bims-auttor Biomed News
on Autophagy and mTOR
Issue of 2022‒01‒23
fifty-four papers selected by
Viktor Korolchuk, Newcastle University
  1. Brain-derived autophagosome profiling reveals the engulfment of nucleoid-enriched mitochondrial fragments by basal autophagy in neurons.
  2. Komagataella phaffii Cue5 Piggybacks on Lipid Droplets for Its Vacuolar Degradation during Stationary Phase Lipophagy.
  3. Mitophagy mechanisms in neuronal physiology and pathology during ageing.
  4. A phospho-switch at Acinus-Serine437 controls autophagic responses to Cadmium exposure and neurodegenerative stress.
  5. Atg39 links and deforms the outer and inner nuclear membranes in selective autophagy of the nucleus.
  6. Autophagy of the Nucleus in Health and Disease.
  7. Regulation of ER-derived membrane dynamics by the DedA domain-containing proteins VMP1 and TMEM41B.
  8. ARF GTPases activate Salmonella effector SopF to ADP-ribosylate host V-ATPase and inhibit endomembrane damage-induced autophagy.
  9. Tfeb-Mediated Transcriptional Regulation of Autophagy Induces Autosis during Ischemia/Reperfusion in the Heart.
  10. Chaperone mediated autophagy contributes to the newly synthesized histones H3 and H4 quality control.
  11. DRAM-4 and DRAM-5 are compensatory regulators of autophagy and cell survival in nutrient-deprived conditions.
  12. Anti-Inflammatory Anthranilate Analogue Enhances Autophagy through mTOR and Promotes ER-Turnover through TEX264 during Alzheimer-Associated Neuroinflammation.
  13. Mitophagy-regulated mitochondrial health strongly protects the heart against cardiac dysfunction after acute myocardial infarction.
  14. Autophagy: mechanisms and applications-a session at the 20th IUPAB congress/45th SBBf annual meeting/50th SBBq annual meeting.
  15. Human Respiratory Syncytial Virus NS2 Protein Induces Autophagy by Modulating Beclin1 Protein Stabilization and ISGylation.
  16. The autophagy-resistant Mycobacterium tuberculosis Beijing strain upregulates KatG to evade starvation-induced autophagic restriction.
  17. Mutation of the Conserved Threonine 8 within the Human ARF Tumour Suppressor Protein Regulates Autophagy.
  18. Cellular autophagy, an unbidden effect of caspase inhibition by zVAD-fmk.
  19. Selective localization of Mfn2 near PINK1 enables its preferential ubiquitination by Parkin on mitochondria.
  20. Idebenone improves motor dysfunction, learning and memory by regulating mitophagy in MPTP-treated mice.
  21. STAT3 Enhances Sensitivity of Glioblastoma to Drug-Induced Autophagy-Dependent Cell Death.
  22. Orthodontic loading activates cell-specific autophagy in a force-dependent manner.
  23. Regulation of Neurodegeneration-associated Protein Fragments by the N-degron Pathways.
  24. Desferrioxamine Ameliorates Lipopolysaccharide-Induced Lipocalin-2 Upregulation via Autophagy Activation in Primary Astrocytes.
  25. Mapping of a N-terminal α-helix domain required for human PINK1 stabilization, Serine228 autophosphorylation and activation in cells.
  26. TFEB signaling attenuates NLRP3-driven inflammatory responses in severe asthma.
  27. Bupivacaine Induces ROS-Dependent Autophagic Damage in DRG Neurons via TUG1/mTOR in a High-Glucose Environment.
  28. A novel therapeutic strategy for atherosclerosis: autophagy-dependent cholesterol efflux.
  29. One-Carbon Metabolism: Pulling the Strings behind Aging and Neurodegeneration.
  30. Mitophagy Regulation Following Myocardial Infarction.
  31. Blocking mitophagy does not significantly improve fuel ethanol production in bioethanol yeast Saccharomyces cerevisiae.
  32. PGK1 represses autophagy-mediated cell death to promote the proliferation of liver cancer cells by phosphorylating PRAS40.
  33. Mitochondrial quality control in stroke: From the mechanisms to therapeutic potentials.
  34. Clearance or Hijack: Universal Interplay Mechanisms Between Viruses and Host Autophagy From Plants to Animals.
  35. Lysosomal dysfunction in neurodegeneration: emerging concepts and methods.
  36. Lysosome-Targeting Strategy Using Polypeptides and Chimeric Molecules.
  37. Selective elimination of pluripotent stem cells by PIKfyve specific inhibitors.
  38. LAPped in Proof: LC3-Associated Phagocytosis and the Arms Race Against Bacterial Pathogens.
  39. The Lysosomal Rag-Ragulator Complex Licenses RIPK1 and Caspase-8-mediated Pyroptosis by Yersinia.
  40. SURF4-induced tubular ERGIC selectively expedites ER-to-Golgi transport.
  41. Inhibition of DUSP6 Activates Autophagy and Rescues the Retinal Pigment Epithelium in Sodium Iodate-Induced Retinal Degeneration Models In Vivo and In Vitro.
  42. PINK1 Alleviates Cognitive Impairments via Attenuating Pathological Tau Aggregation in a Mouse Model of Tauopathy.
  43. Progranulin as a therapeutic target in neurodegenerative diseases.
  44. Intravitreal gene therapy restores the autophagy-lysosomal pathway and attenuates retinal degeneration in cathepsin D-deficient mice.
  45. Nickel particles are present in Crohn's disease tissue and exacerbate intestinal inflammation in IBD susceptible mice.
  46. Sensing of RNA stress by mTORC1 drives autoinflammation.
  47. Engineering Nanoplatform for Combined Cancer Therapeutics via Complementary Autophagy Inhibition.
  48. Renal mTORC1 activation is associated with disease activity and prognosis in lupus nephritis.
  49. RAS protein activator like 2 promotes the proliferation and migration of pulmonary artery smooth muscle cell through AKT/mammalian target of Rapamycin complex 1 pathway in pulmonary hypertension.
  50. Drosophila ZIP13 overexpression or transferrin1 RNAi influences the muscle degeneration of Pink1 RNAi by elevating iron levels in mitochondria.
  51. Emerging Role of cAMP/AMPK Signaling.
  52. Parkinson's disease protein PARK7 prevents metabolite and protein damage caused by a glycolytic metabolite.
  53. A New Insight into an Alternative Therapeutic Approach to Restore Redox Homeostasis and Functional Mitochondria in Neurodegenerative Diseases.
  54. Icariin inhibits isoproterenol-induced cardiomyocyte hypertropic injury through activating autophagy via the AMPK/mTOR signaling pathway.
  1. Neuron. 2022 Jan 13. pii: S0896-6273(21)01046-1. [Epub ahead of print]
    Brain-derived autophagosome profiling reveals the engulfment of nucleoid-enriched mitochondrial fragments by basal autophagy in neurons.
    Juliet Goldsmith, Alban Ordureau, J Wade Harper, Erika L F Holzbaur.
      Neurons depend on autophagy to maintain cellular homeostasis, and defects in autophagy are pathological hallmarks of neurodegenerative disease. To probe the role of basal autophagy in the maintenance of neuronal health, we isolated autophagic vesicles from mouse brain tissue and used proteomics to identify the major cargos engulfed within autophagosomes, validating our findings in rodent primary and human iPSC-derived neurons. Mitochondrial proteins were identified as a major cargo in the absence of mitophagy adaptors such as OPTN. We found that nucleoid-associated proteins are enriched compared with other mitochondrial components. In the axon, autophagic engulfment of nucleoid-enriched mitochondrial fragments requires the mitochondrial fission machinery Drp1. We proposed that localized Drp1-dependent fission of nucleoid-enriched fragments in proximity to the sites of autophagosome biogenesis enhances their capture. The resulting efficient autophagic turnover of nucleoids may prevent accumulation of mitochondrial DNA in the neuron, thus mitigating activation of proinflammatory pathways that contribute to neurodegeneration.
    Keywords:  Drp1; TFAM; autophagy; mitochondria; mitochondrial division; mitochondrial nucleoids; mitophagy; neurodegeneration; neuronal homeostasis
    DOI:  https://doi.org/10.1016/j.neuron.2021.12.029
  2. Cells. 2022 Jan 10. pii: 215. [Epub ahead of print]11(2):
    Komagataella phaffii Cue5 Piggybacks on Lipid Droplets for Its Vacuolar Degradation during Stationary Phase Lipophagy.
    Ravinder Kumar, Ankit Shroff, Taras Y Nazarko.
      Recently, we developed Komagataella phaffii (formerly Pichia pastoris) as a model for lipophagy, the selective autophagy of lipid droplets (LDs). We found that lipophagy pathways induced by acute nitrogen (N) starvation and in stationary (S) phase have different molecular mechanisms. Moreover, both types of lipophagy are independent of Atg11, the scaffold protein that interacts with most autophagic receptors and, therefore, is essential for most types of selective autophagy in yeast. Since yeast aggrephagy, the selective autophagy of ubiquitinated protein aggregates, is also independent of Atg11 and utilizes the ubiquitin-binding receptor, Cue5, we studied the relationship of K. phaffii Cue5 with differentially induced LDs and lipophagy. While there was no relationship of Cue5 with LDs and lipophagy under N-starvation conditions, Cue5 accumulated on LDs in S-phase and degraded together with LDs via S-phase lipophagy. The accumulation of Cue5 on LDs and its degradation by S-phase lipophagy strongly depended on the ubiquitin-binding CUE domain and Prl1, the positive regulator of lipophagy 1. However, unlike Prl1, which is required for S-phase lipophagy, Cue5 was dispensable for it suggesting that Cue5 is rather a new substrate of this pathway. We propose that a similar mechanism (Prl1-dependent accumulation on LDs) might be employed by Prl1 to recruit another ubiquitin-binding protein that is essential for S-phase lipophagy.
    Keywords:  CUE; Cue5; Komagataella phaffii; Pichia pastoris; Prl1; lipid droplets; lipophagy; selective autophagy; stationary phase; yeast
    DOI:  https://doi.org/10.3390/cells11020215
  3. Biophys Rev. 2021 Dec;13(6): 955-965
    Mitophagy mechanisms in neuronal physiology and pathology during ageing.
    Maria Markaki, Dikaia Tsagkari, Nektarios Tavernarakis.
      Ageing in diverse species ranging from the simple nematode Caenorhabditis elegans to humans is associated with a marked decrease of neuronal function and increased susceptibility to neurodegeneration. Accumulating findings also indicate that alterations in neuronal functionality with age are associated with a decline in mitochondrial integrity and function. The rate at which a mitochondrial population is refreshed is determined by the coordination of mitochondrial biogenesis with mitophagy, a selective type of autophagy targeting damaged or superfluous mitochondria for degradation. Coupling of these opposing processes is crucial for maintaining cellular energy homeostasis, which eventually contributes to health span. Here, we focus on the role of mitophagy in nervous system function in the context of normal physiology and disease. First, we consider the progress that has been made over the last decade in elucidating the mechanisms that govern and regulate mitophagy, placing emphasis on the PINK1/Parkin-mediated mitophagy. We further discuss the contribution of mitophagy to the maintenance of neuronal homeostasis and health as well as recent findings implicating impaired mitophagy in age-related decline of the nervous system function and consequently in the pathogenesis of neurodegenerative diseases.
    Keywords:  Ageing; Energy homeostasis; Mitophagy; Neurodegeneration; Neuron; Neuronal health
    DOI:  https://doi.org/10.1007/s12551-021-00894-7
  4. Elife. 2022 Jan 17. pii: e72169. [Epub ahead of print]11
    A phospho-switch at Acinus-Serine437 controls autophagic responses to Cadmium exposure and neurodegenerative stress.
    Nilay Nandi, Zuhair Zaidi, Charles Tracy, Helmut Krämer.
      Neuronal health depends on quality control functions of autophagy, but mechanisms regulating neuronal autophagy are poorly understood. Previously, we showed that in Drosophila starvation-independent quality control autophagy is regulated by Acinus and the Cdk5-dependent phosphorylation of its serine437 (Nandi et al., 2017). Here, we identify the phosphatase that counterbalances this activity and provides for the dynamic nature of Acinus-S437 phosphorylation. A genetic screen identified six phosphatases that genetically interacted with an Acinus gain-of-function model. Among these, loss of function of only one, the PPM-type phosphatase Nil (CG6036), enhanced pS437-Acinus levels. Cdk5-dependent phosphorylation of Acinus serine437 in nil1 animals elevates neuronal autophagy and reduces the accumulation of polyQ proteins in a Drosophila Huntington's disease model. Consistent with previous findings that Cd2+ inhibits PPM-type phosphatases, Cd2+-exposure elevated Acinus-serine437 phosphorylation which was necessary for increased neuronal autophagy and protection against Cd2+-induced cytotoxicity. Together, our data establish the Acinus-S437 phospho-switch as critical integrator of multiple stress signals regulating neuronal autophagy.
