bims-auttor Biomed News
on Autophagy and mTOR
Issue of 2023–08–27
seventy papers selected by
Viktor Korolchuk, Newcastle University
  1. A new regulator of autophagy initiation in glia.
  2. The molecular basis of nutrient sensing and signalling by mTORC1 in metabolism regulation and disease.
  3. Autophagy preserves hematopoietic stem cells by restraining MTORC1-mediated cellular anabolism.
  4. The CTNS-MTORC1 axis couples lysosomal cystine to epithelial cell fate decisions and is a targetable pathway in cystinosis.
  5. Nix interacts with WIPI2 to induce mitophagy.
  6. Neuronal atg1 Coordinates Autophagy Induction and Physiological Adaptations to Balance mTORC1 Signalling.
  7. LC3 conjugation to lipid droplets.
  8. The evolution of selective autophagy as a mechanism of oxidative stress response: The evolutionarily acquired ability of selective autophagy receptors to respond to oxidative stress is beneficial for human longevity.
  9. Treponema pallidum promoted microglia apoptosis and prevented itself from clearing by human microglia via blocking autophagic flux.
  10. Loss of Prom1 impairs autophagy and promotes epithelial-mesenchymal transition in mouse retinal pigment epithelial cells.
  11. Fatty acid availability controls autophagy and associated cell functions.
  12. The deubiquitinase Leon/USP5 interacts with Atg1/ULK1 and antagonizes autophagy.
  13. Disrupted endoplasmic reticulum-mediated autophagosomal biogenesis in a Drosophila model of C9-ALS-FTD.
  14. p62 and NBR1 functions are dispensable for aggrephagy in mouse ESCs and ESC-derived neurons.
  15. An update on the bridging factors connecting autophagy and Nrf2 antioxidant pathway.
  16. The mTOR pathway genes mTOR , Rheb , Depdc5 , Pten , and Tsc1 have convergent and divergent impacts on cortical neuron development and function.
  17. Autophagy/Mitophagy in Airway Diseases: Impact of Oxidative Stress on Epithelial Cells.
  18. The actin binding protein profilin 1 is critical for mitochondria function.
  19. Membrane localization of LGG-1/GABARAP is dispensable for autophagy in C. elegans.
  20. The AKT2/SIRT5/TFEB pathway as a potential therapeutic target in atrophic AMD.
  21. Role of Mitochondria-ER Contact Sites in Mitophagy.
  22. Autophagy is regulated by endoplasmic reticulum calcium homeostasis and sphingolipid metabolism.
  23. Autophagy in Heart Failure: Insights into Mechanisms and Therapeutic Implications.
  24. Drosophila as a Robust Model System for Assessing Autophagy: A Review.
  25. mTORC1 regulates phagosome digestion of symbiotic bacteria for intracellular nutritional symbiosis in a deep-sea mussel.
  26. The ABL-MYC axis controls WIPI1-enhanced autophagy in lifespan extension.
  27. Polyphenols, Autophagy and Neurodegenerative Diseases: A Review.
  28. Endogenous PTEN acts as the key determinant for mTOR inhibitor sensitivity by inducing the stress-sensitized PTEN-mediated death axis in KSHV-associated malignant cells.
  29. Relationship between ferroptosis and mitophagy in renal fibrosis: a systematic review.
  30. An autophagy-inducing stapled peptide induces mitochondria dysfunction and triggers autotic cell death in triple-negative breast cancer.
  31. Landspersky T, Saçma M, Rivière J, et al. Autophagy in mesenchymal progenitors protects mice against bone marrow failure after severe intermittent stress. Blood. 2022;139(5):690-703.
  32. Analysis of autophagy deficiency and cytotoxicity in autophagy-deficient human embryonic stem cell-derived neurons.
  33. Mitochondrial Transfer Between Cell Crosstalk - An Emerging Role in Mitochondrial Quality Control.
  34. Autophagy critically controls skin inflammation and apoptosis-induced stem cell activation.
  35. Cytoprotective, Cytotoxic and Cytostatic Roles of Autophagy in Response to BET Inhibitors.
  36. Interplay of Impaired Cellular Bioenergetics and Autophagy in PMM2-CDG.
  37. Proteostasis plays an important role in demyelinating Charcot Marie Tooth disease.
  38. Alterations of lipid-mediated mitophagy result in aging-dependent sensorimotor defects.
  39. Autophagy deficiency protects against ocular hypertension and neurodegeneration in experimental and spontanous glaucoma mouse models.
  40. Ubiquitination Is a Novel Post-Translational Modification of VMP1 in Autophagy of Human Tumor Cells.
  41. Novel insights into autophagosome biogenesis revealed by cryo-electron tomography.
  42. AMPK promotes lysosomal and mitochondrial biogenesis via folliculin:FNIP1.
  43. LC-MS Reveals Isomeric Inhibition of Proteolysis by Lysosomal Cathepsins.
  44. Ca2+ signalling: A common language for organelles crosstalk in Parkinson's disease.
  45. The interplay between autophagy and chloroplast vesiculation pathways under dark-induced senescence.
  46. HSPB2 facilitates neural regeneration through autophagy for sensorimotor recovery after traumatic brain injury.
  47. Lipocalin-2 induces mitochondrial dysfunction in renal tubular cells via mTOR pathway activation.
  48. PINK1 and Parkin regulate IP3R-mediated ER calcium release.
  49. MAPK13 stabilization via m6A mRNA modification limits anti-cancer efficacy of rapamycin.
  50. Impairment of Autophagic Flux After Hypobaric Hypoxia Potentiates Oxidative Stress and Cognitive Function Disturbances in Mice.
  51. Transcription Factor Forkhead Box P (Foxp) 1 Reduces Brain Damage During Cerebral Ischemia-Reperfusion Injury in Mice Through FUNDC1.
  52. Targeting ANXA7/LAMP5-mTOR axis attenuates spinal cord injury by inhibiting neuronal apoptosis via enhancing autophagy in mice.
  53. Glycerol 3-phosphate phosphatase/PGPH-2 counters metabolic stress and promotes healthy aging via a glycogen sensing-AMPK-HLH-30-autophagy axis in C. elegans.
  54. TorS - Reframing a rational for type 2 diabetes treatment.
  55. IGF/mTORC1/S6 Signaling Is Potentiated and Prolonged by Acute Loading of Subtoxicological Manganese Ion.
  56. Diosgenin Targets CaMKK2 to Alleviate Type II Diabetic Nephropathy through Improving Autophagy, Mitophagy and Mitochondrial Dynamics.
  57. Lysine methylation of PPP1CA by the methyltransferase SUV39H2 disrupts TFEB-dependent autophagy and promotes intervertebral disc degeneration.
  58. Linderanidins A-F: Rare oligomeric flavonoids with an unusual C-3-C-4 linkage from the roots of Lindera erythrocarpa and their inhibitory activities on autophagy.
  59. Topology and Function of the S. cerevisiae Autophagy Protein Atg15.
  60. A focus on leucine in the nutritional regulation of human skeletal muscle metabolism in ageing, exercise and unloading states.
  61. SIRT5 Activation and Inorganic Phosphate Binding Reduce Cancer Cell Vitality by Modulating Autophagy/Mitophagy and ROS.
  62. Signaling Pathways Leading to mTOR Activation Downstream Cytokine Receptors in Lymphocytes in Health and Disease.
  63. The Great Game between Plants and Viruses: A Focus on Protein Homeostasis.
  64. Atg2 Regulates Cellular and Humoral Immunity in Drosophila.
  65. An Update on Nucleolar Stress: The Transcriptional Control of Autophagy.
  66. Vanadium complex as a potential modulator of the autophagic mechanism through proteins PI3K and ULK1: development, validation and biological implications of a specific force field for [VO(bpy)2Cl].
  67. Nanoparticle-Mediated Therapy with miR-198 Sensitizes Pancreatic Cancer to Gemcitabine Treatment through Downregulation of VCP-Mediated Autophagy.
  68. Research progress of mitophagy in chronic cerebral ischemia.
  69. Acid ground nano-realgar processed product inhibits breast cancer by inducing mitophagy via the p53/BNIP3/NIX pathway.
  70. Autophagy Alters the Susceptibility of Candida albicans Biofilms to Antifungal Agents.
  1. Autophagy. 2023 Aug 24.
    A new regulator of autophagy initiation in glia.
    Linfang Wang, Shiping Zhang, Shuanglong Yi, Margaret S Ho.
      Macroautophagy/autophagy is the major degradation pathway in neurons for eliminating damaged proteins and organelles in Parkinson disease (PD). Like neurons, glial cells are important contributors to PD, yet how autophagy is executed in glia and whether it is using similar interplay as in neurons or other tissues, remain largely elusive. Recently, we reported that the PD risk factor, GAK/aux (cyclin-G-associated kinase/auxilin), regulates the onset of glial autophagy. In the absence of GAK/aux, the number and size of the autophagosomes and autophagosomal precursors increase in adult fly glia and mouse microglia. The protein levels of components in the initiation and class III phosphatidylinositol 3-kinase (PtdIns3K) complexes are generally upregulated. GAK/aux interacts with the master initiation regulator ULK1/Atg1 (unc-51 like autophagy activating kinase 1) via its uncoating domain, hinders autophagy activation by competing with ATG13 (autophagy related 13) for binding to the ULK1 C terminus, and regulates ULK1 trafficking to phagophores. Nonetheless, lack of GAK/aux impairs the autophagic flux and blocks substrate degradation, suggesting that GAK/aux might play additional roles. Overall, our findings reveal a new regulator of autophagy initiation in glia, advancing our understanding on how glia contribute to PD in terms of eliminating pathological protein aggregates.
    Keywords:  GAK/aux; Parkinson’s disease; ULK1/Atg1; autophagy; autophagy initiation; glia
    DOI:  https://doi.org/10.1080/15548627.2023.2251821
  2. Nat Rev Mol Cell Biol. 2023 Aug 23.
    The molecular basis of nutrient sensing and signalling by mTORC1 in metabolism regulation and disease.
    Claire Goul, Roberta Peruzzo, Roberto Zoncu.
      The Ser/Thr kinase mechanistic target of rapamycin (mTOR) is a central regulator of cellular metabolism. As part of mTOR complex 1 (mTORC1), mTOR integrates signals such as the levels of nutrients, growth factors, energy sources and oxygen, and triggers responses that either boost anabolism or suppress catabolism. mTORC1 signalling has wide-ranging consequences for the growth and homeostasis of key tissues and organs, and its dysregulated activity promotes cancer, type 2 diabetes, neurodegeneration and other age-related disorders. How mTORC1 integrates numerous upstream cues and translates them into specific downstream responses is an outstanding question with major implications for our understanding of physiology and disease mechanisms. In this Review, we discuss recent structural and functional insights into the molecular architecture of mTORC1 and its lysosomal partners, which have greatly increased our mechanistic understanding of nutrient-dependent mTORC1 regulation. We also discuss the emerging involvement of aberrant nutrient-mTORC1 signalling in multiple diseases.
    DOI:  https://doi.org/10.1038/s41580-023-00641-8
  3. Autophagy. 2023 Aug 23.
    Autophagy preserves hematopoietic stem cells by restraining MTORC1-mediated cellular anabolism.
    Mariana Borsa, Sandrine Obba, Felix C Richter, Hanlin Zhang, Thomas Riffelmacher, Joana Carrelha, Ghada Alsaleh, Sten Eirik W Jacobsen, Anna Katharina Simon.
      Adult stem cells are long-lived and quiescent with unique metabolic requirements. Macroautophagy/autophagy is a fundamental survival mechanism that allows cells to adapt to metabolic changes by degrading and recycling intracellular components. Here we address why autophagy depletion leads to a drastic loss of the stem cell compartment. Using inducible deletion of autophagy specifically in adult hematopoietic stem cells (HSCs) and in mice chimeric for autophagy-deficient and normal HSCs, we demonstrate that the stem cell loss is cell-intrinsic. Mechanistically, autophagy-deficient HSCs showed higher expression of several amino acid transporters (AAT) when compared to autophagy-competent cells, resulting in increased amino acid (AA) uptake. This was followed by sustained MTOR (mechanistic target of rapamycin) activation, with enlarged cell size, glucose uptake and translation, which is detrimental to the quiescent HSCs. MTOR inhibition by rapamycin treatment in vivo was able to rescue autophagy-deficient HSC loss and bone marrow failure and resulted in better reconstitution after transplantation. Our results suggest that targeting MTOR may improve aged stem cell function, promote reprogramming and stem cell transplantation.
    Keywords:  Autophagy; MTOR; amino acids; hematopoietic stem cells; rapamycin; translation
    DOI:  https://doi.org/10.1080/15548627.2023.2247310
  4. Autophagy. 2023 Aug 24. 1-3
    The CTNS-MTORC1 axis couples lysosomal cystine to epithelial cell fate decisions and is a targetable pathway in cystinosis.
    Alessandro Luciani, Olivier Devuyst.
      Differentiation and fate decisions are critical for the epithelial cells lining the proximal tubule (PT) of the kidney, but the signals involved remain unknown. Defective cystine mobilization from lysosomes through CTNS (cystinosin, lysosomal cystine transporter), which is mutated in cystinosis, triggers the dedifferentiation and dysfunction of the PT cells, causing kidney disease and severe metabolic complications. Using preclinical models and physiologically relevant cellular systems, along with functional assays and a generative artificial intelligence (AI)-powered engine, we found that cystine storage imparted by CTNS deficiency stimulates Ragulator-RRAG GTPase-dependent recruitment of MTORC1 and its constitutive activation. In turn, this diverts the catabolic trajectories and differentiating states of PT cells toward growth and proliferation, disrupting homeostasis and their specialized functions. Therapeutic MTORC1 inhibition by using low doses of rapamycin corrects lysosome function and differentiation downstream of cystine storage and ameliorates PT dysfunction in preclinical models of cystinosis. These discoveries suggest that cystine may act as a lysosomal fasting signal that tailors MTORC1 signaling to direct fate decisions in the kidney PT epithelium, highlighting novel therapeutic paradigms for cystinosis and other lysosome-related disorders.
    Keywords:  autophagy; chronic kidney disease; cystinosis; drug repurposing; lysosome; nutrient sensing
    DOI:  https://doi.org/10.1080/15548627.2023.2250165
  5. EMBO J. 2023 Aug 25. e113491
    Nix interacts with WIPI2 to induce mitophagy.
    Eric N Bunker, François Le Guerroué, Chunxin Wang, Marie-Paule Strub, Achim Werner, Nico Tjandra, Richard J Youle.
      Nix is a membrane-anchored outer mitochondrial protein that induces mitophagy. While Nix has an LC3-interacting (LIR) motif that binds to ATG8 proteins, it also contains a minimal essential region (MER) that induces mitophagy through an unknown mechanism. We used chemically induced dimerization (CID) to probe the mechanism of Nix-mediated mitophagy and found that both the LIR and MER are required for robust mitophagy. We find that the Nix MER interacts with the autophagy effector WIPI2 and recruits WIPI2 to mitochondria. The Nix LIR motif is also required for robust mitophagy and converts a homogeneous WIPI2 distribution on the surface of the mitochondria into puncta, even in the absence of ATG8s. Together, this work reveals unanticipated mechanisms in Nix-induced mitophagy and the elusive role of the MER, while also describing an interesting example of autophagy induction that acts downstream of the canonical initiation complexes.
    Keywords:  Autophagy; BNIP3; FIP200; LIR; p62
    DOI:  https://doi.org/10.15252/embj.2023113491
  6. Cells. 2023 Aug 08. pii: 2024. [Epub ahead of print]12(16):
    Neuronal atg1 Coordinates Autophagy Induction and Physiological Adaptations to Balance mTORC1 Signalling.
