bims-auttor Biomed News
on Autophagy and mTOR
Issue of 2025–06–22
39 papers selected by
Viktor Korolchuk, Newcastle University
  1. Lysosomal membrane permeabilization enhances the anticancer effects of POLR1 (RNA polymerase I) transcription inhibitors.
  2. Autophagy in disease management: Exploring the potential of natural products as targeted therapies.
  3. ATG9 not just an Autophagy Related Protein.
  4. DMXL1 promotes recruitment of V1-ATPase to lysosomes upon TRPML1 activation.
  5. Biallelic SIDT2 loss-of-function in a child with cerebellar ataxia and lysosomal dysfunction mimics impairment of SIDT2 in mice.
  6. Exercise as a Metabolic Regulator: Targeting AMPK/mTOR-Autophagy Crosstalk to Counteract Sarcopenic Obesity.
  7. Hexokinase 2 interacts with PINK1 to facilitate mitophagy in astrocytes and restrain inflammation-induced neurotoxicity.
  8. Lysosomal targeting of liposomes with acidic pH and Cathepsin B induces protein aggregate clearance.
  9. The Golgi Stacking Protein GORASP2 Regulates Mouse Primordial Follicle Activation by Suppressing the Autophagy Lysosome Pathway via RAP1 Competing With mTOR for RAPTOR Binding.
  10. Biphasic Cellular Response Triggered by Tetrandrine-Mediated Dysfunction and Lysophagic Clearance of Lysosomes.
  11. ATP6V0A1 protects dopaminergic neurons via the autophagy-lysosomal pathway in Parkinson's disease.
  12. Pbs2 regulates late-stage macroautophagy in Saccharomyces cerevisiae.
  13. Resistance training alleviates muscle atrophy and muscle dysfunction by reducing inflammation and regulating compromised autophagy in aged skeletal muscle.
  14. ACLY links mutant α-synuclein to metabolism, autophagy and neurodegeneration.
  15. The evolutionarily conserved PRP4K-CHMP4B/vps32 splicing circuit regulates autophagy.
  16. ATR promotes mTORC1 activity via de novo cholesterol synthesis.
  17. Nanomedicine Approaches for Autophagy Modulation in Cancer Therapy.
  18. Mitochondrial dynamics dysfunction and neurodevelopmental disorders: From pathological mechanisms to clinical translation.
  19. Itraconazole and Posaconazole, Inhibitors of NPC1 Sterol Transport, Act as Pharmacological Chaperones After Washout.
  20. NIPSNAP1 and NIPSNAP2 facilitate healthy aging independent of mitophagy.
  21. Oleanolic acid activates the JNK-Sp1-DJ-1 axis to promote mitophagy-mediated neuroprotection in dopaminergic neurons for Parkinson's disease treatment.
  22. Fumarate hits the brakes on mitophagy.
  23. ENPP1 governs the metabolic regulation of effector T cells in autoimmunity by detecting cytosolic mitochondrial DNA.
  24. PINK1 Deficiency Facilitates Palmitic Acid-Induced Inflammation by Disrupting Mitochondrial Function to Activate mtDNA-cGAS-STING Signaling.
  25. Gut Metabolite Indole-3-Propionic Acid Regulates Macrophage Autophagy Through PPT1 Inhibiting Aging-Related Myocardial Fibrosis.
  26. Role of mitochondria in physiological activities, diseases, and therapy.
  27. The Arg/N-degron pathway mediates the secretion of apoptotic exosomes under oxidative stress in cancer cell.
  28. Co-chaperones fine-tune the function of heat shock protein 70 (Hsp70), whether to fold, hold, or degrade substrates in ensuring cellular protein homeostasis.
  29. Tumor-promoting UBR4 coordinates impaired mitophagy-associated senescence and lung adenocarcinoma pathogenesis.
  30. The Mitochondrial Foundations of Parkinson's Disease: Therapeutic Implications.
  31. Lysosomal Acidification: A New Perspective on the Pathogenesis and Treatment of Pulmonary Fibrosis.
  32. Emodin Inhibits NLRP3 Inflammasome Activation and Protects Against Sepsis via Promoting FUNDC1-Mediated Mitophagy.
  33. CryoEM provides detailed insights into how VPS15 regulates VPS34 activity.
  34. Dopamine and cortical neurons with different Parkinsonian mutations show variation in lysosomal and mitochondrial dysfunction.
  35. Mitochondrial dysfunction in the regulation of aging and aging-related diseases.
  36. Fasting the mitochondria to prevent neurodegeneration: the role of ceramides.
  37. Dolutegravir Inhibits Autophagy In Vitro in a Mouse Blood-Brain Barrier Model.
  38. Aneuploidy-induced proteostasis disruption impairs mitochondrial functions and mediates aggregation of mitochondrial precursor proteins through SQSTM1/p62.
  39. Dysfunctional mitochondria trap proteins in the intermembrane space.
  1. Autophagy. 2025 Jun 18. 1-20
    Lysosomal membrane permeabilization enhances the anticancer effects of POLR1 (RNA polymerase I) transcription inhibitors.
    Lucille Ferret, Jonathan G Pol, Allan Sauvat, Gautier Stoll, Karla Alvarez-Valadez, Alexandra Muller, Julie Le Naour, Felix Peyre, Gerasimos Anagnostopoulos, Isabelle Martins, Maria Chiara Maiuri, Harald Wodrich, Lionel Guittat, Jean-Louis Mergny, Guido Kroemer, Mojgan Djavaheri-Mergny.
      Lysosomes contribute to the development of drug resistance through various mechanisms that include drug sequestration and the activation of adaptive stress pathways. While inhibitors of DNA-to-RNA transcription exhibit potent anticancer effects, the role of lysosomes in modulating responses to such transcription inhibitors remains largely unexplored. This study investigates this aspect in the context of two potent POLR1 (RNA polymerase I) transcription inhibitors, CX-3543 (quarfloxin) and CX-5461 (pidnarulex). Unexpectedly, CX-3543 was found to accumulate within lysosomes, leading to lysosomal membrane permeabilization (LMP) and the subsequent activation of cellular stress adaptation pathways, including those regulated by the transcription factor TFEB and autophagy. Disrupting TFEB or autophagy increased cell sensitivity to CX-3543, highlighting the cytoprotective role of these processes in counteracting CX-3543-induced cell death. Moreover, targeting lysosomal membranes with chloroquine derivatives or blue light exposure induced substantial LMP, releasing compound CX-3543 from lysosomes. This effect enhanced both the inhibition of DNA-to-RNA transcription and CX-3543-induced cell death. Similar effects were observed when chloroquine derivatives were combined with CX-5461. Additionally, combining CX-3543 with the chloroquine derivative DC661 more effectively reduced the fibrosarcoma growth in immunocompetent mice than either agent alone. Altogether, our results reveal an unanticipated lysosome-related mechanism that contributes to cancer cell resistance to POLR1 inhibitors and propose a strategy to overcome this resistance.Abbreviations: ATG7: autophagy related 7; ATG13: autophagy related 13; Baf A1: bafilomycin A1; CTSB: cathepsin B; DKO: double knockout; G4: Guanine quadruplex; KO: knockout; LAMP1: lysosomal associated membrane protein 1; LAMP2: lysosomal associated membrane protein 2; LGALS3: galectin 3; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MTORC1: mechanistic target of rapamycin kinase complex 1; NCL: nucleolin; POLR1: RNA polymerase I; SQSTM1/p62: sequestosome 1; TFEB: transcription factor EB; TFE3: transcription factor E3; ULK1: unc-51 like autophagy activating kinase 1.
    Keywords:  Autophagy; TFEB; cancer; cell death; guanine quadruplex ligands; resistance to therapy
    DOI:  https://doi.org/10.1080/15548627.2025.2497614
  2. Pathol Res Pract. 2025 Jun 09. pii: S0344-0338(25)00270-5. [Epub ahead of print]272 156077
    Autophagy in disease management: Exploring the potential of natural products as targeted therapies.
    Laila A Eissa, Amani M Marawan, Mohamed E Marawan, Shimaa A Abass.
      Autophagy is a vital cellular process that degrades and recycles intracellular components via lysosomes, playing a key role in maintaining cellular homeostasis. Alteration of this mechanism has been implicated in the occurrence and progression of numerous diseases, including cancer, neurodegenerative disorders, cardiovascular conditions, and microbial and viral infections. Recent studies have identified several mutations affecting autophagy-related genes and elucidated how defective degradation of specific substrates contributes to disease mechanisms. Natural products are gaining attention for their ability to modulate autophagy through several molecular targets. Herin, we highlight the complicated role of autophagy in disease pathogenesis. We also illustrate how natural products may offer therapeutic value by targeting autophagy in different pathological contexts.
    Keywords:  Autophagy; Cancer; Cardiovascular disease; Microbial infection; Natural products; Neurodegenerative diseases
    DOI:  https://doi.org/10.1016/j.prp.2025.156077
  3. J Mol Biol. 2025 Jun 11. pii: S0022-2836(25)00354-7. [Epub ahead of print] 169288
    ATG9 not just an Autophagy Related Protein.
    Emily Millard, Sharon A Tooze.