    Keywords:  D. melanogaster; cell biology
    DOI:  https://doi.org/10.7554/eLife.72169
  5. J Cell Biol. 2022 Feb 07. pii: e202103178. [Epub ahead of print]221(2):
    Atg39 links and deforms the outer and inner nuclear membranes in selective autophagy of the nucleus.
    Keisuke Mochida, Toshifumi Otani, Yuto Katsumata, Hiromi Kirisako, Chika Kakuta, Tetsuya Kotani, Hitoshi Nakatogawa.
      In selective autophagy of the nucleus (hereafter nucleophagy), nucleus-derived double-membrane vesicles (NDVs) are formed, sequestered within autophagosomes, and delivered to lysosomes or vacuoles for degradation. In Saccharomyces cerevisiae, the nuclear envelope (NE) protein Atg39 acts as a nucleophagy receptor, which interacts with Atg8 to target NDVs to the forming autophagosomal membranes. In this study, we revealed that Atg39 is anchored to the outer nuclear membrane via its transmembrane domain and also associated with the inner nuclear membrane via membrane-binding amphipathic helices (APHs) in its perinuclear space region, thereby linking these membranes. We also revealed that autophagosome formation-coupled Atg39 crowding causes the NE to protrude toward the cytoplasm, and the tips of the protrusions are pinched off to generate NDVs. The APHs of Atg39 are crucial for Atg39 crowding in the NE and subsequent NE protrusion. These findings suggest that the nucleophagy receptor Atg39 plays pivotal roles in NE deformation during the generation of NDVs to be degraded by nucleophagy.
    DOI:  https://doi.org/10.1083/jcb.202103178
  6. Front Cell Dev Biol. 2021 ;9 814955
    Autophagy of the Nucleus in Health and Disease.
    Georgios Konstantinidis, Nektarios Tavernarakis.
      Nucleophagy is an organelle-selective subtype of autophagy that targets nuclear material for degradation. The macroautophagic delivery of micronuclei to the vacuole, together with the nucleus-vacuole junction-dependent microautophagic degradation of nuclear material, were first observed in yeast. Nuclear pore complexes and ribosomal DNA are typically excluded during conventional macronucleophagy and micronucleophagy, indicating that degradation of nuclear cargo is tightly regulated. In mammals, similarly to other autophagy subtypes, nucleophagy is crucial for cellular differentiation and development, in addition to enabling cells to respond to various nuclear insults and cell cycle perturbations. A common denominator of all nucleophagic processes characterized in diverse organisms is the dependence on the core autophagic machinery. Here, we survey recent studies investigating the autophagic processing of nuclear components. We discuss nucleophagic events in the context of pathology, such as neurodegeneration, cancer, DNA damage, and ageing.
    Keywords:  ageing; autophagy; cancer; neurodegeneration; nucleophagy
    DOI:  https://doi.org/10.3389/fcell.2021.814955
  7. EMBO Rep. 2022 Jan 19. e53894
    Regulation of ER-derived membrane dynamics by the DedA domain-containing proteins VMP1 and TMEM41B.
    Yutaro Hama, Hideaki Morishita, Noboru Mizushima.
      The endoplasmic reticulum (ER) is a central hub for the biogenesis of various organelles and lipid-containing structures. Recent studies suggest that vacuole membrane protein 1 (VMP1) and transmembrane protein 41B (TMEM41B), multispanning ER membrane proteins, regulate the formation of many of these ER-derived structures, including autophagosomes, lipid droplets, lipoproteins, and double-membrane structures for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication. VMP1 and TMEM41B possess a DedA domain that is widely distributed not only in eukaryotes but also in prokaryotes and predicted to adopt a characteristic structure containing two reentrant loops. Furthermore, recent studies show that both proteins have lipid scrambling activity. Based on these findings, the potential roles of VMP1 and TMEM41B in the dynamic remodeling of ER membranes and the biogenesis of ER-derived structures are discussed.
    Keywords:  SARS-CoV-2; TMEM41B; VMP1; autophagy; scramblase
    DOI:  https://doi.org/10.15252/embr.202153894
  8. Nat Struct Mol Biol. 2022 Jan;29(1): 67-77
    ARF GTPases activate Salmonella effector SopF to ADP-ribosylate host V-ATPase and inhibit endomembrane damage-induced autophagy.
    Yue Xu, Sen Cheng, Huan Zeng, Ping Zhou, Yan Ma, Lin Li, Xiaoyun Liu, Feng Shao, Jingjin Ding.
      Selective autophagy helps eukaryotes to cope with endogenous dangers or foreign invaders; its initiation often involves membrane damage. By studying a Salmonella effector SopF, we recently identified the vacuolar ATPase (V-ATPase)-ATG16L1 axis that initiates bacteria-induced autophagy. Here we show that SopF is an ADP-ribosyltransferase specifically modifying Gln124 of ATP6V0C in V-ATPase. We identify GTP-bound ADP-ribosylation factor (ARF) GTPases as a cofactor required for SopF functioning. Crystal structures of SopF-ARF1 complexes not only reveal structural basis of SopF ADP-ribosyltransferase activity but also a unique effector-binding mode adopted by ARF GTPases. Further, the N terminus of ARF1, although dispensable for high-affinity binding to SopF, is critical for activating SopF to modify ATP6V0C. Moreover, lysosome or Golgi damage-induced autophagic LC3 activation is inhibited by SopF or Q124A mutation of ATP6V0C, thus also mediated by the V-ATPase-ATG16L1 axis. In this process, the V-ATPase functions to sense membrane damages, which can be uncoupled from its proton-pumping activity.
    DOI:  https://doi.org/10.1038/s41594-021-00710-6
  9. Cells. 2022 Jan 13. pii: 258. [Epub ahead of print]11(2):
    Tfeb-Mediated Transcriptional Regulation of Autophagy Induces Autosis during Ischemia/Reperfusion in the Heart.
    Jihoon Nah, Eun-Ah Sung, Peiyong Zhai, Daniela Zablocki, Junichi Sadoshima.
      Autosis is a unique form of cell death with characteristic morphological and biochemical features caused by dysregulated autophagy. Autosis is observed in the heart during the late phase of ischemia/reperfusion (I/R), when marked accumulation of autophagosomes is induced. We previously showed that the excessive accumulation of autophagosomes promotes autosis in cardiomyocytes. Although the inhibition of autophagic flux via the upregulation of Rubicon induces the accumulation of autophagosomes during I/R, it appears that additional mechanisms exacerbating autophagosome accumulation are required for the induction of autosis. Here, we show that Tfeb contributes to the induction of autosis during the late phase of I/R in the heart. During myocardial reperfusion, Tfeb is activated and translocated into the nucleus, which in turn upregulates genes involved in autophagy and lysosomal function. The overexpression of Tfeb enhanced cardiomyocyte death induced by a high dose of TAT-Beclin 1, an effect that was inhibited by the downregulation of Atg7. Conversely, the knockdown of Tfeb attenuated high-dose TAT-Beclin1-induced death in cardiomyocytes. Although the downregulation of Tfeb in the heart significantly decreased the number of autophagic vacuoles and inhibited autosis during I/R, the activation of Tfeb activity via 3,4-dimethoxychalcone, an activator of Tfeb, aggravated myocardial injury during I/R. These findings suggest that Tfeb promotes cardiomyocyte autosis during the late phase of reperfusion in the heart.
    Keywords:  Tfeb; autophagic cell death; autosis; ischemia/reperfusion
    DOI:  https://doi.org/10.3390/cells11020258
  10. Nucleic Acids Res. 2022 Jan 17. pii: gkab1296. [Epub ahead of print]
    Chaperone mediated autophagy contributes to the newly synthesized histones H3 and H4 quality control.
    Juan Hormazabal, Francisco Saavedra, Claudia Espinoza-Arratia, Nicolas W Martinez, Tatiana Cruces, Iván E Alfaro, Alejandra Loyola.
      Although there are several pathways to ensure that proteins are folded properly in the cell, little is known about the molecular mechanisms regulating histone folding and proteostasis. In this work, we identified that chaperone-mediated autophagy (CMA) is the main pathway involved in the degradation of newly synthesized histones H3 and H4. This degradation is finely regulated by the interplay between HSC70 and tNASP, two histone interacting proteins. tNASP stabilizes histone H3 levels by blocking the direct transport of histone H3 into lysosomes. We further demonstrate that CMA degrades unfolded histone H3. Thus, we reveal that CMA is the main degradation pathway involved in the quality control of histone biogenesis, evidencing an additional mechanism in the intricate network of histone cellular proteostasis.
    DOI:  https://doi.org/10.1093/nar/gkab1296
  11. FEBS J. 2022 Jan 21.
    DRAM-4 and DRAM-5 are compensatory regulators of autophagy and cell survival in nutrient-deprived conditions.
    Valentin J A Barthet, Michaela Mrschtik, Elzbieta Kania, David G McEwan, Dan Croft, James O'Prey, Jaclyn S Long, Kevin M Ryan.
      Macroautophagy is a membrane-trafficking process that delivers cytoplasmic material to lysosomes for degradation. The process preserves cellular integrity by removing damaged cellular constituents and can promote cell survival by providing substrates for energy production during hiatuses of nutrient availability. The process is also highly responsive to other forms of cellular stress. For example, DNA damage can induce autophagy and this involves up-regulation of the Damage-Regulated Autophagy Modulator-1 (DRAM-1) by the tumor suppressor p53. DRAM-1 belongs to an evolutionarily-conserved protein family, which has five members in humans and we describe here the initial characterization of two members of this family, which we term DRAM-4 and DRAM-5 for DRAM-Related/Associated Member 4/5. We show that the genes encoding these proteins are not regulated by p53, but instead are induced by nutrient deprivation. Similar to other DRAM family proteins, however, DRAM-4 principally localizes to endosomes and DRAM-5 to the plasma membrane and both modulate autophagy flux when over-expressed. Deletion of DRAM-4 using CRISPR/Cas-9 also increased autophagy flux, but we found that DRAM-4 and DRAM-5 undergo compensatory regulation, such that deletion of DRAM-4 does not affect autophagy flux in the absence of DRAM-5. Similarly, deletion of DRAM-4 also promotes cell survival following growth of cells in the absence of amino acids, serum or glucose, but this effect is also impacted by the absence of DRAM-5. In summary, DRAM-4 and DRAM-5 are nutrient-responsive members of the DRAM family that exhibit interconnected roles in the regulation of autophagy and cell survival under nutrient-deprived conditions.
    DOI:  https://doi.org/10.1111/febs.16365
  12. ACS Chem Neurosci. 2022 Jan 21.
    Anti-Inflammatory Anthranilate Analogue Enhances Autophagy through mTOR and Promotes ER-Turnover through TEX264 during Alzheimer-Associated Neuroinflammation.
    Zhiyu Wang, Junbo Huang, Seung-Pil Yang, Donald F Weaver.
      Autophagy degrades impaired organelles and toxic proteins to maintain cellular homeostasis. Dysregulated autophagy is a pathogenic participant in Alzheimer's disease (AD) progression. In early-stage AD, autophagy is beneficially initiated by mild endoplasmic reticulum (ER) stress to alleviate cellular damage and inflammation. However, chronic overproduction of toxic Aβ oligomers eventually causes Ca2+ dysregulation in the ER, subsequently elevating ER-stress and impairing autophagy. Our previous work showed that a novel anthranilate analogue (SI-W052) inhibited lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF)-α and interleukin (IL)-6 on microglia. To investigate its mechanism of action, herein, we postulate that SI-W052 exhibits anti-inflammatory activity through ER-stress-mediated autophagy. We initially demonstrate that autophagy inhibits inflammation, but it becomes impaired during acute inflammation. SI-W052 significantly induces the conversion ratio of LC3 II/I and inhibits LPS-upregulated p-mTOR, thereby restoring impaired autophagy to modulate inflammation. Our signaling study further indicates that SI-W052 inhibits the upregulation of ER-stress marker genes, including Atf4 and sXbp1/tXbp1, explaining compound activity against IL-6. This evidence encouraged us to evaluate ER-stress-triggered ER-phagy using TEX264. ER-phagy mediates ER-turnover by the degradation of ER fragments to maintain homeostasis. TEX264 is an important ER-phagy receptor involved in ATF4-mediated ER-phagy under ER-stress. In our study, elevated TEX264 degradation is identified during inflammation; SI-W052 enhances TEX264 expression, producing a positive effect in ER-turnover. Our knockdown experiment further verifies the important role of TEX264 in SI-W052 activity against IL-6 and ER-stress. In conclusion, this study demonstrates that an anthranilate analogue is a novel neuroinflammation agent functioning through ER-stress-mediated autophagy and ER-phagy mechanisms.