    Athanasios Metaxakis, Michail Pavlidis, Nektarios Tavernarakis.
      The mTORC1 nutrient-sensing pathway integrates metabolic and endocrine signals into the brain to evoke physiological responses to food deprivation, such as autophagy. Nevertheless, the impact of neuronal mTORC1 activity on neuronal circuits and organismal metabolism remains obscure. Here, we show that mTORC1 inhibition acutely perturbs serotonergic neurotransmission via proteostatic alterations evoked by the autophagy inducer atg1. Neuronal ATG1 alters the intracellular localization of the serotonin transporter, which increases the extracellular serotonin and stimulates the 5HTR7 postsynaptic receptor. 5HTR7 enhances food-searching behaviour and ecdysone-induced catabolism in Drosophila. Along similar lines, the pharmacological inhibition of mTORC1 in zebrafish also stimulates food-searching behaviour via serotonergic activity. These effects occur in parallel with neuronal autophagy induction, irrespective of the autophagic activity and the protein synthesis reduction. In addition, ectopic neuronal atg1 expression enhances catabolism via insulin pathway downregulation, impedes peptidergic secretion, and activates non-cell autonomous cAMP/PKA. The above exert diverse systemic effects on organismal metabolism, development, melanisation, and longevity. We conclude that neuronal atg1 aligns neuronal autophagy induction with distinct physiological modulations, to orchestrate a coordinated physiological response against reduced mTORC1 activity.
    Keywords:  5HTR7 receptor; ATG1; ageing; autophagy; behaviour; cAMP/PKA; ecdysone; longevity; mTORC1; metabolism; serotonin transporter
    DOI:  https://doi.org/10.3390/cells12162024
  7. Autophagy. 2023 Aug 23. 1-3
    LC3 conjugation to lipid droplets.
    Mohyeddine Omrane, Thomas J Melia, Abdou Rachid Thiam.
      Macroautophagy/autophagy and lipid droplet (LD) biology are intricately linked, with autophagosome-dependent degradation of LDs in response to different signals. LDs play crucial roles in forming autophagosomes possibly by providing essential lipids and serving as a supportive autophagosome assembly platform at the endoplasmic reticulum (ER)-LD interface. LDs and autophagosomes share common proteins, such as VPS13, ATG2, ZFYVE1/DFCP1, and ATG14, but their dual functions remain poorly understood. In our recent study, we found that prolonged starvation leads to ATG3 localizing to large LDs and lipidating LC3B, revealing a non-canonical autophagic role on LDs. In vitro, ATG3 associates with purified and artificial LDs, and conjugated Atg8-family proteins. In long-term starved cells, only LC3B is found on the specific large LDs, positioned near LC3B-positive membranes that undergo lysosome-mediated acidification. This implies that LD-lipidated LC3B acts as a tethering factor, connecting phagophores to LDs and promoting degradation. Our data also support the notion that certain LD surfaces may function as lipidation stations for LC3B, which may move to nearby sites of autophagosome formation. Overall, our study unveils an unknown non-canonical implication of LDs in autophagy processes.Abbreviation: ATG: autophagy-related enzyme, ATP: adenosine triphosphate, E2 enzyme: ubiquitin-conjugating enzyme, ER: endoplasmic reticulum, LD: lipid droplet, LIR motif: LC3-interacting region, MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta, PE: phosphatidylethanolamine, PLIN1: perilipin 1, PNPLA2/ATGL: patatin-like phospholipase domain containing 2, SQSTM1/p62: sequestosome 1, VSP13: vacuolar protein sorting 13, ZFYVE1/DFCP1: zinc finger, FYVE domain containing 1.
    Keywords:  ATG3; LC3B; lipid droplets; membrane contact sites; noncanonical autophagy; prolonged starvation
    DOI:  https://doi.org/10.1080/15548627.2023.2249390
  8. Bioessays. 2023 Aug 21. e2300076
    The evolution of selective autophagy as a mechanism of oxidative stress response: The evolutionarily acquired ability of selective autophagy receptors to respond to oxidative stress is beneficial for human longevity.
    Joshua Ratliffe, Tetsushi Kataura, Elsje G Otten, Viktor I Korolchuk.
      Ageing is associated with a decline in autophagy and elevated reactive oxygen species (ROS), which can breach the capacity of antioxidant systems. Resulting oxidative stress can cause further cellular damage, including DNA breaks and protein misfolding. This poses a challenge for longevous organisms, including humans. In this review, we hypothesise that in the course of human evolution selective autophagy receptors (SARs) acquired the ability to sense and respond to localised oxidative stress. We posit that in the vicinity of protein aggregates and dysfunctional mitochondria oxidation of key cysteine residues in SARs induces their oligomerisation which initiates autophagy. The degradation of damaged cellular components thus could reduce ROS production and restore redox homeostasis. This evolutionarily acquired function of SARs may represent one of the biological adaptations that contributed to longer lifespan. Inversely, loss of this mechanism can lead to age-related diseases associated with impaired autophagy and oxidative stress.
    Keywords:  ageing; aggrephagy; autophagy; mitophagy; neurodegeneration; oxidative stress; selective autophagy receptors
    DOI:  https://doi.org/10.1002/bies.202300076
  9. PLoS Pathog. 2023 Aug;19(8): e1011594
    Treponema pallidum promoted microglia apoptosis and prevented itself from clearing by human microglia via blocking autophagic flux.
    Yun-Ting Hu, Kai-Xuan Wu, Xiao-Tong Wang, Yuan-Yi Zhao, Xiao-Yong Jiang, Dan Liu, Man-Li Tong, Li-Li Liu.
      Treponema pallidum (Tp) has a well-known ability to evade the immune system and can cause neurosyphilis by invading the central nervous system (CNS). Microglia are resident macrophages of the CNS that are essential for host defense against pathogens, this study aims to investigate the interaction between Tp and microglia and the potential mechanism. Here, we found that Tp can exert significant toxic effects on microglia in vivo in Tg (mpeg1: EGFP) transgenic zebrafish embryos. Single-cell RNA sequencing results showed that Tp downregulated autophagy-related genes in human HMC3 microglial cells, which is negatively associated with apoptotic gene expression. Biochemical and cell biology assays further established that Tp inhibits microglial autophagy by interfering with the autophagosome-lysosome fusion process. Transcription factor EB (TFEB) is a master regulator of lysosome biogenesis, Tp activates the mechanistic target of rapamycin complex 1 (mTORC1) signaling to inhibit the nuclear translocation of TFEB, leading to decreased lysosomal biogenesis and accumulated autophagosome. Importantly, the inhibition of autophagosome formation reversed Tp-induced apoptosis and promoted microglial clearance of Tp. Taken together, these findings show that Tp blocks autophagic flux by inhibiting TFEB-mediated lysosomal biosynthesis in human microglia. Autophagosome accumulation was demonstrated to be a key mechanism underlying the effects of Tp in promoting apoptosis and preventing itself from clearing by human microglia. This study offers novel perspectives on the potential mechanism of immune evasion employed by Tp within CNS. The results not only establish the pivotal role of autophagy dysregulation in the detrimental effects of Tp on microglial cells but also bear considerable implications for the development of therapeutic strategies against Tp, specifically involving mTORC1 inhibitors and autophagosome formation inhibitors, in the context of neurosyphilis patients.
    DOI:  https://doi.org/10.1371/journal.ppat.1011594
  10. J Cell Physiol. 2023 Aug 23.
    Loss of Prom1 impairs autophagy and promotes epithelial-mesenchymal transition in mouse retinal pigment epithelial cells.
    Sujoy Bhattacharya, Jinggang Yin, Weihong Huo, Edward Chaum.
      Mutations in the Prominin-1 (Prom1) gene disrupt photoreceptor disk morphogenesis, leading to macular dystrophies. We have shown that human retinal pigment epithelial (RPE) homeostasis is under the control of Prom1-dependent autophagy, demonstrating that Prom1 plays different roles in the photoreceptors and RPE. It is unclear if retinal and macular degeneration caused by the loss of Prom1 function is a cell-autonomous feature of the RPE or a generalized disease of photoreceptor degeneration. In this study, we investigated whether Prom1 is required for mouse RPE (mRPE) autophagy and phagocytosis, which are cellular processes essential for photoreceptor survival. We found that Prom1-KO decreases autophagy flux, activates mTORC1, and concomitantly decreases transcription factor EB (TFEB) and Cathepsin-D activities in mRPE cells. In addition, Prom1-KO reduces the clearance of bovine photoreceptor outer segments in mRPE cells due to increased mTORC1 and reduced TFEB activities. Dysfunction of Prom1-dependent autophagy correlates with both a decrease in ZO-1 and E-cadherin and a concomitant increase in Vimentin, SNAI1, and ZEB1 levels, consistent with induction of epithelial-mesenchymal transition (EMT) in Prom1-KO mRPE cells. Our results demonstrate that Prom1-mTORC1-TFEB signaling is a central driver of cell-autonomous mRPE homeostasis. We show that Prom1-KO in mRPE leads to RPE defects similar to that seen in atrophic age-related macular degeneration and opens new avenues of investigation targeting Prom1 in retinal degenerative diseases.
    Keywords:  Stargardt-like macular dystrophy; TFEB; age-related macular degeneration; lysosomal activity; mTORC1; phagocytosis
    DOI:  https://doi.org/10.1002/jcp.31094
  11. Autophagy. 2023 Aug 21. 1-2
    Fatty acid availability controls autophagy and associated cell functions.
    Leslie A Rowland, Michael P Czech.
      Macroautophagy/autophagy requires enormous membrane expansions during concerted actions of transient autophagic vesicles and lysosomes, yet the source of the membrane lipids is poorly understood. Recent work in adipocytes has now pinpointed the de novo lipogenesis pathway as the preferred source of fatty acids for phospholipid in autophagic membrane synthesis, as loss of FASN (fatty acid synthase) disrupts autophagic flux and lysosome function in vivo and in vitro. These data indicate fatty acid synthesis channels lipid for membrane expansions, whereas fatty acids from circulating lipoproteins provide for adipose lipid storage. Importantly, autophagy blockade upon loss of fatty acids promotes a strong thermogenic phenotype in adipocytes, another striking example whereby autophagy controls cell behavior.
    Keywords:  Adipocyte; FASN; autophagosome; lipogenesis; lipophagy; p62
    DOI:  https://doi.org/10.1080/15548627.2023.2246357
  12. Cell Death Dis. 2023 08 22. 14(8): 540
    The deubiquitinase Leon/USP5 interacts with Atg1/ULK1 and antagonizes autophagy.
    Yueh-Ling Pai, Yuchieh Jay Lin, Wen-Hsin Peng, Li-Ting Huang, He-Yen Chou, Chien-Hsiang Wang, Cheng-Ting Chien, Guang-Chao Chen.
      Accumulating evidence has shown that the quality of proteins must be tightly monitored and controlled to maintain cellular proteostasis. Misfolded proteins and protein aggregates are targeted for degradation through the ubiquitin proteasome (UPS) and autophagy-lysosome systems. The ubiquitination and deubiquitinating enzymes (DUBs) have been reported to play pivotal roles in the regulation of the UPS system. However, the function of DUBs in the regulation of autophagy remain to be elucidated. In this study, we found that knockdown of Leon/USP5 caused a marked increase in the formation of autophagosomes and autophagic flux under well-fed conditions. Genetic analysis revealed that overexpression of Leon suppressed Atg1-induced cell death in Drosophila. Immunoblotting assays further showed a strong interaction between Leon/USP5 and the autophagy initiating kinase Atg1/ULK1. Depletion of Leon/USP5 led to increased levels of Atg1/ULK1. Our findings indicate that Leon/USP5 is an autophagic DUB that interacts with Atg1/ULK1, negatively regulating the autophagic process.
    DOI:  https://doi.org/10.1038/s41419-023-06062-x
  13. Autophagy. 2023 Aug 20.
    Disrupted endoplasmic reticulum-mediated autophagosomal biogenesis in a Drosophila model of C9-ALS-FTD.
    Hyun Sung, Thomas E Lloyd.
      Macroautophagy/autophagy is a major pathway for the clearance of protein aggregates and damaged organelles, and multiple intracellular organelles participate in the process of autophagy, from autophagosome formation to maturation and degradation. Dysregulation of the autophagy pathway has been implicated in the pathogenesis of neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), however the mechanisms underlying autophagy impairment in these diseases are incompletely understood. Since the expansion of GGGGCC (G4C2) repeats in the first intron of the C9orf72 gene is the most common inherited cause of both ALS and FTD (C9-ALS-FTD), we investigated autophagosome dynamics in Drosophila motor neurons expressing 30 G4C2 repeats (30 R). In vivo imaging demonstrates that expression of expanded G4C2 repeats markedly impairs biogenesis of autophagosomes at synaptic termini, whereas trafficking and maturation of axonal autophagosomes are unaffected. Motor neurons expressing 30 R display marked disruption in endoplasmic reticulum (ER) structure and dynamics in the soma, axons, and synapses. Disruption of ER morphology with mutations in Rtnl1 (Reticulon-like 1) or atl (atlastin) also impairs autophagosome formation in motor neurons, suggesting that ER integrity is critical for autophagosome formation. Furthermore, live imaging demonstrates that autophagosomes are generated from dynamic ER tubules at synaptic boutons, and this process fails to occur in a C9-ALS-FTD model. Together, these findings suggest that dynamic ER tubules are required for formation of autophagosomes at the neuromuscular junction, and that this process is disrupted by expanded G4C2 repeats that cause ALS-FTD.
    Keywords:  Autophagy; C9-ALS-FTD; Drosophila; axonal transport; endoplasmic reticulum (ER) dynamics; motor neuron
    DOI:  https://doi.org/10.1080/15548627.2023.2249750
  14. Life Sci Alliance. 2023 Nov;pii: e202301936. [Epub ahead of print]6(11):
    p62 and NBR1 functions are dispensable for aggrephagy in mouse ESCs and ESC-derived neurons.
    Riccardo Trapannone, Julia Romanov, Sascha Martens.
      Accumulation of protein aggregates is a hallmark of various neurodegenerative diseases. Selective autophagy mediates the delivery of specific cytoplasmic cargo material into lysosomes for degradation. In aggrephagy, which is the selective autophagy of protein aggregates, the cargo receptors p62 and NBR1 were shown to play important roles in cargo selection. They bind ubiquitinated cargo material via their ubiquitin-associated domains and tether it to autophagic membranes via their LC3-interacting regions. We used mouse embryonic stem cells (ESCs) in combination with genome editing to obtain further insights into the roles of p62 and NBR1 in aggrephagy. Unexpectedly, our data reveal that both ESCs and ESC-derived neurons do not show strong defects in the clearance of protein aggregates upon knockout of p62 or NBR1 and upon mutation of the p62 ubiquitin-associated domain and the LC3-interacting region motif. Taken together, our results show a robust aggregate clearance in ESCs and ESC-derived neurons. Thus, redundancy between the cargo receptors, other factors, and pathways, such as the ubiquitin-proteasome system, may compensate for the loss of function of p62 and NBR1.
    DOI:  https://doi.org/10.26508/lsa.202301936
  15. Front Cell Dev Biol. 2023 ;11 1232241
    An update on the bridging factors connecting autophagy and Nrf2 antioxidant pathway.
    Baike Ning, Shuqi Hang, Wenhe Zhang, Caiwen Mao, Dan Li.