      Autophagy proteins coordinate the biogenesis of a phagophore, the formation and maturation of an autophagosome. Genetic mutations of these proteins can result in dysregulated autophagy, stalled autophagosome biogenesis, and lead to cell death. ATG9, the sole transmembrane ATG (autophagy related) protein governs the nucleation of the phagophore. At a molecular level ATG9 has been shown to be a lipid scramblase capable of redistributing lipids across the lipid bilayer. ATG9-positive vesicles can also deliver lipid-modifying enzymes to alter the lipid composition of membranes. Both functions are required for autophagy. However, ATG proteins, including ATG9, play key molecular roles in pathways unrelated to autophagy. ATG9 has been shown to function in multiple pathways at the Golgi, plasma membrane, and lysosomes. ATG9 can also play an important role in immune signalling. The trafficking of ATG9 in ATG9-positive vesicles is essential to many of these pathways. In this review we highlight the functions of ATG9 in autophagy and autophagy-unrelated pathways, here referred to as "non-canonical functions", and summarise the broader role of ATG9A in cell homeostasis.
    Keywords:  ATG9A; Atg9; autophagy; membrane trafficking
    DOI:  https://doi.org/10.1016/j.jmb.2025.169288
  4. Nat Struct Mol Biol. 2025 Jun 17.
    DMXL1 promotes recruitment of V1-ATPase to lysosomes upon TRPML1 activation.
    Chan Lee, Matthew J G Eldridge, Miguel A Gonzalez-Lozano, Thomas Bresnahan, Zachary Niday, Donato Del Camino, Tao Fu, Joao A Paulo, Magdalene M Moran, Sophie Helaine, J Wade Harper.
      Lysosomes, central hydrolytic organelles, are regulated by ion flow, including calcium and protons, via transporters and channels to maintain an acidified lumen for hydrolytic activity. TRPML1, a lysosomal ion channel, effluxes cations upon activation, promoting rapid conjugation of ATG8 proteins to the lysosomal membrane in a process known as conjugation of ATG8 to single membranes (CASM). However, our understanding of how TRPML1 activation reorganizes the lysosomal proteome is poorly understood. Here, we identify DMXL1 as a key regulator of lysosomal homeostasis through quantitative proteomics of lysosomes during TRPML1 activation by the agonist MLSA5. DMXL1 is recruited to lysosomes and Salmonella-containing vacuoles, both in a CASM-dependent manner. As the mammalian ortholog of yeast Rav1, DMXL1 assembles with Rav2 ortholog ROGDI and WDR7, and associates with V0 and V1 subunits of the lysosomal V-ATPase. TRPML1 activation drives V1 subunit recruitment to lysosomes in a DMXL1- and DMXL2-dependent manner. DMXL1- and DMXL2-deficient cells display reduced V1-ATPase recruitment, increased lysosomal pH and diminished hydrolytic capacity. Using AlphaFold modeling supported by cross-linking proteomics, we identify interaction interfaces within the DMXL1-ROGDI-WDR7 complex, as well as an ATP6V1A binding interface in DMXL1, whose mutation affects interaction and function. Our findings suggest CASM-dependent DMXL1 recruitment, coupled with V-ATPase assembly, is critical for maintaining lumenal pH and lysosomal function in response to TRPML1 activation.
    DOI:  https://doi.org/10.1038/s41594-025-01581-x
  5. J Med Genet. 2025 Jun 20. pii: jmg-2025-110654. [Epub ahead of print]
    Biallelic SIDT2 loss-of-function in a child with cerebellar ataxia and lysosomal dysfunction mimics impairment of SIDT2 in mice.
    Tan Nguyen, Grace Yoon, Blake R C Smith, Martine Tétreault, Jeiwook Chae, Sean Massey, Simranpreet Kaur, John Christodoulou, Craig P Hunter, Ken C Pang.
      SIDT2 (Systemic Interference Deficient 1 Transmembrane Family Member 2) is a lysosomal membrane protein involved in RNA degradation via RNAutophagy. While animal models have indicated a link between SIDT2 deficiency and lysosomal storage disorders, no human cases have been reported. Here, we report a child with biallelic SIDT2 missense variants (p.Arg529Trp, p.Arg678Trp), who developed progressive neurological decline with cerebellar atrophy and Parkinsonian features. Functional studies revealed that the affected individual's variants disrupted the ability of SIDT2 to interact with RNA. Fibroblasts from the affected individual showed impaired autophagy, characterised by abnormal accumulation of autophagy markers. In mouse models, Sidt2 was found to be highly expressed in the brain, particularly in the hippocampus and cerebellum. Sidt2 loss-of-function in mice resulted in not only impaired autophagy in the brain but also neurological dysfunction, including motor incoordination and eventual seizures. These findings suggest that SIDT2 deficiency contributes to both autophagic dysfunction and neurodegenerative processes, providing insight into a potential role in human neurological disease.
    Keywords:  Genetic Diseases, Inborn; Neurodegenerative Diseases
    DOI:  https://doi.org/10.1136/jmg-2025-110654
  6. Aging Dis. 2025 Jun 07.
    Exercise as a Metabolic Regulator: Targeting AMPK/mTOR-Autophagy Crosstalk to Counteract Sarcopenic Obesity.
    Daoqi Zhang, Congfei Lu, Kai Sang.
      Sarcopenic obesity (SO), a geriatric syndrome characterized by the coexistence of progressive skeletal muscle atrophy and excessive adipose tissue accumulation, represents a growing public health challenge associated with aging populations. While multifactorial pathogenesis involves chronic inflammation, hormonal changes, and mitochondrial dysfunction, sedentary lifestyles and aging remain primary modifiable and non-modifiable risk factors, respectively. Mechanistically, exercise exerts dual therapeutic effects: (1) hypertrophy of type II muscle fibers through IGF-1/Akt/mTORC1 signaling activation, and (2) enhanced lipid β-oxidation via AMPK/PGC1α axis stimulation, thereby mitigating both sarcopenia and adiposity. The autophagy-lysosome system, a conserved cellular quality-control mechanism, orchestrates organelle turnover and nutrient recycling through three distinct pathways: macroautophagic, chaperone-mediated autophagy, and mitophagy. In SO, impaired proteolytic and lipolytic processes converge to induce autophagic flux blockade, manifested by accumulated p62/SQSTM1 and reduced LC3-II/LC3-I ratio. Targeting the AMPK/mTOR signaling nexus, which senses cellular energy status, emerges as a strategic intervention. Exercise-mediated ATP depletion activates AMPK while suppressing mTORC1, thereby synchronously inducing autophagy initiation (ULK1 phosphorylation) and lysosomal biogenesis (TFEB nuclear translocation). This metabolic reprogramming ultimately restores proteostasis and lipid homeostasis in myocytes and adipocytes.
    DOI:  https://doi.org/10.14336/AD.2025.0419
  7. Cell Rep. 2025 Jun 17. pii: S2211-1247(25)00580-7. [Epub ahead of print]44(6): 115809
    Hexokinase 2 interacts with PINK1 to facilitate mitophagy in astrocytes and restrain inflammation-induced neurotoxicity.
    Jack H Howden, Hanna Hakansson, Manuela Nieto-Rostro, Robyn McAdam, Charles Arber, Nicholas J Brandon, Josef T Kittler.
      Mitochondria are essential for ATP production, calcium buffering, and apoptotic signaling, with mitophagy playing a critical role in removing dysfunctional mitochondria. This study demonstrates that PINK1-dependent mitophagy occurs more rapidly and is less spatially restricted in astrocytes compared to neurons. We identified hexokinase 2 (HK2) as a key regulator of mitophagy in astrocytes, forming a glucose-dependent complex with PINK1 in response to mitochondrial damage. Additionally, exposure to neuroinflammatory stimuli enhances PINK1/HK2-dependent mitophagy, providing neuroprotection. These findings contribute to our understanding of mitophagy mechanisms in astrocytes and underscore the importance of PINK1 in cellular health and function within the context of neurodegenerative diseases.
    Keywords:  CP: Metabolism; CP: Neuroscience; PINK1; Parkinson’s disease; astrocyte; hexokinase; inflammation; metabolism; mitochondria; mitophagy; neurodegeneration
    DOI:  https://doi.org/10.1016/j.celrep.2025.115809
  8. Cell Commun Signal. 2025 Jun 19. 23(1): 296
    Lysosomal targeting of liposomes with acidic pH and Cathepsin B induces protein aggregate clearance.
    Minsol Jeon, Da-Eun Kim, So Young Choi, Seoyoung Kim, Seongchan Kim, Hyojin Lee, Hyunkyung Kim.
      The autophagy-lysosomal pathway is a cellular degradation mechanism that regulates protein quality by eliminating aggregates and maintaining normal protein function. It has been reported that aging itself reduces lysosomal proteolytic activity in age-related neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease. Reduction in lysosomal function may underlie the accumulation of protein aggregates such as amyloid beta (Aβ), tau, and α-synuclein. Some of these protein aggregates may cause additional lysosomal dysfunction and create a vicious cycle leading to a gradual increase in protein aggregation. In this study, liposome-based lysosomal pH-modulating particles (LPPs), containing a liquid solution to adjust lysosomal pH, have been developed to restore lysosomal function. The results demonstrate that acidic LPPs effectively restore lysosomal function by recovering lysosomal pH and facilitating the removal of protein aggregates. These findings demonstrated that acidic LPPs could effectively recover the abnormal lysosomal function via restoration of lysosomal pH and enhance the clearance of protein aggregates. Furthermore, the simultaneous introduction of Cathepsin B (CTSB) proteins and acidic LPP revealed a synergistic effect, promoting lysosomal pH recovery and enhancing aggregates removal. These findings suggest a novel strategy for improving lysosomal clearance activity in proteinopathies.
    Keywords:  Aggregate clearance; Autophagy; Cathepsin; Lysosome; Proteinopathy
    DOI:  https://doi.org/10.1186/s12964-025-02310-z
  9. FASEB J. 2025 Jun 30. 39(12): e70729
    The Golgi Stacking Protein GORASP2 Regulates Mouse Primordial Follicle Activation by Suppressing the Autophagy Lysosome Pathway via RAP1 Competing With mTOR for RAPTOR Binding.
