bims-auttor Biomed News
on Autophagy and mTOR
Issue of 2023‒12‒10
33 papers selected by
Viktor Korolchuk, Newcastle University
  1. mTOR takes charge: Relaying uncharged tRNA levels by mTOR ubiquitination.
  2. Crosstalk between the mTOR pathway and primary cilia in human diseases.
  3. UVRAG: orchestrating the initiation of reticulophagy.
  4. The sensitivity of mTORC1 signaling activation renders tissue regenerative capacity.
  5. Naringin Protects against Non-Alcoholic Fatty Liver Disease by Promoting Autophagic Flux and Lipophagy.
  6. An Arabidopsis Rab18 GTPase promotes autophagy by tethering ATG18a to the ER in response to nutrient starvation.
  7. Ubiquitin-specific protease 22 promotes tumorigenesis and progression by an FKBP12/mTORC1/autophagy positive feedback loop in hepatocellular carcinoma.
  8. Ceramide regulation of autophagy: A biophysical approach.
  9. Therapeutic potential of natural products against Alzheimer's disease via autophagic removal of Aβ.
  10. Transcription Factor EB-Mediated Lysosomal Function Regulation for Determining Stem Cell Fate under Metabolic Stress.
  11. Human WIPI β-propeller function in autophagy and neurodegeneration.
  12. Unveiling autophagy complexity in leukemia: The molecular landscape and possible interactions with apoptosis and ferroptosis.
  13. The AMPK-Sirtuin 1-YAP axis is regulated by fluid flow intensity and controls autophagy flux in kidney epithelial cells.
  14. Apolipoproteins L1 and L3 control mitochondrial membrane dynamics.
  15. Salmonella actively modulates TFEB in murine macrophages in a growth-phase and time-dependent manner.
  16. HSP90 Inhibition Attenuated Isoflurane-Induced Neurotoxicity in Mice and Human Neuroglioma Cells.
  17. Targeting autophagy and beyond: Deconvoluting the complexity of Beclin-1 from biological function to cancer therapy.
  18. Fission Yeast TORC1 Promotes Cell Proliferation through Sfp1, a Transcription Factor Involved in Ribosome Biogenesis.
  19. RABGGTB plays a critical role in ALS pathogenesis.
  20. Complete set of the Atg8-E1-E2-E3 conjugation machinery forms an interaction web that mediates membrane shaping.
  21. Loss of Autophagy Disrupts Stemness of Ameloblast-Lineage Cells in Aging.
  22. The Mechanistic Target of Rapamycin Complex 1 Pathway Contributes to the Anti-Tumor Effect of Granulocyte-Macrophage-Colony-Stimulating Factor-Producing T Helper Cells in Mouse Colorectal Cancer.
  23. Determination of Autophagy in Human Cervicovaginal Smears by Cytological and İmmunocytochemical Methods.
  24. Ubiquitin-proteasome pathway in skeletal muscle atrophy.
  25. Ubiquitin-conjugating enzyme E2 for regulating autophagy in diabetic cardiomyopathy: A mini-review.
  26. Sestrin2 can alleviate endoplasmic reticulum stress to improve traumatic brain injury by activating AMPK/mTORC1 signaling pathway.
  27. Metformin ameliorates valve interstitial cell calcification by promoting autophagic flux.
  28. Early-adult methionine restriction reduces methionine sulfoxide and extends lifespan in Drosophila.
  29. Malonate differentially affects cell survival and confers chemoresistance in cancer cells via the induction of p53-dependent autophagy.
  30. Trehalose Promotes Clearance of Proteotoxic Aggregation of Neurodegenerative Disease-Associated Aberrant Proteins.
  31. Construction of a polymer-based fluorescent probe with dual responsive sites for monitoring changes of lysosomal viscosity.
  32. Atg18 oligomer organization in assembled tubes and on lipid membrane scaffolds.
  33. ALS-linked SOD1 mutations impair mitochondrial-derived vesicle formation and accelerate aging.
  1. Cell Metab. 2023 Dec 05. pii: S1550-4131(23)00417-5. [Epub ahead of print]35(12): 2097-2099
    mTOR takes charge: Relaying uncharged tRNA levels by mTOR ubiquitination.
    Estela Jacinto.
      Nutrient availability is conveyed to the mechanistic target of rapamycin (mTOR), which couples metabolic processes with cell growth and proliferation. How mTOR itself is modulated by amino acid levels remains poorly understood. Ge and colleagues now demonstrate that broad sensing of uncharged tRNAs by GCN2/FBXO22 inactivates mTOR complex 1 (mTORC1) via mTOR ubiquitination.
    DOI:  https://doi.org/10.1016/j.cmet.2023.11.006
  2. Curr Top Dev Biol. 2023 ;pii: S0070-2153(23)00072-8. [Epub ahead of print]155 1-37
    Crosstalk between the mTOR pathway and primary cilia in human diseases.
    Philipp P Prosseda, Svenja Dannewitz Prosseda, Matthew Tran, Paloma B Liton, Yang Sun.
      Autophagy is a fundamental catabolic process whereby excessive or damaged cytoplasmic components are degraded through lysosomes to maintain cellular homeostasis. Studies of mTOR signaling have revealed that mTOR controls biomass generation and metabolism by modulating key cellular processes, including protein synthesis and autophagy. Primary cilia, the assembly of which depends on kinesin molecular motors, serve as sensory organelles and signaling platforms. Given these pathways' central role in maintaining cellular and physiological homeostasis, a connection between mTOR and primary cilia signaling is starting to emerge in a variety of diseases. In this review, we highlight recent advances in our understanding of the complex crosstalk between the mTOR pathway and cilia and discuss its function in the context of related diseases.
    DOI:  https://doi.org/10.1016/bs.ctdb.2023.09.004
  3. Autophagy. 2023 Dec 06.
    UVRAG: orchestrating the initiation of reticulophagy.
    Xuehong Qian, Jiajia Sun, Yixian Cui.
      Reticulophagy is a selective autophagy of the endoplasmic reticulum (ER) mediated by cargo receptors. It plays a crucial role in ER quality control, yet the mechanisms that initiate reticulophagy remain poorly understood. Our study identified the multifunctional protein UVRAG (UV radiation resistance associated gene) as a novel regulator of reticulophagy. UVRAG interacts with sheet and tubular reticulophagy receptors, regulates the oligomerization of receptors and facilitates their interaction with LC3/GABARAP, critical for ER fragmentation and autophagosome targeting. Remarkably, we found that UVRAG's function in reticulophagy initiation is independent of its traditional role in macroautophagy. Furthermore, UVRAG enhances the degradation of ER-associated mutant proteins linked to diseases like diabetes. Our findings offer insights into the mechanisms of reticulophagy initiation and highlight UVRAG's therapeutic potential in ER-related diseases.
    Keywords:  Autophagy; LC3/GABARAP; UVRAG; cargo receptor; reticulophagy
    DOI:  https://doi.org/10.1080/15548627.2023.2291937
  4. Cell Regen. 2023 Dec 07. 12(1): 38
    The sensitivity of mTORC1 signaling activation renders tissue regenerative capacity.