    Keywords:  Alzheimer’s disease; ER-phagy; TEX264; autophagy; microglia; neuroinflammation
    DOI:  https://doi.org/10.1021/acschemneuro.1c00818
  13. J Cell Mol Med. 2022 Jan 18.
    Mitophagy-regulated mitochondrial health strongly protects the heart against cardiac dysfunction after acute myocardial infarction.
    Chunling Xu, Yangpo Cao, Ruxia Liu, Lei Liu, Weilin Zhang, Xuan Fang, Shi Jia, Jingjing Ye, Yingying Liu, Lin Weng, Xue Qiao, Bo Li, Ming Zheng.
      Autophagy including mitophagy serves as an important regulatory mechanism in the heart to maintain the cellular homeostasis and to protect against heart damages caused by myocardial infarction (MI). The current study aims to dissect roles of general autophagy and specific mitophagy in regulating cardiac function after MI. By using Beclin1+/- , Fundc1 knockout (KO) and Fundc1 transgenic (TG) mouse models, combined with starvation and MI models, we found that Fundc1 KO caused more severe mitochondrial and cardiac dysfunction damages than Beclin1+/- after MI. Interestingly, Beclin1+/- caused notable decrease of total autophagy without detectable change to mitophagy, and Fundc1 KO markedly suppressed mitophagy but did not change the total autophagy activity. In contrast, starvation increased total autophagy without changing mitophagy while Fundc1 TG elevated total autophagy and mitophagy in mouse hearts. As a result, Fundc1 TG provided much stronger protective effects than starvation after MI. Moreover, Beclin1+/- /Fundc1 TG showed increased total autophagy and mitophagy to a level comparable to Fundc1 TG per se, and completely reversed Beclin1+/- -caused aggravation of mitochondrial and cardiac injury after MI. Our results reveal that mitophagy but not general autophagy contributes predominantly to the cardiac protective effect through regulating mitochondrial function.
    Keywords:  Beclin1; Fundc1; acute myocardial infarction; autophagy; mitophagy
    DOI:  https://doi.org/10.1111/jcmm.17190
  14. Biophys Rev. 2021 Dec;13(6): 857-858
    Autophagy: mechanisms and applications-a session at the 20th IUPAB congress/45th SBBf annual meeting/50th SBBq annual meeting.
    Marcelo A Mori.
      Autophagy is a conserved biological process used by cells to degrade and recycle components. Defects in autophagy are associated with multiple disease states, while interventions that promote autophagy may improve health. In a session at the 20th Congress of the International Union for Pure and Applied Biophysics (IUPAB), which was held along with the annual meetings of the Brazilian Society of Biophysics (SBBf) and the Brazilian Society of Biochemistry and Molecular Biology (SBBq), four speakers presented their studies linking autophagy to neurodegenerative diseases, heart failure, stress response, metabolism, and aging. They also proposed strategies to target autophagy as a way to ameliorate health.
    DOI:  https://doi.org/10.1007/s12551-021-00888-5
  15. mBio. 2022 Jan 18. e0352821
    Human Respiratory Syncytial Virus NS2 Protein Induces Autophagy by Modulating Beclin1 Protein Stabilization and ISGylation.
    Kim Chiok, Swechha M Pokharel, Indira Mohanty, Lindsay Grace Miller, Shou-Jiang Gao, Arthur L Haas, Kim C Tran, Michael N Teng, Santanu Bose.
      Paramyxoviruses such as respiratory syncytial virus (RSV) are the leading cause of pneumonia in infants, the elderly, and immunocompromised individuals. Understanding host-virus interactions is essential for the development of effective interventions. RSV induces autophagy to modulate the immune response. The viral factors and mechanisms underlying RSV-induced autophagy are unknown. Here, we identify the RSV nonstructural protein NS2 as the virus component mediating RSV-induced autophagy. We show that NS2 interacts and stabilizes the proautophagy mediator Beclin1 by preventing its degradation by the proteasome. NS2 further impairs interferon-stimulated gene 15 (ISG15)-mediated Beclin1 ISGylation and generates a pool of "hypo-ISGylated" active Beclin1 to engage in functional autophagy. Studies with NS2-deficient RSV revealed that NS2 contributes to RSV-mediated autophagy during infection. The present study is the first report to show direct activation of autophagy by a paramyxovirus nonstructural protein. We also report a new viral mechanism for autophagy induction wherein the viral protein NS2 promotes hypo-ISGylation of Beclin1 to ensure availability of active Beclin1 to engage in the autophagy process. IMPORTANCE Understanding host-virus interactions is essential for the development of effective interventions against respiratory syncytial virus (RSV), a paramyxovirus that is a leading cause of viral pneumonia in infants. RSV induces autophagy following infection, although the viral factors involved in this mechanism are unknown. Here, we identify the RSV nonstructural protein 2 (NS2) as the virus component involved in autophagy induction. NS2 promotes autophagy by interaction with and stabilization of the proautophagy mediator Beclin1 and by impairing its ISGylation to overcome autophagy inhibition. To the best of our knowledge, this is the first report of a viral protein regulating the autophagy pathway by modulating ISGylation of autophagy mediators. Our studies highlight a direct role of a paramyxovirus nonstructural protein in activating autophagy by interacting with the autophagy mediator Beclin1. NS2-mediated regulation of the autophagy and ISGylation processes is a novel function of viral nonstructural proteins to control the host response against RSV.
    Keywords:  autophagy; paramyxovirus; respiratory syncytial virus
    DOI:  https://doi.org/10.1128/mbio.03528-21
  16. Pathog Dis. 2022 Jan 17. pii: ftac004. [Epub ahead of print]
    The autophagy-resistant Mycobacterium tuberculosis Beijing strain upregulates KatG to evade starvation-induced autophagic restriction.
    Tegar Adriansyah Putra Siregar, Pinidphon Prombutara, Phongthon Kanjanasirirat, Nawapol Kunkaew, Alisa Tubsuwan, Atsadang Boonmee, Tanapat Palaga, Tanawadee Khumpanied, Suparerk Borwornpinyo, Angkana Chaiprasert, Pongsak Utaisincharoen, Marisa Ponpuak.
      Mycobacterium tuberculosis utilizes several mechanisms to block phagosome-lysosome fusion to evade host cell restriction. However, induction of host cell autophagy by starvation was shown to overcome this block, resulting in enhanced lysosomal delivery to mycobacterial phagosomes and the killing of the M. tuberculosis reference strain H37Rv. Nevertheless, our previous studies found that strains belonging to the M. tuberculosis Beijing genotype can resist starvation-induced autophagic elimination, though the mycobacterial factors involved remain unclear. In this study, we showed that KatG expression is upregulated in the autophagy-resistant M. tuberculosis Beijing strain (BJN) during autophagy induction by the starvation of host macrophages, while such increase was not observed in the H37Rv. KatG depletion using the CRISPR-dCas9 interference system in the BJN resulted in increased lysosomal delivery to its phagosome and decreased its survival upon autophagy induction by starvation. As KatG functions by catabolizing ROS, we determined the source of ROS contributing to the starvation-induced autophagic elimination of mycobacteria. Using siRNA-mediated knockdown, we found that Superoxide dismutase 2, which generates mitochondrial ROS but not NADPH oxidase 2, is important for the starvation-induced lysosomal delivery to mycobacterial phagosomes. Taken together, these findings showed that KatG is vital for the BJN to evade starvation-induced autophagic restriction.
    Keywords:   Mycobacterium tuberculosis ; Autophagy; CRISPR; KatG; ROS; Tuberculosis
    DOI:  https://doi.org/10.1093/femspd/ftac004
  17. Biomolecules. 2022 Jan 13. pii: 126. [Epub ahead of print]12(1):
    Mutation of the Conserved Threonine 8 within the Human ARF Tumour Suppressor Protein Regulates Autophagy.
    Rosa Fontana, Daniela Guidone, Tiziana Angrisano, Viola Calabrò, Alessandra Pollice, Girolama La Mantia, Maria Vivo.
      BACKGROUND: The ARF tumour suppressor plays a well-established role as a tumour suppressor, halting cell growth by both p53-dependent and independent pathways in several cellular stress response circuits. However, data collected in recent years challenged the traditional role of this protein as a tumour suppressor. Cancer cells expressing high ARF levels showed that its expression, far from being dispensable, is required to guarantee tumour cell survival. In particular, ARF can promote autophagy, a self-digestion pathway that helps cells cope with stressful growth conditions arising during both physiological and pathological processes.METHODS: We previously showed that ARF is regulated through the activation of the protein kinase C (PKC)-dependent pathway and that an ARF phospho-mimetic mutant on the threonine residue 8, ARF-T8D, sustains cell proliferation in HeLa cells. We now explored the role of ARF phosphorylation in both basal and starvation-induced autophagy by analysing autophagic flux in cells transfected with either WT and ARF phosphorylation mutants by immunoblot and immunofluorescence.
    RESULTS: Here, we show that endogenous ARF expression in HeLa cells is required for starvation-induced autophagy. Further, we provide evidence that the hyper-expression of ARF-T8D appears to inhibit autophagy in both HeLa and lung cancer cells H1299. This effect is due to the cells' inability to elicit autophagosomes formation upon T8D expression.
    CONCLUSIONS: Our results lead to the hypothesis that ARF phosphorylation could be a mechanism through which the protein promotes or counteracts autophagy. Several observations underline how autophagy could serve a dual role in cancer progression, either protecting healthy cells from damage or aiding cancerous cells to survive. Our results indicate that ARF phosphorylation controls protein's ability to promote or counteract autophagy, providing evidence of the dual role played by ARF in cancer progression.
    Keywords:  INK4a/ARF locus; LC3; autophagy; cancer; cytoskeleton
    DOI:  https://doi.org/10.3390/biom12010126
  18. FEBS J. 2022 Jan 18.
    Cellular autophagy, an unbidden effect of caspase inhibition by zVAD-fmk.
    Dharaniya Sakthivel, Beatriz E Bolívar, Lisa Bouchier-Hayes.
      zVAD-fmk is a widely used pan-caspase inhibitor that blocks apoptosis but has undesirable side effects, including autophagy. In this issue, Needs et al. propose that zVAD-fmk induces autophagy by inhibiting the N-glycanase NGLY1 rather than caspases. NGLY1 is essential for the ERAD response and patients with inactivating mutations in NGLY1 present with neurodevelopmental defects and organ dysfunction. The ability of NGLY1 to inhibit basal levels of autophagy may contribute to this pathology. This study demonstrates possible crosstalk between protein turnover and autophagy while also underscoring the importance of specificity when using chemical tools to interrogate these pathways. Comment on https://doi.org/10.1111/febs.16345.
    Keywords:  NLGY1; apoptosis; autophagy; caspase; zVAD-fmk
    DOI:  https://doi.org/10.1111/febs.16346
  19. Open Biol. 2022 Jan;12(1): 210255
    Selective localization of Mfn2 near PINK1 enables its preferential ubiquitination by Parkin on mitochondria.
    Marta Vranas, Yang Lu, Shafqat Rasool, Nathalie Croteau, Jonathan D Krett, Véronique Sauvé, Kalle Gehring, Edward A Fon, Thomas M Durcan, Jean-François Trempe.
      Mutations in Parkin and PINK1 cause early-onset familial Parkinson's disease. Parkin is a RING-In-Between-RING E3 ligase that transfers ubiquitin from an E2 enzyme to a substrate in two steps: (i) thioester intermediate formation on Parkin and (ii) acyl transfer to a substrate lysine. The process is triggered by PINK1, which phosphorylates ubiquitin on damaged mitochondria, which in turn recruits and activates Parkin. This leads to the ubiquitination of outer mitochondrial membrane proteins and clearance of the organelle. While the targets of Parkin on mitochondria are known, the factors determining substrate selectivity remain unclear. To investigate this, we examined how Parkin catalyses ubiquitin transfer to substrates. We found that His433 in the RING2 domain contributes to the catalysis of acyl transfer. In cells, the mutation of His433 impairs mitophagy. In vitro ubiquitination assays with isolated mitochondria show that Mfn2 is a kinetically preferred substrate. Using proximity-ligation assays, we show that Mfn2 specifically co-localizes with PINK1 and phospho-ubiquitin (pUb) in U2OS cells upon mitochondrial depolarization. We propose a model whereby ubiquitination of Mfn2 is efficient by virtue of its localization near PINK1, which leads to the recruitment and activation of Parkin via pUb at these sites.