      Macroautophagy/autophagy is a lysosome-dependent catabolic pathway for the degradation of intracellular proteins and organelles. Autophagy dysfunction is related to many diseases, including lysosomal storage diseases, cancer, neurodegenerative diseases, cardiomyopathy, and chronic metabolic diseases, in which increased reactive oxygen species (ROS) levels are also observed. ROS can randomly oxidize proteins, lipids, and DNA, causing oxidative stress and damage. Cells have developed various antioxidant pathways to reduce excessive ROS and maintain redox homeostasis. Treatment targeting only one aspect of diseases with autophagy dysfunction and oxidative stress shows very limited effects. Herein, identifying the bridging factors that can regulate both autophagy and antioxidant pathways is beneficial for dual-target therapies. This review intends to provide insights into the current identified bridging factors that connect autophagy and Nrf2 antioxidant pathway, as well as their tight interconnection with each other. These factors could be potential dual-purpose targets for the treatment of diseases implicated in both autophagy dysfunction and oxidative stress.
    Keywords:  Nrf2-Keap1; SQSTM1; Sestrin2; TRIM16; autophagy; bridging factors
    DOI:  https://doi.org/10.3389/fcell.2023.1232241
  16. bioRxiv. 2023 Aug 11. pii: 2023.08.11.553034. [Epub ahead of print]
    The mTOR pathway genes mTOR , Rheb , Depdc5 , Pten , and Tsc1 have convergent and divergent impacts on cortical neuron development and function.
    Lena H Nguyen, Youfen Xu, Maanasi Nair, Angelique Bordey.
      Brain somatic mutations in various components of the mTOR complex 1 (mTORC1) pathway have emerged as major causes of focal malformations of cortical development and intractable epilepsy. While these distinct gene mutations converge on excessive mTORC1 signaling and lead to common clinical manifestations, it remains unclear whether they cause similar cellular and synaptic disruptions underlying cortical network hyperexcitability. Here, we show that in utero activation of the mTORC1 activators, Rheb or mTOR , or biallelic inactivation of the mTORC1 repressors, Depdc5 , Tsc1 , or Pten in mouse medial prefrontal cortex leads to shared alterations in pyramidal neuron morphology, positioning, and membrane excitability but different changes in excitatory synaptic transmission. Our findings suggest that, despite converging on mTORC1 signaling, mutations in different mTORC1 pathway genes differentially impact cortical excitatory synaptic activity, which may confer gene-specific mechanisms of hyperexcitability and responses to therapeutic intervention.
    DOI:  https://doi.org/10.1101/2023.08.11.553034
  17. Biomolecules. 2023 Aug 04. pii: 1217. [Epub ahead of print]13(8):
    Autophagy/Mitophagy in Airway Diseases: Impact of Oxidative Stress on Epithelial Cells.
    Giusy Daniela Albano, Angela Marina Montalbano, Rosalia Gagliardo, Mirella Profita.
      Autophagy is the key process by which the cell degrades parts of itself within the lysosomes. It maintains cell survival and homeostasis by removing molecules (particularly proteins), subcellular organelles, damaged cytoplasmic macromolecules, and by recycling the degradation products. The selective removal or degradation of mitochondria is a particular type of autophagy called mitophagy. Various forms of cellular stress (oxidative stress (OS), hypoxia, pathogen infections) affect autophagy by inducing free radicals and reactive oxygen species (ROS) formation to promote the antioxidant response. Dysfunctional mechanisms of autophagy have been found in different respiratory diseases such as chronic obstructive lung disease (COPD) and asthma, involving epithelial cells. Several existing clinically approved drugs may modulate autophagy to varying extents. However, these drugs are nonspecific and not currently utilized to manipulate autophagy in airway diseases. In this review, we provide an overview of different autophagic pathways with particular attention on the dysfunctional mechanisms of autophagy in the epithelial cells during asthma and COPD. Our aim is to further deepen and disclose the research in this direction to stimulate the develop of new and selective drugs to regulate autophagy for asthma and COPD treatment.
    Keywords:  COPD; asthma; autophagy; lung disease; mitophagy; oxidative stress
    DOI:  https://doi.org/10.3390/biom13081217
  18. bioRxiv. 2023 Aug 16. pii: 2023.08.07.552354. [Epub ahead of print]
    The actin binding protein profilin 1 is critical for mitochondria function.
    Tracy-Ann Read, Bruno A Cisterna, Kristen Skruber, Samah Ahmadieh, Halli L Lindamood, Josefine A Vitriol, Yang Shi, Austin E Y T Lefebvre, Joseph B Black, Mitchell T Butler, James A Bear, Alena Cherezova, Daria V Ilatovskaya, Neil L Weintraub, Eric A Vitriol.
      Profilin 1 (PFN1) is an actin binding protein that is vital for the polymerization of monomeric actin into filaments. Here we screened knockout cells for novel functions of PFN1 and discovered that mitophagy, a type of selective autophagy that removes defective or damaged mitochondria from the cell, was significantly upregulated in the absence of PFN1. Despite successful autophagosome formation and fusion with the lysosome, and activation of additional mitochondrial quality control pathways, PFN1 knockout cells still accumulate damaged, dysfunctional mitochondria. Subsequent imaging and functional assays showed that loss of PFN1 significantly affects mitochondria morphology, dynamics, and respiration. Further experiments revealed that PFN1 is located to the mitochondria matrix and is likely regulating mitochondria function from within rather than through polymerizing actin at the mitochondria surface. Finally, PFN1 mutants associated with amyotrophic lateral sclerosis (ALS) fail to rescue PFN1 knockout mitochondrial phenotypes and form aggregates within mitochondria, further perturbing them. Together, these results suggest a novel function for PFN1 in regulating mitochondria and identify a potential pathogenic mechanism of ALS-linked PFN1 variants.
    DOI:  https://doi.org/10.1101/2023.08.07.552354
  19. Autophagy. 2023 Aug 23. 1-2
    Membrane localization of LGG-1/GABARAP is dispensable for autophagy in C. elegans.
    Romane Leboutet, Céline Largeau, Emmanuel Culetto, Christophe Lefebvre, Thorsten Hoppe, Renaud Legouis.
      Most of the functions of LC3/GABARAP in macroautophagy/autophagy are considered to depend on their association with the phagophore membrane through a conjugation to a lipid. Using site-directed mutagenesis, we inhibited the conjugation of LGG-1, the single homolog of GABARAP in C. elegans. Mutants that express only cytosolic forms revealed an essential role for the cleaved form of LGG-1 in autophagy but also in an autophagy-independent embryonic function.
    Keywords:  Atg8; autophagosome biogenesis; conjugation; embryonic development; lipidation; ubiquitin-like
    DOI:  https://doi.org/10.1080/15548627.2023.2249393
  20. bioRxiv. 2023 Aug 09. pii: 2023.08.08.552343. [Epub ahead of print]
    The AKT2/SIRT5/TFEB pathway as a potential therapeutic target in atrophic AMD.
    Sayan Ghosh, Ruchi Sharma, Sridhar Bammidi, Victoria Koontz, Mihir Nemani, Meysam Yazdankhah, Katarzyna M Kedziora, Callen T Wallace, Cheng Yu-Wei, Jonathan Franks, Devika Bose, Dhivyaa Rajasundaram, Stacey Hose, José-Alain Sahel, Rosa Puertollano, Toren Finkel, J Samuel Zigler, Yuri Sergeev, Simon C Watkins, Eric S Goetzman, Miguel Flores-Bellver, Kai Kaarniranta, Akrit Sodhi, Kapil Bharti, James T Handa, Debasish Sinha.
      Age-related macular degeneration (AMD), the leading cause of geriatric blindness, is a multi-factorial disease with retinal-pigmented epithelial (RPE) cell dysfunction as a central pathogenic driver. With RPE degeneration, lysosomal function is a core process that is disrupted. Transcription factors EB/E3 (TFEB/E3) tightly control lysosomal function; their disruption can cause aging disorders, such as AMD. Here, we show that induced pluripotent stem cells (iPSC)-derived RPE cells with the complement factor H variant [ CFH (Y402H)] have increased AKT2, which impairs TFEB/TFE3 nuclear translocation and lysosomal function. Increased AKT2 can inhibit PGC1α, which downregulates SIRT5, an AKT2 binding partner. SIRT5 and AKT2 co-regulate each other, thereby modulating TFEB-dependent lysosomal function in the RPE. Failure of the AKT2/SIRT5/TFEB pathway in the RPE induced abnormalities in the autophagy-lysosome cellular axis by upregulating secretory autophagy, thereby releasing a plethora of factors that likely contribute to drusen formation, a hallmark of AMD. Finally, overexpressing AKT2 in RPE cells in mice led to an AMD-like phenotype. Thus, targeting the AKT2/SIRT5/TFEB pathway could be a potential therapy for atrophic AMD.
    DOI:  https://doi.org/10.1101/2023.08.08.552343
  21. Biomolecules. 2023 Jul 31. pii: 1198. [Epub ahead of print]13(8):
    Role of Mitochondria-ER Contact Sites in Mitophagy.
    Alina Rühmkorf, Angelika Bettina Harbauer.
      Mitochondria are often referred to as the "powerhouse" of the cell. However, this organelle has many more functions than simply satisfying the cells' metabolic needs. Mitochondria are involved in calcium homeostasis and lipid metabolism, and they also regulate apoptotic processes. Many of these functions require contact with the ER, which is mediated by several tether proteins located on the respective organellar surfaces, enabling the formation of mitochondria-ER contact sites (MERCS). Upon damage, mitochondria produce reactive oxygen species (ROS) that can harm the surrounding cell. To circumvent toxicity and to maintain a functional pool of healthy organelles, damaged and excess mitochondria can be targeted for degradation via mitophagy, a form of selective autophagy. Defects in mitochondria-ER tethers and the accumulation of damaged mitochondria are found in several neurodegenerative diseases, including Parkinson's disease and amyotrophic lateral sclerosis, which argues that the interplay between the two organelles is vital for neuronal health. This review provides an overview of the different mechanisms of mitochondrial quality control that are implicated with the different mitochondria-ER tether proteins, and also provides a novel perspective on how MERCS are involved in mediating mitophagy upon mitochondrial damage.
    Keywords:  mitochondria; mitophagy; organellar contact sites
    DOI:  https://doi.org/10.3390/biom13081198
  22. Autophagy. 2023 Aug 23. 1-2
    Autophagy is regulated by endoplasmic reticulum calcium homeostasis and sphingolipid metabolism.
    Shiyan Liu, Mutian Chen, Yichang Wang, Huihui Li, Shiqian Qi, Jia Geng, Kefeng Lu.
      Calcium is involved in a variety of cellular processes. As the crucial components of cell membranes, sphingolipids also play important roles as signaling molecules. Intracellular calcium homeostasis, autophagy initiation and sphingolipid synthesis are associated with the endoplasmic reticulum (ER). Recently, through genetic screening and lipidomics analysis in Saccharomyces cerevisiae, we found that the ER calcium channel Csg2 converts sphingolipid metabolism into macroautophagy/autophagy regulation by controlling ER calcium homeostasis. The results showed that Csg2 acts as a calcium channel to mediate ER calcium efflux into the cytoplasm, and deletion of CSG2 causes a distinct increase of ER calcium concentration, thereby disrupting the stability of the sphingolipid synthase Aur1, leading to the accumulation of the bioactive sphingolipid phytosphingosine (PHS), which specifically and completely blocks autophagy. In summary, our work links calcium homeostasis, sphingolipid metabolism, and autophagy initiation via the ER calcium channel Csg2.
    Keywords:  Autophagosome; Csg2; ER; calcium; sphingolipid; starvation
    DOI:  https://doi.org/10.1080/15548627.2023.2249761
  23. J Cardiovasc Dev Dis. 2023 Aug 18. pii: 352. [Epub ahead of print]10(8):
    Autophagy in Heart Failure: Insights into Mechanisms and Therapeutic Implications.
    Magdalena Bielawska, Marta Warszyńska, Monika Stefańska, Przemysław Błyszczuk.
      Autophagy, a dynamic and complex process responsible for the clearance of damaged cellular components, plays a crucial role in maintaining myocardial homeostasis. In the context of heart failure, autophagy has been recognized as a response mechanism aimed at counteracting pathogenic processes and promoting cellular health. Its relevance has been underscored not only in various animal models, but also in the human heart. Extensive research efforts have been dedicated to understanding the significance of autophagy and unravelling its complex molecular mechanisms. This review aims to consolidate the current knowledge of the involvement of autophagy during the progression of heart failure. Specifically, we provide a comprehensive overview of published data on the impact of autophagy deregulation achieved by genetic modifications or by pharmacological interventions in ischemic and non-ischemic models of heart failure. Furthermore, we delve into the intricate molecular mechanisms through which autophagy regulates crucial cellular processes within the three predominant cell populations of the heart: cardiomyocytes, cardiac fibroblasts, and endothelial cells. Finally, we emphasize the need for future research to unravel the therapeutic potential associated with targeting autophagy in the management of heart failure.
    Keywords:  autophagy; heart failure; molecular mechanisms; pharmacological interventions
    DOI:  https://doi.org/10.3390/jcdd10080352
  24. Toxics. 2023 Aug 08. pii: 682. [Epub ahead of print]11(8):
    Drosophila as a Robust Model System for Assessing Autophagy: A Review.
    Esref Demir, Sam Kacew.
      Autophagy is the process through which a body breaks down and recycles its own cellular components, primarily inside lysosomes. It is a cellular response to starvation and stress, which plays decisive roles in various biological processes such as senescence, apoptosis, carcinoma, and immune response. Autophagy, which was first discovered as a survival mechanism during starvation in yeast, is now known to serve a wide range of functions in more advanced organisms. It plays a vital role in how cells respond to stress, starvation, and infection. While research on yeast has led to the identification of many key components of the autophagy process, more research into autophagy in more complex systems is still warranted. This review article focuses on the use of the fruit fly Drosophila melanogaster as a robust testing model in further research on autophagy. Drosophila provides an ideal environment for exploring autophagy in a living organism during its development. Additionally, Drosophila is a well-suited compact tool for genetic analysis in that it serves as an intermediate between yeast and mammals because evolution conserved the molecular machinery required for autophagy in this species. Experimental tractability of host-pathogen interactions in Drosophila also affords great convenience in modeling human diseases on analogous structures and tissues.
    Keywords:  Atg; Drosophila melanogaster; autophagy; development; fat body; in vivo animal model system
    DOI:  https://doi.org/10.3390/toxics11080682
  25. Sci Adv. 2023 Aug 25. 9(34): eadg8364
    mTORC1 regulates phagosome digestion of symbiotic bacteria for intracellular nutritional symbiosis in a deep-sea mussel.
    Akihiro Tame, Tadashi Maruyama, Tetsuro Ikuta, Yoshihito Chikaraishi, Nanako O Ogawa, Masashi Tsuchiya, Kiyotaka Takishita, Miwako Tsuda, Miho Hirai, Yoshihiro Takaki, Naohiko Ohkouchi, Katsunori Fujikura, Takao Yoshida.
      Phagocytosis is one of the methods used to acquire symbiotic bacteria to establish intracellular symbiosis. A deep-sea mussel, Bathymodiolus japonicus, acquires its symbiont from the environment by phagocytosis of gill epithelial cells and receives nutrients from them. However, the manner by which mussels retain the symbiont without phagosome digestion remains unknown. Here, we show that controlling the mechanistic target of rapamycin complex 1 (mTORC1) in mussels leads to retaining symbionts in gill cells. The symbiont is essential for the host mussel nutrition; however, depleting the symbiont's energy source triggers the phagosome digestion of symbionts. Meanwhile, the inhibition of mTORC1 by rapamycin prevented the digestion of the resident symbionts and of the engulfed exogenous dead symbionts in gill cells. This indicates that mTORC1 promotes phagosome digestion of symbionts under reduced nutrient supply from the symbiont. The regulation mechanism of phagosome digestion by mTORC1 through nutrient signaling with symbionts is key for maintaining animal-microbe intracellular nutritional symbiosis.