    Hanyu Dou, Jianzhou Li, Taomin Huang, Xiaolei Ding.
      A better understanding of how and why the regenerative capacity differs among species will not only provide insights into the regeneration process but also hold value for the development of regenerative medicine and the improvement of healing procedures. In a recent Nature article, Zhulyn et al. identify a critical role played by the activation of mechanistic target of rapamycin complex 1 (mTORC1) signaling in enhancing tissue regenerative capacity in animals.
    DOI:  https://doi.org/10.1186/s13619-023-00183-6
  5. Mol Nutr Food Res. 2023 Dec 06. e2200812
    Naringin Protects against Non-Alcoholic Fatty Liver Disease by Promoting Autophagic Flux and Lipophagy.
    Lingling Guan, Lan Guo, Heng Zhang, Hao Liu, Wenling Zhou, Yuanyuan Zhai, Xu Yan, Xiuli Men, Liang Peng.
      The autophagic degradation of lipid droplets, termed lipophagy, is the main mechanism contributing to lipid consumption in hepatocytes. Identifying effective and safe natural compounds that target lipophagy to eliminate excess lipids may be a potential therapeutic strategy for non-alcoholic fatty liver disease (NAFLD). Here the effects of naringin on NAFLD and the underlying mechanisms involved are investigated. Naringin treatment effectively relieves HFD-induced hepatic steatosis in mice and inhibits PA-induced lipid accumulation in hepatocytes. Increased p62 and LC3-II levels are observed with excess lipid support autophagosome accumulation and impaired autophagic flux. Treatment with naringin restores TFEB-mediated lysosomal biogenesis, thereby promoting the fusion of autophagosomes and lysosomes, restoring impaired autophagic flux and further inducing lipophagy. However, the knockdown of TFEB in hepatocytes or the hepatocyte-specific knockout of TFEB in mice abrogates naringin-induced lipophagy, eliminating its therapeutic effect on hepatic steatosis. These results demonstrate that TFEB-mediated lysosomal biogenesis and subsequent lipophagy play essential roles in the ability of naringin to mitigate hepatic steatosis and suggest that naringin is a promising drug for treating NAFLD.
    Keywords:  TFEB; autophagic flux; lipophagy; naringin; non-alcoholic fatty liver disease
    DOI:  https://doi.org/10.1002/mnfr.202200812
  6. Dev Cell. 2023 Nov 24. pii: S1534-5807(23)00582-8. [Epub ahead of print]
    An Arabidopsis Rab18 GTPase promotes autophagy by tethering ATG18a to the ER in response to nutrient starvation.
    Jiaqi Sun, Yang Shao, Songyang Wang, Xunzheng Li, Shuqing Feng, Weina Wang, Pierre Leroy, Chengyang Li, Huanquan Zheng.
      The expansion of autophagosomes requires a controlled association with the endoplasmic reticulum (ER). However, the mechanisms governing this process are not well defined. In plants, ATG18a plays a key role in autophagosome formation in response to stress, yet the factors regulating the process are unknown. This study finds that ATG18a acts as a downstream effector of RABC1, a member of the poorly characterized Rab18/RabC GTPase subclass in plants. Active RABC1 interacts with ATG18a on the ER, particularly under nutrient starvation. In rabc1 mutants, autophagy is compromised, especially under nutrient deprivation, affecting the ER association and expansion of ATG18a-positive autophagosomes. Furthermore, both dominant-negative and constitutively active RABC1 forms inhibit autophagy. The dominant inactive RABC1 impedes the ER association of ATG18a, whereas the constitutively active RABC1 delays ATG18a detachment from the ER. Collectively, RABC1 regulates the ER association and the subsequent detachment of ATG18a-positive autophagosomes during nutrient starvation.
    Keywords:  ATG18a; RABC1; Rab18; autophagosomes; autophagy; endoplasmic reticulum; plant stress responses; small Rab GTPase
    DOI:  https://doi.org/10.1016/j.devcel.2023.11.006
  7. MedComm (2020). 2023 Dec;4(6): e439
    Ubiquitin-specific protease 22 promotes tumorigenesis and progression by an FKBP12/mTORC1/autophagy positive feedback loop in hepatocellular carcinoma.
    Qianwei Ye, Wei Zhou, Shengjun Xu, Qingyang Que, Qifan Zhan, Lincheng Zhang, Shusen Zheng, Sunbin Ling, Xiao Xu.
      Ubiquitin-specific protease 22 (USP22) has been identified as a potential marker for cancer stem cells in hepatocellular carcinoma (HCC). It can promote HCC stemness, which is considered a driver of tumorigenesis. Here, we sought to determine the role of USP22 in tumorigenesis, elucidate its underlying mechanism, and explore its therapeutic significance in HCC. As a result, we found that tissue-specific Usp22 overexpression accelerated tumorigenesis, whereas Usp22 ablation decelerated it in a c-Myc/NRasGV12-induced HCC mouse model and that the mammalian target of rapamycin complex 1 (mTORC1) pathway was activated downstream. USP22 overexpression resulted in increased tumorigenic properties that were reversed by rapamycin in vitro and in vivo. In addition, USP22 activated mTORC1 by deubiquitinating FK506-binding protein 12 (FKBP12) and activated mTORC1, in turn, further stabilizing USP22 by inhibiting autophagic degradation. Clinically, HCC patients with high USP22 expression tend to benefit from mTOR inhibitors after liver transplantation (LT). Our results revealed that USP22 promoted tumorigenesis and progression via an FKBP12/mTORC1/autophagy positive feedback loop in HCC. Clinically, USP22 may be an effective biomarker for selecting eligible recipients with HCC for anti-mTOR-based therapy after LT.
    Keywords:  FK506‐binding protein 12 (FKBP12); autophagy; hepatocellular carcinoma (HCC); mammalian target of rapamycin complex 1 (mTORC1); tumorigenesis; ubiquitin‐specific protease 22 (USP22)
    DOI:  https://doi.org/10.1002/mco2.439
  8. Biochim Biophys Acta Mol Cell Biol Lipids. 2023 Dec 04. pii: S1388-1981(23)00168-3. [Epub ahead of print] 159444
    Ceramide regulation of autophagy: A biophysical approach.
    Yaiza R Varela, Marina N Iriondo, Félix M Goñi, Alicia Alonso, L Ruth Montes.
      Specific membrane lipids play unique roles in (macro)autophagy. Those include phosphatidylethanolamine, to which LC3/GABARAP autophagy proteins become covalently bound in the process, or cardiolipin, an important effector in mitochondrial autophagy (or mitophagy). Ceramide (Cer), or N-acyl sphingosine, is one of the simplest sphingolipids, known as a stress signal in the apoptotic pathway. Moreover, Cer is increasingly being recognized as an autophagy activator, although its mechanism of action is unclear. In the present review, the proposed Cer roles in autophagy are summarized, together with some biophysical properties of Cer in membranes. Possible pathways for Cer activation of autophagy are discussed, including specific protein binding of the lipid, and Cer-dependent perturbation of bilayer properties. Cer generation of lateral inhomogeneities (domain formation) is given special attention. Recent biophysical results, including fluorescence and atomic force microscopy data, show Cer-promoted enhanced binding of LC3/GABARAP to lipid bilayers. These observations could be interpreted in terms of the putative formation of Cer-rich nanodomains.