    Saifei Hu, Yipin Wang, Tian Wu, Hui Luo, Jianhua Chen, Yingnan Wang, Cao Li, Siyue Yin, Zhihan Guo, Yanyan Zhu, Haijun Bian, Yun Qian, Ruizhi Feng.
      Primordial follicle pool is the foundation of female reproductive life and abnormal primordial follicle activation may lead to severe diseases such as premature ovarian failure and premature ovarian insufficiency. Golgi reassembly stacking protein 2 (GORASP2) plays an important role in autophagy by regulating autophagy maturation through glycosylation modification. In the current study we found that GORASP2 is a key factor in mammalian primordial follicle activation through autophagy lysosome pathway. Knocking down of Gorasp2 in the ovaries of newborn mice led to decreased number of activated primary follicles, and the level of FSH (Follicle-stimulating Hormone) in the primary follicles was increased. Comparing with negative control ovaries, transcription profiling showed differentially expressed genes were mainly enriched in the autophagic lysosome, HIF-1 signaling pathway and PI3K-AKT signaling pathway. We found that the ratio of autophagy marker protein LC3-II/LC3-I increased and the level of SQSTM1 protein decreased by Western blot, indicating an elevated autophagy level in GORASP2-knockdown ovaries. Further examination demonstrated that the small G protein Rap1, a member of the Ras superfamily was activated after GORASP2 inhibition and the phosphorylation of mTOR was inhibited by disrupting the mTOR-Raptor interaction, thus initiating autophagy in primordial follicles. In addition, levels of ROS and ATP were increased and citrate lyase was decreased, suggesting a putative disrupted mitochondrial function. Finally, AKT signaling pathways were blocked and may also affect the developmental potential of these affected primordial follicles. In summary, our study emphasized the Golgi stacking protein GORASP2 as an important regulator in primordial follicle activation by participating in the initiation of autophagy, providing an experimental basis for the involvement of Golgi related components in the activation process of primordial follicles through autophagy pathway. This study also shed light upon the deeper understanding of primordial follicle activation related diseases and may contribute a new angle for their future treatment.
    Keywords:  GORASP2; RAPTOR; autophagy; mTOR; primordial follicle activation
    DOI:  https://doi.org/10.1096/fj.202500019R
  10. ACS Chem Biol. 2025 Jun 16.
    Biphasic Cellular Response Triggered by Tetrandrine-Mediated Dysfunction and Lysophagic Clearance of Lysosomes.
    Zhe Yang, Tomoki Takahashi, Ayase Hoshino, Tatsuya Yamamoto, Hideyuki Shigemori, Yusaku Miyamae.
      Lysosomes play an important role in the degradation of cellular components and are correlated with various other physiological phenomena. Lysophagy is a cellular quality control system that maintains homeostasis by removing damaged lysosomes through autophagy. The involvement of lysosomal dysfunction in the pathogenesis of certain illnesses (e.g., neurodegeneration) highlights the potential of small molecules that regulate lysophagy as drug candidates. Here, we found that tetrandrine, a bis-benzylisoquinoline alkaloid, induces lysophagy, leading to the clearance of damaged lysosomes in mammalian cells. To visualize the target organelles of tetrandrine, we synthesized a chimeric compound in which tetrandrine was connected to boron-dipyrromethene via a polyethylene glycol linker. Flow cytometry analysis confirmed the cellular uptake of the synthesized probe. An organelle-staining assay showed that the fluorescent signal of the probe was specifically colocalized with lysosomes. Tetrandrine transiently increased the lysosomal pH level, which returned to normal at 24 h post treatment. Consistently, the level of mCherry-tagged galectin-3, a marker protein for lysophagy, transiently increased and then diminished under treatment with tetrandrine. Tetrandrine also induced dephosphorylation of transcription factor EB, a regulator of lysosomal biogenesis, promoting its translocation from the cytosol to the nucleus. These results suggest that tetrandrine induces a biphasic cellular response, first disrupting lysosomal function before facilitating cellular lysosomal homeostasis through lysophagy and lysosomal biogenesis. This dual effect distinguishes tetrandrine from existing lysosomal modulators.
    DOI:  https://doi.org/10.1021/acschembio.5c00220
  11. Neural Regen Res. 2025 Jun 19.
    ATP6V0A1 protects dopaminergic neurons via the autophagy-lysosomal pathway in Parkinson's disease.
    Yuwan Lin, Zixin Tan, Wenfeng Ye, Weimin Li, Hao Chen, Yuping Lin, Miaomiao Zhou, Hanqun Liu, Qin Liu, Zhiling Zhang, Weixin Kong, Zongtang Xu, Hao Lin, Mingshu Mo, Wenyuan Guo, Keye Lin, Jiaxin Tang, Yueying Zheng, Wenlong Zhang, Pingyi Xu, Xiang Chen.
       ABSTRACT: Parkinson's disease is the second most common neurodegenerative disorder. ATPase H+ transporting V0 subunit A1 (ATP6V0A1) is a component of vacuolar H+-ATPase (V-ATPase), an ATP-dependent proton pump. Our previous research identified an association between the ATP6V0A1 rs601999 variant and Parkinson's disease; however, the underlying mechanisms of ATP6V0A1 in Parkinson's disease remain elusive. In this study, we generated ATP6V0A1 knockdown and overexpression models and then examined the degeneration of dopaminergic neurons, lysosomal function, and the autophagy-lysosomal pathway using immunohistochemistry, western blotting, and transmission electron microscopy. We found that ATP6V0A1 protected against lysosomal dysfunction, regulated autophagic flux, and decreased phosphorylated α-synuclein levels in vitro. In vivo, ATP6V0A1 reduced levels of α-synuclein and phosphorylated α-synuclein proteins, mitigated degeneration of dopaminergic neurons, and improved motor dysfunction. Collectively, these findings show that ATP6V0A1 plays a protective role in Parkinson's disease by modulating the autophagy-lysosomal pathway. A correlation between ATP6V0A1 and Parkinson's disease susceptibility may serve as a biomarker for Parkinson's disease, while the protective effects of ATP6V0A1 could represent a potential therapeutic target for the disease.
    Keywords:  ; ATP6V0A1; Parkinson’s disease; autophagy; dopaminergic neurons; lysosome; mTORC; α-synuclein
    DOI:  https://doi.org/10.4103/NRR.NRR-D-24-01420
  12. Animal Model Exp Med. 2025 Jun 16.
    Pbs2 regulates late-stage macroautophagy in Saccharomyces cerevisiae.
    Jianing Song, Haolin Zhang, Xingyu Cao, Zizhang Ren, Chao Tian, Miao Jia, Meiling Wu, Xiaoli Wang, Juan Wang.
      Autophagy is crucial for maintaining cellular homeostasis and is linked to various diseases. In Saccharomyces cerevisiae, the Polymyxin B Sensitivity 2 (Pbs2) protein is a member of the mitogen-activated protein kinase (MAPK) family and plays a role in mitophagy. To explore the potential role of Pbs2 in macroautophagy, we engineered wild-type and PBS2-deficient cells using plasmid construction and yeast transformation techniques, followed by a series of autophagy assays. First, after nitrogen starvation, the levels of autophagic activity were evaluated with the classical GFP-Atg8 cleavage assay and the Pho8Δ60 activity assay at different time points. Deleting PBS2 significantly decreased both GFP-Atg8 protein cleavage and Pho8Δ60 activity, indicating that Pbs2 is essential for macroautophagy. Furthermore, the influence of Pbs2 on macroautophagy was shown to be independent of Hog1, a well-known downstream factor of Pbs2. Second, the Atg8 lipidation assay demonstrated that Atg8 lipidation levels increased upon PBS2 deletion, suggesting that Pbs2 acts after Atg8 lipidation. Third, the proteinase K protection assay indicated that the loss of PBS2 led to a higher proportion of closed autophagosomes, implying that Pbs2 impacts the later stages of macroautophagy following autophagosome closure. In conclusion, Pbs2 regulates the late stages of macroautophagy induced by nitrogen starvation.
    Keywords:  Hog1; MAPK; Pbs2; autophagy
    DOI:  https://doi.org/10.1002/ame2.70042
  13. Front Immunol. 2025 ;16 1597222
    Resistance training alleviates muscle atrophy and muscle dysfunction by reducing inflammation and regulating compromised autophagy in aged skeletal muscle.
    Yangfan Cao, Jiawei Zhou, Helong Quan, Wei Li, Ting Li, Lifeng Wang.
       Background: Age related muscle atrophy is associated with chronic inflammation and impaired autophagy. Resistance training serves as an effective intervention for enhancing skeletal muscle hypertrophy.
    Methods: This study utilized a naturally aged mouse model to investigate the role of the mammalian target of rapamycin complex 1 (mTORC1) pathway in mediating the effects of resistance training on chronic inflammation and autophagy in aged skeletal muscle.
    Results: Our findings demonstrate that resistance training increased the wet weight of the gastrocnemius (GAS) and quadriceps (Quad), absolute number of fibers and the cross-sectional areas (CSA) of skeletal muscles, as well as enhanced the maximum load and maximum grip strength. These findings indicate that resistance training improved the quality and strength of skeletal muscles in aging mice. Resistance training alleviated inflammation in aged skeletal muscle by promoting M2 macrophage polarization, reducing the mRNA levels of tumor necrosis factor alpha (TNF-α), nuclear factor-kappaB (NF-κB) and interleukin-1beta (IL-1β), and increasing the mRNA levels of interleukin-6 (IL-6) and interleukin-10 (IL-10). In aged skeletal muscle, resistance training decreased the protein expression of mTOR, regulatory-associated protein of mTOR (Raptor), p70 ribosomal protein s6 kinase (p70S6K), IL-1β, and hypoxia-inducible factor 1-alpha (HIF-1α) without affecting protein kinase B (AKT) activity. Moreover, autophagy, which is reduced in aged muscle, was increased by resistance training through increased AMP-activated protein kinase (AMPK) activity and increased BCL-2-interacting protein 1 (Beclin1) and transcriptional factor EB (TFEB) expression.