    DOI:  https://doi.org/10.1126/sciadv.adg8364
  26. Commun Biol. 2023 Aug 24. 6(1): 872
    The ABL-MYC axis controls WIPI1-enhanced autophagy in lifespan extension.
    Katharina Sporbeck, Maximilian L Haas, Carmen J Pastor-Maldonado, David S Schüssele, Catherine Hunter, Zsuzsanna Takacs, Ana L Diogo de Oliveira, Mirita Franz-Wachtel, Chara Charsou, Simon G Pfisterer, Andrea Gubas, Patricia K Haller, Roland L Knorr, Manuel Kaulich, Boris Macek, Eeva-Liisa Eskelinen, Anne Simonsen, Tassula Proikas-Cezanne.
      Human WIPI β-propellers function as PI3P effectors in autophagy, with WIPI4 and WIPI3 being able to link autophagy control by AMPK and TORC1 to the formation of autophagosomes. WIPI1, instead, assists WIPI2 in efficiently recruiting the ATG16L1 complex at the nascent autophagosome, which in turn promotes lipidation of LC3/GABARAP and autophagosome maturation. However, the specific role of WIPI1 and its regulation are unknown. Here, we discovered the ABL-ERK-MYC signalling axis controlling WIPI1. As a result of this signalling, MYC binds to the WIPI1 promoter and represses WIPI1 gene expression. When ABL-ERK-MYC signalling is counteracted, increased WIPI1 gene expression enhances the formation of autophagic membranes capable of migrating through tunnelling nanotubes to neighbouring cells with low autophagic activity. ABL-regulated WIPI1 function is relevant to lifespan control, as ABL deficiency in C. elegans increased gene expression of the WIPI1 orthologue ATG-18 and prolonged lifespan in a manner dependent on ATG-18. We propose that WIPI1 acts as an enhancer of autophagy that is physiologically relevant for regulating the level of autophagic activity over the lifespan.
    DOI:  https://doi.org/10.1038/s42003-023-05236-9
  27. Biomolecules. 2023 Jul 31. pii: 1196. [Epub ahead of print]13(8):
    Polyphenols, Autophagy and Neurodegenerative Diseases: A Review.
    Vichitra Chandrasekaran, Tousif Ahmed Hediyal, Nikhilesh Anand, Pavan Heggadadevanakote Kendaganna, Vasavi Rakesh Gorantla, Arehally M Mahalakshmi, Ruchika Kaul Ghanekar, Jian Yang, Meena Kishore Sakharkar, Saravana Babu Chidambaram.
      Polyphenols are secondary metabolites from plant origin and are shown to possess a wide range of therapeutic benefits. They are also reported as regulators of autophagy, inflammation and neurodegeneration. The autophagy pathway is vital in degrading outdated organelles, proteins and other cellular wastes. The dysregulation of autophagy causes proteinopathies, mitochondrial dysfunction and neuroinflammation thereby contributing to neurodegeneration. Evidence reveals that polyphenols improve autophagy by clearing misfolded proteins in the neurons, suppress neuroinflammation and oxidative stress and also protect from neurodegeneration. This review is an attempt to summarize the mechanism of action of polyphenols in modulating autophagy and their involvement in pathways such as mTOR, AMPK, SIRT-1 and ERK. It is evident that polyphenols cause an increase in the levels of autophagic proteins such as beclin-1, microtubule-associated protein light chain (LC3 I and II), sirtuin 1 (SIRT1), etc. Although it is apparent that polyphenols regulate autophagy, the exact interaction of polyphenols with autophagy markers is not known. These data require further research and will be beneficial in supporting polyphenol supplementation as a potential alternative treatment for regulating autophagy in neurodegenerative diseases.
    Keywords:  autophagy; neurodegenerative diseases; neuroinflammation; polyphenols; proteinopathies
    DOI:  https://doi.org/10.3390/biom13081196
  28. Front Mol Biosci. 2023 ;10 1062462
    Endogenous PTEN acts as the key determinant for mTOR inhibitor sensitivity by inducing the stress-sensitized PTEN-mediated death axis in KSHV-associated malignant cells.
    Piyanki Das, Sonali Pal, Nilanjana Das, Koushik Chakraborty, Koustav Chatterjee, Sudipa Mal, Tathagata Choudhuri.
      As a part of viral cancer evolution, KSHV-infected human endothelial cells exert a unique transcriptional program via upregulated mTORC1 signaling. This event makes them sensitive to mTOR inhibitors. Master transcriptional regulator PTEN acts as the prime regulator of mTOR and determining factor for mTOR inhibitory drug resistance and sensitivity. PTEN is post-translationally modified in KSHV-associated cell lines and infected tissues. Our current study is an attempt to understand the functional role of upstream modulator PTEN in determining the sensitivity of mTOR inhibitors against KSHV-infected cells in an in vitro stress-responsive model. Our analysis shows that, despite phosphorylation, endogenous levels of intact PTEN in different KSHV-infected cells compared to normal and non-infected cells are quite high. Genetic overexpression of intact PTEN showed functional integrity of this gene in the infected cells in terms of induction of a synchronized cell death process via cell cycle regulation and mitochondria-mediated apoptosis. PTEN overexpression enhanced the mTOR inhibitory drug activity, the silencing of which hampers the process against KSHV-infected cells. Additionally, we have shown that endogenous PTEN acts as a stress balancer molecule inside KSHV-infected cells and can induce stress-sensitized death program post mTOR inhibitor treatment, lined up in the ATM-chk2-p53 axis. Moreover, autophagic regulation was found as a major regulator in mTOR inhibitor-induced PTEN-mediated death axis from our study. The current work critically intersected the PTEN-mediated stress balancing mechanism where autophagy has been utilized as a part of the KSHV stress management system and is specifically fitted and switched toward autophagy-mediated apoptosis directing toward a therapeutic perspective.
    Keywords:  KSHV-associated malignancy; PTEN; PTEN-mediated cell death; drug sensitivity determinant; mTOR inhibitors; stress
    DOI:  https://doi.org/10.3389/fmolb.2023.1062462
  29. J Drug Target. 2023 Aug 23. 1-9
    Relationship between ferroptosis and mitophagy in renal fibrosis: a systematic review.
    Mingyu Zhang, Ziyuan Tong, Yaqing Wang, Wenjing Fu, Yilin Meng, Jiayi Huang, Li Sun.
      Renal fibrosis, characterised by glomerulosclerosis and tubulointerstitial fibrosis, is a typical pathological alteration in the progression of chronic kidney disease (CKD) to end-stage renal disease (ESRD). However, the limited and expensive options for treating renal fibrosis place a heavy financial burden on patients and healthcare systems. Therefore, it is significant to find an effective treatment for renal fibrosis. Ferroptosis, a non-traditional form of cell death, has been found to play an important role in acute kidney injury (AKI), tumours, neurodegenerative diseases, and so on. Moreover, a growing body of research suggests that ferroptosis might be a potential target of renal fibrosis. Meanwhile, mitophagy is a type of selective autophagy that can selectively degrade damaged or dysfunctional mitochondria as a form of mitochondrial quality control, reducing the production of reactive oxygen species (ROS), the accumulation of which is the main cause of renal fibrosis. Additionally, as a receptor of mitophagy, NIX can release beclin1 to induce mitophagy, which can also bind to solute carrier family 7 member 11 (SLC7A11) to block the activity of cystine/glutamate antitransporter (system Xc-) and inhibit ferroptosis, thereby suggesting a link between mitophagy and ferroptosis. However, there have been only limited studies on the relationship among mitophagy, ferroptosis and renal fibrosis. In this paper, we review the mechanisms of mitophagy, and describe how ferroptosis and mitophagy are related to renal fibrosis in an effort to identify potential novel targets for the treatment of renal fibrosis.
    Keywords:  Mitophagy; ferroptosis; mechanism; relationship; renal fibrosis
    DOI:  https://doi.org/10.1080/1061186X.2023.2250574
  30. Cell Death Discov. 2023 Aug 19. 9(1): 303
    An autophagy-inducing stapled peptide induces mitochondria dysfunction and triggers autotic cell death in triple-negative breast cancer.
    Xiaozhe Zhang, Gao Shan, Na Li, Jingyi Chen, Changyang Ji, Xiaoxiao Li, Liwen Jiang, Terence Kin Wah Lee, Vincent W Keng, Yanxiang Zhao.
      Autophagy is a lysosome-dependent bulk degradation process essential for cell viability but excessive autophagy leads to a unique form of cell death termed autosis. Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer with notable defect in its autophagy process. In previous studies, we developed stapled peptides that specifically targeted the essential autophagy protein Beclin 1 to induce autophagy and promote endolysosomal trafficking. Here we show that one lead peptide Tat-SP4 induced mild increase of autophagy in TNBC cells but showed potent anti-proliferative effect that could not be rescued by inhibitors of programmed cell death pathways. The cell death induced by Tat-SP4 showed typical features of autosis including sustained adherence to the substrate surface, rupture of plasma membrane and effective rescue by digoxin, a cardioglycoside that blocks the Na+/K+ ATPase. Tat-SP4 also induced prominent mitochondria dysfunction including loss of mitochondria membrane potential, elevated mitochondria reactive oxygen species and reduced oxidative phosphorylation. The anti-proliferative effect of Tat-SP4 was confirmed in a TNBC xenograft model. Our study uncovers three notable aspects of autosis. Firstly, autosis can be triggered by moderate increase in autophagy if such increase exceeds the endogenous capacity of the host cells. Secondly, mitochondria may play an essential role in autosis with dysregulated autophagy leading to mitochondria dysfunction to trigger autosis. Lastly, intrinsic autophagy deficiency and quiescent mitochondria bioenergetic profile likely render TNBC cells particularly susceptible to autosis. Our designed peptides like Tat-SP4 may serve as potential therapeutic candidates against TNBC by targeting this vulnerability.
    DOI:  https://doi.org/10.1038/s41420-023-01600-0
  31. Blood. 2023 Aug 24. 142(8): 748-750
    Landspersky T, Saçma M, Rivière J, et al. Autophagy in mesenchymal progenitors protects mice against bone marrow failure after severe intermittent stress. Blood. 2022;139(5):690-703.
      
    DOI:  https://doi.org/10.1182/blood.2023021108
  32. STAR Protoc. 2023 Aug 24. pii: S2666-1667(23)00496-3. [Epub ahead of print]4(3): 102529
    Analysis of autophagy deficiency and cytotoxicity in autophagy-deficient human embryonic stem cell-derived neurons.
    Miriam E Korsgen, Congxin Sun, Elena Seranova, Malgorzata Zatyka, Dewi Astuti, Tetsushi Kataura, Timothy Barrett, Viktor I Korolchuk, Sovan Sarkar.
      Autophagy, a catabolic process governing cellular and energy homeostasis, is essential for cell survival and human health. Here, we present a protocol for generating autophagy-deficient (ATG5-/-) human neurons from human embryonic stem cell (hESC)-derived neural precursors. We describe steps for analyzing loss of autophagy by immunoblotting. We then detail analysis of cell death by luminescence-based cytotoxicity assay and fluorescence-based TUNEL staining. This hESC-based experimental platform provides a genetic knockout model for undertaking autophagy studies relevant to human biology. For complete details on the use and execution of this protocol, please refer to Sun et al. (2023).1.
    Keywords:  Cell Biology; Cell Culture; Cell Differentiation; Cell-Based Assays; Stem Cells
    DOI:  https://doi.org/10.1016/j.xpro.2023.102529
  33. Ageing Res Rev. 2023 Aug 23. pii: S1568-1637(23)00197-6. [Epub ahead of print] 102038
    Mitochondrial Transfer Between Cell Crosstalk - An Emerging Role in Mitochondrial Quality Control.
    Yi Liu, Tinglv Fu, Guorui Li, Boyang Li, Guoqing Luo, Ning Li, Qing Geng.
      Intercellular signaling and component conduction are essential for multicellular organisms' homeostasis, and mitochondrial transcellular transport is a key example of such cellular component exchange. In physiological situations, mitochondrial transfer is linked with biological development, energy coordination, and clearance of harmful components, remarkably playing important roles in maintaining mitochondrial quality. Mitochondria are engaged in many critical biological activities, like oxidative metabolism and biomolecular synthesis, and are exclusively prone to malfunction in pathological processes. Importantly, severe mitochondrial damage will further amplify the defects in the mitochondrial quality control system, which will mobilize more active mitochondrial transfer, replenish exogenous healthy mitochondria, and remove endogenous damaged mitochondria to facilitate disease outcomes. This review explores intercellular mitochondrial transport in cells, its role in cellular mitochondrial quality control, and the linking mechanisms in cellular crosstalk. We also describe advances in therapeutic strategies for diseases that target mitochondrial transfer.
    Keywords:  cell crosstalk; intercellular mitochondrial transfer; mitochondrial quality control; therapy
    DOI:  https://doi.org/10.1016/j.arr.2023.102038
  34. Autophagy. 2023 Aug 24.
    Autophagy critically controls skin inflammation and apoptosis-induced stem cell activation.
    Lisette Van Hove, Annagiada Toniolo, Mohammad Ghiasloo, Kim Lecomte, Fleur Boone, Maarten Ciers, Kris Raaijmakers, Niels Vandamme, Jana Roels, Sophia Maschalidi, Kodi S Ravichandran, Maria Kasper, Geert Van Loo, Esther Hoste.
      Macroautophagy/autophagy is a cellular recycling program regulating cell survival and controlling inflammatory responses in a context-dependent manner. Here, we demonstrate that keratinocyte-selective ablation of Atg16l1, an essential autophagy mediator, results in exacerbated inflammatory and neoplastic skin responses. In addition, mice lacking keratinocyte autophagy exhibit precocious onset of hair follicle growth, indicating altered activation kinetics of hair follicle stem cells (HFSCs). These HFSCs also exhibit expanded potencies in an autophagy-deficient context as shown by de novo hair follicle formation and improved healing of abrasion wounds. ATG16L1-deficient keratinocytes are markedly sensitized to apoptosis. Compound deletion of RIPK3-dependent necroptotic and CASP8-dependent apoptotic responses or of TNFRSF1A/TNFR1 reveals that the enhanced sensitivity of autophagy-deficient keratinocytes to TNF-dependent cell death is driving altered activation of HFSCs. Together, our data demonstrate that keratinocyte autophagy dampens skin inflammation and tumorigenesis but curtails HFSC activation by restraining apoptotic responses.
    Keywords:  Adult stem cell activation; apoptosis; autophagy; hair cycling; hair follicle stem cells; skin cancer; wound healing
    DOI:  https://doi.org/10.1080/15548627.2023.2247742
  35. Int J Mol Sci. 2023 Aug 11. pii: 12669. [Epub ahead of print]24(16):
    Cytoprotective, Cytotoxic and Cytostatic Roles of Autophagy in Response to BET Inhibitors.
    Ahmed M Elshazly, David A Gewirtz.
      The bromodomain and extra-terminal domain (BET) family inhibitors are small molecules that target the dysregulated epigenetic readers, BRD2, BRD3, BRD4 and BRDT, at various transcription-related sites, including super-enhancers. BET inhibitors are currently under investigation both in pre-clinical cell culture and tumor-bearing animal models, as well as in clinical trials. However, as is the case with other chemotherapeutic modalities, the development of resistance is likely to constrain the therapeutic benefits of this strategy. One tumor cell survival mechanism that has been studied for decades is autophagy. Although four different functions of autophagy have been identified in the literature (cytoprotective, cytotoxic, cytostatic and non-protective), primarily the cytoprotective and cytotoxic forms appear to function in different experimental models exposed to BET inhibitors (with some evidence for the cytostatic form). This review provides an overview of the cytoprotective, cytotoxic and cytostatic functions of autophagy in response to BET inhibitors in various tumor models. Our aim is to determine whether autophagy targeting or modulation could represent an effective therapeutic strategy to enhance the response to these modalities and also potentially overcome resistance to BET inhibition.