    Keywords:  Autophagy; Ceramide; Lateral phase separation; Membrane biophysics; Mitophagy; Nanodomains
    DOI:  https://doi.org/10.1016/j.bbalip.2023.159444
  9. Brain Res Bull. 2023 Dec 01. pii: S0361-9230(23)00260-5. [Epub ahead of print] 110835
    Therapeutic potential of natural products against Alzheimer's disease via autophagic removal of Aβ.
    Min Hu, Xinyi Ying, Miao Zheng, Can Wang, Qin Li, G U Lili, Xinyue Zhang.
      The pathological features of Alzheimer's disease (AD), a progressive neurodegenerative disorder, include the deposition of extracellular amyloid beta (Aβ) plaques and intracellular tau neurofibrillary tangles. A decline in cognitive ability is related to the accumulation of Aβ in patients with AD. Autophagy, which is a primary intracellular mechanism for degrading aggregated proteins and damaged organelles, plays a crucial role in AD. In this review, we summarize the most recent research progress regarding the process of autophagy and the effect of autophagy on Aβ. We further discuss some typical monomers of natural products that contribute to the clearance of Aβ by autophagy, which can alleviate AD. This provides a new perspective for the application of autophagy modulation in natural product therapy for AD.
    Keywords:  Alzheimer's disease; amyloid beta; autophagy; natural products
    DOI:  https://doi.org/10.1016/j.brainresbull.2023.110835
  10. Mol Cells. 2023 Dec 31. 46(12): 727-735
    Transcription Factor EB-Mediated Lysosomal Function Regulation for Determining Stem Cell Fate under Metabolic Stress.
    Chang Woo Chae, Young Hyun Jung, Ho Jae Han.
      Stem cells require high amounts of energy to replicate their genome and organelles and differentiate into numerous cell types. Therefore, metabolic stress has a major impact on stem cell fate determination, including self-renewal, quiescence, and differentiation. Lysosomes are catabolic organelles that influence stem cell function and fate by regulating the degradation of intracellular components and maintaining cellular homeostasis in response to metabolic stress. Lysosomal functions altered by metabolic stress are tightly regulated by the transcription factor EB (TFEB) and TFE3, critical regulators of lysosomal gene expression. Therefore, understanding the regulatory mechanism of TFEB-mediated lysosomal function may provide some insight into stem cell fate determination under metabolic stress. In this review, we summarize the molecular mechanism of TFEB/TFE3 in modulating stem cell lysosomal function and then elucidate the role of TFEB/TFE3-mediated transcriptional activity in the determination of stem cell fate under metabolic stress.
    Keywords:  lysosomal function; metabolic stress; stem cell fate; transcription factor EB
    DOI:  https://doi.org/10.14348/molcells.2023.0143
  11. FEBS Lett. 2023 Dec 06.
    Human WIPI β-propeller function in autophagy and neurodegeneration.
    Tassula Proikas-Cezanne, Maximilian L Haas, Carmen J Pastor-Maldonado, David S Schüssele.
      The four human WIPI β-propellers, WIPI1 through WIPI4, belong to the ancient PROPPIN family and fulfill scaffold functions in the control of autophagy. In this context, WIPI β-propellers function as PI3P effectors during autophagosome formation and loss of WIPI function negatively impacts autophagy and contributes to neurodegeneration. Of particular interest are mutations in WDR45, the human gene that encodes WIPI4. Sporadic WDR45 mutations are the cause of a rare human neurodegenerative disease called BPAN, hallmarked by high brain iron accumulation. Here we discuss the current understanding of the functions of human WIPI β-propellers and address unanswered questions with a particular focus on the role of WIPI4 in autophagy and BPAN.
    Keywords:  Autophagy; BPAN; PI3P; WDR45; WDR45B; WIPI1; WIPI2; WIPI3; WIPI4; neurodegeneration
    DOI:  https://doi.org/10.1002/1873-3468.14782
  12. Cancer Lett. 2023 Dec 01. pii: S0304-3835(23)00469-X. [Epub ahead of print] 216518
    Unveiling autophagy complexity in leukemia: The molecular landscape and possible interactions with apoptosis and ferroptosis.
    Young Yun Jung, Kwang Seok Ahn, Mingzhi Shen.
      Autophagy is a self-digestion multistep process in which causes the homeostasis through degradation of macromolecules and damaged organelles. The autophagy-mediated tumor progression regulation has been a critical point in recent years, revealing the function of this process in reduction or acceleration of carcinogenesis. Leukemia is a haematological malignancy in which abnormal expansion of hematopoietic cells occurs. The current and conventional therapies from chemotherapy to cell transplantation have failed to appropriately treat the leukemia patients. Among the mechanisms dysregulated in leukemia, autophagy is a prominent one in which can regulate the hallmarks of this tumor. The protective autophagy inhibits apoptosis and ferroptosis in leukemia, while toxic autophagy accelerates cell death. The proliferation and invasion of tumor cells are tightly regulated by the autophagy. The direction of regulation depends on the function of autophagy that is protective or lethal. The protective autophagy accelerates chemoresistance and radio-resistsance. The non-coding RNAs, histone transferases and other pathways such as PI3K/Akt/mTOR are among the regulators of autophagy in leukemia progression. The pharmacological intervention for the inhibition or induction of autophagy by the compounds including sesamine, tanshinone IIA and other synthetic compounds can chance progression of leukemia.
    Keywords:  Apoptosis; Autophagy; Chemoresistance; Leukemia; Molecular pathways
    DOI:  https://doi.org/10.1016/j.canlet.2023.216518
  13. Nat Commun. 2023 Dec 05. 14(1): 8056
    The AMPK-Sirtuin 1-YAP axis is regulated by fluid flow intensity and controls autophagy flux in kidney epithelial cells.
    Aurore Claude-Taupin, Pierre Isnard, Alessia Bagattin, Nicolas Kuperwasser, Federica Roccio, Biagina Ruscica, Nicolas Goudin, Meriem Garfa-Traoré, Alice Regnier, Lisa Turinsky, Martine Burtin, Marc Foretz, Marco Pontoglio, Etienne Morel, Benoit Viollet, Fabiola Terzi, Patrice Codogno, Nicolas Dupont.