    Discussion: Our study suggests that resistance training was associated with alleviated inflammation and regulated autophagy, potentially involving the mTORC1-HIF-1α and mTORC1-AMPK pathways, which may contribute to improved skeletal muscle mass in aged mice.
    Keywords:  aging; autophagy; chronic inflammation; mTORC1; skeletal muscle
    DOI:  https://doi.org/10.3389/fimmu.2025.1597222
  14. Neuron. 2025 Jun 18. pii: S0896-6273(25)00425-8. [Epub ahead of print]113(12): 1847-1849
    ACLY links mutant α-synuclein to metabolism, autophagy and neurodegeneration.
    Frédéric Saudou.
      In this issue of Neuron, Son et al.1 reveal how pathologic α-synuclein inhibits autophagy, leading to neurodegeneration. Their work highlights the key roles of the acetyl-CoA-producing enzyme ACLY and aberrant cytoplasmic p300 acetylation, uncovering new therapeutic strategies for Parkinson's disease.
    DOI:  https://doi.org/10.1016/j.neuron.2025.05.027
  15. Cell Rep. 2025 Jun 17. pii: S2211-1247(25)00641-2. [Epub ahead of print]44(7): 115870
    The evolutionarily conserved PRP4K-CHMP4B/vps32 splicing circuit regulates autophagy.
    Sabateeshan Mathavarajah, Sandhya Chipurupalli, Elias B Habib, William D Kim, Megan M Aoki, Dale P Corkery, Kennedy I T Whelan, Jordan Lukacs, Melis Erkan, Victor D Martinez, Kevin S Smith, Stephen B Montgomery, Jayme Salsman, Robert J Huber, Graham Dellaire.
      The pre-mRNA processing factor 4 kinase (PRP4K) is an essential gene in animal cells, making interrogation of its function challenging. Here, we report characterization of a viable knockout model of PRP4K in the social amoeba Dictyostelium discoideum, revealing a function for PRP4K in splicing events controlling autophagy. When prp4k knockout amoebae undergo multicellular development, we observe defects in differentiation linked to abnormal autophagy and aberrant secretion of stalk cell inducer c-di-GMP. Autophagosome-lysosome fusion is impaired after PRP4K loss in both human cell lines and amoebae. PRP4K loss results in mis-splicing and reduced expression of the ESCRT-III gene CHMP4B in human cells and its ortholog vps32 in Dictyostelium, and re-expression of CHMP4B or Vps32 cDNA (respectively) restores normal autophagosome-lysosome fusion in PRP4K-deficient cells. Thus, our work reveals a PRP4K-CHMP4B/vps32 splicing circuit regulating autophagy that is conserved over at least 600 million years of evolution.
    Keywords:  CHMP4B; CP: Cell biology; CP: Developmental biology; Dictyostelium; ESCRT III; PRP4K; PRPF4B; autophagy; splicing kinase
    DOI:  https://doi.org/10.1016/j.celrep.2025.115870
  16. EMBO Rep. 2025 Jun 13.
    ATR promotes mTORC1 activity via de novo cholesterol synthesis.
    Naveen Kumar Tangudu, Alexandra N Grumet, Richard Fang, Raquel Buj, Aidan R Cole, Apoorva Uboveja, Amandine Amalric, Baixue Yang, Zhentai Huang, Cassandra Happe, Mai Sun, Stacy L Gelhaus, Matthew L MacDonald, Nadine Hempel, Nathaniel W Snyder, Katarzyna M Kedziora, Alexander J Valvezan, Katherine M Aird.
      DNA damage and cellular metabolism exhibit a complex interplay characterized by bidirectional feedback. Key mediators of these pathways include ATR and mTORC1, respectively. Previous studies established ATR as a regulatory upstream factor of mTORC1 during replication stress; however, the precise mechanisms remain poorly defined. Additionally, the activity of this signaling axis in unperturbed cells has not been extensively investigated. We demonstrate that ATR promotes mTORC1 activity across various human cancer cells and both human and mouse normal cells under basal conditions. This effect is enhanced in human cancer cells (SKMEL28, RPMI-7951, HeLa) following knockdown of p16, a cell cycle inhibitor that we have previously found increases mTORC1 activity and here found increases ATR activity. Mechanistically, ATR promotes de novo cholesterol synthesis and mTORC1 activation through the phosphorylation and upregulation of lanosterol synthase (LSS), independently of both CHK1 and the TSC complex. Interestingly, this pathway is distinct from the regulation of mTORC1 by ATM and may be specific to cancer cells. Finally, ATR-mediated increased cholesterol correlates with enhanced localization of mTOR to lysosomes. Collectively, our findings demonstrate a novel connection linking ATR and mTORC1 signaling through the modulation of cholesterol metabolism.
    Keywords:  Cholesterol; Lanosterol Synthase; Lysosome; Metabolism; p16
    DOI:  https://doi.org/10.1038/s44319-025-00451-3
  17. Small Sci. 2025 Jun;5(6): 2400607
    Nanomedicine Approaches for Autophagy Modulation in Cancer Therapy.
    Sohaib Mahri, Rodolfo Villa, Ya-Ping Shiau, Menghuan Tang, Kelsey Jane Racacho, Qiufang Zong, Saiful Islam Chowdhury, Tan Hua, Felipe Godinez, Andrew Birkeland, Tzu-Yin Lin, Yuanpei Li.
      Cancer is a daunting global health problem with a steadily rising incidence. Despite the wide arsenal of current anticancer therapies, challenges such as drug resistance, tumor heterogeneity, poor targeting, and severe side effects often lead to suboptimal efficacy and poor patient outcomes, highlighting the need for innovative therapies. Autophagy modulation has emerged as an attractive approach to complement existing therapies. The dual role of autophagy in cancer promotion and suppression has inspired the development of new drugs and therapeutic strategies focusing on both inhibition and induction. Despite the promising results of current autophagy modulators in preclinical studies, challenges such as the lack of selectivity and potency, toxicity, poor pharmacokinetics, and inadequate tumor targeting continue to limit their successful clinical translation. Many of these challenges could be overcome using nanomedicine. This review explores recent advancements in nanomedicine strategies for autophagy modulation. Successful combination strategies leveraging nanoparticles and autophagy modulators in synergy with chemotherapy, immunotherapy, phototherapy, gene therapy, and other modalities are presented. Additionally, nanomaterials with intrinsic autophagy-modulating capabilities, such as self-assembling autophagy inhibitors, are discussed. Finally, limitations of autophagy modulators currently in clinical trials are discussed, and future perspectives on designing nanomedicine for successful clinical implementation are explored.
    Keywords:  autophagy inhibitions; autophagy modulations; cancer therapies; clinical translations; drug resistances; nanomedicines
    DOI:  https://doi.org/10.1002/smsc.202400607
  18. Neural Regen Res. 2025 Jun 19.
    Mitochondrial dynamics dysfunction and neurodevelopmental disorders: From pathological mechanisms to clinical translation.
    Ziqi Yang, Yiran Luo, Zaiqi Yang, Zheng Liu, Meihua Li, Xiao Wu, Like Chen, Wenqiang Xin.
       ABSTRACT: Mitochondrial dysfunction has emerged as a critical factor in the etiology of various neurodevelopmental disorders, including autism spectrum disorders, attention-deficit/hyperactivity disorder, and Rett syndrome. Although these conditions differ in clinical presentation, they share fundamental pathological features that may stem from abnormal mitochondrial dynamics and impaired autophagic clearance, which contribute to redox imbalance and oxidative stress in neurons. This review aimed to elucidate the relationship between mitochondrial dynamics dysfunction and neurodevelopmental disorders. Mitochondria are highly dynamic organelles that undergo continuous fusion and fission to meet the substantial energy demands of neural cells. Dysregulation of these processes, as observed in certain neurodevelopmental disorders, causes accumulation of damaged mitochondria, exacerbating oxidative damage and impairing neuronal function. The phosphatase and tensin homolog-induced putative kinase 1/E3 ubiquitin-protein ligase pathway is crucial for mitophagy, the process of selectively removing malfunctioning mitochondria. Mutations in genes encoding mitochondrial fusion proteins have been identified in autism spectrum disorders, linking disruptions in the fusion-fission equilibrium to neurodevelopmental impairments. Additionally, animal models of Rett syndrome have shown pronounced defects in mitophagy, reinforcing the notion that mitochondrial quality control is indispensable for neuronal health. Clinical studies have highlighted the importance of mitochondrial disturbances in neurodevelopmental disorders. In autism spectrum disorders, elevated oxidative stress markers and mitochondrial DNA deletions indicate compromised mitochondrial function. Attention-deficit/hyperactivity disorder has also been associated with cognitive deficits linked to mitochondrial dysfunction and oxidative stress. Moreover, induced pluripotent stem cell models derived from patients with Rett syndrome have shown impaired mitochondrial dynamics and heightened vulnerability to oxidative injury, suggesting the role of defective mitochondrial homeostasis in these disorders. From a translational standpoint, multiple therapeutic approaches targeting mitochondrial pathways show promise. Interventions aimed at preserving normal fusion-fission cycles or enhancing mitophagy can reduce oxidative damage by limiting the accumulation of defective mitochondria. Pharmacological modulation of mitochondrial permeability and upregulation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha, an essential regulator of mitochondrial biogenesis, may also ameliorate cellular energy deficits. Identifying early biomarkers of mitochondrial impairment is crucial for precision medicine, since it can help clinicians tailor interventions to individual patient profiles and improve prognoses. Furthermore, integrating mitochondria-focused strategies with established therapies, such as antioxidants or behavioral interventions, may enhance treatment efficacy and yield better clinical outcomes. Leveraging these pathways could open avenues for regenerative strategies, given the influence of mitochondria on neuronal repair and plasticity. In conclusion, this review indicates mitochondrial homeostasis as a unifying therapeutic axis within neurodevelopmental pathophysiology. Disruptions in mitochondrial dynamics and autophagic clearance converge on oxidative stress, and researchers should prioritize validating these interventions in clinical settings to advance precision medicine and enhance outcomes for individuals affected by neurodevelopmental disorders.
