under nutrient limitation.

Keywords:  Cell biology; Cholesterol; Lipidomics; Lysosomes; Metabolism

DOI:  https://doi.org/10.1172/JCI193099
Sci Rep. 2025 Jul 02. 15(1): 23001

Circadian gene BMAL1 ameliorates renal ischaemia-reperfusion injury in diabetic mice by enhancing mitophagy via the HIF-1/BNIP3 pathway.

Xinqi Deng, Yan Leng, Yonghong Xiong, Wenyuan Li, Wu Chen, Yuhang Yang, Bihan Wang, Siyuan Gong, Yunhao Wang, Baichuan Yang, Wei Li.

  Diabetic kidneys are particularly vulnerable to ischemia/reperfusion injury (I/RI). Although previous research has suggested that the circadian gene brain and muscle ARNT-like 1 (BMAL1) plays a role in regulating renal function, the exact functions and mechanisms of BMAL1 in diabetic renal I/RI remain elusive. In this study, bilateral renal artery ligation and release were performed in non-diabetic (db/+) and diabetic (db/db) mice. In diabetic kidneys, experimental findings demonstrated a significant decrease in BMAL1 expression, along with the inhibition of the HIF-1α/BNIP3 signaling pathway and compromised mitophagy. BMAL1 overexpression alleviated cell damage and apoptosis under high glucose and hypoxia/reoxygenation stimulation. Inhibition of the Hypoxia-inducible factor-1α (HIF-1α)/ B-cell lymphoma-2 interacting protein 3 (BNIP3) pathway by the HIF-1α inhibitor PX-478 intensified cellular damage and reduced the protective effect of BMAL1 overexpression in TCMK-1 cells. These results indicate that BMAL1 regulates mitophagy in diabetic renal I/RI through the HIF-1α/BNIP3 pathway, providing valuable insights for the development of targeted therapies for diabetic renal I/RI.

Keywords:  BMAL1; Diabetes; HIF-1α; Ischemia/reperfusion injury; Mitophagy

DOI:  https://doi.org/10.1038/s41598-025-03515-5
Sci Rep. 2025 Jul 01. 15(1): 21283

SRT2104 enhances dendritic outgrowth and spine formation through Sirtuin 1-mediated mTORC1 signaling.

Mi Kyoung Seo, Jung Goo Lee, Ji Hyun Kim, Dae-Hyun Seog, Sehoon Jeong, Seong-Ho Kim, Jin Young Lee, Sung Woo Park.

  Impaired neuroplasticity is a one of the key pathological mechanism of depression. Sirtuin 1 plays a crucial role in neuroplasticity; however, its precise mechanisms remain unclear. This study examined whether sirtuin 1 regulates dendritic outgrowth and spine formation via mTORC1 signaling in rat primary cortical cells under dexamethasone-induced neurotoxic conditions. Cortical cells were treated with SRT2104 (0.1, 1, and 10 µM), a selective sirtuin 1 activator, in the presence of dexamethasone (500 µM). Protein levels of sirtuin 1, mTORC1 signaling components, and synaptic markers (PSD-95 and GluA1) were analyzed by Western blotting, while dendritic outgrowth and spine density were assessed via immunofluorescence. SRT2104 significantly increased sirtuin 1 expression and ERK1/2 (a downstream target of sirtuin 1) phosphorylation. SRT2104 led to a substantial augmentation in the phosphorylation levels of mTORC1, as well as 4E-BP1 and p70S6K, which are downstream targets of mTORC1. Furthermore, SRT2104 led to an increase in dendritic outgrowth and spine density. Conversely, sirtuin 1 knockdown by siRNA transfection markedly reduced ERK1/2 and mTORC1 phosphorylation, as well as dendritic complexity and spine formation. These results suggest that sirtuin 1 promotes neuroplasticity by activating mTORC1 signaling, providing potential therapeutic implications for depression treatment.

Keywords:  Depression; Dexamethasone; Neuroplasticity; SRT2104; Sirtuin 1; mTORC1 signaling

DOI:  https://doi.org/10.1038/s41598-025-06203-6
Ageing Res Rev. 2025 Jun 28. pii: S1568-1637(25)00164-3. [Epub ahead of print]110 102818

Targeting autophagy in doxorubicin-induced cardiotoxicity: A comprehensive review of scientific landscapes and therapeutic innovations.