      Shear stress generated by urinary fluid flow is an important regulator of renal function. Its dysregulation is observed in various chronic and acute kidney diseases. Previously, we demonstrated that primary cilium-dependent autophagy allows kidney epithelial cells to adapt their metabolism in response to fluid flow. Here, we show that nuclear YAP/TAZ negatively regulates autophagy flux in kidney epithelial cells subjected to fluid flow. This crosstalk is supported by a primary cilium-dependent activation of AMPK and SIRT1, independently of the Hippo pathway. We confirm the relevance of the YAP/TAZ-autophagy molecular dialog in vivo using a zebrafish model of kidney development and a unilateral ureteral obstruction mouse model. In addition, an in vitro assay simulating pathological accelerated flow observed at early stages of chronic kidney disease (CKD) activates YAP, leading to a primary cilium-dependent inhibition of autophagic flux. We confirm this YAP/autophagy relationship in renal biopsies from patients suffering from diabetic kidney disease (DKD), the leading cause of CKD. Our findings demonstrate the importance of YAP/TAZ and autophagy in the translation of fluid flow into cellular and physiological responses. Dysregulation of this pathway is associated with the early onset of CKD.
    DOI:  https://doi.org/10.1038/s41467-023-43775-1
  14. Cell Rep. 2023 Dec 01. pii: S2211-1247(23)01540-1. [Epub ahead of print]42(12): 113528
    Apolipoproteins L1 and L3 control mitochondrial membrane dynamics.
    Laurence Lecordier, Paul Heo, Jonas H Graversen, Dorle Hennig, Maria Kløjgaard Skytthe, Alexandre Cornet d'Elzius, Frédéric Pincet, David Pérez-Morga, Etienne Pays.
      Apolipoproteins L1 and L3 (APOLs) are associated at the Golgi with the membrane fission factors phosphatidylinositol 4-kinase-IIIB (PI4KB) and non-muscular myosin 2A. Either APOL1 C-terminal truncation (APOL1Δ) or APOL3 deletion (APOL3-KO [knockout]) reduces PI4KB activity and triggers actomyosin reorganization. We report that APOL3, but not APOL1, controls PI4KB activity through interaction with PI4KB and neuronal calcium sensor-1 or calneuron-1. Both APOLs are present in Golgi-derived autophagy-related protein 9A vesicles, which are involved in PI4KB trafficking. Like APOL3-KO, APOL1Δ induces PI4KB dissociation from APOL3, linked to reduction of mitophagy flux and production of mitochondrial reactive oxygen species. APOL1 and APOL3, respectively, can interact with the mitophagy receptor prohibitin-2 and the mitophagosome membrane fusion factor vesicle-associated membrane protein-8 (VAMP8). While APOL1 conditions PI4KB and APOL3 involvement in mitochondrion fission and mitophagy, APOL3-VAMP8 interaction promotes fusion between mitophagosomal and endolysosomal membranes. We propose that APOL3 controls mitochondrial membrane dynamics through interactions with the fission factor PI4KB and the fusion factor VAMP8.
    Keywords:  APOL1 risk variants; COVAN; COVID-19-associated nephropathy; CP: Cell biology; HIV-associated nephropathy; HIVAN; inflammation; interferon 1; kidney disease; mitochondrion fission/fusion; mitophagy
    DOI:  https://doi.org/10.1016/j.celrep.2023.113528
  15. Microbiol Spectr. 2023 Dec 05. e0498122
    Salmonella actively modulates TFEB in murine macrophages in a growth-phase and time-dependent manner.
    Subothan Inpanathan, Erika Ospina-Escobar, Vanessa Cruz Li, Zainab Adamji, Tracy Lackraj, Youn Hee Cho, Natasha Porco, Christopher H Choy, Joseph B McPhee, Roberto J Botelho.
      IMPORTANCE: Activation of the host transcription factor TFEB helps mammalian cells adapt to stresses such as starvation and infection by upregulating lysosome, autophagy, and immuno-protective gene expression. Thus, TFEB is generally thought to protect host cells. However, it may also be that pathogenic bacteria like Salmonella orchestrate TFEB in a spatio-temporal manner to harness its functions to grow intracellularly. Indeed, the relationship between Salmonella and TFEB is controversial since some studies showed that Salmonella actively promotes TFEB, while others have observed that Salmonella degrades TFEB and that compounds that promote TFEB restrict bacterial growth. Our work provides a path to resolve these apparent discordant observations since we showed that stationary-grown Salmonella actively delays TFEB after infection, while late-log Salmonella is permissive of TFEB activation. Nevertheless, the exact function of this manipulation remains unclear, but conditions that erase the conditional control of TFEB by Salmonella may be detrimental to the microbe.
    Keywords:  Salmonella; bacteria; cell adaptation; culture; innate immunity; lysosomes; macrophages; transcription factors
    DOI:  https://doi.org/10.1128/spectrum.04981-22
  16. Neurochem Res. 2023 Dec 06.
    HSP90 Inhibition Attenuated Isoflurane-Induced Neurotoxicity in Mice and Human Neuroglioma Cells.
    Chunlu Zhang, Xi Chen, Ruizhu Liu, Guoqing Zhao.
      Isoflurane, a widely used inhalation anesthetic in clinical practice, is associated with an increased risk of neuronal injury. Heat shock protein 90 (HSP90) plays a crucial role in maintaining neuronal homeostasis under stress conditions; however, its role during isoflurane exposure remains poorly understood. In this study, we aimed to investigate the protective effects of HSP90 inhibition and explore the regulatory mechanisms underlying these effects during isoflurane exposure. We found that the HSP90 inhibitor 17-N-allylamino-17-demethoxygeldanamycin (17 AAG) has great protective effects in mitigating isoflurane-induced ferroptosis of mouse hippocampus and cultured neuronal cells. We focused on the activity of the crucial protein GPX4 in ferroptosis and found that 17 AAG exerted protective effects, preserving the physiological GPX4 activity under isoflurane exposure; further, 17 AAG restored the protein level of GPX4. Further, we observed that the chaperone-mediated autophagy (CMA) pathway was activated; 17 AAG also mediated GPX4 degradation under isoflurane exposure. Additionally, it interfered with the formation of complexes between HSP90 and Lamp-2a, inhibiting CMA activity, followed by the blockade of GPX4 degradation, further affecting the isoflurane-induced ferroptosis. Based on these findings, we proposed HSP90 inhibition as a protective mechanism against isoflurane-induced ferroptosis in neurons.
    Keywords:  Anesthetic neurotoxicity; Chaperone-mediated autophagy (CMA); Ferroptosis; Heat shock protein 90 (HSP90)
    DOI:  https://doi.org/10.1007/s11064-023-04060-1
  17. Acta Pharm Sin B. 2023 Dec;13(12): 4688-4714
    Targeting autophagy and beyond: Deconvoluting the complexity of Beclin-1 from biological function to cancer therapy.
    Jing Ye, Jin Zhang, Yanghui Zhu, Lian Wang, Xian Jiang, Bo Liu, Gu He.