    Keywords:  BET family; BRD4; autophagy; cytoprotective; cytotoxic; senescence
    DOI:  https://doi.org/10.3390/ijms241612669
  36. Genes (Basel). 2023 Aug 04. pii: 1585. [Epub ahead of print]14(8):
    Interplay of Impaired Cellular Bioenergetics and Autophagy in PMM2-CDG.
    Anna N Ligezka, Rohit Budhraja, Yurika Nishiyama, Fabienne C Fiesel, Graeme Preston, Andrew Edmondson, Wasantha Ranatunga, Johan L K Van Hove, Jens O Watzlawik, Wolfdieter Springer, Akhilesh Pandey, Eva Morava, Tamas Kozicz.
      Congenital disorders of glycosylation (CDG) and mitochondrial disorders are multisystem disorders with overlapping symptomatology. Pathogenic variants in the PMM2 gene lead to abnormal N-linked glycosylation. This disruption in glycosylation can induce endoplasmic reticulum stress, contributing to the disease pathology. Although impaired mitochondrial dysfunction has been reported in some CDG, cellular bioenergetics has never been evaluated in detail in PMM2-CDG. This prompted us to evaluate mitochondrial function and autophagy/mitophagy in vitro in PMM2 patient-derived fibroblast lines of differing genotypes from our natural history study. We found secondary mitochondrial dysfunction in PMM2-CDG. This dysfunction was evidenced by decreased mitochondrial maximal and ATP-linked respiration, as well as decreased complex I function of the mitochondrial electron transport chain. Our study also revealed altered autophagy in PMM2-CDG patient-derived fibroblast lines. This was marked by an increased abundance of the autophagosome marker LC3-II. Additionally, changes in the abundance and glycosylation of proteins in the autophagy and mitophagy pathways further indicated dysregulation of these cellular processes. Interestingly, serum sorbitol levels (a biomarker of disease severity) and the CDG severity score showed an inverse correlation with the abundance of the autophagosome marker LC3-II. This suggests that autophagy may act as a modulator of biochemical and clinical markers of disease severity in PMM2-CDG. Overall, our research sheds light on the complex interplay between glycosylation, mitochondrial function, and autophagy/mitophagy in PMM2-CDG. Manipulating mitochondrial dysfunction and alterations in autophagy/mitophagy pathways could offer therapeutic benefits when combined with existing treatments for PMM2-CDG.
    Keywords:  LC3-II autophagy marker; congenital disorders of glycosylation; glycoproteomics; mitophagy; phosphomannomutase 2 deficiency; proteomics; secondary suboptimal mitochondrial function
    DOI:  https://doi.org/10.3390/genes14081585
  37. Biochem Pharmacol. 2023 Aug 19. pii: S0006-2952(23)00351-9. [Epub ahead of print] 115760
    Proteostasis plays an important role in demyelinating Charcot Marie Tooth disease.
    Karen Libberecht, Tim Vangansewinkel, Ludo Van Den Bosch, Ivo Lambrichts, Esther Wolfs.
      Type 1 Charcot-Marie-Tooth disease (CMT1) is the most common demyelinating peripheral neuropathy. Patients suffer from progressive muscle weakness and sensory problems. The underlying disease mechanisms of CMT1 are still unclear and no therapy is currently available, hence patients completely rely on supportive care. Balancing protein levels is a complex multistep process fundamental to maintain cells in their healthy state and a disrupted proteostasis is a hallmark of several neurodegenerative diseases. When protein misfolding occurs, protein quality control systems are activated such as chaperones, the lysosomal-autophagy system and proteasomal degradation to ensure proper degradation. However, in pathological circumstances, these mechanisms are overloaded and thereby become inefficient to clear the load of misfolded proteins. Recent evidence strongly indicates that a disbalance in proteostasis plays an important role in several forms of CMT1. In this review, we present an overview of the protein quality control systems, their role in CMT1, and potential treatment strategies to restore proteostasis.
    Keywords:  Charcot-Marie-Tooth disease; Schwann cells; autophagy; neurodegenerative disease; protein misfolding; proteostasis
    DOI:  https://doi.org/10.1016/j.bcp.2023.115760
  38. Aging Cell. 2023 Aug 23. e13954
    Alterations of lipid-mediated mitophagy result in aging-dependent sensorimotor defects.
    Natalia Oleinik, Onder Albayram, Mohamed Faisal Kassir, F Cansu Atilgan, Chase Walton, Eda Karakaya, John Kurtz, Alexander Alekseyenko, Habeeb Alsudani, Megan Sheridan, Zdzislaw M Szulc, Besim Ogretmen.
      The metabolic consequences of mitophagy alterations due to age-related stress in healthy aging brains versus neurodegeneration remain unknown. Here, we demonstrate that ceramide synthase 1 (CerS1) is transported to the outer mitochondrial membrane by the p17/PERMIT transporter that recognizes mislocalized mitochondrial ribosomes (mitoribosomes) via 39-FLRN-42 residues, inducing ceramide-mediated mitophagy. P17/PERMIT-CerS1-mediated mitophagy attenuated the argininosuccinate/fumarate/malate axis and induced d-glucose and fructose accumulation in neurons in culture and brain tissues (primarily in the cerebellum) of wild-type mice in vivo. These metabolic changes in response to sodium-selenite were nullified in the cerebellum of CerS1to/to (catalytically inactive for C18-ceramide production CerS1 mutant), PARKIN-/- or p17/PERMIT-/- mice that have dysfunctional mitophagy. Whereas sodium selenite induced mitophagy in the cerebellum and improved motor-neuron deficits in aged wild-type mice, exogenous fumarate or malate prevented mitophagy. Attenuating ceramide-mediated mitophagy enhanced damaged mitochondria accumulation and age-dependent sensorimotor abnormalities in p17/PERMIT-/- mice. Reinstituting mitophagy using a ceramide analog drug with selenium conjugate, LCL768, restored mitophagy and reduced malate/fumarate metabolism, improving sensorimotor deficits in old p17/PERMIT-/- mice. Thus, these data describe the metabolic consequences of alterations to p17/PERMIT/ceramide-mediated mitophagy associated with the loss of mitochondrial quality control in neurons and provide therapeutic options to overcome age-dependent sensorimotor deficits and related disorders like amyotrophic lateral sclerosis (ALS).
    Keywords:  CerS1; Drp1; aging; ceramide; mitochondrial metabolism; mitophagy; neurodegeneration; sensorimotor defects
    DOI:  https://doi.org/10.1111/acel.13954
  39. Cell Death Dis. 2023 Aug 24. 14(8): 554
    Autophagy deficiency protects against ocular hypertension and neurodegeneration in experimental and spontanous glaucoma mouse models.
    Angela Dixon, Myoung Sup Shim, April Nettesheim, Aislyn Coyne, Chien-Chia Su, Haiyan Gong, Paloma B Liton.
      Glaucoma is a group of diseases that leads to chronic degeneration of retinal ganglion cell (RGC) axons and progressive loss of RGCs, resulting in vision loss. While aging and elevated intraocular pressure (IOP) have been identified as the main contributing factors to glaucoma, the molecular mechanisms and signaling pathways triggering RGC death and axonal degeneration are not fully understood. Previous studies in our laboratory found that overactivation of autophagy in DBA/2J::GFP-LC3 mice led to RGC death and optic nerve degeneration with glaucomatous IOP elevation. We found similar findings in aging GFP-LC3 mice subjected to chronic IOP elevation. Here, we further investigated the impact of autophagy deficiency on autophagy-deficient DBA/2J-Atg4bko and DBA/2J-Atg4b+/- mice, generated in our laboratory via CRISPR/Cas9 technology; as well as in Atg4bko mice subjected to the experimental TGFβ2 chronic ocular hypertensive model. Our data shows that, in contrast to DBA/2J and DBA/2J-Atg4b+/- littermates, DBA/2J-Atg4bko mice do not develop glaucomatous IOP elevation. Atg4b deficiency also protected against glaucomatous IOP elevation in the experimental TGFβ2 chronic ocular hypertensive model. Atg4 deletion did not compromise RGC or optic nerve survival in Atg4bko mice. Moreover, our results indicate a protective role of autophagy deficiency against RGC death and ON atrophy in the hypertensive DBA/2J-Atg4b+/- mice. Together, our data suggests a pathogenic role of autophagy activation in ocular hypertension and glaucoma.
    DOI:  https://doi.org/10.1038/s41419-023-06086-3
  40. Int J Mol Sci. 2023 Aug 19. pii: 12981. [Epub ahead of print]24(16):
    Ubiquitination Is a Novel Post-Translational Modification of VMP1 in Autophagy of Human Tumor Cells.
    Felipe J Renna, Juliana H Enriqué Steinberg, Claudio D Gonzalez, Maria Manifava, Mariana S Tadic, Tamara Orquera, Carolina V Vecino, Alejandro Ropolo, Daniele Guardavaccaro, Mario Rossi, Nicholas T Ktistakis, Maria I Vaccaro.
      Autophagy is a tightly regulated catabolic process involved in the degradation and recycling of proteins and organelles. Ubiquitination plays an important role in the regulation of autophagy. Vacuole Membrane Protein 1 (VMP1) is an essential autophagy protein. The expression of VMP1 in pancreatic cancer stem cells carrying the activated Kirsten rat sarcoma viral oncogene homolog (KRAS) triggers autophagy and enables therapy resistance. Using biochemical and cellular approaches, we identified ubiquitination as a post-translational modification of VMP1 from the initial steps in autophagosome biogenesis. VMP1 remains ubiquitinated as part of the autophagosome membrane throughout autophagic flux until autolysosome formation. However, VMP1 is not degraded by autophagy, nor by the ubiquitin-proteasomal system. Mass spectrometry and immunoprecipitation showed that the cell division cycle protein cdt2 (Cdt2), the substrate recognition subunit of the E3 ligase complex associated with cancer, cullin-RING ubiquitin ligase complex 4 (CRL4), is a novel interactor of VMP1 and is involved in VMP1 ubiquitination. VMP1 ubiquitination decreases under the CRL inhibitor MLN4924 and increases with Cdt2 overexpression. Moreover, VMP1 recruitment and autophagosome formation is significantly affected by CRL inhibition. Our results indicate that ubiquitination is a novel post-translational modification of VMP1 during autophagy in human tumor cells. VMP1 ubiquitination may be of clinical relevance in tumor-cell-therapy resistance.
    Keywords:  DFCP1; VMP1; autophagosome; tumor cells
    DOI:  https://doi.org/10.3390/ijms241612981
  41. FEBS Lett. 2023 Aug 25.
    Novel insights into autophagosome biogenesis revealed by cryo-electron tomography.
    Eeva-Liisa Eskelinen.
      Autophagosome biogenesis, from the appearance of the phagophore to elongation and closure into an autophagosome, is one of the long-lasting open questions in the autophagy field. Recent studies utilizing cryo-electron tomography and detailed analysis of the image data have revealed new information on the membrane dynamics of these events, including the shape and dimensions of omegasomes, phagophores and autophagosomes, and their relationships with the organelles around them. One of the important predictions from the new results is that 60-80% of the autophagosome membrane area is delivered by direct lipid transfer or lipid synthesis. Cryo-electron tomography can be expected to provide new directions for autophagy research in the near future.
    Keywords:  Phagophore; autophagosome; cryo-electron tomography; electron microscopy; focused ion beam milling; omegasome
    DOI:  https://doi.org/10.1002/1873-3468.14726
  42. Life Metab. 2023 Oct;2(5): load027
    AMPK promotes lysosomal and mitochondrial biogenesis via folliculin:FNIP1.
    Jordana B Freemantle, D Grahame Hardie.
      The AMP-activated protein kinase (AMPK) is known to maintain the integrity of cellular mitochondrial networks by (i) promoting fission, (ii) inhibiting fusion, (iii) promoting recycling of damaged components via mitophagy, (iv) enhancing lysosomal biogenesis to support mitophagy, and (v) promoting biogenesis of new mitochondrial components. While the AMPK targets underlying the first three of these effects are known, a recent paper suggests that direct phosphorylation of the folliculin-interacting protein 1 (FNIP1) by AMPK may be involved in the remaining two.
    DOI:  https://doi.org/10.1093/lifemeta/load027
  43. Anal Sens. 2022 Jul;pii: e202200017. [Epub ahead of print]2(4):
    LC-MS Reveals Isomeric Inhibition of Proteolysis by Lysosomal Cathepsins.
    Gaurav Pandey, Ryan R Julian.
      Defects in autophagy are implicated in many age-related diseases that cause neurodegeneration including both Alzheimer's and Parkinson's. Within autophagy, the lysosome plays a crucial role by enabling the breakdown and recycling of a wide range of biomolecular species. Herein, the effects of isomerization of aspartic acid (Asp) on substrate recognition and degradation are investigated for a collection of lysosomal cathepsins using liquid chromatography coupled to mass spectrometry. By examining a series of synthetic peptides with sequences derived from long-lived proteins known to undergo Asp isomerization, we demonstrate that isomerized forms of Asp significantly perturb cathepsin activity by impeding digestion and shifting preferential sites of proteolysis. Although the sensitivity to isomerization varies for each cathepsin, none of the cathepsins were capable of digesting sites within several residues of the C-terminal side of the isomerized Asp. Under physiological conditions, the peptide fragments left behind after such incomplete digestion would not be suitable substrates for transporter recognition and could precipitate autophagic malfunction in the form of lysosomal storage.
    Keywords:  Alzheimer’s disease; LC-MS; isomerization; long-lived proteins; proteomics
    DOI:  https://doi.org/10.1002/anse.202200017
  44. Cell Calcium. 2023 Jul 27. pii: S0143-4160(23)00094-5. [Epub ahead of print]115 102783
    Ca2+ signalling: A common language for organelles crosstalk in Parkinson's disease.
    Caterina Peggion, Lucia Barazzuol, Elena Poggio, Tito Calì, Marisa Brini.
      Parkinson's disease (PD) is a neurodegenerative disease caused by multifactorial pathogenic mechanisms. Familial PD is linked with genetic mutations in genes whose products are either associated with mitochondrial function or endo-lysosomal pathways. Of note, mitochondria are essential to sustain high energy demanding synaptic activity of neurons and alterations in mitochondrial Ca2+ signaling have been proposed as causal events for neurodegenerative process, although the mechanisms responsible for the selective loss of specific neuronal populations in the different neurodegenerative diseases is still not clear. Here, we specifically discuss the importance of a correct mitochondrial communication with the other organelles occurring at regions where their membranes become in close contact. We discuss the nature and the role of contact sites that mitochondria establish with ER, lysosomes, and peroxisomes, and how PD related proteins participate in the regulation/dysregulation of the tethering complexes. Unravelling molecular details of mitochondria tethering could contribute to identify specific therapeutic targets and develop new strategies to counteract the progression of the disease.
    Keywords:  Calcium signalling; Mitochondria; Organelles contact sites; Parkinson's disease
    DOI:  https://doi.org/10.1016/j.ceca.2023.102783
  45. Plant Cell Environ. 2023 Aug 24.
    The interplay between autophagy and chloroplast vesiculation pathways under dark-induced senescence.
    Jessica A S Barros, João Henrique F Cavalcanti, Karla G Pimentel, Sahar Magen, Yoram Soroka, Shahar Weiss, David B Medeiros, Adriano Nunes-Nesi, Alisdair R Fernie, Tamar Avin-Wittenberg, Wagner L Araújo.