Shiqi Wang, Lu Wang, Hongxin Cheng, Hanbin Li, Qing Zhang, Chengqi He, Chenying Fu, Quan Wei.

  Doxorubicin (DOX)-induced cardiotoxicity (DIC) poses a major threat to elderly cancer patients, often leading to severe cardiac dysfunction and complicating the outcome of cancer treatment. Autophagy is one of the core mechanisms of DIC and is considered a key therapeutic target. We analyzed the status of research in the field of autophagy in DIC via bibliometric methods. A total of 292 publications related to this topic were identified and included. Furthermore, based on included publications and relevant studies in the field of geriatrics, the characteristics of autophagy in the aging heart and DIC, therapeutic strategies targeting autophagy, and challenges in clinical translation were summarized. Our review reveals that research hotspots in the field focus on how to balance the relationship between the effects of cancer treatment and cardiotoxicity, and the frontiers focus on exploring new therapeutic strategies via autophagy regulation. The autophagy ability of aging hearts is significantly reduced, which accelerates the occurrence of myocardial fibrosis, systolic dysfunction, and chronic inflammation. Autophagy has significant bidirectional regulatory effects on DIC. Additionally, the dynamic regulation of autophagy is significantly affected by dose gradients of DOX, exposure time windows, experimental models, and differences in administration methods. Drugs such as dexrazoxane and melatonin, as well as rehabilitation therapies such as aerobic training and resistance training, can regulate cardiomyocyte autophagy and have clinical translational potential. However, age heterogeneity in existing clinical studies undermines the generalizability of findings to elderly cancer patients. Future therapeutic optimization requires regimen customization based on elderly specific organ function decline patterns.

Keywords:  Aging heart; Autophagy; Bibliometrics; Cardiotoxicity; Doxorubicin; Therapeutic strategy

DOI:  https://doi.org/10.1016/j.arr.2025.102818
Sci Rep. 2025 Jul 01. 15(1): 20960

A novel isoquinoline mitophagy inducer ameliorates paclitaxel-induced peripheral neuropathy in Drosophila and mouse models.

Sangwoo Im, Se Myeong Choi, Young Yeon Kim, Dae Jin Jeong, Jee-Hyun Um, Kang-Min Lee, Eunhee Yoo, Jong Hyun Cho, Ji Hyun Lee, Jeanho Yun.

  Chemotherapy-induced peripheral neuropathy (CIPN) resulting from neurodegeneration due to chemotherapy is a challenging complication of widely administered anticancer drugs including paclitaxel. Although CIPN is common and limits the use of chemotherapies, no curative treatment for CIPN has been developed. Recently, stimulation of mitophagy has emerged as a promising strategy for treating neurodegenerative diseases, but studies on its therapeutic effects on CIPN are limited. In this study, we examined the therapeutic effect of the recently developed mitophagy inducer ALT001 on paclitaxel-induced peripheral neuropathy model in Drosophila and mice. Importantly, ALT001 administration in a paclitaxel-induced Drosophila model of peripheral neuropathy significantly ameliorated paclitaxel-induced alterations in sensory neurons and the thermal hyperalgesia phenotype in a mitophagy-dependent manner. Moreover, we demonstrated that ALT001 administration significantly ameliorated paclitaxel-induced mechanical allodynia and the reduction in intraepidermal nerve fiber density in a mouse model. Interestingly, ALT001 did not interfere with the cytotoxic effect of paclitaxel on lung cancer or breast cancer cells. Our results suggest that ALT001 is a potential candidate for the treatment of paclitaxel-induced peripheral neuropathy and that stimulation of mitophagy is a promising strategy for CIPN treatment that does not affect the cytotoxic effect of chemotherapy.

Keywords:  Mitophagy; Neuronal degeneration; Paclitaxel; Peripheral neuropathy

DOI:  https://doi.org/10.1038/s41598-025-04178-y
Sci Rep. 2025 Jul 02. 15(1): 23273

Study on the regulation of gastric cancer cell apoptosis by LACTB through mitochondrial autophagy pathway.

Wei Nie, Lihua Hu, Zhiqiang Yan, Qian Wang, Shui He, Xiaoqiang Gao, Fang Yang.