      Beclin-1 is the firstly-identified mammalian protein of the autophagy machinery, which functions as a molecular scaffold for the assembly of PI3KC3 (class III phosphatidylinositol 3 kinase) complex, thus controlling autophagy induction and other cellular trafficking events. Notably, there is mounting evidence establishing the implications of Beclin-1 in diverse tumorigenesis processes, including tumor suppression and progression as well as resistance to cancer therapeutics and CSC (cancer stem-like cell) maintenance. More importantly, Beclin-1 has been confirmed as a potential target for the treatment of multiple cancers. In this review, we provide a comprehensive survey of the structure, functions, and regulations of Beclin-1, and we discuss recent advances in understanding the controversial roles of Beclin-1 in oncology. Moreover, we focus on summarizing the targeted Beclin-1-regulating strategies in cancer therapy, providing novel insights into a promising strategy for regulating Beclin-1 to improve cancer therapeutics in the future.
    Keywords:  Autophagy; Beclin-1; Cancer therapy; Non-autophagy; PI3KC3 complex
    DOI:  https://doi.org/10.1016/j.apsb.2023.08.008
  18. Mol Cell Biol. 2023 Dec 05. 1-18
    Fission Yeast TORC1 Promotes Cell Proliferation through Sfp1, a Transcription Factor Involved in Ribosome Biogenesis.
    Yen Teng Tai, Tomoyuki Fukuda, Yuichi Morozumi, Hayato Hirai, Arisa H Oda, Yoshiaki Kamada, Yutaka Akikusa, Tomotake Kanki, Kunihiro Ohta, Kazuhiro Shiozaki.
      Target of rapamycin complex 1 (TORC1) is activated in response to nutrient availability and growth factors, promoting cellular anabolism and proliferation. To explore the mechanism of TORC1-mediated proliferation control, we performed a genetic screen in fission yeast and identified Sfp1, a zinc-finger transcription factor, as a multicopy suppressor of temperature-sensitive TORC1 mutants. Our observations suggest that TORC1 phosphorylates Sfp1 and protects Sfp1 from proteasomal degradation. Transcription analysis revealed that Sfp1 positively regulates genes involved in ribosome production together with two additional transcription factors, Ifh1/Crf1 and Fhl1. Ifh1 physically interacts with Fhl1, and the nuclear localization of Ifh1 is regulated in response to nutrient levels in a manner dependent on TORC1 and Sfp1. Taken together, our data suggest that the transcriptional regulation of the genes involved in ribosome biosynthesis by Sfp1, Ifh1, and Fhl1 is one of the key pathways through which nutrient-activated TORC1 promotes cell proliferation.
    Keywords:  Sfp1; TORC1; fission yeast; rapamycin; ribosome; transcription factor
    DOI:  https://doi.org/10.1080/10985549.2023.2282349
  19. Brain Res Bull. 2023 Nov 30. pii: S0361-9230(23)00258-7. [Epub ahead of print] 110833
    RABGGTB plays a critical role in ALS pathogenesis.
    Haiyang Ma, Jia Huo, Cheng Xin, Jing Yang, Qi Liu, Hui Dong, Rui Li, Yaling Liu.
      Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with unknown causes, which mainly affects motor neurons in the anterior horn of the spinal cord, brain stem, and cerebral cortex, also known as motor neuron disease. An important pathological feature of ALS is the formation of aggregates of mutant SOD1 protein, CTF25 of TDP-43, or other abnormal proteins in motor neurons, which require autophagy for degradation. Protein prenylation is known to participate in membrane association and proper localization of proteins. RABGGTB is the β subunit of GGTase II (one of the prenyltransferases) that can regulate autophagy via Rab7 geranylgeranylation. In this study, we overexpressed RABGGTB via lentiviral transfection in NSC34-hSOD1G93A and TDP-43 cells. Overexpression of RABGGTB improved ALS cell proliferation by facilitating autophagosome-lysosome fusion. Furthermore, the abnormal aggregation of SOD1 protein was reduced. This indicates that protein prenylation is important for the proliferation and autophagy of cells autophagy. Enhanced autophagy has been observed in two of the most widely used ALS cell models. These findings indicate the widespread applicability of prenylation in ALS. In summary, overexpression of RABGGTB improved the geranylgeranylation of the Rab7 protein and had a positive effect on cells. These findings provide insights into the development of a novel therapeutic strategy for ALS.
    Keywords:  NSC34-hSOD1G93A; RABGGTB; TDP-25; amyotrophic lateral sclerosis; autophagy; protein prenylation
    DOI:  https://doi.org/10.1016/j.brainresbull.2023.110833
  20. Nat Struct Mol Biol. 2023 Dec 06.
    Complete set of the Atg8-E1-E2-E3 conjugation machinery forms an interaction web that mediates membrane shaping.
    Jahangir Md Alam, Tatsuro Maruyama, Daisuke Noshiro, Chika Kakuta, Tetsuya Kotani, Hitoshi Nakatogawa, Nobuo N Noda.
      Atg8, a ubiquitin-like protein, is conjugated with phosphatidylethanolamine (PE) via Atg7 (E1), Atg3 (E2) and Atg12-Atg5-Atg16 (E3) enzymatic cascade and mediates autophagy. However, its molecular roles in autophagosome formation are still unclear. Here we show that Saccharomyces cerevisiae Atg8-PE and E1-E2-E3 enzymes together construct a stable, mobile membrane scaffold. The complete scaffold formation induces an in-bud in prolate-shaped giant liposomes, transforming their morphology into one reminiscent of isolation membranes before sealing. In addition to their enzymatic roles in Atg8 lipidation, all three proteins contribute nonenzymatically to membrane scaffolding and shaping. Nuclear magnetic resonance analyses revealed that Atg8, E1, E2 and E3 together form an interaction web through multivalent weak interactions, where the intrinsically disordered regions in Atg3 play a central role. These data suggest that all six Atg proteins in the Atg8 conjugation machinery control membrane shaping during autophagosome formation.
    DOI:  https://doi.org/10.1038/s41594-023-01132-2
  21. J Dent Res. 2023 Dec 06. 220345231209931
    Loss of Autophagy Disrupts Stemness of Ameloblast-Lineage Cells in Aging.
    H Ida-Yonemochi, K Otsu, T Irié, A Ohazama, H Harada, H Ohshima.
      Autophagy is one of the intracellular degradation pathways and maintains cellular homeostasis, regulating the stress response, cell proliferation, and signal transduction. To elucidate the role of autophagy in the maintenance of dental epithelial stem cells and the subsequent enamel formation, we analyzed autophagy-deficient mice in epithelial cells (Atg7f/f;KRT14-Cre mice), focusing on the influence of aging and stress environments. We also performed in vitro cell and organ culture experiments with an autophagy inhibitor. In young Atg7f/f;KRT14-Cre mice, morphological change was not obvious in maxillary incisors, except for the remarkable cell death in the stratum intermedium of the transitional stage. However, under stress conditions of hyperglycemia, the incisor color changed to white in diabetes Atg7f/f;KRT14-Cre mice. Regarding dental epithelial stem cells, the shape of the apical bud region of the incisor became irregular with age, and odontoma was formed in aged Atg7f/f;KRT14-Cre mice. In addition, the shape of apical bud culture cells of Atg7f/f;KRT14-Cre mice became irregular and enlarged atypically, with epigenetic changes during culture, suggesting that autophagy deficiency may induce tumorigenesis in dental epithelial cells. The epigenetic change and upregulation of p21 expression were induced by autophagy inhibition in vivo and in vitro. These findings suggest that autophagy is important for the regulation of stem cell maintenance, proliferation, and differentiation of ameloblast-lineage cells, and an autophagy disorder may induce tumorigenesis in odontogenic epithelial cells.