    Keywords:  Mfn2; PINK1; Parkin; mitochondria; ubiquitin
    DOI:  https://doi.org/10.1098/rsob.210255
  20. Cell Death Discov. 2022 Jan 17. 8(1): 28
    Idebenone improves motor dysfunction, learning and memory by regulating mitophagy in MPTP-treated mice.
    Junqiang Yan, Wenjie Sun, Mengmeng Shen, Yongjiang Zhang, Menghan Jiang, Anran Liu, Hongxia Ma, Xiaoyi Lai, Jiannan Wu.
      The progression of Parkinson's disease (PD) is often accompanied by the loss of substantia nigra dopaminergic neurons, mitophagy damage, learning, and memory impairment. Idebenone is a therapeutic drug that targets the mitochondria of neurodegenerative diseases, but its role in Parkinson's disease and its pathological mechanism are still unclear. The purpose of this study was to investigate whether idebenone could improve behavioral disorders, especially motor, learning, and memory disorders, in mouse PD models and to explore its molecular mechanism. In the present study, C57BL-6 mice underwent intraperitoneal injection of MPTP (30 mg/kg) once a day for five consecutive days. Then, a 200 mg/kg dose was given as a single daily gavage of idebenone dissolved in water for 21 days after the successful establishment of the subacute MPTP model. Motor, learning, and memory were measured by a water maze and a rotarod test. Our results showed that idebenone could reduce MPTP-induced dopaminergic neuron damage and improve movement disorders, memory, and learning ability, which may be associated with upregulating mitochondrial autophagy-related outer membrane proteins VDAC1 and BNIP3 and activating the Parkin/PINK1 mitochondrial autophagy pathway. To confirm whether idebenone promotes the smooth progression of autophagy, we used eGFP-mCherry-LC3 mice to construct a subacute model of Parkinson's disease and found that idebenone can increase autophagy in dopaminergic neurons in Parkinson's disease. In summary, our results confirm that idebenone can regulate the expression of the mitochondrial outer membrane proteins VDAC1 and BNIP3, activate Parkin/PINK1 mitophagy, promote the degradation of damaged mitochondria, reduce dopaminergic neuron damage, and improve behavioral disorders in Parkinson's disease mice.
    DOI:  https://doi.org/10.1038/s41420-022-00826-8
  21. Cancers (Basel). 2022 Jan 11. pii: 339. [Epub ahead of print]14(2):
    STAT3 Enhances Sensitivity of Glioblastoma to Drug-Induced Autophagy-Dependent Cell Death.
    Janina Remy, Benedikt Linder, Ulrike Weirauch, Bryan W Day, Brett W Stringer, Christel Herold-Mende, Achim Aigner, Knut Krohn, Donat Kögel.
      Glioblastoma (GBM) is a devastating disease and the most common primary brain malignancy of adults with a median survival barely exceeding one year. Recent findings suggest that the antipsychotic drug pimozide triggers an autophagy-dependent, lysosomal type of cell death in GBM cells with possible implications for GBM therapy. One oncoprotein that is often overactivated in these tumors and associated with a particularly dismal prognosis is Signal Transducer and Activator of Transcription 3 (STAT3). Here, we used isogenic human and murine GBM knockout cell lines, advanced fluorescence microscopy, transcriptomic analysis and FACS-based assessment of cell viability to show that STAT3 has an underappreciated, context-dependent role in drug-induced cell death. Specifically, we demonstrate that depletion of STAT3 significantly enhances cell survival after treatment with Pimozide, suggesting that STAT3 confers a particular vulnerability to GBM. Furthermore, we show that active STAT3 has no major influence on the early steps of the autophagy pathway, but exacerbates drug-induced lysosomal membrane permeabilization (LMP) and release of cathepsins into the cytosol. Collectively, our findings support the concept of exploiting the pro-death functions of autophagy and LMP for GBM therapy and to further determine whether STAT3 can be employed as a treatment predictor for highly apoptosis-resistant, but autophagy-proficient cancers.
    Keywords:  STAT3; autophagy; autophagy-dependent cell death; glioblastoma; lysosomal-dependent cell death; lysosome; pimozide
    DOI:  https://doi.org/10.3390/cancers14020339
  22. Am J Orthod Dentofacial Orthop. 2022 Jan 15. pii: S0889-5406(21)00688-0. [Epub ahead of print]
    Orthodontic loading activates cell-specific autophagy in a force-dependent manner.
    Laura Anne Jacox, Na Tang, Yina Li, Clare Bocklage, Christina Graves, Shannon Coats, Michael Miao, Tim Glesener, Jane Kwon, Natalie Giduz, Feng-Chang Lin, Jennifer Martinez, Ching-Chang Ko.
      INTRODUCTION: Orthodontic tooth movement (OTM) relies on bone remodeling and controlled aseptic inflammation. Autophagy, a conserved homeostatic pathway, has been shown to play a role in bone turnover. We hypothesize that autophagy participates in regulating bone remodeling during OTM in a force-dependent and cell type-specific manner.METHODS: A split-mouth design was used to load molars with 1 of 3 force levels (15, 30, or 45 g of force) in mice carrying a green fluorescent protein-LC3 transgene to detect cellular autophagy. Fluorescent microscopy and quantitative polymerase chain reaction analyses were used to evaluate autophagy activation and its correlation with force level. Cell type-specific antibodies were used to identify cells with green fluorescent protein-positive puncta (autophagosomes) in periodontal tissues.
    RESULTS: Autophagic activity increased shortly after loading with moderate force and was associated with the expression of bone turnover, inflammatory, and autophagy markers. Different load levels resulted in altered degrees of autophagic activation, gene expression, and osteoclast recruitment. Autophagy was specifically induced by loading in macrophages and osteoclasts found in the periodontal ligament and alveolar bone. Data suggest autophagy participates in regulating bone turnover during OTM.
    CONCLUSIONS: Autophagy is induced in macrophage lineage cells by orthodontic loading in a force-dependent manner and plays a role during OTM, possibly through modulation of osteoclast bone resorption. Exploring the roles of autophagy in OTM is medically relevant, given that autophagy is associated with oral and systemic inflammatory conditions.
    DOI:  https://doi.org/10.1016/j.ajodo.2020.09.034
  23. Neurotox Res. 2022 Jan 18.
    Regulation of Neurodegeneration-associated Protein Fragments by the N-degron Pathways.
    Mohamed A Eldeeb, Mohamed A Ragheb, Marwa H Soliman, Richard P Fahlman.
      Among the most salient features that underpin the development of aging-related neurodegenerative disorders are the accumulation of protein aggregates and the decrease in cellular degradation capacity. Mammalian cells have evolved sophisticated quality control mechanisms to repair or eliminate the otherwise abnormal or misfolded proteins. Chaperones identify unstable or abnormal conformations in proteins and often help them regain their correct conformation. However, if repair is not an option, abnormal proteins are selectively degraded to prevent undesired interactions with other proteins or oligomerization into toxic multimeric complexes. The autophagic-lysosomal system and the ubiquitin-proteasome system mediate the selective and targeted degradation of abnormal or aberrant protein fragments. Despite an increasing understanding regarding the molecular responses that counteract the formation and clearance of dysfunctional protein aggregates, the role of N-degrons in these processes is poorly understood. Previous work demonstrated that the Arg-N-end rule degradation pathway (Arg-N-degron pathway) mediates the degradation of neurodegeneration-associated proteins, thereby regulating crucial signaling hubs that modulate the progression of neurodegenerative diseases. Herein, we discuss the functional interconnection between N-degron pathways and proteins associated with neurodegenerative disorders, including Alzheimer's disease, amyotrophic lateral sclerosis, and Parkinson's disease. We also highlight some future prospects related to how the molecular insights gained from these processes will help unveil novel therapeutic approaches.
    Keywords:  N-degron; N-end rule; PINK1; Parkin; Parkinson’s disease; Proteasome; Protein degradation; Synucleinopathies; Aβ; Ubiquitin; Tau
    DOI:  https://doi.org/10.1007/s12640-021-00396-0
  24. Mol Neurobiol. 2022 Jan 18.
    Desferrioxamine Ameliorates Lipopolysaccharide-Induced Lipocalin-2 Upregulation via Autophagy Activation in Primary Astrocytes.
    Juntao Cui, Yu Yuan, Jun Wang, Ning Song, Junxia Xie.
      Lipocalin-2 (LCN2) is an important regulator of both neuroinflammation and iron homeostasis. Upregulated LCN2 was observed in reactive astrocytes in the Parkinson's disease (PD) models. In the present study, we reported iron chelator deferoxamine (DFO) abolished lipopolysaccharide (LPS)-induced LCN2 upregulation in primary astrocytes, although iron overload had no effects. The suppressive effects of DFO were consistent with autophagy inducer rapamycin or carfilzomib, blocked by autophagy inhibitor 3-methyladenine rather than chloroquine or bafilomycin A1, meanwhile, while were not dependent on proteasome system and NF-κB pathway. DFO was not able to ameliorate LCN2 upregulation in α-synuclein-treated astrocytes, because DFO failed to induce autophagy in these cells. We further demonstrated that DFO could not enhance autophagy lysosomal degradation, however promoted secretory autophagy in primary astrocytes with LPS insults. These data suggest that DFO could serve as an autophagy activator, capable of ameliorating the upregulation of LCN2 in astrocytes by acting on the formation of autophagosomes and secretory autophagy. This provides better understandings of DFO-mediated neuroprotection against neuroinflammation and provides new insights that autophagy activation could be beneficial approaches in PD.
    Keywords:  Autophagy; Deferoxamine; Lipocalin-2; Neuroinflammation; Primary astrocytes; Secretory autophagy
    DOI:  https://doi.org/10.1007/s12035-021-02687-1
  25. Open Biol. 2022 Jan;12(1): 210264
    Mapping of a N-terminal α-helix domain required for human PINK1 stabilization, Serine228 autophosphorylation and activation in cells.
    Poonam Kakade, Hina Ojha, Olawale G Raimi, Andrew Shaw, Andrew D Waddell, James R Ault, Sophie Burel, Kathrin Brockmann, Atul Kumar, Mohd Syed Ahangar, Ewelina M Krysztofinska, Thomas Macartney, Richard Bayliss, Julia C Fitzgerald, Miratul M K Muqit.
      Autosomal recessive mutations in the PINK1 gene are causal for Parkinson's disease (PD). PINK1 encodes a mitochondrial localized protein kinase that is a master-regulator of mitochondrial quality control pathways. Structural studies to date have elaborated the mechanism of how mutations located within the kinase domain disrupt PINK1 function; however, the molecular mechanism of PINK1 mutations located upstream and downstream of the kinase domain is unknown. We have employed mutagenesis studies to define the minimal region of human PINK1 required for optimal ubiquitin phosphorylation, beginning at residue Ile111. Inspection of the AlphaFold human PINK1 structure model predicts a conserved N-terminal α-helical extension (NTE) domain forming an intramolecular interaction with the C-terminal extension (CTE), which we corroborate using hydrogen/deuterium exchange mass spectrometry of recombinant insect PINK1 protein. Cell-based analysis of human PINK1 reveals that PD-associated mutations (e.g. Q126P), located within the NTE : CTE interface, markedly inhibit stabilization of PINK1; autophosphorylation at Serine228 (Ser228) and Ubiquitin Serine65 (Ser65) phosphorylation. Furthermore, we provide evidence that NTE and CTE domain mutants disrupt PINK1 stabilization at the mitochondrial Translocase of outer membrane complex. The clinical relevance of our findings is supported by the demonstration of defective stabilization and activation of endogenous PINK1 in human fibroblasts of a patient with early-onset PD due to homozygous PINK1 Q126P mutations. Overall, we define a functional role of the NTE : CTE interface towards PINK1 stabilization and activation and show that loss of NTE : CTE interactions is a major mechanism of PINK1-associated mutations linked to PD.
    Keywords:  PINK1; Parkinson's disease; kinase; mitochondria; phosphorylation; translocase
    DOI:  https://doi.org/10.1098/rsob.210264
  26. Allergy. 2022 Jan 17.
    TFEB signaling attenuates NLRP3-driven inflammatory responses in severe asthma.