  This study aimed to determine whether β-lactamase-like protein (Lactamase-β, LACTB) influences apoptosis in gastric cancer cells by modulating mitochondrial autophagy through the PTEN-induced putative kinase 1 (PINK1) or Parkin pathway. Firstly, the expression level of LACTB in gastric cancer tissues was detected by immunohistochemistry, and the survival data of patients were used to explore the relationship between LACTB expression level and patient prognosis. Secondly, LACTB overexpression (+ LACTB) and knockdown (sh-LACTB) AGS gastric cancer cell lines were constructed; flow cytometry and other experiments were used to detect the effect of LACTB on AGS cell apoptosis; Western Blot was used to detect the expression of PINK1/Parkin mitochondrial autophagy pathway-related proteins and lysosome-related proteins in + LACTB and sh-LACTB gastric cancer cells; kits and electron microscopy were used to detect changes in the number of reactive oxygen species (ROS) and autophagosomes. Finally, Western blot was used to detect the expression of apoptotic proteins Bcl-2 associated x protein (Bax) and B-cell lymphoma-2 (Bcl-2) in + LACTB and sh-LACTB gastric cancer cells treated with mitochondrial autophagy inhibitor 3-methyladenine (3-MA). Immunohistochemistry analysis revealed that LACTB expression in gastric cancer tissues was higher than in adjacent non-cancerous tissues, for patients with tumor diameters exceeding 4.5 cm, high LACTB expression was associated with a poor prognosis (P < 0.05). LACTB overexpression reduced apoptosis in gastric cancer cells. It downregulated the pro-apoptotic protein Bax, while LACTB knockdown promoted apoptosis, upregulated Bax, the expression of pro-apoptotic protein Bax, and downregulated the expression of anti-apoptotic protein Bcl-2. In LACTB overexpressing cell lines, protein sequestosome 1 (P62) protein levels were elevated, lysosomal-associated membrane protein 2 (LAMP2) expression was decreased, Reactive oxygen species (ROS) levels remained significantly stable, and autophagosome counts were reduced. Conversely, LACTB knockdown cells, PINK1, Parkin, protein light chain 3II/I (LC3II/I), LAMP2, cathepsin B (CTSB), continuous traumatic stress disorder (CTSD), and other related proteins, downregulated P62 expression, increased ROS accumulation, and higher number of autophagosomes. In LV-LACTB and sh-LACTB gastric cancer cells treated with the mitochondrial autophagy inhibitor 3-methyladenine (3-MA), apoptotic protein Bax is downregulated, and anti-apoptotic protein Bcl-2 is upregulated. In summary, the LACTB protein may regulate the apoptosis in gastric cancer cells by modulating mitochondrial autophagy through the PINK1/Parkin pathway.

Keywords:  Apoptosis; Gastric cancer; Mitophagy; PINK1/Parkin pathway; β-lactamase-like protein

DOI:  https://doi.org/10.1038/s41598-025-06047-0
iScience. 2025 Jul 18. 28(7): 112816

Genetically encoded and modular subcellular organelle probes reveal dysfunction in lysosomes and mitochondria driven by PRKN knockout.

Camille Goldman, Tatyana Kareva, Lily Sarrafha, Braxton R Schuldt, Abhishek Sahasrabudhe, Tim Ahfeldt, Joel W Blanchard.

  Cellular processes including lysosomal and mitochondrial dysfunction are implicated in the development of many diseases. Quantitative visualization of mitochondria and lysosomes is crucial to understand how these organelles are dysregulated during disease. To address a gap in live-imaging tools, we developed GEM-SCOPe (genetically encoded and modular subcellular organelle probes), a modular toolbox of fluorescent markers designed to inform on localization, distribution, turnover, and oxidative stress of specific organelles. We expressed GEM-SCOPe in differentiated astrocytes and neurons from a human pluripotent stem cell PRKN-knockout model of Parkinson's disease and identified disease-associated changes in proliferation, lysosomal distribution, mitochondrial transport and turnover, and reactive oxygen species. We demonstrate GEM-SCOPe is a powerful panel that provides critical insight into the subcellular mechanisms underlying Parkinson's disease in human cells. GEM-SCOPe can be expanded upon and applied to a diversity of cellular models to glean an understanding of the mechanisms that promote disease onset and progression.

Keywords:  Cell biology; Molecular biology

DOI:  https://doi.org/10.1016/j.isci.2025.112816
Nat Commun. 2025 Jul 01. 16(1): 5639

Imbalanced TGFβ signalling and autophagy drive erythroid priming of hematopoietic stem cells in β-thalassemia.