    Keywords:  amelogenesis; cell differentiation; odontoma, mouse, incisor; stem cell
    DOI:  https://doi.org/10.1177/00220345231209931
  22. Immunol Invest. 2023 Dec 05. 1-20
    The Mechanistic Target of Rapamycin Complex 1 Pathway Contributes to the Anti-Tumor Effect of Granulocyte-Macrophage-Colony-Stimulating Factor-Producing T Helper Cells in Mouse Colorectal Cancer.
    Hongjian Zhou, Bin Jiang, Yuyuan Qian, Chao Ke.
      INTRODUCTION: The role of granulocyte-macrophage-colony-stimulating factor-producing T helper (ThGM) cells in colorectal cancer (CRC) development remains unclear. This study characterizes the function of ThGM cells in mouse CRC.METHODS: Mouse CRC was induced by administrating azoxymethane and dextran sulfate sodium. The presence of ThGM cells in CRC tissues and the mechanistic target of rapamycin complex 1 (mTORC1) signaling in ThGM cells was detected by flow cytometry. The impact of mTORC1 signaling on ThGM cell function was determined by in vitro culture. The effect of ThGM cells on CRC development was evaluated by adoptive transfer assays.
    RESULTS: ThGM cells, which expressed granulocyte-macrophage-colony-stimulating factor (GM-CSF), accumulated in CRC tissues. mTORC1 signaling is activated in CRC ThGM cells. mTORC1 inhibition by rapamycin suppressed ThGM cell differentiation and proliferation and resulted in the death of differentiating ThGM cells. mTORC1 inhibition in already differentiated ThGM cells did not induce significant cell death but decreased the expression of GM-CSF, interleukin-2, and tumor necrosis factor-alpha while impeding cell proliferation. Furthermore, mTORC1 inhibition diminished the effect of ThGM cells on driving macrophage polarization toward the M1 type, as evidenced by lower expression of pro-inflammatory cytokines, major histocompatibility complex class II molecule, and CD80 in macrophages after co-culture with rapamycin-treated ThGM cells. Lentivirus-mediated knockdown/overexpression of regulatory-associated protein of mTOR (Raptor) confirmed the essential role of mTORC1 in ThGM cell differentiation and function. Adoptively transferred ThGM cells suppressed CRC growth whereas mTORC1 inhibition abolished this effect.
    CONCLUSION: mTORC1 is essential for the anti-CRC activity of ThGM cells.
    Keywords:  Colorectal cancer; T helper cells; granulocyte-macrophage colony-stimulating factor; macrophages; mechanistic target of rapamycin complex 1
    DOI:  https://doi.org/10.1080/08820139.2023.2290631
  23. J Cytol. 2023 Oct-Dec;40(4):40(4): 177-183
    Determination of Autophagy in Human Cervicovaginal Smears by Cytological and İmmunocytochemical Methods.
    Merve Özcan Türkmen, Sayeste Demirezen, Mehmet Sinan Beksaç.
      Background: Autophagy is a catabolic process whereby organelles and long-lived proteins are recycled through lysosomes to maintain cellular homeostasis. This process is being widely studied using culture techniques and animal models; however, cervicovaginal smears have not been used to detect autophagy.Aims: Our study aims to detect and evaluate autophagy in normal, malignant, infectious, and atypical cells in cervicovaginal smears by using cytological and immunocytochemical methods.
    Materials and Methods: Papanicolaou-stained 200 cervicovaginal smears were examined and 55 of 200 (27.5%) smears containing negative for intraepithelial lesion or malignancy (NILM) with identifiable infections and/or reactive/reparative changes (INF); briefly, NILM-INF (n = 31, 56.4%), atypical (n = 4, 7.3%), and malignant cells (n = 20, 36.3%) were evaluated as a study group. One hundred forty-five of 200 (72.5%) normal smears were accepted as the NILM without any identifiable infections (control group). The autophagy marker protein Microtubule-associated protein 1 light chain 3 A (MAP1LC3A) was used for immunocytochemical examination.
    Results: The staining intensity of the MAP1LC3A protein and autophagy positivity were lower in the malignant cells; however, they were higher in the NILM-INF and atypical cells. A statistically significant correlation between the malignant and normal cells was obtained for the autophagy positivity (P = 0.012). In view of the staining intensity of MAP1LC3A protein by the H-score method, a significant correlation was found between the NILM-INF and the normal cells (P = 0.015).
    Conclusions: Autophagy was detected in various cervicovaginal smears for the first time in this study. Our findings indicate that an autophagy process is essential in infectious cells as well as in the transformation of atypical cells into malignant cells in carcinogenesis.
    Keywords:  Autophagy; MAP1LC3A; cervicovaginal smear; immunocytochemistry
    DOI:  https://doi.org/10.4103/joc.joc_130_22
  24. Front Physiol. 2023 ;14 1289537
    Ubiquitin-proteasome pathway in skeletal muscle atrophy.
    XiangSheng Pang, Peng Zhang, XiaoPing Chen, WenMing Liu.
      Skeletal muscles underpin myriad human activities, maintaining an intricate balance between protein synthesis and degradation crucial to muscle mass preservation. Historically, disruptions in this balance-where degradation overshadows synthesis-have marked the onset of muscle atrophy, a condition diminishing life quality and, in grave instances, imperiling life itself. While multiple protein degradation pathways exist-including the autophagy-lysosome, calcium-dependent calpain, and cysteine aspartate protease systems-the ubiquitin-proteasome pathway emerges as an especially cardinal avenue for intracellular protein degradation, wielding pronounced influence over the muscle atrophy trajectory. This paper ventures a panoramic view of predominant muscle atrophy types, accentuating the ubiquitin-proteasome pathway's role therein. Furthermore, by drawing from recent scholarly advancements, we draw associations between the ubiquitin-proteasome pathway and specific pathological conditions linked to muscle atrophy. Our exploration seeks to shed light on the ubiquitin-proteasome pathway's significance in skeletal muscle dynamics, aiming to pave the way for innovative therapeutic strategies against muscle atrophy and affiliated muscle disorders.
    Keywords:  cachexia; muscle disuse; sarcopenia; skeletal muscle atrophy; ubiquitin-proteasom
    DOI:  https://doi.org/10.3389/fphys.2023.1289537
  25. J Diabetes. 2023 Dec 05.
    Ubiquitin-conjugating enzyme E2 for regulating autophagy in diabetic cardiomyopathy: A mini-review.
    Yueran Zhou, Zequn Zheng, Shenglin Wu, Jinxiu Zhu.