      In cellular circumstances where carbohydrates are scarce, plants can use alternative substrates for cellular energetic maintenance. In plants, the main protein reserve is present in the chloroplast, which contains most of the total leaf proteins and represents a rich source of nitrogen and amino acids. Autophagy plays a key role in chloroplast breakdown, a well-recognised symptom of both natural and stress-induced plant senescence. Remarkably, an autophagic-independent route of chloroplast degradation associated with chloroplast vesiculation (CV) gene was previously demonstrated. During extended darkness, CV is highly induced in the absence of autophagy, contributing to the early senescence phenotype of atg mutants. To further investigate the role of CV under dark-induced senescence conditions, mutants with low expression of CV (amircv) and double mutants amircv1xatg5 were characterised. Following darkness treatment, no aberrant phenotypes were observed in amircv single mutants; however, amircv1xatg5 double mutants displayed early senescence and altered dismantling of chloroplast and membrane structures under these conditions. Metabolic characterisation revealed that the functional lack of both CV and autophagy leads to higher impairment of amino acid release and differential organic acid accumulation during starvation conditions. The data obtained are discussed in the context of the role of CV and autophagy, both in terms of cellular metabolism and the regulation of chloroplast degradation.
    Keywords:  autophagy; carbon starvation; chloroplast degradation; senescence
    DOI:  https://doi.org/10.1111/pce.14701
  46. JCI Insight. 2023 Aug 22. pii: e168919. [Epub ahead of print]8(16):
    HSPB2 facilitates neural regeneration through autophagy for sensorimotor recovery after traumatic brain injury.
    Yichen Huang, Shan Meng, Biwu Wu, Hong Shi, Yana Wang, Jiakun Xiang, Jiaying Li, Ziyu Shi, Gang Wu, Yanchen Lyu, Xu Jia, Jin Hu, Zhi-Xiang Xu, Yanqin Gao.
      Autophagy is a promising target for promoting neural regeneration, which is essential for sensorimotor recovery following traumatic brain injury (TBI). Whether neuronal heat shock protein B2 (HSPB2), a small molecular heat shock protein, reduces injury and promotes recovery following TBI remains unclear. In this study, we demonstrated that HSPB2 was significantly increased in the neurons of a TBI mouse model, patients, and primary neuron cultures subjected to oxygen/glucose deprivation and reperfusion treatment. Upon creating a tamoxifen-induced neuron-specific HSPB2 overexpression transgenic mouse model, we found that elevated HSPB2 levels promoted long-term sensorimotor recovery and alleviated tissue loss after TBI. We also demonstrated that HSPB2 enhanced white matter structural and functional integrity, promoted central nervous system (CNS) plasticity, and accelerated long-term neural remodeling. Moreover, we found that autophagy occurred around injured brain tissues in patients, and the pro-regenerative effects of HSPB2 relied on its autophagy-promoting function. Mechanistically, HSPB2 may regulate autophagy possibly by forming the HSPB2/BCL2-associated athanogene 3/sequestosome-1 complex to facilitate the clearance of erroneously accumulated proteins in the axons. Treatment with the autophagy inhibitor chloroquine during the acute stage or delayed induction of HSPB2 remarkably impeded HSPB2's long-term reparative function, indicating the importance of acute-stage autophagy in long-term neuro-regeneration. Our findings highlight the beneficial role of HSPB2 in neuro-regeneration and functional recovery following acute CNS injury, thereby emphasizing the therapeutic potential of autophagy regulation for enhancing neuro-regeneration.
    Keywords:  Autophagy; Behavior; Neurological disorders; Neuroscience
    DOI:  https://doi.org/10.1172/jci.insight.168919
  47. Cell Rep. 2023 Aug 24. pii: S2211-1247(23)01043-4. [Epub ahead of print]42(9): 113032
    Lipocalin-2 induces mitochondrial dysfunction in renal tubular cells via mTOR pathway activation.
    Eloïse Marques, Maraiza Alves Teixeira, Clément Nguyen, Fabiola Terzi, Morgan Gallazzini.
      Mitochondrial dysfunction is a critical process in renal epithelial cells upon kidney injury. While its implication in kidney disease progression is established, the mechanisms modulating it remain unclear. Here, we describe the role of Lipocalin-2 (LCN2), a protein expressed in injured tubular cells, in mitochondrial dysfunction. We show that LCN2 expression decreases mitochondrial mass and function and induces mitochondrial fragmentation. Importantly, while LCN2 expression favors DRP1 mitochondrial recruitment, DRP1 inhibition antagonizes LCN2's effect on mitochondrial shape. Remarkably, LCN2 promotes mitochondrial fragmentation independently of its secretion or transport iron activity. Mechanistically, intracellular LCN2 expression increases mTOR activity, and rapamycin inhibits LCN2's effect on mitochondrial shape. In vivo, Lcn2 gene inactivation prevents mTOR activation and mitochondrial length decrease observed upon ischemia-reperfusion-induced kidney injury (IRI) in Lcn2+/+ mice. Our data identify LCN2 as a key regulator of mitochondrial dynamics and further elucidate the mechanisms leading to mitochondrial dysfunction.
    Keywords:  CP: Metabolism; Lipocalin-2; kidney; mTOR pathway; mitochondrial dynamics
    DOI:  https://doi.org/10.1016/j.celrep.2023.113032
  48. Nat Commun. 2023 Aug 25. 14(1): 5202
    PINK1 and Parkin regulate IP3R-mediated ER calcium release.
    Su Jin Ham, Heesuk Yoo, Daihn Woo, Da Hyun Lee, Kyu-Sang Park, Jongkyeong Chung.
      Although defects in intracellular calcium homeostasis are known to play a role in the pathogenesis of Parkinson's disease (PD), the underlying molecular mechanisms remain unclear. Here, we show that loss of PTEN-induced kinase 1 (PINK1) and Parkin leads to dysregulation of inositol 1,4,5-trisphosphate receptor (IP3R) activity, robustly increasing ER calcium release. In addition, we identify that CDGSH iron sulfur domain 1 (CISD1, also known as mitoNEET) functions downstream of Parkin to directly control IP3R. Both genetic and pharmacologic suppression of CISD1 and its Drosophila homolog CISD (also known as Dosmit) restore the increased ER calcium release in PINK1 and Parkin null mammalian cells and flies, respectively, demonstrating the evolutionarily conserved regulatory mechanism of intracellular calcium homeostasis by the PINK1-Parkin pathway. More importantly, suppression of CISD in PINK1 and Parkin null flies rescues PD-related phenotypes including defective locomotor activity and dopaminergic neuronal degeneration. Based on these data, we propose that the regulation of ER calcium release by PINK1 and Parkin through CISD1 and IP3R is a feasible target for treating PD pathogenesis.
    DOI:  https://doi.org/10.1038/s41467-023-40929-z
  49. J Biol Chem. 2023 Aug 18. pii: S0021-9258(23)02203-2. [Epub ahead of print] 105175
    MAPK13 stabilization via m6A mRNA modification limits anti-cancer efficacy of rapamycin.
    Joohwan Kim, Yujin Chun, Cuauhtemoc B Ramirez, Lauren A Hoffner, Sunhee Jung, Ki-Hong Jang, Varvara I Rubtsova, Cholsoon Jang, Gina Lee.
      N6-adenosine methylation (m6A) is the most abundant mRNA modification that controls gene expression through diverse mechanisms. Accordingly, m6A-dependent regulation of oncogenes and tumor suppressors contributes to tumor development. However, the role of m6A-mediated gene regulation upon drug treatment or resistance is poorly understood. Here, we report that m6A modification of mitogen-activated protein kinase 13 (MAPK13) mRNA determines the sensitivity of cancer cells to the mechanistic target of rapamycin complex 1 (mTORC1)-targeting agent rapamycin. mTORC1 induces m6A modification of MAPK13 mRNA at its 3' untranslated region (3'UTR) through the methyltransferase-like 3 (METTL3)-METTL14-Wilms' tumor 1-associating protein (WTAP) methyltransferase complex, facilitating its mRNA degradation via an m6A reader protein YTH domain family protein 2 (YTHDF2). Rapamycin blunts this process and stabilizes MAPK13. On the other hand, genetic or pharmacological inhibition of MAPK13 enhances rapamycin's anti-cancer effects, which suggests that MAPK13 confers a pro-growth signal upon rapamycin treatment, thereby limiting rapamycin efficacy. Together, our data indicate that rapamycin-mediated MAPK13 mRNA stabilization underlies drug resistance, and it should be considered as a promising therapeutic target to sensitize cancer cells to rapamycin.
    Keywords:  MAPK13; RNA modification; RNA stability; Rapamycin; m(6)A; mTORC1; p38
    DOI:  https://doi.org/10.1016/j.jbc.2023.105175
  50. Neurosci Bull. 2023 Aug 22.
    Impairment of Autophagic Flux After Hypobaric Hypoxia Potentiates Oxidative Stress and Cognitive Function Disturbances in Mice.
    Shuhui Dai, Yuan Feng, Chuanhao Lu, Hongchen Zhang, Wenke Ma, Wenyu Xie, Xiuquan Wu, Peng Luo, Lei Zhang, Fei Fei, Zhou Fei, Xia Li.
      Acute hypobaric hypoxic brain damage is a potentially fatal high-altitude sickness. Autophagy plays a critical role in ischemic brain injury, but its role in hypobaric hypoxia (HH) remains unknown. Here we used an HH chamber to demonstrate that acute HH exposure impairs autophagic activity in both the early and late stages of the mouse brain, and is partially responsible for HH-induced oxidative stress, neuronal loss, and brain damage. The autophagic agonist rapamycin only promotes the initiation of autophagy. By proteome analysis, a screen showed that protein dynamin2 (DNM2) potentially regulates autophagic flux. Overexpression of DNM2 significantly increased the formation of autolysosomes, thus maintaining autophagic flux in combination with rapamycin. Furthermore, the enhancement of autophagic activity attenuated oxidative stress and neurological deficits after HH exposure. These results contribute to evidence supporting the conclusion that DNM2-mediated autophagic flux represents a new therapeutic target in HH-induced brain damage.
    Keywords:  Autophagy; Brain injury; Hypobaric hypoxia; Oxidative stress; Proteomics
    DOI:  https://doi.org/10.1007/s12264-023-01099-6
  51. Neuroscience. 2023 Aug 23. pii: S0306-4522(23)00338-X. [Epub ahead of print]
    Transcription Factor Forkhead Box P (Foxp) 1 Reduces Brain Damage During Cerebral Ischemia-Reperfusion Injury in Mice Through FUNDC1.
    Yang Li, Yang Changhong, Yang Liyu, Meng Changchang, Linggao Zeng, Li Yue, Zhao Jing.
      Mitophagy plays a significant role in modulating the activation of pyrin domain-containing protein 3 (NLRP3) inflammasome, which is a major contributor to the inflammatory response that exacerbates cerebral ischemia-reperfusion (I/R) injury. Despite this, the transcriptional regulation mechanism that governs mitophagy remains unclear. This study sought to explore the potential mechanism of Forkhead Box P1 (Foxp1) and its impact on cerebral I/R injury. We investigated the potential neuroprotective role of Foxp1 in cerebral I/R injury by the middle cerebral artery occlusion (MCAO) mouse model. Additionally, we assessed whether FUN14 domain-containing protein 1 (FUNDC1) could rescue the protective effect of Foxp1. Our results showed that overexpression of Foxp1 prevented brain damage during cerebral I/R injury and promoted NLRP3 inflammasome activation, whereas knockdown of Foxp1 had the opposite effect. Notably, Foxp1 overexpression directly promotes FUNDC1 expression, enhanced mitophagy activation, and inhibited the inflammatory response mediated by the NLRP3 inflammasome. Furthermore, we confirmed through chromatin immunoprecipitation (ChIP) and luciferase reporter assays that FUNDC1 is a direct target gene of Foxp1 downstream. Furthermore, the knockdown of FUNDC1 reversed the increased activation of mitophagy and suppressed NLRP3 inflammasome activation induced by Foxp1 overexpression. Collectively, our findings suggest that Foxp1 inhibits NLRP3 inflammasome activation through FUNDC1 to reduce cerebral I/R injury.
    Keywords:  FUN14 domain-containing protein 1; Nod-like receptor protein 3 inflammasome; cerebral ischemia/reperfusion; forkhead Box P 1; mitochondrial autophagy
    DOI:  https://doi.org/10.1016/j.neuroscience.2023.07.029
  52. Cell Death Discov. 2023 Aug 24. 9(1): 309
    Targeting ANXA7/LAMP5-mTOR axis attenuates spinal cord injury by inhibiting neuronal apoptosis via enhancing autophagy in mice.
    Na Li, Lu Chen, Xiaoqing Zhao, Chi Gu, Yong Chang, Shiqing Feng.
      Spinal cord injury (SCI) could lead to severe disabilities in motor and sensory functions, and cause a heavy burden on patient physiology and psychology due to lack of specific repair measures so far. ANXA7 is an annexin with Ca2+ -dependent GTPase activity, which were mainly expressed in neuron in spinal cord and downregulated significantly after SCI in mice. In our study, GTPase activity activation of ANXA7 plays the protective role in neuron after OGD/R through inhibiting neuron apoptosis, which mediated by enhancing autophagy via mTOR/TFEB pathway. We also discovered that ANXA7 has significant interaction with neural-specific lysosomal-associated membrane protein LAMP5, which together with ANXA7 regulates autophagy and apoptosis. Asp411 mutation of ANXA7 obviously impaired the interaction of ANXA7 and LAMP5 compared with the wild type. Furthermore, it was found that activation of ANXA7 could help to stabilize the protein expression of LAMP5. Overexpression of LAMP5 could attenuate the destruction of lysosomal acidic environment, inhibition of autophagy and activation of apoptosis caused by ANXA7 downregulation after OGD/R. We verified that injecting ANXA7 overexpression lentivirus and activation of ANXA7 both have significant repair effects on SCI mice by using CatWalk assay and immunohistochemistry staining. In summary, our findings clarify the new role of ANXA7 and LAMP5 in SCI, provided a new specific target of neuronal repair and discovered new molecular mechanisms of ANXA7 to regulate autophagy and apoptosis. Targeting ANXA7 may be a prospective therapeutic strategy for SCI in future.
    DOI:  https://doi.org/10.1038/s41420-023-01612-w
  53. Nat Commun. 2023 Aug 25. 14(1): 5214
    Glycerol 3-phosphate phosphatase/PGPH-2 counters metabolic stress and promotes healthy aging via a glycogen sensing-AMPK-HLH-30-autophagy axis in C. elegans.
    Elite Possik, Laura-Lee Klein, Perla Sanjab, Ruyuan Zhu, Laurence Côté, Ying Bai, Dongwei Zhang, Howard Sun, Anfal Al-Mass, Abel Oppong, Rasheed Ahmad, Alex Parker, S R Murthy Madiraju, Fahd Al-Mulla, Marc Prentki.
      Metabolic stress caused by excess nutrients accelerates aging. We recently demonstrated that the newly discovered enzyme glycerol-3-phosphate phosphatase (G3PP; gene Pgp), which operates an evolutionarily conserved glycerol shunt that hydrolyzes glucose-derived glycerol-3-phosphate to glycerol, counters metabolic stress and promotes healthy aging in C. elegans. However, the mechanism whereby G3PP activation extends healthspan and lifespan, particularly under glucotoxicity, remained unknown. Here, we show that the overexpression of the C. elegans G3PP homolog, PGPH-2, decreases fat levels and mimics, in part, the beneficial effects of calorie restriction, particularly in glucotoxicity conditions, without reducing food intake. PGPH-2 overexpression depletes glycogen stores activating AMP-activate protein kinase, which leads to the HLH-30 nuclear translocation and activation of autophagy, promoting healthy aging. Transcriptomics reveal an HLH-30-dependent longevity and catabolic gene expression signature with PGPH-2 overexpression. Thus, G3PP overexpression activates three key longevity factors, AMPK, the TFEB homolog HLH-30, and autophagy, and may be an attractive target for age-related metabolic disorders linked to excess nutrients.