    Keywords:  autism spectrum disorders; autophagic clearance; cellular homeostasis; fusion and fission; mitochondrial dynamics; mitophagy; neural regeneration; neurodevelopmental disorders; neuronal energy metabolism; oxidative stress
    DOI:  https://doi.org/10.4103/NRR.NRR-D-24-01422
  19. J Biol Chem. 2025 Jun 12. pii: S0021-9258(25)02220-3. [Epub ahead of print] 110370
    Itraconazole and Posaconazole, Inhibitors of NPC1 Sterol Transport, Act as Pharmacological Chaperones After Washout.
    Weixiang A Wang, Cheng-I J Ma, Noah Steinfeld, Frederick R Maxfield.
      Niemann-Pick type C (NPC) disease is a rare lysosomal storage disorder primarily caused by mutations in the NPC Cholesterol Transporter 1 (NPC1) gene, resulting in cholesterol and lipid accumulation in late endosomes and lysosomes. While several therapeutic drugs show promise in reducing cholesterol accumulation, none of the current treatments are highly effective. Itraconazole and posaconazole, widely used antifungal drugs, have been shown to stabilize misfolded NPC1 proteins, enabling their escape from endoplasmic reticulum-associated degradation. This chaperone-like property makes them attractive candidates for testing chaperones as possible treatments for NPC disease, but both drugs also inhibit NPC1 function. In this study, we employed a washout approach to reverse the inhibitory effects of these drugs, leveraging the fact that wildtype NPC1 proteins have a half-life of about 42 hours. Treating NPC1I1061T/I1061T human fibroblasts with itraconazole or posaconazole for 72 hours followed by 24-48 hours of washout, we observed a significant reduction in lysosomal cholesterol accumulation. A modest rebound was observed 72 hours after drug removal, likely due to protein turnover. We also tested a repeated pulsed exposure treatment, in which short drug treatments were followed by extended washout periods. This strategy preserved the functional benefit of NPC1 stabilization while minimizing inhibitory effects. These findings indicate that a washout strategy can enhance the functional benefits of pharmacological chaperones, offering a potential future therapeutic approach for NPC disease.
    Keywords:  Cholesterol; Lysosomal storage disease; NPC1; Pharmacological chaperones
    DOI:  https://doi.org/10.1016/j.jbc.2025.110370
  20. Metabolism. 2025 Jun 13. pii: S0026-0495(25)00193-3. [Epub ahead of print]170 156324
    NIPSNAP1 and NIPSNAP2 facilitate healthy aging independent of mitophagy.
    Jian Lv, Junmei Wang, Qin Chen, Qianhua Zhong, Hongchao Zhan, Qiuxiao Guo, Jiajie Li, Ningning Guo, Yu Fang, Jingjing Tong, Zhihua Wang.
      Mitochondrial dysfunction is a hallmark of aging and has been implicated in aging-related diseases. NIPSNAP1 and NIPSNAP2 are functionally redundant homologs involved in mitochondrial quality control, yet their roles in healthy aging and longevity remain unclear. Here, we generated a Nipsnap1/2 double knockout (DKO) mouse line and examined its impacts on mitochondrial physiology and natural aging. We demonstrated that the loss of Nipsnap1/2 impaired mitochondrial function and enhanced glycolysis activity, but it did not affect mitophagy despite the significant accumulation of Parkin. Compared with wild-type mice, DKO mice exhibited reduced body weight, deteriorated muscle strength, and pronounced fragility at 24 months of age. Moreover, Nipsnap1/2 depletion exacerbates aging-associated fibrosis and inflammation in the heart, liver and kidney. RNA-seq revealed a pro-aging transcriptome reprogramming toward energy exhaustion in DKO mice, eventually leading to cachexia-like adverse metabolic remodeling. Our findings demonstrate an anti-aging role of NIPSNAP1/2 via the surveillance of mitochondrial health.
    Keywords:  Aging; Cardiac aging; Metabolic disorder; Mitochondrial dysfunction; NIPSNAP1/2
    DOI:  https://doi.org/10.1016/j.metabol.2025.156324
  21. Arch Pharm Res. 2025 Jun 19.
    Oleanolic acid activates the JNK-Sp1-DJ-1 axis to promote mitophagy-mediated neuroprotection in dopaminergic neurons for Parkinson's disease treatment.
    Han-Bin Yang, Chien-Hsing Lee, Nguyen Thao Nhung, Shih-Ya Hung.
      Parkinson's disease (PD) is a prevalent neurodegenerative disorder marked by mitochondrial dysfunction and oxidative stress. Although levodopa remains the gold standard for managing PD motor symptoms, it lacks neuroprotective and disease-modifying effects, highlighting the need for new neuroprotective therapies. Mitophagy, the selective mitochondrial degradation by autophagy, is critical for neuronal health. Oleanolic acid, a natural hepatoprotective compound, shows uncertain efficacy in PD treatment. This study investigated the neuroprotective effects and underlying mechanisms of oleanolic acid using the 1-methyl-4-phenylpyridinium (MPP⁺)-induced cellular model and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD. In vitro, oleanolic acid demonstrated dopaminergic neuroprotection by reducing mitochondrial dysfunction and reactive oxygen species accumulation in PD cells. It upregulated the mitophagic protein DJ-1, enhancing the sequestration of damaged mitochondria into autophagosomes by mitophagy. DJ-1 knockdown attenuated oleanolic acid's neuroprotection, confirming DJ-1's role in oleanolic acid's action. In vivo, pre-treatment with oleanolic acid in MPTP-induced PD mice prevented PD-like motor symptoms, reduced neuronal death in the substantia nigra, and mitigated striatal neurodegeneration. Post-treatment with oleanolic acid not only reduced these effects but also increased Bcl-2 and DJ-1 levels in the substantia nigra and striatum. In vitro, oleanolic acid activated JNK for Sp1 upregulation and nuclear translocation, which induced DJ-1 expression. Computational modeling predicted that oleanolic acid likely interacts with JNK, suggesting this binding might be necessary for JNK-Sp1-DJ-1 axis activation for mitophagy-driven neuroprotection. These results highlight oleanolic acid's potential as a therapeutic agent in PD prevention and treatment via the JNK-Sp1-DJ-1 pathway. Further studies are required to validate its efficacy.
    Keywords:  DJ-1; JNK-Sp1 pathway; Mitophagy; Neuroprotection; Oleanolic acid; Parkinson’s disease
    DOI:  https://doi.org/10.1007/s12272-025-01550-4
  22. Mol Cell. 2025 Jun 19. pii: S1097-2765(25)00471-X. [Epub ahead of print]85(12): 2261-2263
    Fumarate hits the brakes on mitophagy.
    Ana Paula Magalhães Rebelo, Christian Frezza.
      In this issue of Molecular Cell, Ham et al.1 demonstrate that the metabolite fumarate, when accumulated in cells, can influence mitochondrial quality control by inhibiting Parkin translocation to mitochondria and blocking its E3 ligase activity via the fumarate-dependent post-translational modification called succination.
    DOI:  https://doi.org/10.1016/j.molcel.2025.05.032
  23. Cell Rep. 2025 Jun 13. pii: S2211-1247(25)00622-9. [Epub ahead of print]44(6): 115851
    ENPP1 governs the metabolic regulation of effector T cells in autoimmunity by detecting cytosolic mitochondrial DNA.
    Huiyan Ji, Wanwan Jiang, Juan Zhang, Mengdi Liu, Danhua Su, Jiaxin Lei, Lingyi Li, Ming Zheng, Ting Liu, Zhichun Liu, Qinghua Cao, Lin Xu, Sidong Xiong, Zhenke Wen.
      T cells play a pivotal role in the pathogenesis of systemic lupus erythematosus (SLE), yet the underlying molecular mechanisms governing their fate remain elusive. Here, we identify cytosolic mitochondrial DNA (mtDNA) as an intrinsic trigger for driving effector T cell differentiation in patients with SLE. Specifically, accumulated cytosolic mtDNA is sensed by ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), which enhances the transcription of GLUT1 and glycolysis in SLE T cells. This metabolic shift reduces lipogenesis and depletes free fatty acids (FFAs), impairing the N-myristylation and lysosomal localization of AMP-activated protein kinase (AMPK). Inactive AMPK fails to restrain mammalian target of rapamycin complex 1 (mTORC1), leading to its hyperactivation and driving the mal-differentiation of effector T cells. Consequently, interventions targeting ENPP1, glycolysis, AMPK, and mTORC1 effectively inhibit the generation of immunoglobulin (Ig)G anti-double-stranded DNA (dsDNA) and the progression of lupus nephritis in humanized SLE chimeras. Overall, our findings uncover an mtDNA-ENPP1-metabolic axis that governs effector T cell fate in autoimmunity.