      The prevalence of diabetic cardiomyopathy (DCM) increases year by year with the increase in the prevalence of diabetes mellitus (DM), which is one of the most serious cardiovascular complications of DM and a major cause of death in diabetic patients. Although the pathological molecular features of DCM have not been fully elucidated, increasing evidence suggests that impaired autophagy in cardiomyocytes plays a nonnegligible role in the development of DCM. It has been shown that SUMOylation [SUMO = small ubiquitin-like modifier], a post-translational modification of proteins, and its associated ubiquitin-proteasome system mediates protein quality control in the heart and plays an important role in the proteotoxic environment of the heart. Specifically, the expression of ubiquitin-conjugating enzyme E2 (Ubc9), the only SUMO-E2 enzyme, exerts a positive regulatory effect on autophagy in cardiomyocytes with potential cardioprotective effects. This review focuses on the role that autophagy plays in DCM and the potential for Ubc9-regulated autophagy pathways to ameliorate DCM, highlighting the potential of Ubc9 as an interventional target in DCM and providing new insights into the pathogenesis of the disease.
    Keywords:  Ubc9; autophagy; diabetic cardiomyopathy; target
    DOI:  https://doi.org/10.1111/1753-0407.13511
  26. Metab Brain Dis. 2023 Dec 04.
    Sestrin2 can alleviate endoplasmic reticulum stress to improve traumatic brain injury by activating AMPK/mTORC1 signaling pathway.
    Yu Zhou, Yong Zhang, Benson O A Botchway, Min Huang, Xuehong Liu.
      Traumatic brain injury (TBI), as a serious central nervous system disease, can result in severe neurological dysfunction or even disability and death of patients. The early and effective intervention of secondary brain injury can improve the prognosis of TBI. Endoplasmic reticulum (ER) stress is one of the main reasons to recover TBI. ER stress inhibition may be beneficial in treating TBI. Sestrin2 is a crucial regulator of ER stress, and its activation can significantly improve TBI. In this paper, we analyze the biological function of sestrin2, the latest findings on ER stress, and the relationship between ER stress and TBI. We elucidate the relationship of sestrin2 inhibiting ER stress via activating the AMP-activated protein kinase (AMPK)/mammalian target of rapamycin complex 1 (MTORC1) signaling. Finally, we elaborate on the possible role of sestrin2 in TBI and explain how its activation potentially improves TBI.
    Keywords:  Apoptosis; Inflammatory response; Injury; Mitochondrial dysfunction; Neurological dysfunction
    DOI:  https://doi.org/10.1007/s11011-023-01323-2
  27. Sci Rep. 2023 Dec 05. 13(1): 21435
    Metformin ameliorates valve interstitial cell calcification by promoting autophagic flux.
    K Phadwal, X Tan, E Koo, D Zhu, V E MacRae.
      Calcific aortic valve disease (CAVD) is the most common heart disease of the developed world. It has previously been established that metformin administration reduces arterial calcification via autophagy; however, whether metformin directly regulates CAVD has yet to be elucidated. In the present study we investigated whether metformin alleviates valvular calcification through the autophagy-mediated recycling of Runx2. Calcification was reduced in rat valve interstitial cells (RVICs) by metformin treatment (0.5-1.5 mM) (P < 0.01), with a marked decrease in Runx2 protein expression compared to control cells (P < 0.05). Additionally, upregulated expression of Atg3 and Atg7 (key proteins required for autophagosome formation), was observed following metformin treatment (1 mM). Blocking autophagic flux using Bafilomycin-A1 revealed colocalisation of Runx2 with LC3 puncta in metformin treated RVICs (P < 0.001). Comparable Runx2 accumulation was seen in LC3 positive autolysosomes present within cells that had been treated with both metformin and hydroxychloroquine in combination (P < 0.001). Mechanistic studies employing three-way co-immunoprecipitation with Runx2, p62 and LC3 suggested that Runx2 binds to LC3-II upon metformin treatment in VICs. Together these studies suggest that the utilisation of metformin may represent a novel strategy for the treatment of CAVD.
    DOI:  https://doi.org/10.1038/s41598-023-47774-6
  28. Nat Commun. 2023 Dec 05. 14(1): 7832
    Early-adult methionine restriction reduces methionine sulfoxide and extends lifespan in Drosophila.
    Hina Kosakamoto, Fumiaki Obata, Junpei Kuraishi, Hide Aikawa, Rina Okada, Joshua N Johnstone, Taro Onuma, Matthew D W Piper, Masayuki Miura.
      Methionine restriction (MetR) extends lifespan in various organisms, but its mechanistic understanding remains incomplete. Whether MetR during a specific period of adulthood increases lifespan is not known. In Drosophila, MetR is reported to extend lifespan only when amino acid levels are low. Here, by using an exome-matched holidic medium, we show that decreasing Met levels to 10% extends Drosophila lifespan with or without decreasing total amino acid levels. MetR during the first four weeks of adult life only robustly extends lifespan. MetR in young flies induces the expression of many longevity-related genes, including Methionine sulfoxide reductase A (MsrA), which reduces oxidatively-damaged Met. MsrA induction is foxo-dependent and persists for two weeks after cessation of the MetR diet. Loss of MsrA attenuates lifespan extension by early-adulthood MetR. Our study highlights the age-dependency of the organismal response to specific nutrients and suggests that nutrient restriction during a particular period of life is sufficient for healthspan extension.
    DOI:  https://doi.org/10.1038/s41467-023-43550-2
  29. Biochem Pharmacol. 2023 Dec 02. pii: S0006-2952(23)00543-9. [Epub ahead of print]219 115950
    Malonate differentially affects cell survival and confers chemoresistance in cancer cells via the induction of p53-dependent autophagy.
    Hao Cui, Bao Zhu, Huiyan Li, Yuanyuan Meng, Meng Cai, Hui Wang, Min Yuan, Xuefei Zhong, Bingwu Wang, Hongjian Shan, Michael Zhe Miao, Keli Chai, Junnian Zheng, Longzhen Zhang, Yong Liu.
      Metabolic network intertwines with cancerous signaling and drug responses. Malonate is a prevailing metabolite in cancer and a competitive inhibitor of succinate dehydrogenase (SDH). Recent studies showed that malonate induced reactive oxygen species (ROS)-dependent apoptosis in neuroblastoma cells, but protected cells from ischemia-reperfusion injury. We here revealed that malonate differentially regulated cell death and survival in cancer cells. While high-dose malonate triggered ROS-dependent apoptosis, the low-dose malonate induced autophagy and conferred resistance to multiple chemotherapeutic agents. Mechanistically, our results showed that malonate increased p53 stability and transcriptionally up-regulated autophagy modulator DRAM (damage-regulated autophagy modulator), thus promoting autophagy. We further proved that autophagy is required for malonate-associated chemoresistance. Collectively, our findings suggest that malonate plays a double-edge function in cancer response to stressors, and highlights a pro-cancer impact of p53-induced autophagy in response to malonate.
    Keywords:  Autophagy; Chemoresistance; Malonate; ROS; p53
    DOI:  https://doi.org/10.1016/j.bcp.2023.115950
  30. Mol Neurobiol. 2023 Dec 07.
    Trehalose Promotes Clearance of Proteotoxic Aggregation of Neurodegenerative Disease-Associated Aberrant Proteins.