    Efthymia Theofani, Maria Semitekolou, Konstantinos Samitas, Annie Mais, Ioanna E Galani, Vasiliki Triantafyllia, Joanna Lama, Ioannis Morianos, Athanasios Stavropoulos, Se-Jin Jeong, Evangelos Andreakos, Babak Razani, Nikoletta Rovina, Georgina Xanthou.
      BACKGROUND: NLRP3-driven inflammatory responses by circulating and lung-resident monocytes are critical drivers of asthma pathogenesis. Autophagy restrains NLRP3-induced monocyte activation in asthma models. Yet, the effects of autophagy and its master regulator, transcription factor EB (TFEB), on monocyte responses in human asthma remain unexplored. Here, we investigated whether activation of autophagy and TFEB signaling suppress inflammatory monocyte responses in asthmatic individuals.METHODS: Peripheral blood CD14+ monocytes from asthmatic patients (n=83) and healthy controls (n=46) were stimulated with LPS/ATP to induce NLRP3 activation with or without the autophagy inducer, rapamycin. ASC specks, caspase-1 activation, IL-1β and IL-18 levels, mitochondrial function, ROS release and mTORC1 signaling were examined. Autophagy was evaluated by LC3 puncta formation, p62/SQSTM1 degradation and TFEB activation. In a severe asthma (SA) model, we investigated the role of NLRP3 signaling using Nlrp3-/- mice and/or MCC950 administration, and the effects of TFEB activation using myeloid-specific TFEB-overexpressing mice or administration of the TFEB activator, trehalose.
    RESULTS: We observed increased NLRP3 inflammasome activation, concomitant with impaired autophagy in circulating monocytes that correlated with asthma severity. SA patients also exhibited mitochondrial dysfunction and ROS accumulation. Autophagy failed to inhibit NLRP3-driven monocyte responses, due to defective TFEB activation and excessive mTORC1 signaling. NLRP3 blockade restrained inflammatory cytokine release and linked airway disease. TFEB activation restored impaired autophagy, attenuated NLRP3-driven pulmonary inflammation and ameliorated SA phenotype.
    CONCLUSIONS: Our studies uncover a crucial role for TFEB-mediated reprogramming of monocyte inflammatory responses, raising the prospect that this pathway can be therapeutically harnessed for the management of SA.
    Keywords:  NLRP3; TFEB; asthma; autophagy; monocytes
    DOI:  https://doi.org/10.1111/all.15221
  27. Neurotox Res. 2022 Jan 18.
    Bupivacaine Induces ROS-Dependent Autophagic Damage in DRG Neurons via TUG1/mTOR in a High-Glucose Environment.
    Luying Lai, Yongwei Wang, Shenghui Peng, Wenjing Guo, Guanshan Wei, Le Li, Zhengyuan Xia, Fengxian Li, Shiyuan Xu.
      Bupivacaine (BP) is a commonly clinically used local anesthetic (LA). Current studies suggest that neurological complications are increased in diabetic patients after LA application, but the molecular mechanism is poorly understood. LA-induced autophagy and neuronal injury have been reported. We hypothesized that a high-glucose environment aggravates BP-induced autophagic damage. Mouse dorsal root ganglion (DRG) neurons were treated with BP in a high-glucose environment, and the results showed that reactive oxygen species (ROS) levels increased, autophagy was activated, autophagy flux was blocked, and cell viability decreased. Pretreatment with the ROS scavenger N-acetyl-cysteine (NAC) attenuated ROS-mediated autophagy regulation. Moreover, the expression of the long noncoding RNA (lncRNA) taurine upregulated gene 1 (TUG1) increased, and NAC and TUG1 siRNA inhibited the expression of TUG1/mammalian target of rapamycin (mTOR) in DRGs treated with BP in a high-glucose environment. Intriguingly, contrary to previous reports on a positive effect on neurons, we found that rapamycin, an autophagy activator, and chloroquine, an autophagy and lysosome inhibitor, both exacerbated autophagic damage. These data suggest that a high-glucose environment exacerbated BP induced ROS-dependent autophagic damage in DRG neurons through the TUG1/mTOR signaling pathway, which provides a theoretical basis and target for the clinical prevention and treatment of BP neurotoxicity in diabeties.
    Keywords:  Autophagy; Bupivacaine; High glucose; ROS; TUG1; mTOR
    DOI:  https://doi.org/10.1007/s12640-021-00461-8
  28. J Physiol Biochem. 2022 Jan 22.
    A novel therapeutic strategy for atherosclerosis: autophagy-dependent cholesterol efflux.
    Haipeng Guo, Dongmei Wei, Rui Liu, Chao Zhang, Song Jiang, Weijia Wang, Hongzhe Hu, Lijuan Shen, Xiaofei Liang.
      Atherosclerosis (AS) is a chronic inflammatory disease characterized by abnormal lipid metabolism. Foam cell formation is also known as an early event of AS. Cholesterol efflux is a process whereby cholesterol is excreted from foam cells through transporters, which serves as one of the effective regulatory mechanisms to prevent AS. Autophagy is a biodegradable mechanism, and lipophagy is a special form of autophagy that selectively degrades lipids. Cholesterol efflux is regulated by several mechanisms. Moreover, numerous studies have shown that autophagy is also process whereby cholesterol efflux is regulated. In early studies, scholars found that cholesterol efflux is related to autophagy. Subsequent studies have shown that various targeted molecules can induce autophagy and promote the expression of cholesterol transporters (such as LXRα, ABCA1, and ABCG1) through specific signaling pathways. Several novel treatments for AS use these small molecules as entry points for research and development based on autophagy. However, this autophagy-dependent cholesterol efflux involves many different molecular mechanisms. This not only indicates that cholesterol efflux is the result of multiple factors, but also that autophagy, which mediates cholesterol efflux, is a complex physiological mechanism. Through a literature review, we found that the role of autophagy in cholesterol efflux is related to cell type and is regulated by both the level of autophagy and the mechanism that triggers autophagy. In this review, we aim to discuss the role of autophagy in cholesterol efflux from many aspects based on recent relevant studies to aid in the treatment of AS.
    Keywords:  ABCA1; ABCG1; Atherosclerosis; Autophagy; Cholesterol efflux; Foam cell
    DOI:  https://doi.org/10.1007/s13105-021-00870-5
  29. Cells. 2022 Jan 09. pii: 214. [Epub ahead of print]11(2):
    One-Carbon Metabolism: Pulling the Strings behind Aging and Neurodegeneration.
    Eirini Lionaki, Christina Ploumi, Nektarios Tavernarakis.
      One-carbon metabolism (OCM) is a network of biochemical reactions delivering one-carbon units to various biosynthetic pathways. The folate cycle and methionine cycle are the two key modules of this network that regulate purine and thymidine synthesis, amino acid homeostasis, and epigenetic mechanisms. Intersection with the transsulfuration pathway supports glutathione production and regulation of the cellular redox state. Dietary intake of micronutrients, such as folates and amino acids, directly contributes to OCM, thereby adapting the cellular metabolic state to environmental inputs. The contribution of OCM to cellular proliferation during development and in adult proliferative tissues is well established. Nevertheless, accumulating evidence reveals the pivotal role of OCM in cellular homeostasis of non-proliferative tissues and in coordination of signaling cascades that regulate energy homeostasis and longevity. In this review, we summarize the current knowledge on OCM and related pathways and discuss how this metabolic network may impact longevity and neurodegeneration across species.
    Keywords:  Alzheimer’s disease; Parkinson disease; aging; diet; folate; metabolism; methionine; mitochondria; neurodegeneration; one-carbon vitamins
    DOI:  https://doi.org/10.3390/cells11020214
  30. Cells. 2022 Jan 07. pii: 199. [Epub ahead of print]11(2):
    Mitophagy Regulation Following Myocardial Infarction.
    Annie Turkieh, Yara El Masri, Florence Pinet, Emilie Dubois-Deruy.
      Mitophagy, which mediates the selective elimination of dysfunctional mitochondria, is essential for cardiac homeostasis. Mitophagy is regulated mainly by PTEN-induced putative kinase protein-1 (PINK1)/parkin pathway but also by FUN14 domain-containing 1 (FUNDC1) or Bcl2 interacting protein 3 (BNIP3) and BNIP3-like (BNIP3L/NIX) pathways. Several studies have shown that dysregulated mitophagy is involved in cardiac dysfunction induced by aging, aortic stenosis, myocardial infarction or diabetes. The cardioprotective role of mitophagy is well described, whereas excessive mitophagy could contribute to cell death and cardiac dysfunction. In this review, we summarize the mechanisms involved in the regulation of cardiac mitophagy and its role in physiological condition. We focused on cardiac mitophagy during and following myocardial infarction by highlighting the role and the regulation of PI NK1/parkin-; FUNDC1-; BNIP3- and BNIP3L/NIX-induced mitophagy during ischemia and reperfusion.
    Keywords:  cardioprotection; heart; ischemia/reperfusion; mitophagy
    DOI:  https://doi.org/10.3390/cells11020199
  31. Appl Environ Microbiol. 2022 Jan 19. aem0206821
    Blocking mitophagy does not significantly improve fuel ethanol production in bioethanol yeast Saccharomyces cerevisiae.
    Kevy Pontes Eliodório, Gabriel Caetano de Gois E Cunha, Brianna A White, Demisha H M Patel, Fangyi Zhang, Ewald H Hettema, Thiago Olitta Basso, Andreas Karoly Gombert, Vijayendran Raghavendran.
      Ethanolic fermentation is frequently performed under conditions of low nitrogen. In Saccharomyces cerevisiae, nitrogen limitation induces macroautophagy, including the selective removal of mitochondria, also called mitophagy. Shiroma and co-workers (2014) showed that blocking mitophagy by deletion of the mitophagy specific gene ATG32 increased the fermentation performance during the brewing of Ginjo sake. In this study, we tested if a similar strategy could enhance alcoholic fermentation in the context of fuel ethanol production from sugarcane in Brazilian biorefineries. Conditions that mimic the industrial fermentation process indeed induce Atg32-dependent mitophagy in cells of S. cerevisiae PE-2, a strain frequently used in the industry. However, after blocking mitophagy, no significant differences in CO2 production, final ethanol titres or cell viability were observed after five rounds of ethanol fermentation, cell recycling and acid treatment, as commonly performed in sugarcane biorefineries. To test if S. cerevisiae's strain background influences this outcome, cultivations were carried out in a synthetic medium with strains PE-2, Ethanol Red (industrial) and BY (laboratory), with and without a functional ATG32 gene, under oxic and oxygen restricted conditions. Despite the clear differences in sugar consumption, cell viability and ethanol titres, among the three strains, we could not observe any significant improvement in fermentation performance related to the blocking of mitophagy. We conclude with caution that results obtained with Ginjo sake yeast is an exception and cannot be extrapolated to other yeast strains and that more research is needed to ascertain the role of autophagic processes during fermentation. Importance Bioethanol is the largest (per volume) ever biobased bulk chemical produced globally. The fermentation process is very well established, and industries regularly attain nearly 85% of maximum theoretical yields. However, because of the volume of fuel produced, even a small improvement will have huge economic benefits. To this end, besides already implemented process improvements, various free energy conservation strategies have been successfully exploited at least in laboratory strains to increase ethanol yields and decrease by-product formation. Cellular housekeeping processes have been an almost unexplored territory in strain improvement. Shiroma and co-workers previously reported that blocking mitophagy by deletion of the mitophagy receptor gene ATG32 in Saccharomyces cerevisiae led to a 2.1% increase in final ethanol titres during Japanese sake fermentation. We found in two commercially used bioethanol strains (PE-2 and Ethanol Red) that ATG32 deficiency does not lead to a significant improvement in cell viability or ethanol levels during fermentation with molasses or in a synthetic complete medium. More research is required to ascertain the role of autophagic processes during fermentation conditions.
    DOI:  https://doi.org/10.1128/aem.02068-21
  32. Cell Death Dis. 2022 Jan 20. 13(1): 68
    PGK1 represses autophagy-mediated cell death to promote the proliferation of liver cancer cells by phosphorylating PRAS40.
    Tianhua Zhang, Yuzhen Wang, Hongjiu Yu, Ting Zhang, Lianying Guo, Jie Xu, Xiaoqing Wei, Ning Wang, Yingjie Wu, Xiuli Wang, Lin Huang.