    DOI:  https://doi.org/10.1038/s41467-023-40857-y
  54. Diabetes Metab Res Rev. 2023 Aug 24. e3712
    TorS - Reframing a rational for type 2 diabetes treatment.
    Jacob Bar-Tana.
      The mammalian target of rapamycin complex 1 syndrome (Tors), paradigm implies an exhaustive cohesive disease entity driven by a hyperactive mTORC1, and which includes obesity, type 2 diabetic hyperglycemia, diabetic dyslipidemia, diabetic cardiomyopathy, diabetic nephropathy, diabetic peripheral neuropathy, hypertension, atherosclerotic cardiovascular disease, non-alcoholic fatty liver disease, some cancers, neurodegeneration, polycystic ovary syndrome, psoriasis and other. The TorS paradigm may account for the efficacy of standard-of-care treatments of type 2 diabetes (T2D) in alleviating the glycaemic and non-glycaemic diseases of TorS in T2D and non-T2D patients. The TorS paradigm may generate novel treatments for TorS diseases.
    Keywords:  insulin; mTORC1syndrome (TorS); metabolic stress; metabolic syndrome (MetS); type 2 diabetes (T2D)
    DOI:  https://doi.org/10.1002/dmrr.3712
  55. Biomolecules. 2023 Aug 08. pii: 1229. [Epub ahead of print]13(8):
    IGF/mTORC1/S6 Signaling Is Potentiated and Prolonged by Acute Loading of Subtoxicological Manganese Ion.
    Xueqi Tang, Rekha C Balachandran, Michael Aschner, Aaron B Bowman.
      The insulin-like growth factor (IGF)/insulin signaling (IIS) pathway is involved in cellular responses against intracellular divalent manganese ion (Mn2+) accumulation. As a pathway where multiple nodes utilize Mn2+ as a metallic co-factor, how the IIS signaling patterns are affected by Mn2+ overload is unresolved. In our prior studies, acute Mn2+ exposure potentiated IIS kinase activity upon physiological-level stimulation, indicated by elevated phosphorylation of protein kinase B (PKB, also known as AKT). AKT phosphorylation is associated with IIS activity; and provides direct signaling transduction input for the mammalian target of rapamycin complex 1 (mTORC1) and its downstream target ribosomal protein S6 (S6). Here, to better define the impact of Mn2+ exposure on IIS function, Mn2+-induced IIS activation was evaluated with serial concentrations and temporal endpoints. In the wild-type murine striatal neuronal line STHdh, the acute treatment of Mn2+ with IGF induced a Mn2+ concentration-sensitive phosphorylation of S6 at Ser235/236 to as low as 5 μM extracellular Mn2+. This effect required both the essential amino acids and insulin receptor (IR)/IGF receptor (IGFR) signaling input. Similar to simultaneous stimulation of Mn2+ and IGF, when a steady-state elevation of Mn2+ was established via a 24-h pre-exposure, phosphorylation of S6 also displayed higher sensitivity to sub-cytotoxic Mn2+ when compared to AKT phosphorylation at Ser473. This indicates a synergistic effect of sub-cytotoxic Mn2+ on IIS and mTORC1 signaling. Furthermore, elevated intracellular Mn2+, with both durations, led to a prolonged activation in AKT and S6 upon stimulation. Our data demonstrate that the downstream regulator S6 is a highly sensitive target of elevated Mn2+ and is well below the established acute cytotoxicity thresholds (<50 μM). These findings indicate that the IIS/mTORC1 pathways, in which Mn2+ normally serves as an essential co-factor, are dually responsible for the cellular changes in exposures to real-world Mn2+ concentrations.
    Keywords:  insulin-like growth factor/insulin signaling; mammalian target of rapamycin complex 1; manganese; striatal neuronal cells
    DOI:  https://doi.org/10.3390/biom13081229
  56. Nutrients. 2023 Aug 11. pii: 3554. [Epub ahead of print]15(16):
    Diosgenin Targets CaMKK2 to Alleviate Type II Diabetic Nephropathy through Improving Autophagy, Mitophagy and Mitochondrial Dynamics.
    Yujie Zhong, Ruyi Jin, Ruilin Luo, Jiayu Liu, Luting Ren, Yinghan Zhang, Zhongguo Shan, Xiaoli Peng.
      Diabetic nephropathy (DN) is a worldwide health problem with increasing incidence. Diosgenin (DIO) is a natural active ingredient extracted from Chinese yams (Rhizoma dioscoreae) with potential antioxidant, anti-inflammatory, and antidiabetic effects. However, the protective effect of DIO on DN is still unclear. The present study explored the mitigating effects and underlying mechanisms of DIO on DN in vivo and in vitro. In the current study, the DN rats were induced by a high-fat diet and streptozotocin and then treated with DIO and metformin (Mef, a positive control) for 8 weeks. The high-glucose (HG)-induced HK-2 cells were treated with DIO for 24 h. The results showed that DIO decreased blood glucose, biomarkers of renal damage, and renal pathological changes with an effect comparable to that of Mef, indicating that DIO is potential active substance to relieve DN. Thus, the protective mechanism of DIO on DN was further explored. Mechanistically, DIO improved autophagy and mitophagy via the regulation of the AMPK-mTOR and PINK1-MFN2-Parkin pathways, respectively. Knockdown of CaMKK2 abolished AMPK-mTOR and PINK1-MFN2-Parkin pathways-mediated autophagy and mitophagy. Mitophagy and mitochondrial dynamics are closely linked physiological processes. DIO also improved mitochondrial dynamics through inhibiting fission-associated proteins (DRP1 and p-DRP1) and increasing fusion proteins (MFN1/2 and OPA1). The effects were abolished by CaMKK2 and PINK1 knockdown. In conclusion, DIO ameliorated DN by enhancing autophagy and mitophagy and by improving mitochondrial dynamics in a CaMKK2-dependent manner. PINK1 and MFN2 are proteins that concurrently regulated mitophagy and mitochondrial dynamics.
    Keywords:  CaMKK2; autophagy; diabetic nephropathy; diosgenin; mitochondrial dynamics; mitophagy
    DOI:  https://doi.org/10.3390/nu15163554
  57. Cell Death Differ. 2023 Aug 21.
    Lysine methylation of PPP1CA by the methyltransferase SUV39H2 disrupts TFEB-dependent autophagy and promotes intervertebral disc degeneration.
    Huaizhen Liang, Rongjin Luo, Gaocai Li, Weifeng Zhang, Dingchao Zhu, Di Wu, Xingyu Zhou, Bide Tong, Bingjin Wang, Xiaobo Feng, Kun Wang, Yu Song, Cao Yang.
      Impaired transcription factor EB (TFEB) function and deficient autophagy activity have been shown to aggravate intervertebral disc (IVD) degeneration (IDD), yet the underlying mechanisms remain less clear. Protein posttranslational modifications (PTMs) are critical for determining TFEB trafficking and transcriptional activity. Here, we demonstrate that TFEB activity is controlled by protein methylation in degenerated nucleus pulposus cells (NPCs), even though TFEB itself is incapable of undergoing methylation. Specifically, protein phosphatase 1 catalytic subunit alpha (PPP1CA), newly identified to dephosphorylate TFEB, contains a K141 mono-methylated site. In degenerated NPCs, increased K141-methylation of PPP1CA disrupts its interaction with TEFB and subsequently blocks TEFB dephosphorylation and nuclear translocation, which eventually leads to autophagy deficiency and NPC senescence. In addition, we found that the PPP1CA-mediated targeting of TFEB is facilitated by the protein phosphatase 1 regulatory subunit 9B (PPP1R9B), which binds with PPP1CA and is also manipulated by K141 methylation. Further proteomic analysis revealed that the protein lysine methyltransferase suppressor of variegation 3-9 homologue 2 (SUV39H2) is responsible for the K141 mono-methylation of PPP1CA. Targeting SUV39H2 effectively mitigates NPC senescence and IDD progression, providing a potential therapeutic strategy for IDD intervention.
    DOI:  https://doi.org/10.1038/s41418-023-01210-4
  58. Phytochemistry. 2023 Aug 22. pii: S0031-9422(23)00252-2. [Epub ahead of print] 113836
    Linderanidins A-F: Rare oligomeric flavonoids with an unusual C-3-C-4 linkage from the roots of Lindera erythrocarpa and their inhibitory activities on autophagy.
    Byeol Ryu, Eun-Jin Park, Thi-Phuong Doan, Hyo-Moon Cho, Ponce-Zea Jorge Eduardo, Van-Hieu Mai, Vahideh Oveissi, Won-Keun Oh.
      Autophagy is a crucial process for maintaining cellular homeostasis by degrading and recycling unnecessary or damaged cellular components. In the process of exploring autophagy regulators in plants, unique nine oligomeric flavonoids linked by the bonding of C-3 and C-4, consisting of three pairs of biflavonoids, linderanidins A-C [(+)-1/(-)-1, (+)-2/(-)-2, and (+)-3/(-)-3], and three trimeric A-type proanthocyanidins, linderanidins D-F (4-6), were isolated from the roots of Lindera erythrocarpa. The structures and absolute configurations of these compounds were determined using various techniques, such as 1D and 2D NMR, mass spectrometry, X-ray crystallography, and electronic circular dichroism. All isolates were evaluated for their ability to regulate autophagy, and compounds (±)-1-(±)-3, (-)-1-(-)-3, (+)-1-(+)-3 and 4 were found to inhibit autophagy by blocking the fusion process between autophagosome and lysosome in HEK293 cells. This study suggests that unique oligomeric flavonoids possessing a C-3-C-4 linkage derived from the roots of L. erythrocarpa are potent autophagy inhibitors.
    Keywords:  Autophagy inhibition; Lauraceae; Lindera erythrocarpa; Oligomeric flavonoids
    DOI:  https://doi.org/10.1016/j.phytochem.2023.113836
  59. Cells. 2023 Aug 12. pii: 2056. [Epub ahead of print]12(16):
    Topology and Function of the S. cerevisiae Autophagy Protein Atg15.
    Lisa Marquardt, Marco Montino, Yvonne Mühe, Petra Schlotterhose, Michael Thumm.
      The putative phospholipase Atg15 is required for the intravacuolar lysis of autophagic bodies and MVB vesicles. Intracellular membrane lysis is a highly sophisticated mechanism that is not fully understood. The amino-terminal transmembrane domain of Atg15 contains the sorting signal for entry into the MVB pathway. By replacing this domain, we generated chimeras located in the cytosol, the vacuole membrane, and the lumen. The variants at the vacuole membrane and in the lumen were highly active. Together with the absence of Atg15 from the phagophore and autophagic bodies, this suggests that, within the vacuole, Atg15 can lyse vesicles where it is not embedded. In-depth topological analyses showed that Atg15 is a single membrane-spanning protein with the amino-terminus in the cytosol and the rest, including the active site motif, in the ER lumen. Remarkably, only membrane-embedded Atg15 variants affected growth when overexpressed. The growth defects depended on its active site serine 332, showing that it was linked to the enzymatic activity of Atg15. Interestingly, the growth defects were independent of vacuolar proteinase A and vacuolar acidification.
    Keywords:  autophagic body; lysis; macroautophagy; microautophagy; phospholipase; yeast
    DOI:  https://doi.org/10.3390/cells12162056
  60. Clin Nutr. 2023 Aug 12. pii: S0261-5614(23)00258-3. [Epub ahead of print]42(10): 1849-1865
    A focus on leucine in the nutritional regulation of human skeletal muscle metabolism in ageing, exercise and unloading states.
    Isabel A Ely, Bethan E Phillips, Kenneth Smith, Daniel J Wilkinson, Mathew Piasecki, Leigh Breen, Mads S Larsen, Philip J Atherton.
      Muscle protein synthesis (MPS) and muscle protein breakdown (MPB) are influenced through dietary protein intake and physical (in)activity, which it follows, regulate skeletal muscle (SKM) mass across the lifespan. Following consumption of dietary protein, the bio-availability of essential amino acids (EAA), and primarily leucine (LEU), drive a transient increase in MPS with an ensuing refractory period before the next MPS stimulation is possible (due to the "muscle full" state). At the same time, MPB is periodically constrained via reflex insulin actions. Layering exercise on top of protein intake increases the sensitivity of SKM to EAA, therefore extending the muscle full set-point (∼48 h), to permit long-term remodelling (e.g., hypertrophy). In contrast, ageing and physical inactivity are associated with a premature muscle full set-point in response to dietary protein/EAA and contractile activity. Of all the EAA, LEU is the most potent stimulator of the mechanistic target of rapamycin complex 1 (mTORC1)-signalling pathway, with the phosphorylation of mTORC1 substrates increasing ∼3-fold more than with all other EAA. Furthermore, maximal MPS stimulation is also achieved following low doses of LEU-enriched protein/EAA, negating the need for larger protein doses. As a result, LEU supplementation has been of long term interest to maximise muscle anabolism and subsequent net protein accretion, especially when in tandem with resistance exercise. This review highlights current knowledge vis-à-vis the anabolic effects of LEU supplementation in isolation, and in enriched protein/EAA sources (i.e., EAA and/or protein sources with added LEU), in the context of ageing, exercise and unloading states.
    Keywords:  Ageing; Exercise; Leucine; Muscle anabolism; Physical inactivity
    DOI:  https://doi.org/10.1016/j.clnu.2023.08.010
  61. Antioxidants (Basel). 2023 Aug 18. pii: 1635. [Epub ahead of print]12(8):
    SIRT5 Activation and Inorganic Phosphate Binding Reduce Cancer Cell Vitality by Modulating Autophagy/Mitophagy and ROS.
    Federica Barreca, Michele Aventaggiato, Laura Vitiello, Luigi Sansone, Matteo Antonio Russo, Antonello Mai, Sergio Valente, Marco Tafani.
      Cancer cells show increased glutamine consumption. The glutaminase (GLS) enzyme controls a limiting step in glutamine catabolism. Breast tumors, especially the triple-negative subtype, have a high expression of GLS. Our recent study demonstrated that GLS activity and ammonia production are inhibited by sirtuin 5 (SIRT5). We developed MC3138, a selective SIRT5 activator. Treatment with MC3138 mimicked the deacetylation effect mediated by SIRT5 overexpression. Moreover, GLS activity was regulated by inorganic phosphate (Pi). Considering the interconnected roles of GLS, SIRT5 and Pi in cancer growth, our hypothesis is that activation of SIRT5 and reduction in Pi could represent a valid antitumoral strategy. Treating cells with MC3138 and lanthanum acetate, a Pi chelator, decreased cell viability and clonogenicity. We also observed a modulation of MAP1LC3B and ULK1 with MC3138 and lanthanum acetate. Interestingly, inhibition of the mitophagy marker BNIP3 was observed only in the presence of MC3138. Autophagy and mitophagy modulation were accompanied by an increase in cytosolic and mitochondrial reactive oxygen species (ROS). In conclusion, our results show how SIRT5 activation and/or Pi binding can represent a valid strategy to inhibit cell proliferation by reducing glutamine metabolism and mitophagy, leading to a deleterious accumulation of ROS.
    Keywords:  ROS; autophagy; glutaminase; glutamine; hypoxia; mitophagy; sirtuins
    DOI:  https://doi.org/10.3390/antiox12081635
  62. Int J Mol Sci. 2023 Aug 13. pii: 12736. [Epub ahead of print]24(16):
    Signaling Pathways Leading to mTOR Activation Downstream Cytokine Receptors in Lymphocytes in Health and Disease.