    Prashant Kumar, Sumit Kinger, Ankur Rakesh Dubey, Yuvraj Anandrao Jagtap, Akash Choudhary, Amit Prasad, Hem Chandra Jha, Rohan Dhiman, Ravi Kumar Gutti, Amit Mishra.
      Accumulation of misfolded proteins compromises overall cellular health and fitness. The failure to remove misfolded proteins is a critical reason for their unwanted aggregation in dense cellular protein pools. The accumulation of various inclusions serves as a clinical feature for neurodegenerative diseases. Previous findings suggest that different cellular compartments can store these abnormal inclusions. Studies of transgenic mice and cellular models of neurodegenerative diseases indicate that depleted chaperone capacity contributes to the aggregation of damaged or aberrant proteins, which consequently disturb proteostasis and cell viability. However, improving these abnormal proteins' selective elimination is yet to be well understood. Still, molecular strategies that can promote the effective degradation of abnormal proteins without compromising cellular viability are unclear. Here, we reported that the trehalose treatment elevates endogenous proteasome levels and enhances the activities of the proteasome. Trehalose-mediated proteasomal activation elevates the removal of both bona fide misfolded and various neurodegenerative disease-associated proteins. Our current study suggests that trehalose may retain a proteasome activation potential, which seems helpful in the solubilization of different mutant misfolded proteins, improving cell viability. These results reveal a possible molecular approach to reduce the overload of intracellular misfolded proteins, and such cytoprotective functions may play a critical role against protein conformational diseases.
    Keywords:  Aberrant proteins; Diseases; Neurodegeneration; Proteasome; Proteasome activator; Trehalose
    DOI:  https://doi.org/10.1007/s12035-023-03824-8
  31. J Mater Chem B. 2023 Dec 05.
    Construction of a polymer-based fluorescent probe with dual responsive sites for monitoring changes of lysosomal viscosity.
    Faqi Yu, Ruiyang Fan, Yansheng Zhao, Yijun Chen, Xiuqi Kong, Weiying Lin.
      As highly dynamic organelles, lysosomes are involved in various physiological processes. The viscosity of lysosomes plays critical roles in maintaining their normal physiological function and abnormal variations of viscosity are associated with many diseases. Monitoring the changes of lysosomal viscosity could contribute to understanding lysosome-related physiological and pathological processes. In this work, based on an indole fluorophore and fluorescent polymer, poly(2-hydroxyethyl methacrylate) (PHEM), a new polymeric fluorescent probe, In-PHEM, with dual responsive sites for tracking changes of lysosomal viscosity is presented. In-PHEM showed excellent fluorescence properties and high photostability. With this robust probe, the variation of the lysosomal viscosity in cells under different physiological conditions, including inducer stimulation, the process of starvation and apoptosis, was monitored using dual-channel imaging. Therefore, this work may provide a powerful tool for monitoring changes of lysosomal viscosity and helping to understand the relationship between the viscosity changes of lysosomes and their related diseases.
    DOI:  https://doi.org/10.1039/d3tb02232c
  32. Nat Commun. 2023 Dec 06. 14(1): 8086
    Atg18 oligomer organization in assembled tubes and on lipid membrane scaffolds.
    Daniel Mann, Simon A Fromm, Antonio Martinez-Sanchez, Navin Gopaldass, Ramona Choy, Andreas Mayer, Carsten Sachse.
      Autophagy-related protein 18 (Atg18) participates in the elongation of early autophagosomal structures in concert with Atg2 and Atg9 complexes. How Atg18 contributes to the structural coordination of Atg2 and Atg9 at the isolation membrane remains to be understood. Here, we determined the cryo-EM structures of Atg18 organized in helical tubes, Atg18 oligomers in solution as well as on lipid membrane scaffolds. The helical assembly is composed of Atg18 tetramers forming a lozenge cylindrical lattice with remarkable structural similarity to the COPII outer coat. When reconstituted with lipid membranes, using subtomogram averaging we determined tilted Atg18 dimer structures bridging two juxtaposed lipid membranes spaced apart by 80 Å. Moreover, lipid reconstitution experiments further delineate the contributions of Atg18's FRRG motif and the amphipathic helical extension in membrane interaction. The observed structural plasticity of Atg18's oligomeric organization and membrane binding properties provide a molecular framework for the positioning of downstream components of the autophagy machinery.
    DOI:  https://doi.org/10.1038/s41467-023-43460-3
  33. Redox Biol. 2023 Nov 24. pii: S2213-2317(23)00373-7. [Epub ahead of print]69 102972
    ALS-linked SOD1 mutations impair mitochondrial-derived vesicle formation and accelerate aging.
    Ying Guo, Teng Guan, Qiang Yu, Nitesh Sanghai, Kashfia Shafiq, Meiyu Li, Xin Jiao, Donghui Na, Guohui Zhang, Jiming Kong.
      Oxidative stress (OS) is regarded as the dominant theory for aging. While compelling correlative data have been generated to support the OS theory, a direct cause-and-effect relationship between the accumulation of oxidation-mediated damage and aging has not been firmly established. Superoxide dismutase 1 (SOD1) is a primary antioxidant in all cells. It is, however, susceptible to oxidation due to OS and gains toxic properties to cells. This study investigates the role of oxidized SOD1 derived from amyotrophic lateral sclerosis (ALS) linked SOD1 mutations in cell senescence and aging. Herein, we have shown that the cell line NSC34 expressing the G93A mutation of human SOD1 (hSOD1G93A) entered premature senescence as evidenced by a decreased number of the 5-ethynyl-2'-deoxyuridine (EdU)-positive cells. There was an upregulation of cellular senescence markers compared to cells expressing the wild-type human SOD1 (hSOD1WT). Transgenic mice carrying the hSOD1G93A gene showed aging phenotypes at an early age (135 days) with high levels of P53 and P16 but low levels of SIRT1 and SIRT6 compared with age-matched hSOD1WT transgenic mice. Notably, the levels of oxidized SOD1 were significantly elevated in both the senescent NSC34 cells and 135-day hSOD1G93A mice. Selective removal of oxidized SOD1 by our CT4-directed autophagy significantly decelerated aging, indicating that oxidized SOD1 is a causal factor of aging. Intriguingly, mitochondria malfunctioned in both senescent NSC34 cells and middle-aged hSODG93A transgenic mice. They exhibited increased production of mitochondrial-derived vesicles (MDVs) in response to mild OS in mutant humanSOD1 (hSOD1) transgenic mice at a younger age; however, the mitochondrial response gradually declined with aging. In conclusion, our data show that oxidized SOD1 derived from ALS-linked SOD1 mutants is a causal factor for cellular senescence and aging. Compromised mitochondrial responsiveness to OS may serve as an indicator of premature aging.
    Keywords:  Aging; Cellular senescence; Mitochondrial dysfunction; Mitochondrial-derived vesicles; Oxidative stress; Superoxide dismutase 1
    DOI:  https://doi.org/10.1016/j.redox.2023.102972
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