      Autophagy predominantly promotes cell survival by recycling cell components, while it kills cells in specific contexts. Cell death related to autophagy plays important roles in multiple physiological and pathological situations including tumorigenesis, and the mechanism needs to be defined further. PRAS40 was found to be crucial in various cancers, and phosphorylation was reported to be involved in autophagy inhibition in monocytes. However, the detailed role of PRAS40 in autophagy and the relationship to tumorigenesis remain largely unknown. Herein we screened the binding partners of PRAS40, and found that PRAS40 interacted with Phosphoglycerate kinase 1 (PGK1). PGK1 phosphorylated PRAS40 at Threonine 246, which could be inhibited by blocking the interaction. Both in vitro and in vivo results revealed that PRAS40 mediated PGK1-induced cell growth. By tracing the mechanism, we found that PGK1 suppressed autophagy-mediated cell death, in which PRAS40 was crucial. Thus PGK1 phosphorylates PRAS40 to repress autophagy-mediated cell death under normoxia, promoting cellular proliferation. The binding of PGK1 to PRAS40 was transferred to Beclin1 under hypoxia, resulting in the increase of Beclin1 phosphorylation. These results suggest a novel model of tumorigenesis, in which PGK1 switches between repressing autophagy-mediated cell death via PRAS40 and inducing autophagy through Beclin1 according to the environmental oxygen level. Our study is anticipated to be able to offer novel insights in understanding PGK1/PRAS40 signaling hyperactivated cancers.
    DOI:  https://doi.org/10.1038/s41419-022-04499-0
  33. J Cell Mol Med. 2022 Jan 17.
    Mitochondrial quality control in stroke: From the mechanisms to therapeutic potentials.
    Heyan Tian, Xiangyu Chen, Jun Liao, Tong Yang, Shaowu Cheng, Zhigang Mei, Jinwen Ge.
      Mitochondrial damage is a critical contributor to stroke-induced injury, and mitochondrial quality control (MQC) is the cornerstone of restoring mitochondrial homeostasis and plays an indispensable role in alleviating pathological process of stroke. Mitochondria quality control promotes neuronal survival via various adaptive responses for preserving mitochondria structure, morphology, quantity and function. The processes of mitochondrial fission and fusion allow for damaged mitochondria to be segregated and facilitate the equilibration of mitochondrial components such as DNA, proteins and metabolites. The process of mitophagy is responsible for the degradation and recycling of damaged mitochondria. This review aims to offer a synopsis of the molecular mechanisms involved in MQC for recapitulating our current understanding of the complex role that MQC plays in the progression of stroke. Speculating on the prospect that targeted manipulation of MQC mechanisms may be exploited for the rationale design of novel therapeutic interventions in the ischaemic stroke and haemorrhagic stroke. In the review, we highlight the potential of MQC as therapeutic targets for stroke treatment and provide valuable insights for clinical strategies.
    Keywords:  mitochondrial biogenesis; mitochondrial dynamics; mitochondrial quality control; mitophagy; stroke
    DOI:  https://doi.org/10.1111/jcmm.17189
  34. Front Cell Infect Microbiol. 2021 ;11 786348
    Clearance or Hijack: Universal Interplay Mechanisms Between Viruses and Host Autophagy From Plants to Animals.
    Wenxian Wu, Xiumei Luo, Maozhi Ren.
      Viruses typically hijack the cellular machinery of their hosts for successful infection and replication, while the hosts protect themselves against viral invasion through a variety of defense responses, including autophagy, an evolutionarily ancient catabolic pathway conserved from plants to animals. Double-membrane vesicles called autophagosomes transport trapped viral cargo to lysosomes or vacuoles for degradation. However, during an ongoing evolutionary arms race, viruses have acquired a strong ability to disrupt or even exploit the autophagy machinery of their hosts for successful invasion. In this review, we analyze the universal role of autophagy in antiviral defenses in animals and plants and summarize how viruses evade host immune responses by disrupting and manipulating host autophagy. The review provides novel insights into the role of autophagy in virus-host interactions and offers potential targets for the prevention and control of viral infection in both plants and animals.
    Keywords:  autophagy; immune response; infection; virus manipulation; virus–host interaction
    DOI:  https://doi.org/10.3389/fcimb.2021.786348
  35. Trends Neurosci. 2022 Jan 13. pii: S0166-2236(21)00252-6. [Epub ahead of print]
    Lysosomal dysfunction in neurodegeneration: emerging concepts and methods.
    Vinod Udayar, Yu Chen, Ellen Sidransky, Ravi Jagasia.
      The understanding of lysosomes has come a long way since the initial discovery of their role in degrading cellular waste. The lysosome is now recognized as a highly dynamic organelle positioned at the crossroads of cell signaling, transcription, and metabolism. Underscoring its importance is the observation that, in addition to rare monogenic lysosomal storage disorders, genes regulating lysosomal function are implicated in common sporadic neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Developing therapies for these disorders is particularly challenging, largely due to gaps in knowledge of the underlying molecular and cellular processes. In this review, we discuss technological advances that have propelled deeper understanding of the lysosome in neurodegeneration, from elucidating the functions of lysosome-related disease risk variants at the level of the organelle, cell, and tissue, to the development of disease-specific biological models that recapitulate disease manifestations. Finally, we identify key questions to be addressed to successfully bridge the gap to the clinic.
    Keywords:  Alzheimer’s disease; Parkinson’s disease; amyotrophic lateral sclerosis; frontotemporal dementia; lysosomes
    DOI:  https://doi.org/10.1016/j.tins.2021.12.004
  36. ACS Omega. 2022 Jan 11. 7(1): 5-16
    Lysosome-Targeting Strategy Using Polypeptides and Chimeric Molecules.
    Basudeb Mondal, Tahiti Dutta, Abinash Padhy, Sabyasachi Das, Sayam Sen Gupta.
      Lysosomes are membranous compartments containing hydrolytic enzymes, where cellular degradation of proteins and enzymes among others occurs in a controlled manner. Lysosomal dysfunction results in various pathological situations, such as several lysosomal storage disorders, neurodegeneration, infectious diseases, cancers, and aging. In this review, we have discussed different strategies for synthesizing peptides/chimeric molecules, their lysosome-targeting ability, and their ability to treat several lysosomal associated diseases, including lysosomal storage diseases and cancers. We have also discussed the delivery of cargo molecules into the lysosome using lysosome-targeting ligand-decorated nanocarriers. The introduction of a protein-binding ligand along with a lysosome-targeting ligand to manufacture a chimeric architecture for cell-specific protein (extracellular and membrane protein) degradation ability has been discussed thoroughly. Finally, the future applications of these lysosome-targeting peptides, nanocarriers, and chimeric molecules have been pointed out.
    DOI:  https://doi.org/10.1021/acsomega.1c04771
  37. Stem Cell Reports. 2022 Jan 03. pii: S2213-6711(21)00652-4. [Epub ahead of print]
    Selective elimination of pluripotent stem cells by PIKfyve specific inhibitors.
    Arup R Chakraborty, Alex Vassilev, Sushil K Jaiswal, Constandina E O'Connell, John F Ahrens, Barbara S Mallon, Martin F Pera, Melvin L DePamphilis.
      Inhibition of PIKfyve phosphoinositide kinase selectively kills autophagy-dependent cancer cells by disrupting lysosome homeostasis. Here, we show that PIKfyve inhibitors can also selectively eliminate pluripotent embryonal carcinoma cells (ECCs), embryonic stem cells, and induced pluripotent stem cells under conditions where differentiated cells remain viable. PIKfyve inhibitors prevented lysosome fission, induced autophagosome accumulation, and reduced cell proliferation in both pluripotent and differentiated cells, but they induced death only in pluripotent cells. The ability of PIKfyve inhibitors to distinguish between pluripotent and differentiated cells was confirmed with xenografts derived from ECCs. Pretreatment of ECCs with the PIKfyve specific inhibitor WX8 suppressed their ability to form teratocarcinomas in mice, and intraperitoneal injections of WX8 into mice harboring teratocarcinoma xenografts selectively eliminated pluripotent cells. Differentiated cells continued to proliferate, but at a reduced rate. These results provide a proof of principle that PIKfyve specific inhibitors can selectively eliminate pluripotent stem cells in vivo as well as in vitro.
    Keywords:  autophagosome; autophagy; cancer stem cells; embryonal carcinoma stem cells; embryonic stem cells; induced pluripotent stem cells; lysosome
    DOI:  https://doi.org/10.1016/j.stemcr.2021.12.013
  38. Front Cell Infect Microbiol. 2021 ;11 809121
    LAPped in Proof: LC3-Associated Phagocytosis and the Arms Race Against Bacterial Pathogens.
    Bart J M Grijmans, Sander B van der Kooij, Monica Varela, Annemarie H Meijer.
      Cells of the innate immune system continuously patrol the extracellular environment for potential microbial threats that are to be neutralized by phagocytosis and delivery to lysosomes. In addition, phagocytes employ autophagy as an innate immune mechanism against pathogens that succeed to escape the phagolysosomal pathway and invade the cytosol. In recent years, LC3-associated phagocytosis (LAP) has emerged as an intermediate between phagocytosis and autophagy. During LAP, phagocytes target extracellular microbes while using parts of the autophagic machinery to label the cargo-containing phagosomes for lysosomal degradation. LAP contributes greatly to host immunity against a multitude of bacterial pathogens. In the pursuit of survival, bacteria have developed elaborate strategies to disarm or circumvent the LAP process. In this review, we will outline the nature of the LAP mechanism and discuss recent insights into its interplay with bacterial pathogens.
    Keywords:  LC3-associated phagocytosis; autophagy; immune evasion; innate immunity; intracellular pathogens; macrophages; neutrophils; virulence mechanisms
    DOI:  https://doi.org/10.3389/fcimb.2021.809121
  39. Science. 2021 Jun 25. pii: eabg0269. [Epub ahead of print]372(6549):
    The Lysosomal Rag-Ragulator Complex Licenses RIPK1 and Caspase-8-mediated Pyroptosis by Yersinia.
    Zengzhang Zheng, Wanyan Deng, Yang Bai, Rui Miao, Shenglin Mei, Zhibin Zhang, Youdong Pan, Yi Wang, Rui Min, Fan Deng, Zeyu Wu, Wu Li, Pengcheng Chen, Tianchi Ma, Xiwen Lou, Judy Lieberman, Xing Liu.
      Host cells initiate cell death programs to limit pathogen infection. Inhibition of transforming growth factor-β-activated kinase 1 (TAK1) by pathogenic Yersinia in macrophages triggers receptor-interacting serine/threonine-protein kinase 1 (RIPK1)-dependent caspase-8 cleavage of gasdermin D (GSDMD) and inflammatory cell death (pyroptosis). A genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) screen to uncover mediators of caspase-8-dependent pyroptosis identified an unexpected role of the lysosomal FLCN-FNIP2-Rag-Ragulator supercomplex, which regulates metabolic signalling and the mechanistic target of rapamycin complex 1 (mTORC1). In response to Yersinia infection, FADD, RIPK1 and caspase-8 were recruited to Rag-Ragulator, causing RIPK1 phosphorylation and caspase-8 activation. Pyroptosis activation depended on Rag GTPase activity and lysosomal tethering of Rag-Ragulator, but not mTORC1. Thus, the lysosomal metabolic regulator Rag-Ragulator instructs the inflammatory response to Yersinia.
    DOI:  https://doi.org/10.1126/science.abg0269
  40. Dev Cell. 2022 Jan 11. pii: S1534-5807(21)01038-8. [Epub ahead of print]
    SURF4-induced tubular ERGIC selectively expedites ER-to-Golgi transport.
    Rui Yan, Kun Chen, Bowen Wang, Ke Xu.
      The endoplasmic reticulum (ER)-to-Golgi transport is critical to protein secretion and intracellular sorting. Here, we report a highly elongated tubular ER-Golgi intermediate compartment (t-ERGIC) that selectively expedites the ER-to-Golgi transport for soluble cargoes of the receptor SURF4. Lacking the canonical ERGIC marker ERGIC-53 yet positive for the small GTPases Rab1A/B, the t-ERGIC is further marked by its extraordinarily elongated and thinned shape. With its large surface-to-volume ratio, high intracellular traveling speeds, and ER-Golgi recycling capabilities, the t-ERGIC accelerates the trafficking of SURF4-bound cargoes. The biogenesis and cargo selectivity of t-ERGIC both depend on SURF4, which recognizes the N terminus of soluble cargoes and co-clusters with the selected cargoes to expand the ER-exit site. In the steady state, the t-ERGIC-mediated fast ER-to-Golgi transport is antagonized by the KDEL-mediated ER retrieval. Together, our results argue that specific cargo-receptor interactions give rise to distinct transport carriers that regulate the trafficking kinetics.