    Lucie Fallone, Thierry Walzer, Antoine Marçais.
      CD8+ T cells and Natural Killer (NK) cells are cytotoxic lymphocytes important in the response to intracellular pathogens and cancer. Their activity depends on the integration of a large set of intracellular and environmental cues, including antigenic signals, cytokine stimulation and nutrient availability. This integration is achieved by signaling hubs, such as the mechanistic target of rapamycin (mTOR). mTOR is a conserved protein kinase that controls cellular growth and metabolism in eukaryotic cells and, therefore, is essential for lymphocyte development and maturation. However, our current understanding of mTOR signaling comes mostly from studies performed in transformed cell lines, which constitute a poor model for comprehending metabolic pathway regulation. Therefore, it is only quite recently that the regulation of mTOR in primary cells has been assessed. Here, we review the signaling pathways leading to mTOR activation in CD8+ T and NK cells, focusing on activation by cytokines. We also discuss how this knowledge can contribute to immunotherapy development, particularly for cancer treatment.
    Keywords:  CD8+ T cell; NK cell; cytokine signaling; mTOR
    DOI:  https://doi.org/10.3390/ijms241612736
  63. Int J Mol Sci. 2023 Aug 09. pii: 12582. [Epub ahead of print]24(16):
    The Great Game between Plants and Viruses: A Focus on Protein Homeostasis.
    Hangjun Sun, Xinxin Jing, Chaonan Wang, Pengyue Wang, Ziting Huang, Bingjian Sun, Pengbai Li, Honglian Li, Chao Zhang.
      Plant viruses are tiny pathogenic obligate parasites that cause significant damage to global crop production. They exploit and manipulate the cellular components of host plants to ensure their own survival. In response, plants activate multiple defense signaling pathways, such as gene silencing and plant hormone signaling, to hinder virus propagation. Growing evidence suggests that the regulation of protein homeostasis plays a vital role in the ongoing battle between plants and viruses. The ubiquitin-proteasome-degradation system (UPS) and autophagy, as two major protein-degradation pathways, are widely utilized by plants and viruses in their arms race. One the one hand, these pathways act as essential components of plant's antiviral defense system by facilitating the degradation of viral proteins; on the other hand, viruses exploit the UPS and autophagy to create a favorable intracellular environment for viral infection. This review aims to provide a comprehensive summary of the events involved in protein homeostasis regulation during viral infection in plants. Gaining knowledge in this area will enhance our understanding of the complex interplay between plants and viruses.
    Keywords:  autophagy; protein homeostasis; protein stability; ubiquitin-proteasome degradation
    DOI:  https://doi.org/10.3390/ijms241612582
  64. Insects. 2023 Aug 14. pii: 706. [Epub ahead of print]14(8):
    Atg2 Regulates Cellular and Humoral Immunity in Drosophila.
    Bo Qin, Shichao Yu, Qiming Chen, Li Hua Jin.
      Autophagy is a process that promotes the lysosomal degradation of cytoplasmic proteins and is highly conserved in eukaryotic organisms. Autophagy maintains homeostasis in organisms and regulates multiple developmental processes, and autophagy disruption is related to human diseases. However, the functional roles of autophagy in mediating innate immune responses are largely unknown. In this study, we sought to understand how Atg2, an autophagy-related gene, functions in the innate immunity of Drosophila melanogaster. The results showed that a large number of melanotic nodules were produced upon inhibition of Atg2. In addition, inhibiting Atg2 suppressed the phagocytosis of latex beads, Staphylococcus aureus and Escherichia coli; the proportion of Nimrod C1 (one of the phagocytosis receptors)-positive hemocytes also decreased. Moreover, inhibiting Atg2 altered actin cytoskeleton patterns, showing longer filopodia but with decreased numbers of filopodia. The expression of AMP-encoding genes was altered by inhibiting Atg2. Drosomycin was upregulated, and the transcript levels of Attacin-A, Diptericin and Metchnikowin were decreased. Finally, the above alterations caused by the inhibition of Atg2 prevented flies from resisting invading pathogens, showing that flies with low expression of Atg2 were highly susceptible to Staphylococcus aureus and Erwinia carotovora carotovora 15 infections. In conclusion, Atg2 regulated both cellular and humoral innate immunity in Drosophila. We have identified Atg2 as a crucial regulator in mediating the homeostasis of immunity, which further established the interactions between autophagy and innate immunity.
    Keywords:  Atg2; Drosophila; autophagy; innate immunity
    DOI:  https://doi.org/10.3390/insects14080706
  65. Cells. 2023 Aug 15. pii: 2071. [Epub ahead of print]12(16):
    An Update on Nucleolar Stress: The Transcriptional Control of Autophagy.
    Astrid S Pfister.
      Nucleolar stress reflects a misfunction of the nucleolus caused by a failure in ribosome biogenesis and defective nucleolar architecture. Various causes have been reported, most commonly mutation of ribosomal proteins and ribosome processing factors, as well as interference with these processes by intracellular or ectopic stress, such as RNA polymerase I inhibition, ROS, UV and others. The nucleolus represents the place for ribosome biogenesis and serves as a crucial hub in the cellular stress response. It has been shown to stimulate multiple downstream consequences, interfering with cell growth and survival. Nucleolar stress induction is most classically known to stimulate p53-dependent cell cycle arrest and apoptosis. Nucleolar stress represents a friend and enemy at the same time: From a pathophysiological perspective, inactivation of the nucleolar function by mutation or stress conditions is connected to multiple diseases, such as neurodegeneration, cancer and ribosomopathy syndromes. However, triggering the nucleolar stress response via specific chemotherapeutics, which interfere with nucleolar function, has beneficial effects for anti-cancer therapy. Interestingly, since the nucleolar stress response also triggers p53-independent mechanisms, it possesses the potential to specifically target p53-mutated tumors, which reflects the most common aberration in human cancer. More recent data have shown that the nucleolar stress response can activate autophagy and diverse signaling cascades that might allow initial pro-survival mechanisms. Nevertheless, it depends on the situation whether the cells undergo autophagy-mediated apoptosis or survive, as seen for autophagy-dependent drug resistance of chemotherapy-exposed tumor cells. Given the relatively young age of the research field, precise mechanisms that underly the involvement of autophagy in nucleolar stress are still under investigation. This review gives an update on the emerging contribution of nucleolar stress in the regulation of autophagy at a transcriptional level. It also appears that in autophagy p53-dependent as well as -independent responses are induced. Those could be exploited in future therapies against diseases connected to nucleolar stress.
    Keywords:  autophagy; nucleolar stress; ribosome biogenesis; signaling; transcription factor
    DOI:  https://doi.org/10.3390/cells12162071
  66. J Biomol Struct Dyn. 2023 Aug 22. 1-15
    Vanadium complex as a potential modulator of the autophagic mechanism through proteins PI3K and ULK1: development, validation and biological implications of a specific force field for [VO(bpy)2Cl].
    Taináh M R Santos, Camila A Tavares, Elaine F F da Cunha, Teodorico C Ramalho.
      The modulation of autophagy has been presented as a very useful strategy in anticancer treatments. In this sense, the vanadium complex (VC) bis(2,2'-bipyridine)chlorooxovanadium(IV), [VO(bpy)2Cl], is known for its ability to induce autophagy in triple-negative breast cancer cells (TNBC). An excellent resource to investigate the role of VC in the induction of autophagy is to make use of Molecular Dynamics (MD) simulations. However, until now, the scarcity of force field parameters for the VC prevented a reliable analysis. The autophagy signaling pathway starts with the PI3K protein and ends with ULK1. Therefore, in the first stage of this work, we developed a new AMBER force field for the VC (VCFF) from a quantum structure, obtained by DFT calculations. In the second stage, the VCFF was validated through structural analyses. From this, it was possible to investigate, through docking and MD (200 ns), the performance of the PI3K-VC and ULK1-VC systems (third stage). The analyses of this last stage involved RMSD, hydrogen bonds, RMSF and two pathways for the modulation of autophagy. In general, this work fills in the absence of force field parameters (FF) for VC by proposing an efficient and new FF, in addition to investigating, at the molecular level, how VC is able to induce autophagy in TNBC cells. This study encourages new parameterizations of metallic complexes and contributes to the understanding of the duality of autophagic processes.Communicated by Ramaswamy H. Sarma.
    Keywords:  AMBER force field; Autophagy; modulation; molecular dynamics; vanadium complex
    DOI:  https://doi.org/10.1080/07391102.2023.2250453
  67. Pharmaceutics. 2023 Jul 28. pii: 2038. [Epub ahead of print]15(8):
    Nanoparticle-Mediated Therapy with miR-198 Sensitizes Pancreatic Cancer to Gemcitabine Treatment through Downregulation of VCP-Mediated Autophagy.
    Christian Marin-Muller, Dali Li, Jian-Ming Lü, Zhengdong Liang, Osvaldo Vega-Martínez, Sue E Crawford, Mary K Estes, William E Fisher, Changyi Chen, Qizhi Yao.
      Pancreatic ductal adenocarcinoma (PDAC) remains an extremely aggressive disease characterized by rapidly acquired multi-drug resistance, including to first-line chemotherapeutic agent gemcitabine. Autophagy is a process that is often exploited by cancer and is one of several intrinsic factors associated with resistance to gemcitabine. We have previously found that miR-198 acts as a tumor suppressor in PDAC through the targeting of factors including Valosin-containing protein (VCP). VCP has been reported to play an important role in autophagic flux. In this study, we investigated whether the repression of VCP through miR-198 administration disrupts the autophagy process and sensitizes PDAC cells to gemcitabine treatment in vitro. Moreover, we used LGA-PEI (LPNP) nanoparticles to effectively administer miR-198 to tumors in vivo, inducing tumor sensitization to gemcitabine and leading to a significant reduction in tumor burden and metastases and a concomitant downregulation of VCP expression and autophagy maturation. Our results indicate a potential therapeutic strategy for targeting gemcitabine resistant PDAC and establishes the use of LPNPs for effective therapeutic delivery of nucleic acids in vitro and in vivo.
    Keywords:  RNAi therapeutic; VCP; autophagy; drug resistance; gemcitabine; microRNA-198; nanoparticles; pancreatic cancer
    DOI:  https://doi.org/10.3390/pharmaceutics15082038
  68. Front Aging Neurosci. 2023 ;15 1224633
    Research progress of mitophagy in chronic cerebral ischemia.
    Mayue Yu, Manqing Zhang, Peijie Fu, Moxin Wu, Xiaoping Yin, Zhiying Chen.
      Chronic cerebral ischemia (CCI), a condition that can result in headaches, dizziness, cognitive decline, and stroke, is caused by a sustained decrease in cerebral blood flow. Statistics show that 70% of patients with CCI are aged > 80 years and approximately 30% are 45-50 years. The incidence of CCI tends to be lower, and treatment for CCI is urgent. Studies have confirmed that CCI can activate the corresponding mechanisms that lead to mitochondrial dysfunction, which, in turn, can induce mitophagy to maintain mitochondrial homeostasis. Simultaneously, mitochondrial dysfunction can aggravate the insufficient energy supply to cells and various diseases caused by CCI. Regulation of mitophagy has become a promising therapeutic target for the treatment of CCI. This article reviews the latest progress in the important role of mitophagy in CCI and discusses the induction pathways of mitophagy in CCI, including ATP synthesis disorder, oxidative stress injury, induction of reactive oxygen species, and Ca2+ homeostasis disorder, as well as the role of drugs in CCI by regulating mitophagy.
    Keywords:  chronic cerebral ischemia; mitochondrial autophagy; oxidative stress; stroke; treatment
    DOI:  https://doi.org/10.3389/fnagi.2023.1224633
  69. J Cell Mol Med. 2023 Aug 23.
    Acid ground nano-realgar processed product inhibits breast cancer by inducing mitophagy via the p53/BNIP3/NIX pathway.
    Jiahui Fang, Xue Zou, Ling Gong, Juan Xi, Yi Liu, Xiaoli Yang, Xiuqiao Zhang, Chun Gui.
      Breast cancer is a highly prevalent malignancy with the first morbidity and the primary reason for female cancer-related deaths worldwide. Acid ground nano-realgar processed product (NRPP) could inhibit breast cancer cell proliferation and induce autophagy in our previous research; however, the underlying mechanisms are still unclear. Therefore, this research aimed to verify whether NRPP induces breast cancer mitophagy and explore the mitophagy-mediated mechanism. Primarily, rhodamine-123 assay and transmission electron microscopy were applied to detect mitochondrial membrane potential (MMP) and ultrastructural changes in the MDA-MB-435S cells, respectively. Mito-Tracker Green/Lyso-Tracker Red staining, western blot, immunofluorescence and RT-PCR were used to explore molecular mechanisms of NRPP-induced mitophagy in vitro. MDA-MB-435S breast cancer xenograft models were established to assess the activity and mechanisms of NRPP in vivo. Our results showed that NRPP decreased MMP and increased autophagosome numbers in MDA-MB-435S cells and activated mitophagy. Furthermore, mitophagy was consolidated because mitochondria and lysosomes colocalized phenomenology were observed, and the expression of LC3II/I and COXIV was upregulated. Additionally, we found the p53/BNIP3/NIX pathway was activated. Finally, NRPP inhibited tumour growth and downregulated the levels of TNF-α, IL-1β and IL-6. Necrosis, damaged mitochondria and autophagosomes were observed in xenograft tumour cells, and proteins and mRNA levels of LC3, p53, BNIP3 and NIX were increased. Overall, NRPP inhibited MDA-MB-435S cell proliferation and tumour growth by inducing mitophagy via the p53/BNIP3/NIX pathway. Thus, NRPP is a promising candidate for breast cancer treatment.
    Keywords:  MDA-MB-435S cell; acid ground nano-realgar processed product; breast cancer; mitophagy; p53/BNIP3/NIX
    DOI:  https://doi.org/10.1111/jcmm.17917
  70. Microorganisms. 2023 Aug 05. pii: 2015. [Epub ahead of print]11(8):
    Autophagy Alters the Susceptibility of Candida albicans Biofilms to Antifungal Agents.
    Jiadi Shen, Ming Ma, Wei Duan, Yun Huang, Banruo Shi, Qiaochu Wu, Xin Wei.
      Candida albicans (C. albicans) reigns as a major cause of clinical candidiasis. C. albicans biofilms are known to increase resistance to antifungal agents, making biofilm-related infections particularly challenging to treat. Drug resistance is of particular concern due to the spread of multidrug-resistant fungal pathogens, while autophagy is crucial for the maintenance of cellular homeostasis. Therefore, this study aimed to investigate the effects of an activator and an inhibitor of autophagy on the susceptibility of C. albicans biofilms to antifungal agents and the related mechanisms. The susceptibility of C. albicans biofilms to different antifungal agents after treatment with or without the autophagy activator or inhibitor was evaluated using XTT assay. Alkaline phosphatase (ALP) activity and reactive oxygen species (ROS) level, as well as the expression of ROS-related and autophagy-related genes, were examined to evaluate the autophagic activity of C. albicans biofilms when treated with antifungal agents. The autophagosomes were observed by transmission electron microscopy (TEM). The susceptibility of C. albicans biofilms to antifungal agents changed when autophagy changed. The ALP activity and ROS level of C. albicans biofilms increased with the treatment of antifungal agents, and autophagosomes could be observed in C. albicans biofilms. Autophagy was involved in the susceptibility of C. albicans biofilms to antifungal agents.
    Keywords:  Candida albicans; antifungal agents; autophagy; biofilm; drug resistance
    DOI:  https://doi.org/10.3390/microorganisms11082015
This page is being maintained by Thomas Krichel. It was last updated on 2024‒11‒22 at 4:11.