    Keywords:  AMPK; CP: Immunology; CP: Molecular biology; ENPP1; SLE; T cell; mitochondrial DNA
    DOI:  https://doi.org/10.1016/j.celrep.2025.115851
  24. Cell Biochem Funct. 2025 Jun;43(6): e70092
    PINK1 Deficiency Facilitates Palmitic Acid-Induced Inflammation by Disrupting Mitochondrial Function to Activate mtDNA-cGAS-STING Signaling.
    Bin Ye, Yingting Pei, Henian Li, Yuqi Jiang, Wenying Jin, Yueqiu Gao, Wen Liu, Xin Guan, Yu Qiao, Xu Gao, Yanfen Zhang, Ning Ma, Hao Chang.
      Metabolic cells exhibit low-grade chronic inflsammation characterized by excessive production and secretion of proinflammatory cytokines and chemokines in response to overnutrition and energy excess. Mitochondrial dysfunction is closely associated with metabolic inflammation. PINK1 (phosphatase and tensin homology-induced putative kinase 1) is a crucial pathway controlling mitochondrial autophagy, essential for maintaining mitochondrial quality control and metabolic homeostasis. The aim of this study was to investigate the role of PINK1 in metabolic inflammation. Our findings indicate that in adipocytes, palmitic acid (PA) activates the expression of PINK1. Additionally, knockdown of PINK1 exacerbates PA-induced adipocyte inflammation. Mechanistically, PINK1 deficiency impairs mitochondrial function, leading to the release of mtDNA and further activation of the cGAS-STING pathway. Therefore, targeting mitochondrial autophagy in adipocytes and the cGAS-STING pathway may represent effective approaches to alleviate the chronic inflammation associated with obesity and related metabolic disorders.
    Keywords:  PINK1; cGAS‐STING; inflammation; mitochondria; obesity
    DOI:  https://doi.org/10.1002/cbf.70092
  25. Adv Sci (Weinh). 2025 Jun 20. e01070
    Gut Metabolite Indole-3-Propionic Acid Regulates Macrophage Autophagy Through PPT1 Inhibiting Aging-Related Myocardial Fibrosis.
    Jing Lu, Hongyan Wang, Haiyu Zhang, Jiahao Li, Hanqi Li, Qiuyu Chen, Dongyu Han, Jialiang Liu, Lin Lv, Jie Xiong, Keying Yuan, Xianpeng Wei, Siqi Sheng, Fukai Liu, Yuanqi Shi, Zengxiang Dong, Yue Li.
      Cardiac fibrosis, a key pathological feature of cardiac remodeling, is a major contributor to mortality in older patients with heart failure. The underlying mechanisms are complex, involving alterations in intercellular communication and chronic inflammation. This study investigates the role of indole-3-propionic acid (IPA) in aging-related myocardial fibrosis and its regulatory effects on autophagy through palmitoyl-protein thioesterase 1 (PPT1). Here, plasma levels of IPA, a tryptophan-derived metabolite, are found to be reduced in older patients with heart failure, and this reduction is associated with deteriorating cardiac function. Notably, IPA supplementation significantly attenuated aging-related myocardial fibrosis. PPT1, a lysosomal enzyme involved in autophagy, is upregulated in macrophages during aging. IPA reversed aging-induced increase in PPT1 expression. Using PPT1flox/flox Lyz2-cre mice, it is demonstrated that macrophage-specific deletion of PPT1 significantly reduced cardiac inflammation and myocardial fibrosis in aged mice. Furthermore, PPT1 silencing in macrophages reduced the expression of myocardial fibrosis markers in vitro. Mechanistically, IPA regulated PPT1 expression to modulate the PI3K-AKT-mTOR pathway, thereby restoring autophagic activity in senescent macrophages and suppressing both inflammation and aging-related myocardial fibrosis. Additionally, IPA influenced the cGAS-STING signaling pathway to regulate PPT1 expression. These findings demonstrate that IPA inhibits PPT1, activates autophagy in macrophages, and mitigates aging-related myocardial fibrosis.
    Keywords:  IPA; aging‐related cardiac fibrosis; autophagy; macrophages; palmitoyl‐protein thioesterase 1
    DOI:  https://doi.org/10.1002/advs.202501070
  26. Mol Biomed. 2025 Jun 19. 6(1): 42
    Role of mitochondria in physiological activities, diseases, and therapy.
    Lilin Wang, Xiaoting Zhou, Tianqi Lu.
      Mitochondria are generally considered essential for life in eukaryotic organisms because they produce most of the energy or adenosine triphosphate (ATP) needed by the cell. Beyond energy production, it is now widely accepted that mitochondria also play a pivotal role in maintaining cellular homeostasis and signaling. The two core processes of mitochondrial dynamics, fission and fusion, serve as crucial foundations for maintaining mitochondrial morphology, distribution, and quantity, thereby ensuring cellular homeostasis. Mitochondrial autophagy (mitophagy) ensures the selective degradation of damaged mitochondria, maintaining quality control. Mitochondrial transport and communication further enhance their role in cellular processes. In addition, mitochondria are susceptible to damage, resulting in dysfunction and disruption of intracellular homeostasis, which is closely associated with the development of numerous diseases. These include mitochondrial diseases, neurodegenerative diseases, cardiovascular diseases (CVDs) and stroke, metabolic disorders such as diabetes mellitus, cancer, infectious diseases, and the aging process. Given the central role of mitochondria in disease pathology, there is a growing need to understand their mechanisms and develop targeted therapies. This review aims to provide a comprehensive overview of mitochondrial structure and functions, with a particular focus on their roles in disease development and the current therapeutic strategies targeting mitochondria. These strategies include mitochondrial-targeted antioxidants, modulation of mitochondrial dynamics and quality control, mitochondrial genome editing and genetic therapy, and mitochondrial transplantation. We also discuss the challenges currently facing mitochondrial research and highlight potential future directions for development. By summarizing the latest advancements and addressing gaps in knowledge, this review seeks to guide future research and clinical efforts in the field of mitochondrial medicine.
    Keywords:  Cancer; Mitochondria; Mitochondrial diseases; Mitochondrial homeostasis; Therapy
    DOI:  https://doi.org/10.1186/s43556-025-00284-5
  27. iScience. 2025 Jun 20. 28(6): 112637
    The Arg/N-degron pathway mediates the secretion of apoptotic exosomes under oxidative stress in cancer cell.
    Su Bin Kim, Ji Su Lee, Chan Hoon Jung, Eun Hye Cho, Ho Seok Seo, Gee Eun Lee, Hye Yeon Kim, Su Jin Lee, Min Ju Lee, Hans Jin-Young Oh, Ah Jung Heo, Do Hyun Han, Yong Tae Kwon, Chang Hoon Ji.
      Exosomes from cancer cells are versatile mediators of cell-to-cell communication, whose cargoes are dynamically loaded in response to various stress conditions. In this study, we demonstrate that under oxidative stress, cancer cells secrete exosomes that induce apoptosis in neighboring cells via the Arg/N-degron pathway. In this mechanism, Rab interacting lysosomal protein (RILP) is cleaved at Asp75 in response to oxidative stress which requires ATE1 R-transferase. The cleaved form of RILP recruits the ESCRT-II proteins VPS22 and VPS36 to endosomes from which the interluminal vesicles are invaginated generating exosomes. By using proteomics analyses, we also demonstrate that exosomes secreted from cancer cells upon oxidative stress are enriched apoptotic proteins including pro-apoptotic and anti-inflammatory cytokine ANXA1. These exosomes induce apoptosis of normal cancer cells transporting ANXA1 in an Arg/N-degron pathway-dependent manner. Our results show that the Arg/N-degron pathway modulates exosome-mediated apoptosis in cancer cells under oxidative stress underlying RILP-dependent secretion of ANXA1.
    Keywords:  Cancer; Cell biology
    DOI:  https://doi.org/10.1016/j.isci.2025.112637
  28. J Biosci. 2025 ;pii: 48. [Epub ahead of print]50
    Co-chaperones fine-tune the function of heat shock protein 70 (Hsp70), whether to fold, hold, or degrade substrates in ensuring cellular protein homeostasis.
    Pramit Bhattacharjee, Joydeep Roy, Atin Kumar Mandal.
      The molecular chaperone Hsp70 is a pivotal player in cellular protein quality control due to its wide range of substrates ranging from unfolded, native, to misfolded proteins. Increasing evidence suggests that Hsp70 decides the fate of proteins; however, the inherent rules that govern the decision-making capacity of Hsp70 are not clear. In this review, we have articulated the functions of Hsp70 with respect to proteostasis and established a link between its co-chaperones in deciding the fate of the substrate. The substrate binding of Hsp70 is mediated by its catalytic cycle where Hsp70 achieves high- and low-substrate-affinity ADP- and ATP-bound forms, respectively. This catalytic cycle of Hsp70 is maintained by co-chaperones J-domain proteins (JDPs), and nucleotide exchange factors (NEFs). JDPs bind to the ATP-bound form of Hsp70 and hydrolyze ATP that enhances substrate binding, whereas NEFs exchange ADP with ATP and facilitate substrate release. During evolution, several isoforms of Hsp70 and its co-chaperones have emerged which may have functional significance. Apart from facilitating the catalytic cycle of Hsp70, co-chaperones often mediate collaboration between Hsp70 and downstream protein quality-control pathways such as the ubiquitin proteasome system, autophagy, or disaggregase machinery. Therefore, co-chaperones have a significant role in Hsp70's triage decision of whether to fold, hold, or degrade.