    Keywords:  ER-Golgi intermediate compartment; ER-exit site expansion; ER-to-Golgi transport; N-terminal selective binding; SURF4-KDELR antagonism; SURF4-cargo co-clustering; membrane vesicle trafficking; protein secretion kinetics; soluble cargo; tubular carrier
    DOI:  https://doi.org/10.1016/j.devcel.2021.12.018
  41. Biomedicines. 2022 Jan 12. pii: 159. [Epub ahead of print]10(1):
    Inhibition of DUSP6 Activates Autophagy and Rescues the Retinal Pigment Epithelium in Sodium Iodate-Induced Retinal Degeneration Models In Vivo and In Vitro.
    Hao-Yu Tsai, Henkie Isahwan Ahmad Mulyadi Lai, Zhang-Yuan Chen, Tai-Chi Lin, Winnie Khor, Wen-Chuan Kuo, Jia-Pu Syu, Ping-Hsing Tsai, Yi-Ping Yang, Yueh Chien, Shih-Jen Chen, De-Kuang Hwang, Shih-Hwa Chiou, Shih-Jie Chou.
      Autophagy plays a protective role in the retinal pigment epithelium (RPE) by eliminating damaged organelles in response to reactive oxygen species (ROS). Dual-specificity protein phosphatase 6 (DUSP6), which belongs to the DUSP subfamily, works as a negative-feedback regulator of the extracellular signal-regulated kinase (ERK) pathway. However, the complex interplay between DUSP6 and autophagy induced by ROS in RPE is yet to be investigated. To investigate the relationship between DUSP6 and autophagy, we exposed the ARPE-19 cell line and C57BL/6N mice to sodium iodate (NaIO3) as an oxidative stress inducer. Our data showed that the inhibition of DUSP6 activity promotes autophagy flux through the ERK pathway via the upregulation of immunoblotting expression in ARPE-19 cells. Live imaging showed a significant increase in autophagic flux activities, which suggested the restoration autophagy after treatment with the DUSP6 inhibitor. Furthermore, the mouse RPE layer exhibited an irregular structure and abnormal deposits following NaIO3 injection. The retina layer was recovered after being treated with DUSP6 inhibitor; this suggests that DUSP6 inhibitor can rescue retinal damage by restoring the mouse retina's autophagy flux. This study suggests that the upregulation of DUSP6 can cause autophagy flux malfunctions in the RPE. The DUSP6 inhibitor can restore autophagy induction, which may serve as a potential therapeutic approach for retinal degeneration disease.
    Keywords:  DUSP6; ERK; NaIO3; autophagy; autophagy flux; retinal degeneration; retinal pigment epithelium
    DOI:  https://doi.org/10.3390/biomedicines10010159
  42. Front Cell Dev Biol. 2021 ;9 736267
    PINK1 Alleviates Cognitive Impairments via Attenuating Pathological Tau Aggregation in a Mouse Model of Tauopathy.
    Xing Jun Jiang, Yan Qing Wu, Rong Ma, Yan Min Chang, Lu Lu Li, Jia Hui Zhu, Gong Ping Liu, Gang Li.
      As a primary cause of dementia and death in older people, Alzheimer's disease (AD) has become a common problem and challenge worldwide. Abnormal accumulation of tau proteins in the brain is a hallmark pathology of AD and is closely related to the clinical progression and severity of cognitive deficits. Here, we found that overexpression of phosphatase and tensin homolog (PTEN)-induced kinase 1 (PINK1) effectively promoted the degradation of tau, thereby rescuing neuron loss, synaptic damage, and cognitive impairments in a mouse model of tauopathy with AAV-full-length human Tau (hTau) injected into the hippocampal CA1 area (hTau mice). Overexpression of PINK1 activated autophagy, and chloroquine but not MG132 reversed the PINK1-induced decrease in human Tau levels and cognitive improvement in hTau mice. Furthermore, PINK1 also ameliorated mitochondrial dysfunction induced by hTau. Taken together, our data revealed that PINK1 overexpression promoted degradation of abnormal accumulated tau via the autophagy-lysosome pathway, indicating that PINK1 may be a potential target for AD treatment.
    Keywords:  Alzheimer’s disease; PINK1; autophagy; memory; tau
    DOI:  https://doi.org/10.3389/fcell.2021.736267
  43. Trends Pharmacol Sci. 2022 Jan 15. pii: S0165-6147(21)00232-7. [Epub ahead of print]
    Progranulin as a therapeutic target in neurodegenerative diseases.
    Herve Rhinn, Nadine Tatton, Stella McCaughey, Michael Kurnellas, Arnon Rosenthal.
      Progranulin (PGRN, encoded by the GRN gene) plays a key role in the development, survival, function, and maintenance of neurons and microglia in the mammalian brain. It regulates lysosomal biogenesis, inflammation, repair, stress response, and aging. GRN loss-of-function mutations cause neuronal ceroid lipofuscinosis or frontotemporal dementia-GRN (FTD-GRN) in a gene dosage-dependent manner. Mutations that reduce PGRN levels increase the risk for developing Alzheimer's disease, Parkinson's disease, and limbic-predominant age-related transactivation response DNA-binding protein 43 encephalopathy, as well as exacerbate the progression of amyotrophic lateral sclerosis (ALS) and FTD caused by the hexanucleotide repeat expansion in the C9orf72 gene. Elevating and/or restoring PGRN levels is an attractive therapeutic strategy and is being investigated for neurodegenerative diseases through multiple mechanisms of action.
    Keywords:  AL001; GRN; frontotemporal dementia; loss of function; neurodegenerative disorders; progranulin
    DOI:  https://doi.org/10.1016/j.tips.2021.11.015
  44. Neurobiol Dis. 2022 Jan 13. pii: S0969-9961(22)00019-5. [Epub ahead of print]164 105628
    Intravitreal gene therapy restores the autophagy-lysosomal pathway and attenuates retinal degeneration in cathepsin D-deficient mice.
    Junling Liu, Mahmoud Bassal, Stefanie Schlichting, Ingke Braren, Alessandro Di Spiezio, Paul Saftig, Udo Bartsch.
      Loss of vision due to progressive retinal degeneration is a hallmark of neuronal ceroid lipofuscinoses (NCL), a group of fatal neurodegenerative lysosomal storage diseases. Enzyme substitution therapies represent promising treatment options for NCLs caused by dysfunctions of soluble lysosomal enzymes. Here, we compared the efficacy of a cell-based enzyme substitution strategy and a gene therapy approach to attenuate the retinal pathology in cathepsin D- (CTSD) deficient mice, an animal model of CLN10 disease. Levels of enzymatically active CTSD in mutant retinas were significantly higher after an adeno-associated virus vector-mediated CTSD transfer to retinal glial cells and retinal pigment epithelial cells than after intravitreal transplantations of a CTSD overexpressing clonal neural stem cell line. In line with this finding, the gene therapy treatment restored the disrupted autophagy-lysosomal pathway more effectively than the cell-based approach, as indicated by a complete clearance of storage, significant attenuation of lysosomal hypertrophy, and normalized levels of the autophagy marker sequestosome 1/p62 and microtubule-associated protein 1 light chain 3-II. While the cell-based treatment did not prevent the rapidly progressing loss of various retinal cell types, the gene therapy approach markedly attenuated retinal degeneration as demonstrated by a pronounced rescue of photoreceptor cells and rod bipolar cells.
    Keywords:  Autophagy; CLN10 disease; Cathepsin D; Enzyme replacement therapy; Gene therapy; Lysosome; Neural stem cells; Neuronal ceroid lipofuscinosis; Retinal degeneration
    DOI:  https://doi.org/10.1016/j.nbd.2022.105628
  45. Biochem Biophys Res Commun. 2022 Jan 01. pii: S0006-291X(21)01762-9. [Epub ahead of print]592 74-80
    Nickel particles are present in Crohn's disease tissue and exacerbate intestinal inflammation in IBD susceptible mice.
    Hiroki Matsuda, Yoichi Nibe-Shirakihara, Akiko Tamura, Emi Aonuma, Satoko Arakawa, Kana Otsubo, Yasuhiro Nemoto, Takashi Nagaishi, Kiichiro Tsuchiya, Shigeomi Shimizu, Averil Ma, Mamoru Watanabe, Motohiro Uo, Ryuichi Okamoto, Shigeru Oshima.
      Crohn's disease is an inflammatory disease of the gut caused by a complex interplay among genetic, microbial, and environmental factors. The intestinal tract is constantly exposed to metals and other trace elements ingested as food. Synchrotron radiation-induced X-ray fluorescence spectroscopy and X-ray absorption fine structure analysis revealed the deposition of nickel particles within Crohn's disease tissue specimens. After nickel particle stimulation, THP-1 cells showed filopodia formation and autophagic vacuoles containing lipid bodies. Nickel particles precipitated colitis in mice bearing mutations of the IBD susceptibility protein A20/TNFAIP3. Nickel particles also exacerbated dextran sulfate sodium-induced colitis in mice harboring myeloid cell-specific Atg5 deficiency. These findings illustrate that nickel particle ingestion may worsen Crohn's disease by perturbing autophagic processes in the intestine, providing new insights into environmental factors in Crohn's disease pathogenesis.
    Keywords:  A20/TNFAIP3; Autophagy; Crohn's disease; Macrophage; Nickel
    DOI:  https://doi.org/10.1016/j.bbrc.2021.12.111
  46. J Clin Invest. 2022 Jan 18. pii: e156119. [Epub ahead of print]132(2):
    Sensing of RNA stress by mTORC1 drives autoinflammation.
    Min Ae Lee-Kirsch.
      Loss-of-function mutations in SKIV2L underlie trichohepatoenteric syndrome (THES2), a rare inborn error of immunity characterized by diarrhea, skin lesions, brittle hair, and immunodeficiency. SKIV2L is part of a multiprotein complex required for exosome-mediated RNA surveillance through RNA decay. In this issue of the JCI, Yang et al. delineate a mechanism underlying autoinflammatory skin disease in Skiv2l-deficient mice. Thus, a lack of SKIV2L activates mTORC1 signaling in keratinocytes and T cells, impeding skin barrier integrity and T cell homeostasis. Interestingly, treatment with the mTOR inhibitor rapamycin improves skin symptoms in Skiv2l-deficient mice, suggesting a possible therapeutic avenue for patients with THES2.
    DOI:  https://doi.org/10.1172/JCI156119
  47. Int J Mol Sci. 2022 Jan 07. pii: 657. [Epub ahead of print]23(2):
    Engineering Nanoplatform for Combined Cancer Therapeutics via Complementary Autophagy Inhibition.
    Xuan Wang, Yunhao Li, Jianqing Lu, Xiongwei Deng, Yan Wu.
      Despite advances in the development of tumor treatments, mortality from cancer continues to increase. Nanotechnology is expected to provide an innovative anti-cancer therapy, to combat challenges such as multidrug resistance and tumor recurrence. Nevertheless, tumors can greatly rely on autophagy as an alternative source for metabolites, and which desensitizes cancer cells to therapeutic stress, hindering the success of any current treatment paradigm. Autophagy is a conserved process by which cells turn over their own constituents to maintain cellular homeostasis. The multistep autophagic pathway provides potentially druggable targets to inhibit pro-survival autophagy under various therapeutic stimuli. In this review, we focus on autophagy inhibition based on functional nanoplatforms, which may be a potential strategy to increase therapeutic sensitivity in combinational cancer therapies, including chemotherapy, radiotherapy, phototherapy, sonodynamic therapy, and immunotherapy.
    Keywords:  autophagy inhibition; nanoparticles; tumor treatment
    DOI:  https://doi.org/10.3390/ijms23020657
  48. Rheumatology (Oxford). 2022 Jan 18. pii: keac037. [Epub ahead of print]
    Renal mTORC1 activation is associated with disease activity and prognosis in lupus nephritis.
    Zhaomin Mao, Ying Tan, Juan Tao, Linlin Li, Hui Wang, Feng Yu, Andras Perl, Minghui Zhao.
      OBJECTIVE: This study was initiated to evaluate mammalian target of rapamycin (mTOR) activation in renal tissue of lupus nephritis (LN) patients.METHODS: This retrospective study included 187 LN patients, 20 diabetic nephropathy (DN) patients, 10 minimal change disease (MCD) patients, and 10 normal controls (NCs). 7 of 187 LN patients had repeated renal biopsies. mTORC1/2 activation was evaluated by immunohistochemistry and multiplexed immunofluorescence. The association of mTORC1/2 activation with the clinicopathologic indices and prognostic outcomes was analysed among 187 LN patients. Proteomics was performed in renal biopsies of 20 LN patients. Proteomics was employed to comprehensively evaluate the impact of mTOR activation on intrarenal gene expression.