Maria Rosa Lidonnici, Giulia Chianella, Nicole Mende, Hugo P Bastos, Matteo Barcella, Ivan Merelli, Mariangela Storto, Valentina Romeo, Francesca Tiboni, Samantha Scaramuzza, Claudia Rossi, Laura Raggi, Annamaria Aprile, Stefania Crippa, Deena Iskander, Irene Roberts, Anastasios Karamiditris, Julia Keith, Christophe Lechauve, Mitchell J Weiss, Nicola K Wilson, Berthold Göttgens, Maria Ester Bernardo, Fabio Ciceri, Alessandro Aiuti, Sarah Marktel, Elisa Laurenti, Giuliana Ferrari.

The hematopoietic stem cell and multipotent progenitor (HSC/MPP) pool dynamically responds to stress to adapt blood output to specific physiological demands. In β-thalassemia (Bthal), severe anemia and ineffective erythropoiesis generate expansion of erythroid precursors and a chronic stress status in the bone marrow (BM) microenvironment. However, the response to the BM altered status at the level of the HSC/MPP compartment in terms of lineage commitment has not been investigated. Bulk and single-cell RNA-sequencing reveal that Bthal HSCs/MPPs are expanded and activated with enhanced priming along the whole Ery differentiation trajectory. Consistently, HSC/MPP showed an altered TGFβ expression and autophagy transcriptional signatures along with a declined dormancy state. We discovered that the altered TGFβ signaling fosters the Ery potential of HSCs by reducing their autophagic levels, and in vivo stimulation of autophagy is sufficient to rescue the imbalance of the HSC compartment. Our findings identify the interplay between TGFβ and HSC autophagy as a key driver in the context of non-malignant hematopoiesis.

DOI: https://doi.org/10.1038/s41467-025-60676-7
J Cell Biochem. 2025 Jun;126(6): e70050

The Multifaceted Influence of Beta-Hydroxybutyrate on Autophagy, Mitochondrial Metabolism, and Epigenetic Regulation.

Sajad Ehtiati, Behzad Hatami, Seyyed Hossein Khatami, Kiarash Tajernarenj, Saeed Abdi, Majid Sirati-Sabet, Seyyed Amir Hossein Ghazizadeh Hashemi, Reyhane Ahmadzade, Nastran Hamed, Marziyeh Goudarzi, Fatemeh Namvarjah, Melika Hajimohammadebrahim-Ketabforoush, Abbas Tafakhori, Vajiheh Aghamollaii, Saeed Karima.

  Beta-hydroxybutyrate (BHB), a key ketone body produced during fatty acid metabolism, plays critical roles in various physiological and pathological conditions. Synthesized in the liver through ketogenesis, BHB serves as an essential energy substrate during glucose deprivation, supporting survival by efficiently utilizing fat reserves. It crosses the blood-brain barrier, providing energy for neuronal function, enhancing cognitive processes such as learning and memory, and offering neuroprotection by modulating synaptic plasticity and neurotransmitter levels. BHB's impact extends to cellular pathways, including autophagy, mitochondrial biogenesis, and epigenetic regulation. By modulating autophagy, BHB ensures mitochondrial integrity and function through intricate molecular pathways involving AMPK, mTOR, PINK1/Parkin, and others. This regulation plays vital roles in neurodegenerative diseases, metabolic disorders, cancer, and cardiovascular diseases, reducing oxidative stress and preventing cellular dysfunction. Epigenetically, BHB acts as an endogenous histone deacetylase inhibitor, inducing beneficial histone modifications that enhance cellular resilience and stress responses. This epigenetic influence is crucial in conditions like diabetes and cancer, aiding insulin secretion, protecting pancreatic beta cells, and impacting cancer cell gene expression and survival. Furthermore, BHB's therapeutic potential is evident in its ability to improve mitochondrial function across various tissues, including neurons, muscle, and liver. By enhancing mitochondrial respiration, reducing oxidative stress, and altering metabolic pathways, BHB mitigates conditions such as ICU-acquired weakness, nonalcoholic fatty liver disease, and cardiovascular diseases. BHB's modulation of autophagy and epigenetic regulation underscores its comprehensive role in cellular homeostasis and health across multiple physiological contexts, providing a foundation for future therapeutic strategies.

Keywords:  autophagy; beta‐hydroxybutyrate; epigenetic; mitochondrial biogenesis; therapeutic strategies

DOI:  https://doi.org/10.1002/jcb.70050