  29. Proc Natl Acad Sci U S A. 2025 Jun 24. 122(25): e2425015122
    Tumor-promoting UBR4 coordinates impaired mitophagy-associated senescence and lung adenocarcinoma pathogenesis.
    Dawon Jeong, Seo Hyeong Park, Jiwon Kim, Hyeyoon Kim, Yejin Jang, Jaemoon Koh, Yoon Kyung Jeon, Takafumi Tasaki, Yong Tae Kwon, Dohyun Han, Sung-Yup Cho, Min Jae Lee.
      Cellular senescence, an irreversible cell cycle arrest, plays a pivotal role in development, aging, and tumor suppression. However, the fundamental pathway coordinating senescence and neoplastic transformation remains unclear. Here, we describe the tumorigenic involvement of ubiquitin protein ligase E3 component n-recognin 4 (UBR4), an E3 ubiquitin ligase of the N-degron pathway, in lung adenocarcinoma (LUAD). Public genome databases revealed high UBR4 expression in LUAD patients, associated with a dysregulated cell cycle and impaired mitochondrial homeostasis. UBR4 knockout (ΔUBR4) in A549 lung cancer cells induced cellular senescence with defective mitochondria. Restoration of UBR4 or antioxidant treatment reversed the ΔUBR4 phenotypes caused by impaired mitophagy. Mitochondrial stress exacerbated mitochondrial dysfunction in ΔUBR4 cells, contributing to diverse cellular phenotypes. Additionally, ΔUBR4 cells exhibited substantially slow tumor growth in mouse xenograft models. In LUAD patients, UBR4 levels correlated with tumor stage, mitophagy markers, and poor survival. These findings suggest a tumor-promoting function of UBR4 in LUAD by regulating mitochondrial quality control. Further research into the pharmacological inhibition of UBR4 could open promising avenues for developing effective antitumor therapies targeting LUAD.
    Keywords:  UBR4; lung adenocarcinoma; mitophagy; oncogene; senescence
    DOI:  https://doi.org/10.1073/pnas.2425015122
  30. Aging Dis. 2025 Jun 18.
    The Mitochondrial Foundations of Parkinson's Disease: Therapeutic Implications.
    Smijin K Soman, Micah R J Woodruff, Ruben K Dagda.
      Mitochondria are dynamic organelles vital for neuronal function due to their ability to generate ATP, sequester cytosolic calcium (Ca2+), regulate lipid metabolism, and modulate apoptosis signaling. In order to maintain these essential functions in healthy neurons, mitochondria must be continuously replenished through mitochondrial turnover and biogenesis. Conversely, the dysregulation of mitochondrial homeostasis can lead to oxidative stress and contribute to the neuropathology of Parkinson's disease (PD). This review will provide an updated in-depth review of mitochondrial processes such as mitophagy, biogenesis, trafficking, oxidative phosphorylation, Ca2+ sequestration, mitochondrial transfer, and their relevance to PD pathophysiology. We provide an extensive overview of the neuroprotective molecular signaling pathways regulated by PD-associated proteins that converge at the mitochondrion. Importantly, in this review we highlight aspects of mitochondrial pathology that converge across multiple models including iPSCs, patient-derived fibroblasts, cell culture models, rodent models and chemical and genetic models of PD. Finally, we provide a comprehensive update on the molecular toolbox used to interrogate these signaling pathways using in vitro and in vivo models of PD and provide insight into the downstream protein targets that can be leveraged to develop novel therapies against PD.
    DOI:  https://doi.org/10.14336/AD.2025.0440
  31. Compr Physiol. 2025 Jun;15(3): e70023
    Lysosomal Acidification: A New Perspective on the Pathogenesis and Treatment of Pulmonary Fibrosis.
    Kai Tian, Mengjiao Yu, Mengna Jiang, Zhengnan Gao, Dongnan Zheng, Weijian Shi, Demin Cheng, Xinyuan Zhao.
      Pulmonary fibrosis is a complex pathophysiological process characterized by local pulmonary inflammation and fibrosis, along with systemic inflammation and distal organ damage. The acidic environment of lysosomes, as intracellular degradation and recycling centers, is important for cellular homeostasis and function. This review summarizes the potential role of lysosomal acidification in pulmonary fibrosis pathogenesis and its implications for cross-organ effects. Various proteins and ion channels, such as V-ATPase, ClC-7, CFTR, TRPML1, and NHE, regulate lysosomal acidification. Lung fibrosis involves many cells, including lung epithelial cells, endothelial cells, macrophages, fibroblasts, and myofibroblasts. Studies have shown that abnormal lysosomal acidification significantly contributes to the onset and progression of pulmonary fibrosis. Damaged epithelial cells activate inflammatory and fibrotic signals through lysosomal dysfunction; abnormal lysosomal acidification in endothelial cells causes tissue edema and inflammatory responses; macrophages exacerbate inflammatory responses due to impaired lysosomal acidification; and fibroblasts hyperproliferate and transform into myofibroblasts due to deficient lysosomal acidification. Chronic pulmonary inflammation increases blood-gas barrier permeability, facilitating extravasation of inflammatory mediators (e.g., IL-6, TNF-α, and TGF-β) into the circulation, where they act as endocrine signals affecting distant organs. These findings provide a rationale for exploring novel therapeutic targets; future pharmacologic modulation of lysosomal acidification and inhibition of key inflammatory mediators may represent important strategies for preventing and treating pulmonary fibrosis and its systemic complications.
    Keywords:  V‐ATPase; chronic inflammation; distal organ damage; lysosome acidification; pulmonary fibrosis
    DOI:  https://doi.org/10.1002/cph4.70023
  32. Int J Biol Sci. 2025 ;21(8): 3631-3648
    Emodin Inhibits NLRP3 Inflammasome Activation and Protects Against Sepsis via Promoting FUNDC1-Mediated Mitophagy.
    Wei Fu, Shu-Chang Liu, Tong-Xiang Xu, Ying Liu, Teng Zhang, Dong-Jie Liu, Xiao Wang, Jian-Yao Wang, Yu-Xin He, Tao Ma.
      Dysregulated activation of the NLR family pyrin domain-containing 3 (NLRP3) inflammasome contributes to the pathogenesis of numerous inflammatory and infectious diseases; however, effective targeted therapies remain elusive. In this study, we identify emodin-a bioactive anthraquinone derived from Rheum palmatum (radix Rhei) and Polygonum cuspidatum (Polygonaceae)-as a potent and selective inhibitor of NLRP3 inflammasome activation. Notably, emodin disrupts the assembly of the NLRP3 complex without impairing inflammasome priming. Transcriptomic profiling via RNA sequencing reveals that emodin reprograms mitochondrial quality control pathways, markedly enhancing mitophagy flux. Mechanistically, emodin suppresses casein kinase II (CK2)-mediated phosphorylation of FUNDC1, a pivotal mitophagy receptor, thereby promoting mitochondrial clearance and preventing mitochondrial reactive oxygen species-induced NLRP3 inflammasome assembly. Both genetic silencing of FUNDC1 and pharmacological inhibition of mitophagy with 3-methyladenine abrogated abrogate the inhibitory effects of emodin, establishing a direct mechanistic link between FUNDC1-dependent mitophagy and NLRP3 regulation. In vivo, emodin confers significant protection in sepsis models, with these protective effects being lost in NLRP3-deficient mice or upon macrophage-specific deletion of FUNDC1. Collectively, our findings uncover a novel CK2-FUNDC1-mitophagy axis through which emodin inhibits NLRP3 inflammasome activation, highlighting its promise as a clinically translatable candidate for the treatment of NLRP3-driven inflammatory diseases.
    Keywords:  Emodin; FUNDC1; Mitochondrial homeostasis; Mitophagy; NLRP3 inflammasome; Sepsis.
    DOI:  https://doi.org/10.7150/ijbs.110904
  33. Trends Biochem Sci. 2025 Jun 18. pii: S0968-0004(25)00129-X. [Epub ahead of print]
    CryoEM provides detailed insights into how VPS15 regulates VPS34 activity.
    Robyn Duttenhefner, Subeksha Subedi, Sangita C Sinha.
      Cook et al. show that the VPS15 pseudokinase domain binds GTP and sequesters its covalently-linked N-terminal myristate. Together, this enforces VPS15 conformations that interact with and stabilize inactive VPS34 kinase domain conformations. Myristate release disrupts this inhibitory interaction and also helps dock VPS34 on membranes to catalyze phosphatidylinositol-3-phophate (PI3P) production.
    Keywords:  GTP-binding pseudokinase; N-myristate sequestration; autophagy; class III phosphatidylinositol 3-kinase (PI3KC3) or vacuolar protein sorting protein 34 (VPS34) complexes; cryo-electron microscopy (cryo-EM); vacuolar protein sorting protein 15 (VPS15)
    DOI:  https://doi.org/10.1016/j.tibs.2025.05.009
  34. NPJ Parkinsons Dis. 2025 Jun 20. 11(1): 177
    Dopamine and cortical neurons with different Parkinsonian mutations show variation in lysosomal and mitochondrial dysfunction.
    Jessica Chedid, Yan Li, Adahir Labrador-Garrido, Dad Abu-Bonsrah, Chiara Pavan, Tyra Fraser, Dmitry Ovchinnikov, Melanie Zhong, Ryan Davis, Dario Strbenac, Jennifer A Johnston, Lachlan H Thompson, Deniz Kirik, Clare L Parish, Glenda M Halliday, Carolyn M Sue, Gautam Wali, Nicolas Dzamko.