    RESULTS: mTORC1/2 was significantly activated in podocytes, mesangial cells, endothelial cells and tubular epithelial cells of LN patients as compared with those with MCD or NC. The glomerular mTORC1 activation was higher in LN patients compared with DN patients. mTORC1, but not mTORC2, activation strongly correlated with serum albumin, complement C3, proteinuria, and the following pathological biomarkers of LN: crescent formation, interstitial inflammation and fibrosis. Moreover, mTORC1 activation was identified as a prognostic marker in LN patients. Bioinformatic analyses of proteomics and immunohistochemical data unveiled increased complement activation, antigen presentation, and phagocytosis in LN patients with mTORC1 activation.
    CONCLUSION: Renal mTORC1 activation could be a biomarker to reveal disease activity and predict clinical prognosis in LN patients.
    Keywords:  bioinformatics; lupus nephritis; mTOR; proteomics; rapamycin
    DOI:  https://doi.org/10.1093/rheumatology/keac037
  49. Bioengineered. 2022 Jan 19.
    RAS protein activator like 2 promotes the proliferation and migration of pulmonary artery smooth muscle cell through AKT/mammalian target of Rapamycin complex 1 pathway in pulmonary hypertension.
    Sheng Hu, Youguang Zhao, Chenming Qiu, Ying Li.
      RAS protein activator like 2 (Rasal2) exerts pro-proliferative effect in several types of cells. However, whether Rasal2 is involved in the regulation of pulmonary artery smooth muscle cell (PASMC) remains unclear. In the current study, we explored the role of Rasal2 in proliferation, migration of PASMC during the development of pulmonary arterial hypertension (PAH). We found that the protein level of Rasal2 was increased in both pulmonary arteries of chronic hypoxia-induced pulmonary hypertension (CH-PH) mice and hypoxia-challenged PASMC. Overexpression of Rasal2 caused enhanced proliferation and migration of PASMC after hypoxia exposure. Mechanistically, we found elevated phosphorylation of AKT and two downstream effectors of mammalian target of Rapamycin complex 1 (mTORC1), S6 and 4E-Binding Protein 1 (4EBP1) after Rasal2 overexpression in hypoxia-challenged PASMC. Inactivation of mTORC1 abolished Rasal2-mediated enhancement of proliferation and migration of PASMC. Furthermore, we also demonstrated that AKT might act downstream of Rasal2 to enhance the activity of mTORC1. Once AKT was inactivated by MK-2206 application, overexpression of Rasal2 failed to further increase the phosphorylation level of S6 and 4EBP1. Finally, inhibition of AKT also blocked Rasal2-induced proliferation and migration in hypoxia-challenged PASMC. In conclusion, Rasal2 promotes the proliferation and migration of PASMC during the development of PAH via AKT/mTORC1 pathway.
    Keywords:  Rasal2; migration; proliferation; pulmonary arterial hypertension; pulmonary artery smooth muscle cell
    DOI:  https://doi.org/10.1080/21655979.2021.1997879
  50. J Neurochem. 2022 Jan 17.
    Drosophila ZIP13 overexpression or transferrin1 RNAi influences the muscle degeneration of Pink1 RNAi by elevating iron levels in mitochondria.
    Jinsong Xue, Guangying Li, Xiaowen Ji, Zhi-Hua Liu, Hui-Li Wang, Guiran Xiao.
      Disruption of iron homeostasis in the brain of Parkinson's disease (PD) patients has been reported for many years, but the underlying mechanisms remain unclear. To investigate iron metabolism genes related to PTEN-induced kinase 1 (Pink1) and parkin (E3 ubiquitin ligase), two PD-associated proteins that function to coordinate mitochondrial turnover via induction of selective mitophagy, we conducted a genetic screen in Drosophila and found that altered expression of genes involved in iron metabolism, such as Drosophila ZIP13 (dZIP13) or transferrin1 (Tsf1), significantly influences the disease progression related to Pink1 but not parkin. Several phenotypes of Pink1 mutant and Pink1 RNAi but not parkin mutant were significantly rescued by overexpression (OE) of dZIP13 (dZIP13 OE) or silencing of Tsf1 (Tsf1 RNAi) in the flight muscles. The rescue effects of dZIP13 OE or Tsf1 RNAi were not exerted through mitochondrial disruption or mitophagy, instead, the iron levels in mitochondira were significantly increased, resulting in enhanced activity of enzymes participating in respiration and increased ATP synthesis. Consistently, the rescue effects of dZIP13 OE or Tsf1 RNAi on Pink1 RNAi can be inhibited by decreasing the iron levels in mitochondria through mitoferrin (dmfrn) RNAi. This study suggests that dZIP13, Tsf1 and dmfrn might act independently of parkin in a parallel pathway downstream of Pink1 by modulating respiration and indicates that manipulation of iron levels in mitochondria may provide a novel therapeutic strategy for PD associated with Pink1.
    Keywords:  Drosophila; Pink1; activity; iron; mitochondria complex
    DOI:  https://doi.org/10.1111/jnc.15574
  51. Cells. 2022 Jan 17. pii: 308. [Epub ahead of print]11(2):
    Emerging Role of cAMP/AMPK Signaling.
    Muhammad Aslam, Yury Ladilov.
      The 5'-Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a natural energy sensor in mammalian cells that plays a key role in cellular and systemic energy homeostasis. At the cellular level, AMPK supports numerous processes required for energy and redox homeostasis, including mitochondrial biogenesis, autophagy, and glucose and lipid metabolism. Thus, understanding the pathways regulating AMPK activity is crucial for developing strategies to treat metabolic disorders. Mounting evidence suggests the presence of a link between cyclic AMP (cAMP) and AMPK signaling. cAMP signaling is known to be activated in circumstances of physiological and metabolic stress due to the release of stress hormones, such as adrenaline and glucagon, which is followed by activation of membrane-bound adenylyl cyclase and elevation of cellular cAMP. Because the majority of physiological stresses are associated with elevated energy consumption, it is not surprising that activation of cAMP signaling may promote AMPK activity. Aside from the physiological role of the cAMP/AMPK axis, numerous reports have suggested its role in several pathologies, including inflammation, ischemia, diabetes, obesity, and aging. Furthermore, novel reports have provided more mechanistic insight into the regulation of the cAMP/AMPK axis. In particular, the role of distinct cAMP microdomains generated by soluble adenylyl cyclase in regulating basal and induced AMPK activity has recently been demonstrated. In the present review, we discuss current advances in the understanding of the regulation of the cAMP/AMPK axis and its role in cellular homeostasis and explore some translational aspects.
    Keywords:  AMPK; EPAC; PKA; adenylyl cyclase; autophagy; cAMP; mitophagy
    DOI:  https://doi.org/10.3390/cells11020308
  52. Proc Natl Acad Sci U S A. 2022 Jan 25. pii: e2111338119. [Epub ahead of print]119(4):
    Parkinson's disease protein PARK7 prevents metabolite and protein damage caused by a glycolytic metabolite.
    Isaac P Heremans, Francesco Caligiore, Isabelle Gerin, Marina Bury, Marilena Lutz, Julie Graff, Vincent Stroobant, Didier Vertommen, Aurelio A Teleman, Emile Van Schaftingen, Guido T Bommer.
      Cells are continuously exposed to potentially dangerous compounds. Progressive accumulation of damage is suspected to contribute to neurodegenerative diseases and aging, but the molecular identity of the damage remains largely unknown. Here we report that PARK7, an enzyme mutated in hereditary Parkinson's disease, prevents damage of proteins and metabolites caused by a metabolite of glycolysis. We found that the glycolytic metabolite 1,3-bisphosphoglycerate (1,3-BPG) spontaneously forms a novel reactive intermediate that avidly reacts with amino groups. PARK7 acts by destroying this intermediate, thereby preventing the formation of proteins and metabolites with glycerate and phosphoglycerate modifications on amino groups. As a consequence, inactivation of PARK7 (or its orthologs) in human cell lines, mouse brain, and Drosophila melanogaster leads to the accumulation of these damaged compounds, most of which have not been described before. Our work demonstrates that PARK7 function represents a highly conserved strategy to prevent damage in cells that metabolize carbohydrates. This represents a fundamental link between metabolism and a type of cellular damage that might contribute to the development of Parkinson's disease.
    Keywords:  Parkinson's disease; glycolysis; metabolite damage; posttranslational modification; protein damage
    DOI:  https://doi.org/10.1073/pnas.2111338119
  53. Antioxidants (Basel). 2021 Dec 21. pii: 7. [Epub ahead of print]11(1):
    A New Insight into an Alternative Therapeutic Approach to Restore Redox Homeostasis and Functional Mitochondria in Neurodegenerative Diseases.
    Dong-Hoon Hyun, Jaewang Lee.
      Neurodegenerative diseases are accompanied by oxidative stress and mitochondrial dysfunction, leading to a progressive loss of neuronal cells, formation of protein aggregates, and a decrease in cognitive or motor functions. Mitochondrial dysfunction occurs at the early stage of neurodegenerative diseases. Protein aggregates containing oxidatively damaged biomolecules and other misfolded proteins and neuroinflammation have been identified in animal models and patients with neurodegenerative diseases. A variety of neurodegenerative diseases commonly exhibits decreased activity of antioxidant enzymes, lower amounts of antioxidants, and altered cellular signalling. Although several molecules have been approved clinically, there is no known cure for neurodegenerative diseases, though some drugs are focused on improving mitochondrial function. Mitochondrial dysfunction is caused by oxidative damage and impaired cellular signalling, including that of peroxisome proliferator-activated receptor gamma coactivator 1α. Mitochondrial function can also be modulated by mitochondrial biogenesis and the mitochondrial fusion/fission cycle. Mitochondrial biogenesis is regulated mainly by sirtuin 1, NAD+, AMP-activated protein kinase, mammalian target of rapamycin, and peroxisome proliferator-activated receptor γ. Altered mitochondrial dynamics, such as increased fission proteins and decreased fusion products, are shown in neurodegenerative diseases. Due to the restrictions of a target-based approach, a phenotype-based approach has been performed to find novel proteins or pathways. Alternatively, plasma membrane redox enzymes improve mitochondrial function without the further production of reactive oxygen species. In addition, inducers of antioxidant response elements can be useful to induce a series of detoxifying enzymes. Thus, redox homeostasis and metabolic regulation can be important therapeutic targets for delaying the progression of neurodegenerative diseases.
    Keywords:  mitochondrial biogenesis; mitochondrial dynamics; mitochondrial dysfunction; neurodegenerative diseases; neuroinflammation; oxidative stress; plasma membrane redox enzymes
    DOI:  https://doi.org/10.3390/antiox11010007
  54. Biochem Biophys Res Commun. 2022 Jan 10. pii: S0006-291X(22)00044-4. [Epub ahead of print]593 65-72
    Icariin inhibits isoproterenol-induced cardiomyocyte hypertropic injury through activating autophagy via the AMPK/mTOR signaling pathway.
    Lin Hu, Ziyuan Wang, Huan Li, Jiarui Wei, Fengyue Tang, Qing Wang, Jing Wang, Xiaoqiao Zhang, Qiufang Zhang.
      Icariin (ICA), a bioactive flavonoid compound derived from Epimedium, have been demonstrated possessing anti-oxidative stress, anti-inflammation in the cardiovascular disease. But its effects on cardiomyocyte hypertrophy and the underlying mechanisms remains unclear. Here we found that ICA alleviated ISO-induced H9c2 or NRCM myocytes hypertrophy, assessed by surface area and the expression of ANP, BNP and β-MHC. Furthemore, ICA reversed cardiomcytes enlargment by suppresing apoptotic injury and increasing autophagic flux. By contrast, 3-MA, an autophagy inhibitor, could abolished the antihypertrophic and pro-autophagic flux effects of ICA. Mechanistically, ICA increased the phosphorylation levels of AMPK and autophagy-related markers beclin-1, Atg5 and the LC3II/I ratio, and decreased phosphorylated mTOR. But the effects of ICA on ISO-induced cardiomyocytes hypertrophy were attenuated by selective AMPK inhibitor Compound C. In conclusion, these findings indicated that ICA attenuated cardiomyocyte hypertrophy induced by ISO and prevented cell injury, and the specific mechanism was mediated by AMPK/mTOR pathway to enhance autophagy and reduce autophagy-related cardiomyocyte apoptosis.
    Keywords:  AMPK; Autophagy; Cardiac hypertrophy; ISO; Icariin(ICA)
    DOI:  https://doi.org/10.1016/j.bbrc.2022.01.029
This page is being maintained by Thomas Krichel. It was last updated on 2023‒10‒01 at 4:17.