      Mutations causing Parkinson's disease (PD) give diverse pathological phenotypes whose cellular correlates remain to be determined. Those with PRKN mutations have significantly earlier selective vulnerability of dopamine neurons, those with SNCA mutations have increased alpha-synuclein deposition, while those with LRRK2 mutations have additional deposition of tau. Yet all three mutation types are implicated in mitochondrial and/or lysosomal dysfunction. To compare cellular dysfunctions associated with these different pathological phenotypes, an unbiased high-content imaging platform was developed to assess both lysosomal and mitochondrial dysfunction, along with alpha-synuclein and tau protein deposition using induced pluripotent stem cell (iPSC) derived cortical and ventral midbrain neurons. Different PD mutations caused cell type specific dysfunctions, likely to impact on both selective neuronal vulnerability and the pathologies observed in PD. Comparison of dopamine neurons identified that both lysosomal and mitochondrial dysfunction were predominant with PRKN lof mutations, whereas SNCA A53T and LRRK2 R1441G mutations had increased tau deposition. In contrast, cortical neurons with SNCA and LRRK2 mutations both had mitochondrial and autophagy impairments without protein deposition, with LRRK2 cells additionally showing decreased glucocerebrosidase activity and increased alpha-synuclein phosphorylation.
    DOI:  https://doi.org/10.1038/s41531-025-01048-2
  35. Cell Commun Signal. 2025 Jun 19. 23(1): 290
    Mitochondrial dysfunction in the regulation of aging and aging-related diseases.
    Xianhong Zhang, Yue Gao, Siyu Zhang, Yiqi Wang, Xinke Pei, Yufei Chen, Jinhui Zhang, Yichen Zhang, Yitian Du, Shauilin Hao, Yujiong Wang, Ting Ni.
      Aging is an irreversible physiological process that progresses with age, leading to structural disorders and dysfunctions of organs, thereby increasing the risk of chronic diseases such as neurodegenerative diseases, diabetes, hypertension, and cancer. Both organismal and cellular aging are accompanied by the accumulation of damaged organelles and macromolecules, which not only disrupt the metabolic homeostasis of the organism but also trigger the immune response required for physiological repair. Therefore, metabolic remodeling or chronic inflammation induced by damaged tissues, cells, or biomolecules is considered a critical biological factor in the organismal aging process. Notably, mitochondria are essential bioenergetic organelles that regulate both catabolism and anabolism and can respond to specific energy demands and growth repair needs. Additionally, mitochondrial components and metabolites can regulate cellular processes through damage-associated molecular patterns (DAMPs) and participate in inflammatory responses. Furthermore, the accumulation of prolonged, low-grade chronic inflammation can induce immune cell senescence and disrupt immune system function, thereby establishing a vicious cycle of mitochondrial dysfunction, inflammation, and senescence. In this review, we first outline the basic structure of mitochondria and their essential biological functions in cells. We then focus on the effects of mitochondrial metabolites, metabolic remodeling, chronic inflammation, and immune responsesthat are regulated by mitochondrial stress signaling in cellular senescence. Finally, we analyze the various inflammatory responses, metabolites, and the senescence-associated secretory phenotypes (SASP) mediated by mitochondrial dysfunction and their role in senescence-related diseases. Additionally, we analyze the crosstalk between mitochondrial dysfunction-mediated inflammation, metabolites, the SASP, and cellular senescence in age-related diseases. Finally, we propose potential strategies for targeting mitochondria to regulate metabolic remodeling or chronic inflammation through interventions such as dietary restriction or exercise, with the aim of delaying senescence. This reviewprovide a theoretical foundation for organismal antiaging strategies.
    Keywords:  Aging-related diseases; Cellular senescence; Chronic inflammation; Metabolic remodelling; Mitochondria
    DOI:  https://doi.org/10.1186/s12964-025-02308-7
  36. Front Neurosci. 2025 ;19 1602149
    Fasting the mitochondria to prevent neurodegeneration: the role of ceramides.
    Luis Armando Valenzuela-Ahumada, Octavio Fabián Mercado-Gómez, Rubi Viveros-Contreras, Rosalinda Guevara-Guzmán, Alberto Camacho-Morales.
      Neurodegenerative diseases affect up to 349.2 million individuals worldwide. Preclinical and clinical advances have documented that altered energy homeostasis and mitochondria dysfunction is a hallmark of neurological disorders. Diet-derived ceramides species might target and disrupt mitochondria function leading to defective energy balance and neurodegeneration. Ceramides as bioactive lipid species affect mitochondria function by several mechanism including changes in membrane chemical composition, inhibition of the respiratory chain, ROS overproduction and oxidative stress, and also by activating mitophagy. Promising avenues of intervention has documented that intermittent fasting (IF) is able to benefit and set proper energy metabolism. IF is an eating protocol that involves alternating periods of fasting with periods of eating which modulate ceramide metabolism and mitochondria function in neurons. This review will address the detrimental effect of ceramides on mitochondria membrane composition, respiratory chain, ROS dynamics and mitophagy in brain contributing to neurodegeneration. We will focus on effect of IF on ceramide metabolism as a potential avenue to improve mitochondria function and prevention of neurodegeneration.
    Keywords:  ceramides; intermittent fasting; microglia; mitophagy; neurodegeneration
    DOI:  https://doi.org/10.3389/fnins.2025.1602149
  37. FASEB J. 2025 Jun 30. 39(12): e70751
    Dolutegravir Inhibits Autophagy In Vitro in a Mouse Blood-Brain Barrier Model.
    Chang Huang, Qing Rui Qu, Reina Bendayan.
      Despite the effectiveness and tolerability of antiretroviral therapy (ART) in treating HIV infection, integrase strand transfer inhibitors, particularly dolutegravir (DTG)-based ART, have been associated with various brain complications. Our research group has previously reported that DTG disrupts the blood-brain barrier (BBB) by inducing endoplasmic reticulum (ER) stress. To further understand DTG-associated toxicity, this follow-up study assessed autophagy dysfunction, a critical process that is closely linked to ER stress, using primary cultures of mouse brain microvascular endothelial cells as a robust BBB rodent model. We demonstrated that DTG exposure at therapeutically relevant concentrations significantly increased Sqstm/p62, LC3B-I and LC3B-II protein expression, and downregulated autophagy-related genes Ulk1 and Atg14, suggesting an autophagy inhibition as a result of DTG treatment. This study provides new insights into the toxicological mechanisms of DTG and pathogenesis of DTG-associated brain complications.
    DOI:  https://doi.org/10.1096/fj.202500568RR
  38. Nat Commun. 2025 Jun 17. 16(1): 5328
    Aneuploidy-induced proteostasis disruption impairs mitochondrial functions and mediates aggregation of mitochondrial precursor proteins through SQSTM1/p62.
    Prince Saforo Amponsah, Jan-Eric Bökenkamp, Olha Kurpa, Svenja Lenhard, Anna Myronova, Daniel Osmar Vega Velazquez, Celina Hirschelmann, Christian Behrends, Johannes M Herrmann, Markus Räschle, Zuzana Storchová.
      Aneuploidy, or aberrant chromosomal content, disrupts cellular proteostasis through altered expression of numerous proteins. Aneuploid cells accumulate SQSTM1/p62-positive cytosolic bodies, exhibit impaired protein folding, and show altered proteasomal and lysosomal activity. Here, we employ p62 proximity- and affinity-based proteomics to elucidate p62 interactors in aneuploid cells and observe an enrichment of mitochondrial proteins. Increased protein aggregation and colocalization of p62 with both novel interactors and mitochondrial proteins is further confirmed by microscopy. Compared to parental diploids, aneuploid cells suffer from mitochondrial defects, including perinuclearly-clustered mitochondrial networks, elevated reactive oxygen species levels, reduced mitochondrial DNA abundance, and impaired protein import, leading to cytosolic accumulation of mitochondrial precursor proteins. Overexpression of heat shock proteins in aneuploid cells mitigates protein aggregation and decreases the colocalization of p62 with the mitochondrial protein TOMM20. Thus, proteotoxic stress caused by chromosome gains results in the sequestration of mitochondrial precursor proteins into cytosolic p62-bodies, thereby compromising mitochondrial function.
    DOI:  https://doi.org/10.1038/s41467-025-60857-4
  39. EMBO J. 2025 Jun 16.
    Dysfunctional mitochondria trap proteins in the intermembrane space.
    Tamara Flohr, Markus Räschle, Johannes M Herrmann.
      The accumulation of mitochondrial precursor proteins in the cytosol due to mitochondrial dysfunction compromises cellular proteostasis and is a hallmark of diseases. Why non-imported precursors are toxic and how eukaryotic cells prevent their accumulation in the cytosol is still poorly understood. Using a proximity labeling-based assay to globally monitor the intramitochondrial location of proteins, we show that, upon mitochondrial dysfunction, many mitochondrial matrix proteins are sequestered in the intermembrane space (IMS); something we refer to as "mitochondrial triage of precursor proteins" (MitoTraP). MitoTraP is not simply the result of a general translocation block at the level of the inner membrane, but specifically directs a subgroup of matrix proteins into the IMS, many of which are constituents of the mitochondrial ribosome. Using the mitoribosomal protein Mrp17 (bS6m) as a model, we found that IMS sequestration prevents its mistargeting to the nucleus, potentially averting interference with assembly of cytosolic ribosomes. Thus, MitoTraP represents a novel, so far unknown mechanism of the eukaryotic quality control system that protects the cellular proteome against the toxic effects of non-imported mitochondrial precursor proteins.
    Keywords:  Intermembrane Space; Mitochondria; Nucleolus; Protein Targeting; Ribosome
    DOI:  https://doi.org/10.1038/s44318-025-00486-1
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